Treatment of depressive disorder through combination therapy

Abstract

Provided herein are compositions and methods for treating diseases or disorders using a therapeutically effective amount of a rapid-acting antidepressant (RAAD) and a therapeutically effective amount of a mechanistic target of rapamycin (mTOR) inhibitor. Also provided herein are solutions that contain the RAAD and mTOR inhibitor for IV administration, as well as configurations and process thereof.

Description

TREATMENT OF DEPRESSIVE DISORDER THROUGH COMBINATION THERAPYCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 658,913, filed June 12, 2024, which application is incorporated herein by reference.BACKGROUND

[0002] Depression is a globally recognized cause of disability, yet advancements in the development of new antidepressants have slowed substantially. This, coupled with the delayed onset of treatment response and varying effectiveness of available antidepressant treatments, significantly contributes to depression's considerable global health burden. Major Depressive Disorder (MDD) has been shown to curtail life expectancy by an average of 10 years. With a multitude of approved oral antidepressants available, approximately 30% of MDD patients continue to display resistance to treatment. Treatment Resistant Depression (TRD) is characterized by inadequate response to at least two or more antidepressant treatments of adequate dose and duration in the current mood episode. This shows that TRD patients are a uniquely challenging population who do not benefit from current available antidepressant treatments. This reality underscores an urgent and undeniable need for innovative treatment strategies. New methods are required that can circumvent the inherent limitations of conventional therapeutic options, to provide an effective treatment regimen for both MDD and its more intractable subset, TRD.SUMMARY

[0003] Provided herein are methods of treating or preventing a disease, disorder, or condition in a human subject in need thereof comprising: administering a therapeutically effective amount of a rapidacting antidepressant (RAAD) to the human subject, and administering a therapeutically effective amount of a mechanistic target of rapamycin (mTOR) inhibitor to the human subject, wherein the human subject is administered an antidepressant before, during, or after the administration of the RAAD, or the administration of the mTOR inhibitor.

[0004] In some embodiments, the human subject has an inadequate response to the antidepressant. In some embodiments, the human subject has an inadequate response to two or more antidepressant treatments. In some embodiments, the two or more antidepressant treatments includes the administration of the antidepressant. In some embodiments, the two or more antidepressant treatments does not include the administration of the antidepressant.

[0005] In some embodiments, the antidepressant comprises traditional antidepressant (TAD). In some embodiments, the antidepressant comprises RAAD. In some embodiments, the human subject is administered the antidepressant before the administration of the RAAD or the administration of the mTOR inhibitor. In some embodiments, the human subject is administered the antidepressant during the administration of the RAAD or the administration of the mTOR inhibitor. In some embodiments, thehuman subject is administered the antidepressant after the administration of the RAAD or the administration of the mTOR inhibitor.

[0006] In some embodiments, the antidepressant is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route. In some embodiments, the antidepressant is administered through the oral route.

[0007] In some embodiments, the antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRs), serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs), serotonin modulators and stimulators (SMSs), serotonin antagonist and reuptake inhibitors (SARIs), norepinephrine reuptake inhibitors (NRIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), monoamine oxidase inhibitors (MAOIs), norepinephrine and dopamine reuptake inhibitors (NDRIs), atypical antipsychotics, typical antipsychotics, and allowable antidepressants used as sleep medications. In some embodiments, the SSRIs comprise fluoxetine, fluvoxamine, citalopram, sertraline, paroxetine, or escitalopram. In some embodiments, the SNRIs comprise duloxetine, levomilnacipran, milnacipran, venlafaxine, or desvenlafaxine. In some embodiments, the SNDRIs comprise toludesvenlafaxine or nefazodone. In some embodiments, the SMSs comprise vilazodone or vortioxetine. In some embodiments, the SARIs comprise nefazodone or trazodone. In some embodiments, the NRIs comprise reboxetine, teniloxazine, 5- HT2A receptor antagonist, atomoxetine, viloxazine, 5-HT2B receptor antagonist, or 5-HT2C receptor agonist. In some embodiments, the NDRIs comprise bupropion, amphetamines, methylphenidate, modafinil, or non-competitive antagonist of nicotinic acetylcholine receptors. In some embodiments, the TACs comprise amitriptyline, amitriptylinoxide, clomipramine, desipramine, dibenzepin, dimetacrine, dosulepin, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, nortriptyline, noxiptiline, pipofezine, protriptyline, trimipramine, opipramol, or tianeptine. In some embodiments, the TeCAs comprise amoxapine, maprotiline, mianserin, mirtazapine, setiptiline, mianserin, mirtazapine, or setiptiline. In some embodiments, the MAOIs comprise isocarboxazid, phenelzine, tranylcypromine, selegiline, metralindole, moclobemide, pirlindole, or bifemelane. In some embodiments, the atypical antipsychotics comprise amisulpride, lumateperone, lurasidone, aripiprazole, brexpiprazole, quetiapine, risperidone, or olanzapine. In some embodiments, the typical antipsychotics comprise trifluoperazine, buspirone, lithium, or thyroxine. In some embodiments, the allowable antidepressants used as sleep medications comprise trazodone or mirtazapine.

[0008] In some embodiments, the therapeutically effective amount of the RAAD is at a dose of (i) about 0.01 mg / kg to about 100 mg / kg, (ii) about 0.8 mg to about 8 g, or (iii) about 1.2 mg to about 12 g. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of (i) about 0. 1 mg / kg to about 10 mg / kg, (ii) about 8 mg to about 800 mg, or (iii) about 12 mg to about 1200 mg. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of (i) about 0.5 mg / kg to about 2 mg / kg, (ii) about 4 mg to about 160 mg, or (iii) about 6 mg to about 240 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 1 pg / kg to about 100 pg / kg, (ii) about 0.08 mg to about 8 mg, or (iii) about 0.12 mg to about 12 mg. Insome embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 1 pg / kg to about 50 pg / kg, (ii) about 0.08 mg to about 5.6 mg, or (iii) about 0. 12 mg to about 8.4 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 3.125 pg / kg, about 9.375 pg / kg, about 24.2 pg / kg, or about 62.5 pg / kg, (ii) about 0.25 mg, about 0.75 mg, about 1.93 mg, or about 5 mg, or (iii) about 0.375 mg, about 1.125 mg, about 2.9 mg, or about 7.5 mg.

[0009] In some embodiments, the RAAD is selected from the group consisting of ketamine, (R)- ketamine, (S)-ketamine, R, S-ketamine, S-Norketamine, R-Norketamine, 2R, 6 / ?-hydroxynorkctaminc.2S, 6.8-hydroxynorkctaminc. nitrous oxide, memantine, amantadine, racemic dextromethorphan, a fixed dose combination of dextromethorphan and quinidine, dextromethorphan, a fixed dose combination of dextromethophane and bupropion, dextromethadone (d-methadone), D-CCPene, UBP141, UBP145, HA966 ((±)-3-amino-l-hydroxy-pyrrolidin-2-one), NVPAAM077, Ro-25-26981, TCN 201, QNZ46, Neu2000, GM-1020, besonprodil, eliprodil, rislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, traxoprodil (CP-101,606), BMT-108908, onfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1- aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO- PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L- Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7- dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof. In some embodiments, the RAAD comprises aN-methyl-D-aspartate (NMD A) receptor modulator. In some embodiments, the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixture thereof. In some embodiments, the ketamine is ketamine HC1.

[0010] In some embodiments, the mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), umirolimus (Biolimus), KU-0063794, PI-103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI-103 - CAS 371935-74-9), torkinib (PP242), tacrolimus (FK-506, fujimycin,), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, sapanisertib), voxtalisib (XL- 765, SAR245409), torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE 390), GSK1059615,WYE-354 (mTOR Inhibitor II), gedatolisib (PF-05212384, PKI-587), AZD- 2014 (Vistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP- BGT226), palomid-529 (P529, SG 00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC-0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC 223), clemastine (HS-592) fumarate, nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, astragaloside IV, samotolisib (LY3023414), chrysophanic acid, zotarolimus (ABT-578), and any salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, and geometric isomer thereof, and any mixtures thereof. In some embodiments, the mTOR inhibitor comprises rapamycin (sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779).

[0011] In some embodiments, the therapeutically effective amount of the RAAD is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route. In some embodiments, the therapeutically effective amount of the RAAD is administered through an intravenous route.

[0012] In some embodiments, the therapeutically effective amount of the RAAD is administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, seven times per week, once per two weeks, once per three weeks, once per four weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten times per month. In some embodiments, the therapeutically effective amount of the RAAD is administered once per day, once per two days, once per three days, once per four days, once per five days, once per ten days or once per fifteen days. In some embodiments, the mTOR inhibitor is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route. In some embodiments, the mTOR inhibitor is administered through an intravenous route.

[0013] In some embodiments, the mTOR inhibitor is administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, seven times per week, once per two weeks, once per three weeks, once per four weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten times per month. In some embodiments, the mTOR inhibitor is administered once per day, once per two days, once per three days, once per four days, once per five days, once per ten days or once per fifteen days.

[0014] In some embodiments, the disease, disorder, or condition is selected from the group consisting of a major depressive disorder (MDD), a major depressive episode in bipolar disorder (bipolar depression), a persistent depressive disorder (dysthymia), a disruptive mood dysregulation disorder, a major depressive disorder (including major depressive episode), a premenstrual dysphoric disorder, a substance / medication-induced depressive disorder, a depressive disorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, an anxiety disorder, anobsessive-compulsive disorder, a posttraumatic stress disorder, an addictive disorder, bipolar I disorder, bipolar II disorder, generalized anxiety disorder, social anxiety disorder (social phobia), specific phobia, panic disorder, agoraphobia, separation anxiety disorder, selective mutism, substance-induced anxiety disorder, medication-induced anxiety disorder, anxiety disorder due to another medical condition, borderline personality disorder, treatment-resistant depression, unspecified anxiety disorder, chronic pain, and any combinations thereof. In some embodiments, the disease, disorder, or condition is a mood disorder, optionally a depressive disorder. In some embodiments, the disease, disorder, or condition is a treatment-resistant depression (TRD).

[0015] In some embodiments, the RAAD and the mTOR inhibitor are formulated into a pharmaceutical composition prior to administering to the human subject. In some embodiments, the pharmaceutical composition is administered to the human subject through multiple doses. In some embodiments, the multiple doses comprise one or more acute doses and one or more maintenance doses administered after the one or more acute doses.

[0016] In some embodiments, the pharmaceutical composition is formulated as a solution. In some embodiments, the solution comprises dehydrated ethanol, DL-alpha-tocopherol, propylene glycol, anhydrous citric acid, polysorbate 80, or PEG 400. In some embodiments, the solution further comprises about 0.9% (w / v) sodium chloride in water.

[0017] Also provided herein is a method of treating or preventing a disease, disorder, or condition in a human subject in need thereof comprising: administering a therapeutically effective amount of a rapidacting antidepressant (RAAD) to the human subject, and administering a therapeutically effective amount of a mechanistic target of rapamycin (mTOR) inhibitor to the human subject, wherein the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 0.25 mg, about 0.75 mg, about 1.93 mg, or about 5 mg, (ii) about 0.375 mg, about 1.125 mg, about 2.9 mg, or about 7.5 mg, or (iii) about 3.125 pg / kg, about 9.375 pg / kg, about 24.2 pg / kg, or about 62.5 pg / kg.

[0018] In some embodiments, the therapeutically effective amount of the mTOR inhibitor at a dose of about 0.25 mg, about 0.375 mg, or about 3.125 pg / kg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor at a dose of about 0.75 mg, about 1. 125 mg, or about 9.375 pg / kg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor at a dose of about 1.93 mg, about 2.9 mg, or about 24.2 pg / kg.

[0019] In some embodiments, the therapeutically effective amount of the RAAD is at a dose of (i) about 0.01 mg / kg to about 100 mg / kg, (ii) about 0.8 mg to about 8 g, or (iii) about 1.2 mg to about 12 g. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of (i) about 0. 1 mg / kg to about 10 mg / kg, (ii) about 8 mg to about 800 mg, or (iii) about 12 mg to about 1200 mg. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of (i) about 0.5 mg / kg to about 2 mg / kg, (ii) about 4 mg to about 160 mg, or (iii) about 6 mg to about 240 mg.

[0020] In some embodiments, the human subject is administered an antidepressant before, during, or after the administration of the RAAD, or the administration of the mTOR inhibitor. In some embodiments, the human subject has an inadequate response to the antidepressant. In some embodiments,the human subject has an inadequate response to two or more antidepressant treatments. In some embodiments, the two or more antidepressant treatments includes the administration of the antidepressant. In some embodiments, the two or more antidepressant treatments does not include the administration of the antidepressant.

[0021] In some embodiments, the human subject is administered the antidepressant before the administration of the RAAD or the administration of the mTOR inhibitor. In some embodiments, the human subject is administered the antidepressant during the administration of the RAAD or the administration of the mTOR inhibitor. In some embodiments, the human subject is administered the antidepressant after the administration of the RAAD or the administration of the mTOR inhibitor. In some embodiments, the antidepressant is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route. In some embodiments, the antidepressant is administered through the oral route.

[0022] In some embodiments, the therapeutically effective amount of the RAAD is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route. In some embodiments, the therapeutically effective amount of the RAAD is administered through an intravenous route.

[0023] In some embodiments, the therapeutically effective amount of the RAAD is administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, seven times per week, once per two weeks, once per three weeks, once per four weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten times per month. In some embodiments, the therapeutically effective amount of the RAAD is administered once per day, once per two days, once per three days, once per four days, once per five days, once per ten days or once per fifteen days.

[0024] In some embodiments, the mTOR inhibitor is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route. In some embodiments, the mTOR inhibitor is administered through an intravenous route. In some embodiments, the mTOR inhibitor is administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, seven times per week, once per two weeks, once per three weeks, once per four weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten times per month. In some embodiments, the mTOR inhibitor is administered once per day, once per two days, once per three days, once per four days, once per five days, once per ten days or once per fifteen days.

[0025] In some embodiments, the RAAD and the mTOR inhibitor are formulated into a pharmaceutical composition prior to administering to the human subject. In some embodiments, the pharmaceutical composition is administered to the human subject through multiple doses. In some embodiments, the multiple doses comprise one or more acute doses and one or more maintenance doses administered afterthe one or more acute doses. In some embodiments, the pharmaceutical composition is formulated as a solution. In some embodiments, the solution comprises dehydrated ethanol, DL-alpha-tocopherol, propylene glycol, anhydrous citric acid, polysorbate 80, or PEG 400. In some embodiments, the solution further comprises about 0.9% (w / v) sodium chloride in water.

[0026] This disclosure also relates to a dosing regimen for administering to a human subject a pharmaceutical composition comprising (a) a therapeutically effective amount of a rapid-acting antidepressant (RAAD) and (b) a therapeutically effective amount of a mechanistic target of rapamycin (mTOR) inhibitor, wherein the dosing regimen comprises: administering to the human subject one or more acute doses; and administering to the human subject one or more maintenance doses after the administration of the one or more acute doses.

[0027] In some embodiments, the human subject is administered the one or more acute doses once per day, once per two days, once per three days, once per four days, once per five days, once per ten days, once per fifteen days, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, seven times per week, once per two weeks, once per three weeks, once per four weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten times per month. In some embodiments, the human subject is administered the one or more acute doses once per two weeks. In some embodiments, the human subject is administered the one or more acute doses for one week, for two weeks, for three weeks, for four weeks, for a month, for two months or for three months. In some embodiments, the human subject is administered the one or more acute doses for four weeks.

[0028] In some embodiments, the human subject is administered the one or more maintenance doses once per day, once per two days, once per three days, once per four days, once per five days, once per ten days, once per fifteen days, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, seven times per week, once per two weeks, once per three weeks, once per four weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten times per month. In some embodiments, the human subject is administered the one or more maintenance doses for one week, for two weeks, for three weeks, for four weeks, for five weeks, for eight weeks, for a month, for two months, for three months or for five months.

[0029] In some embodiments, the human subject is administered the one or more maintenance doses for two months. In some embodiments, the human subject is administered the one or more maintenance doses periodically as clinically needed.

[0030] In some embodiments, the therapeutically effective amount of the RAAD is at a dose of (i) about 0.01 mg / kg to about 100 mg / kg, (ii) about 0.8 mg to about 8 g, or (iii) about 1.2 mg to about 12 g. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of (i) about 0. 1 mg / kg to about 10 mg / kg, (ii) about 8 mg to about 800 mg, or (iii) about 12 mg to about 1200 mg. In someembodiments, the therapeutically effective amount of the RAAD is at a dose of (i) about 0.5 mg / kg to about 2 mg / kg, (ii) about 4 mg to about 160 mg, or (iii) about 6 mg to about 240 mg.

[0031] In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 1 pg / kg to about 100 pg / kg, (ii) about 0.08 mg to about 8 mg, or (iii) about 0.12 mg to about 12 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 1 pg / kg to about 50 pg / kg, (ii) about 0.08 mg to about 5.6 mg, or (iii) about 0.12 mg to about 8.4 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 3.125 pg / kg, about 9.375 pg / kg, about 24.2 pg / kg, or about 62.5 pg / kg, (ii) about 0.25 mg, about 0.75 mg, about 1.93 mg, or about 5 mg, or (iii) about 0.375 mg, about 1.125 mg, about 2.9 mg, or about 7.5 mg.

[0032] In some embodiments, the pharmaceutical composition is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route. In some embodiments, the pharmaceutical composition is administered through an intravenous route.

[0033] In some embodiments, the pharmaceutical composition is formulated as a solution. In some embodiments, the solution comprises dehydrated ethanol, DL-alpha-tocopherol, propylene glycol, anhydrous citric acid, polysorbate 80, or PEG 400. In some embodiments, the solution further comprises about 0.9% (w / v) sodium chloride in water.

[0034] This disclosure provides a method of treating or preventing a disease, disorder, or condition in a human subject in need thereof comprising administering to the human subject multiple doses of a pharmaceutical composition comprising: a therapeutically effective amount of a rapid-acting antidepressant (RAAD) and a therapeutically effective amount of a mechanistic target of rapamycin (mTOR) inhibitor, wherein the multiple doses comprise (i) one or more acute doses; and (ii) one or more maintenance doses after the one or more acute doses.

[0035] In some embodiments, the human subject is administered the one or more acute doses once per day, once per two days, once per three days, once per four days, once per five days, once per ten days, once per fifteen days, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, seven times per week, once per two weeks, once per three weeks, once per four weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten times per month. In some embodiments, the human subject is administered the one or more acute doses once per two weeks.

[0036] In some embodiments, the human subject is administered the one or more acute doses for one week, for two weeks, for three weeks, for four weeks, for a month, for two months or for three months. In some embodiments, the human subject is administered the one or more acute doses for four weeks.

[0037] In some embodiments, the human subject is administered the one or more maintenance doses once per day, once per two days, once per three days, once per four days, once per five days, once per ten days, once per fifteen days, once per week, twice per week, three times per week, four times per week,five times per week, six times per week, seven times per week, once per two weeks, once per three weeks, once per four weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten times per month. In some embodiments, the human subject is administered the one or more maintenance doses for one week, for two weeks, for three weeks, for four weeks, for five weeks, for eight weeks, for a month, for two months, for three months, or for five months. In some embodiments, the human subject is administered the one or more maintenance doses for two months. In some embodiments, the human subject is administered the one or more maintenance doses periodically as clinically needed.

[0038] In some embodiments, the therapeutically effective amount of the RAAD is at a dose of (i) about 0.01 mg / kg to about 100 mg / kg, (ii) about 0.8 mg to about 8 g, or (iii) about 1.2 mg to about 12 g. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of (i) about 0. 1 mg / kg to about 10 mg / kg, (ii) about 8 mg to about 800 mg, or (iii) about 12 mg to about 1200 mg. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of (i) about 0.5 mg / kg to about 2 mg / kg, (ii) about 4 mg to about 160 mg, or (iii) about 6 mg to about 240 mg.

[0039] In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 1 pg / kg to about 100 pg / kg, (ii) about 0.08 mg to about 8 mg, or (iii) about 0.12 mg to about 12 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 1 pg / kg to about 50 pg / kg, (ii) about 0.08 mg to about 5.6 mg, or (iii) about 0.12 mg to about 8.4 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 3.125 pg / kg, about 9.375 pg / kg, about 24.2 pg / kg, or about 62.5 pg / kg, (ii) about 0.25 mg, about 0.75 mg, about 1.93 mg, or about 5 mg, or (iii) about 0.375 mg, about 1.125 mg, about 2.9 mg, or about 7.5 mg.

[0040] In some embodiments, the human subject is administered an antidepressant before, during, or after administration of the pharmaceutical composition. In some embodiments, the human subject has an inadequate response to the antidepressant. In some embodiments, the human subject has an inadequate response to two or more antidepressant treatments. In some embodiments, the two or more antidepressant treatments includes the administration of the antidepressant. In some embodiments, the two or more antidepressant treatments does not include the administration of the antidepressant.

[0041] In some embodiments, the human subject is administered the antidepressant before the administration of the RAAD or the administration of the mTOR inhibitor. In some embodiments, the human subject is administered the antidepressant during the administration of the RAAD or the administration of the mTOR inhibitor. In some embodiments, the human subject is administered the antidepressant after the administration of the RAAD or the administration of the mTOR inhibitor.

[0042] In some embodiments, the antidepressant is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route. In some embodiments, the antidepressant is administered through the oral route.

[0043] In some embodiments, the pharmaceutical composition is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route. In some embodiments, the pharmaceutical composition is administered through an intravenous route.

[0044] In some embodiments, the pharmaceutical composition is formulated as a solution. In some embodiments, the solution comprises dehydrated ethanol, DL-alpha-tocopherol, propylene glycol, anhydrous citric acid, polysorbate 80, or PEG 400. In some embodiments, the solution further comprises about 0.9% (w / v) sodium chloride in water.

[0045] In some embodiments, the solution comprises the RAAD at a concentration of about 0.05 mg / ml to about 1 mg / ml. In some embodiments, the solution comprises the RAAD at a concentration of about 0.1 mg / ml to about 1 mg / ml. In some embodiments, the solution comprises the RAAD at a concentration of about 0.2 to about 0.5 mg / ml. In some embodiments, the solution comprises the RAAD at a concentration of about 0.2425 mg / ml. In some embodiments, the solution comprises the mTOR inhibitor at a concentration of about 1 to about 50 pg / ml. In some embodiments, the solution comprises the mTOR inhibitor at a concentration of about 1.5 pg / ml, about 4.5 pg / ml, about 11.6 pg / ml or about 30 pg / ml.

[0046] In some embodiments, the solution comprises dehydrated ethanol at a concentration of about 2.8 mg / ml to about 3.2 mg / ml. In some embodiments, the solution comprises dehydrated ethanol at a concentration of about 3.00785 mg / ml or about 3.01222 mg / ml. In some embodiments, the solution comprises polysorbate 80 at a concentration of about 0.8 mg / ml to about 1.2 mg / ml. In some embodiments, the solution comprises polysorbate 80 at a concentration of about 1.0608 mg / ml. In some embodiments, the solution comprises PEG 400 at a concentration of about 0.5 mg / ml to about 0.6 mg / ml. In some embodiments, the solution comprises PEG 400 at a concentration of about 0.54479 mg / ml. In some embodiments, the solution comprises DL-a tocopherol at a concentration of about 2 to about 3 pg / ml. In some embodiments, the solution comprises DL-a tocopherol at a concentration of about 2.44 pg / ml or about 2.448 pg / ml. In some embodiments, the solution comprises citric acid at a concentration of about 0.08 pg / ml to about 0.09 pg / ml. In some embodiments, the solution comprises citric acid at a concentration of about 0.0882 pg / ml or about 0.0885 pg / ml. In some embodiments, the solution comprises propylene glycol at a concentration of about 1 mg / ml to about 2 mg / ml. In some embodiments, the solution comprises propylene glycol at a concentration of about 1.6454 mg / ml or about 1.6509 mg / ml.

[0047] In some embodiments, the solution is in an IV bag. In some embodiments, the IV bag has one or more closed system transfer device (CSTD) ports. In some embodiments, the IV bag has two CSTD ports. In some embodiments, the CSTD ports can allow passage of the solution without leak or aerosolization.

[0048] In certain aspects, the present disclosure provides a solution comprising: (i) ketamine hydrochloride, wherein a concentration of an equivalent ketamine free base is about 0.2425 mg / ml, and (ii) temsirolimus, wherein a concentration of the temsirolimus is about 1.5 pg / ml, about 4.5 pg / ml, about 11.6 pg / ml or about 30 pg / ml.

[0049] In some embodiments, the solution further comprises dehydrated ethanol at a concentration of about 2.8 mg / ml to about 3.2 mg / ml. In some embodiments, the solution comprises the dehydrated ethanol at a concentration of about 3.00785 mg / ml or about 3.01222 mg / ml. In some embodiments, the solution comprises polysorbate 80 at a concentration of about 0.8 mg / ml to about 1.2 mg / ml. In some embodiments, the solution comprises the polysorbate 80 at a concentration of about 1.0608 mg / ml. In some embodiments, the solution comprises PEG 400 at a concentration of about 0.5 mg / ml to about 0.6 mg / ml. In some embodiments, the solution comprises the PEG 400 at a concentration of about 0.54479 mg / ml. In some embodiments, the solution comprises DL-a tocopherol at a concentration of about 2 to about 3 pg / ml. In some embodiments, the solution comprises the DL-a tocopherol at a concentration of about 2.44 pg / ml or about 2.448 pg / ml. In some embodiments, the solution comprises citric acid at a concentration of about 0.08 pg / ml to about 0.09 pg / ml. In some embodiments, the solution comprises the citric acid at a concentration of about 0.0882 pg / ml or about 0.0885 pg / ml. In some embodiments, the solution comprises propylene glycol at a concentration of about 1 mg / ml to about 2 mg / ml. In some embodiments, the solution comprises the propylene glycol at a concentration of about 1.6454 mg / ml or about 1.6509 mg / ml.

[0050] In some embodiments, the solution is in an IV bag. In some embodiments, the IV bag has one or more closed system transfer device (CSTD) ports. In some embodiments, the IV bag has two CSTD ports. In some embodiments, the CSTD ports can allow passage of the solution without leak or aerosolization.

[0051] The present disclosure further relates to a method of treating or preventing a disease, disorder, or condition in a human subject in need thereof comprising: administering a therapeutically effective amount of a composition comprising ketamine HC1 and rapamycin (sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779) to the human subject, wherein the human subject is administered an antidepressant before, during, or after the administration of the composition.

[0052] In additional embodiments, the present disclosure provides a method of treating or preventing a disease, disorder, or condition in a human subject in need thereof comprising: administering a therapeutically effective amount of a composition comprising ketamine HC1 and rapamycin (sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779) to the human subject, wherein the therapeutically effective amount of the rapamycin (sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779) is at a dose of (i) about 0.25 mg, about 0.75 mg, about 1.93 mg, or about 5 mg, (ii) about 0.375 mg, about 1.125 mg, about 2.9 mg, or about 7.5 mg, or (iii) about 3.125 pg / kg, about 9.375 pg / kg, about 24.2 pg / kg, or about 62.5 pg / kg.

[0053] In certain aspects, the present disclosure provides a system for administering a drug solution to a patient in need thereof. In some embodiments, the system comprises a primary intravenous (IV) bag containing a saline solution and a secondary IV bag containing the drug solution. In some embodiments, the drug solution comprises a rapid-acting antidepressant (RAAD) and a mechanistic target of rapamycin (mTOR) inhibitor. In some embodiments, the secondary IV bag comprises a CSTD port.

[0054] In some embodiments, the system further comprises a primary tubing that connects to the primary IV bag. In some embodiments, the system further comprises a secondary tubing that connects to the secondary IV bag. In some embodiments, the secondary tubing is connected to the primary tubing through a Y -site port.

[0055] In some embodiments, the system further comprises a pump. In some embodiments, the system further comprises a roller clamp on the secondary tubing.

[0056] In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.05 mg / ml to about 1 mg / ml. In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.1 mg / ml to about 1 mg / ml. In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.2 to about 0.5 mg / ml. In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.2425 mg / ml.

[0057] In some embodiments, the drug solution comprises the mTOR inhibitor at a concentration of about 1 to about 50 pg / ml. In some embodiments, the drug solution comprises the mTOR inhibitor at a concentration of about 1.5 pg / ml, about 4.5 pg / ml, about 11.6 pg / ml or about 30 pg / ml.

[0058] In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of about 2.8 mg / ml to about 3.2 mg / ml. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of about 3.00785 mg / ml or about 3.01222 mg / ml.

[0059] In some embodiments, the drug solution comprises polysorbate 80 at a concentration of about 0.8 mg / ml to about 1.2 mg / ml. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of about 1.0608 mg / ml.

[0060] In some embodiments, the drug solution comprises PEG 400 at a concentration of about 0.5 mg / ml to about 0.6 mg / ml. In some embodiments, the drug solution comprises PEG 400 at a concentration of about 0.54479 mg / ml.

[0061] In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of about 2 to about 3 pg / ml. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of about 2.44 pg / ml or about 2.448 pg / ml.

[0062] In some embodiments, the drug solution comprises citric acid at a concentration of about 0.08 pg / ml to about 0.09 pg / ml. In some embodiments, the drug solution comprises citric acid at a concentration of about 0.0882 pg / ml or about 0.0885 pg / ml.

[0063] In some embodiments, the drug solution comprises propylene glycol at a concentration of about 1 mg / ml to about 2 mg / ml. In some embodiments, the drug solution comprises propylene glycol at a concentration of about 1.6454 mg / ml or about 1.6509 mg / ml.

[0064] In some embodiments, the RAAD is selected from the group consisting of ketamine, (R)- ketamine, (S)-ketamine, R, S-ketamine, S-Norketamine, R-Norketamine, 2R,6R-hydroxynorketamine, 2S,6S-hydroxynorketamine, nitrous oxide, memantine, amantadine, racemic dextromethorphan, a fixed dose combination of dextromethorphan and quinidine, dextromethorphan, a fixed dose combination of dextromethophane and bupropion, dextromethadone (d-methadone), D-CCPene, UBP141, UBP145, HA966 ((±)-3-amino-l-hydroxy-pyrrolidin-2-one), NVPAAM077, Ro-25-26981, TCN 201, QNZ46,Neu2000, GM-1020, besonprodil, eliprodil, rislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, traxoprodil (CP-101,606), BMT-108908, onfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1- aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO- PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L- Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7- dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof. In some embodiments, the RAAD comprises aN-methyl-D-aspartate (NMD A) receptor modulator. In some embodiments, the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixture thereof. In some embodiments, the ketamine is ketamine HC1.

[0065] In some embodiments, the mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), umirolimus (Biolimus), KU-0063794, PI-103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI-103 - CAS 371935-74-9), torkinib (PP242), tacrolimus (FK-506, fujimycin,), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, sapanisertib), voxtalisib (XL- 765, SAR245409), torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), gedatolisib (PF-05212384, PKI-587), AZD- 2014 (Vistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP- BGT226), palomid-529 (P529, SG 00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC-0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC 223), clemastine (HS-592) fumarate, nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, astragaloside IV, samotolisib (LY3023414), chrysophanic acid, zotarolimus (ABT-578), and any salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, and geometric isomer thereof, and any mixtures thereof. In some embodiments, the mTOR inhibitor comprises rapamycin (sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779).

[0066] In additional aspects, the present disclosure provides a method for administration of a drug solution to a patient in need thereof, comprising: (i) connecting a primary IV bag to a pump through a primary tubing, wherein the primary IV bag contains a saline solution, (ii) closing a roller clamp on a secondary tubing, (iii) connecting a secondary IV bag to a Y -site port on the primary tubing through a secondary tubing, wherein the secondary IV bag contains the drug solution, wherein the drug solution comprises a rapid-acting antidepressant (RAAD) and a mechanistic target of rapamycin (mTOR) inhibitor, (iv) hanging the secondary IV bag below the primary IV bag, (v) opening the roller clamp on the secondary tubing, (vi) allowing the saline solution in the primary IV bag to fdl the secondary tubing and remove air in the secondary tubing, (vii) closing the roller clamp on the secondary tubing, and (viii) hanging the secondary IV bag above the primary IV bag, opening the roller clamp on the secondary tubing, and administering the drug solution in the secondary IV bag to the patient.

[0067] In some embodiments, the secondary IV bag comprises a CSTD port and wherein the secondary tubing is connected to the secondary IV bag through the CSTD port. In some embodiments, the CSTD port is closed before allowing the saline solution in the primary IV bag to fdl the secondary tubing. In some embodiments, the primary tubing comprises a check valve.

[0068] In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.05 mg / ml to about 1 mg / ml. In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.1 mg / ml to about 1 mg / ml. In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.2 to about 0.5 mg / ml. In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.2425 mg / ml.

[0069] In some embodiments, the drug solution comprises the mTOR inhibitor at a concentration of about 1 to about 50 pg / ml. In some embodiments, the drug solution comprises the mTOR inhibitor at a concentration of about 1.5 pg / ml, about 4.5 pg / ml, about 11.6 pg / ml or about 30 pg / ml.

[0070] In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of about 2.8 mg / ml to about 3.2 mg / ml. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of about 3.00785 mg / ml or about 3.01222 mg / ml.

[0071] In some embodiments, the drug solution comprises polysorbate 80 at a concentration of about 0.8 mg / ml to about 1.2 mg / ml. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of about 1.0608 mg / ml.

[0072] In some embodiments, the drug solution comprises PEG 400 at a concentration of about 0.5 mg / ml to about 0.6 mg / ml. In some embodiments, the drug solution comprises PEG 400 at a concentration of about 0.54479 mg / ml.

[0073] In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of about 2 to about 3 pg / ml. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of about 2.44 pg / ml or about 2.448 pg / ml.

[0074] In some embodiments, the drug solution comprises citric acid at a concentration of about 0.08 pg / ml to about 0.09 pg / ml. In some embodiments, the drug solution comprises citric acid at a concentration of about 0.0882 pg / ml or about 0.0885 pg / ml.

[0075] In some embodiments, the drug solution comprises propylene glycol at a concentration of about 1 mg / ml to about 2 mg / ml. In some embodiments, the drug solution comprises propylene glycol at a concentration of about 1.6454 mg / ml or about 1.6509 mg / ml.

[0076] In some embodiments, the RAAD is selected from the group consisting of ketamine, (R)- ketamine, (S)-ketamine, R, S-ketamine, S-Norketamine, R-Norketamine, 2R,6R-hydroxynorketamine, 2S,6S-hydroxynorketamine, nitrous oxide, memantine, amantadine, racemic dextromethorphan, a fixed dose combination of dextromethorphan and quinidine, dextromethorphan, a fixed dose combination of dextromethophane and bupropion, dextromethadone (d-methadone), D-CCPene, UBP141, UBP145, HA966 ((±)-3-amino-l-hydroxy-pyrrolidin-2-one), NVPAAM077, Ro-25-26981, TCN 201, QNZ46, Neu2000, GM-1020, besonprodil, eliprodil, rislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, traxoprodil (CP-101,606), BMT-108908, onfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1- aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO- PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L- Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7- dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof. In some embodiments, the RAAD comprises aN-methyl-D-aspartate (NMD A) receptor modulator. In some embodiments, the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixture thereof. In some embodiments, the ketamine is ketamine HC1.

[0077] In some embodiments, the mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), umirolimus (Biolimus), KU-0063794, PI-103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI-103 - CAS 371935-74-9), torkinib (PP242), tacrolimus (FK-506, fujimycin,), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, sapanisertib), voxtalisib (XL- 765, SAR245409), torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), gedatolisib (PF-05212384, PKI-587), AZD- 2014 (Vistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP- BGT226), palomid-529 (P529, SG 00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611,PA799), Way-600, ETP-46464 (ATRi), GDC-0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MUN0128), MTI-31, PQR620, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC 223), clemastine (HS-592) fumarate, nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, astragaloside IV, samotolisib (LY3023414), chrysophanic acid, zotarolimus (ABT-578), and any salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, and geometric isomer thereof, and any mixtures thereof. In some embodiments, the mTOR inhibitor comprises rapamycin (sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779).

[0078] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.INCORPORATION BY REFERENCE

[0079] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0080] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (“FIGURE.”, “FIGURES.”, “FIG.”, or “FIGS.” herein) of which:

[0081] FIG. 1 illustrates an example of the trial schema, which encompasses three phases: an up to 4- week (28-day) screening phase, a 4-week triple-blind treatment phase, and a 2-week follow-up phase, in accordance with some embodiments of the present disclosure. In some embodiments, the period of each phase may be longer than 4-week.

[0082] FIG. 2 shows an example of an intravenous (IV) bag with built in Closed System Transfer Device (CSTD) ports, in accordance with some embodiments of the present disclosure.

[0083] FIG. 3 shows an example administration configuration of study drug in an IV bag with CSTD port, in accordance with some embodiments of the present disclosure.DETAILED DESCRIPTION

[0084] Traditional antidepressant medications serve as the primary treatment strategy for Major Depressive Disorder (MDD). However, a substantial proportion of patients do not yield a favorableresponse to these therapies, which is a significant clinical challenge. Despite the range of approved oral antidepressants currently available, it is estimated that approximately 30% of MDD patients continue to display resistance to treatment and are referred to as having treatment-resistant depression (TRD). This statistic underscores a significant, unmet need for innovative approaches that can overcome the inherent limitations of traditional therapeutic strategies, in order to offer an effective treatment for MDD. Addressing this need, the present disclosure describes methods and pharmaceutical compositions designed for adjunctive therapy to current antidepressant treatments for the management of TRD. The target demographic for these therapies may consist of patients diagnosed with major depression who have previously demonstrated an inadequate response to at least two conventional antidepressant treatment.

[0085] Ketamine infusions have demonstrated response rates ranging from 40% to 60%, even in patients who failed to respond to conventional antidepressant therapy. Furthermore, both ketamine and S- ketamine have exhibited rapid response efficacy in suicidal patients. The specific mechanisms of action underlying the acute antidepressant effects of ketamine are yet to be fully understood. However, it is postulated that ketamine and its metabolites exert their antidepressant effects primarily by being noncompetitive antagonists of the N-methyl-D-aspartate (NMD A) receptor which triggers a surge in prefrontal glutamate neurotransmission. This leads to the activation of synaptic a-amino-3 -hydroxy-5 - methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs), which, in turn, elevates brain-derived neurotrophic factor (BDNF) levels, intensifies stimulation of tropomyosin receptor kinase B (TrkB) receptors, activates the mechanistic target of rapamycin complex 1 (mTORCl), and ultimately drives synaptogenesis. In relation to its downstream effects, several preclinical studies have reported an increase in mTORCl signaling following ketamine administration, though counter evidence also exists.METHOD

[0086] Provided herein are methods for treating or preventing a disease, disorder, or condition in a human subject in need thereof. The disease, disorder, or condition may be selected from the group consisting of a treatment-resistant depression (TRD), a major depressive disorder (MDD), a major depressive episode in bipolar disorder (bipolar depression), a persistent depressive disorder (dysthymia), a disruptive mood dysregulation disorder, a major depressive disorder (including major depressive episode), a premenstrual dysphoric disorder, a substance / medication-induced depressive disorder, a depressive disorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, a posttraumatic stress disorder, an addictive disorder, bipolar I disorder, bipolar II disorder, generalized anxiety disorder, social anxiety disorder (social phobia), specific phobia, panic disorder, agoraphobia, separation anxiety disorder, selective mutism, substance-induced anxiety disorder, medication-induced anxiety disorder, anxiety disorder due to another medical condition, borderline personality disorder, unspecified anxiety disorder, chronic pain, and any combinations thereof. In some embodiments, the disease, disorder, or condition may be a treatment-resistant depression (TRD). In some embodiments, the disease, disorder, or condition may be a major depressive disorder (MDD). In some embodiments, the disease, disorder, orcondition may be a mood disorder. In some embodiments, the disease, disorder, or condition may be a depressive disorder.

[0087] The method may comprise (i) administering a therapeutically effective amount of a rapid-acting antidepressant (RAAD) to the human subject, and (ii) administering a therapeutically effective amount of a mechanistic target of rapamycin (mTOR) inhibitor to the human subject. In some embodiments, the human subject may be administered an antidepressant before, during, or after the administration of the RAAD or the mTOR inhibitor. In some cases, the human subject may be administered an antidepressant before the administration of the RAAD or the mTOR inhibitor. In some cases, the human subject may be administered an antidepressant during the administration of the RAAD or the mTOR inhibitor. In some cases, the human subject may be administered an antidepressant after the administration of the RAAD or the mTOR inhibitor.

[0088] In certain aspects, the present disclosure also provides the method comprising (i) administering a therapeutically effective amount of an RAAD to the human subject, and (ii) administering a therapeutically effective amount of an mTOR inhibitor to the human subject, wherein the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 0.25 mg, about 0.75 mg, or about 1.93 mg or (ii) about 3.125 pg / kg, about 9.375 pg / kg, or about 24.2 pg / kg. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of (i) about 0.01 mg / kg to about 100 mg / kg, (ii) about 0.8 mg to about 8 g, or (iii) about 1.2 mg to about 12 g.

[0089] In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, or 10 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of about 0. 1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 7.5 mg, about 8.0 mg, about 8.5 mg, about 9.0 mg, about 9.5 mg, or about 10 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of at least 0.1 mg, at least 0.15 mg, at least 0.2 mg, at least 0.25 mg, at least 0.3 mg, at least 0.35 mg, at least 0.4 mg, at least 0.45 mg, at least 0.5 mg, at least 0.55 mg, at least 0.6 mg, at least 0.65 mg, at least 0.7 mg, at least 0.75 mg, at least 0.8 mg, at least 0.85 mg, at least 0.9 mg, at least 0.95 mg, at least 1 mg, at least 1. 1 mg, at least 1.2 mg, at least 1.3 mg, at least 1.4 mg, at least1.5 mg, at least 1.6 mg, at least 1.7 mg, at least 1.8 mg, at least 1.9 mg, at least 2 mg, at least 2.1 mg, at least 2.2 mg, at least 2.3 mg, at least 2.4 mg, at least 2.5 mg, at least 2.6 mg, at least 2.7 mg, at least 2.8 mg, at least 2.9 mg, at least 3.0 mg, at least 3.1 mg, at least 3.2 mg, at least 3.3 mg, at least 3.4 mg, at least 3.5 mg, at least 3.6 mg, at least 3.7 mg, at least 3.8 mg, at least 3.9 mg, at least 4.0 mg, at least 4.5 mg, at least 5.0 mg, at least 5.5 mg, at least 6.0 mg, at least 6.5 mg, at least 7.0 mg, at least 7.5 mg, at least 8.0 mg, at least 8.5 mg, at least 9.0 mg, at least 9.5 mg, or at least 10 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of no more than 0. 1 mg, no more than 0.15 mg, no more than 0.2 mg, no more than 0.25 mg, no more than 0.3 mg, no more than 0.35 mg, no more than 0.4 mg, no more than 0.45 mg, no more than 0.5 mg, no more than 0.55 mg, no more than 0.6 mg, no more than 0.65 mg, no more than 0.7 mg, no more than 0.75 mg, no more than 0.8 mg, no more than 0.85 mg, no more than 0.9 mg, no more than 0.95 mg, no more than 1 mg, no more than 1.1 mg, no more than 1.2 mg, no more than 1.3 mg, no more than 1.4 mg, no more than 1.5 mg, no more than 1.6 mg, no more than 1.7 mg, no more than 1.8 mg, no more than 1.9 mg, no more than 2 mg, no more than 2.1 mg, no more than 2.2 mg, no more than 2.3 mg, no more than 2.4 mg, no more than 2.5 mg, no more than 2.6 mg, no more than 2.7 mg, no more than 2.8 mg, no more than 2.9 mg, no more than 3.0 mg, no more than 3.1 mg, no more than 3.2 mg, no more than 3.3 mg, no more than 3.4 mg, no more than 3.5 mg, no more than 3.6 mg, no more than 3.7 mg, no more than 3.8 mg, no more than 3.9 mg, no more than 4.0 mg, no more than 4.5 mg, no more than 5.0 mg, no more than 5.5 mg, no more than 6.0 mg, no more than 6.5 mg, no more than 7.0 mg, no more than 7.5 mg, no more than 8.0 mg, no more than 8.5 mg, no more than 9.0 mg, no more than 9.5 mg, or no more than 10 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of about 0.25 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of about 0.75 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of about 1.93 mg.

[0090] In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of 3 pg / kg, 4 pg / kg, 5 pg / kg, 6 pg / kg, 7 pg / kg, 8 pg / kg, 9 pg / kg, 10 pg / kg, 11 pg / kg, 12 pg / kg, 13 pg / kg, 14 pg / kg, 15 pg / kg, 16 pg / kg, 17 pg / kg, 18 pg / kg, 19 pg / kg, 20 pg / kg, 21 pg / kg, 22 pg / kg, 23 pg / kg, 24 pg / kg, 25 pg / kg, 26 pg / kg, 27 pg / kg, 28 pg / kg, 29 pg / kg, or 30 pg / kg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of about 3 pg / kg, about 4 pg / kg, about 5 pg / kg, about 6 pg / kg, about 7 pg / kg, about 8 pg / kg, about 9 pg / kg, about 10 pg / kg, about 11 pg / kg, about 12 pg / kg, about 13 pg / kg, about 14 pg / kg, about 15 pg / kg, about 16 pg / kg, about 17 pg / kg, about 18 pg / kg, about 19 pg / kg, about 20 pg / kg, about 21 pg / kg, about 22 pg / kg, about 23 pg / kg, about 24 pg / kg, about 25 pg / kg, about 26 pg / kg, about 27 pg / kg, about 28 pg / kg, about 29 pg / kg, or about 30 pg / kg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of at least 3 pg / kg, at least 4 pg / kg, at least 5 pg / kg, at least 6 pg / kg, at least 7 pg / kg, at least 8 pg / kg, at least 9 pg / kg, at least 10 pg / kg, at least 11 pg / kg, at least 12 pg / kg, at least 13 pg / kg, at least 14 pg / kg, at least 15 pg / kg, at least 16 pg / kg, at least 17 pg / kg, at least 18 pg / kg, at least 19 pg / kg, at least 20 pg / kg, at least 21 pg / kg, at least 22 pg / kg, at least 23 pg / kg, at least 24 pg / kg, at least 25 pg / kg, at least 26pg / kg, at least 27 pg / kg, at least 28 pg / kg, at least 29 pg / kg, or at least 30 pg / kg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of no more than 3 pg / kg, no more than 4 pg / kg, no more than 5 pg / kg, no more than 6 pg / kg, no more than 7 pg / kg, no more than 8 pg / kg, no more than 9 pg / kg, no more than 10 pg / kg, no more than 11 pg / kg, no more than 12 pg / kg, no more than 13 pg / kg, no more than 14 pg / kg, no more than 15 pg / kg, no more than 16 pg / kg, no more than 17 pg / kg, no more than 18 pg / kg, no more than 19 pg / kg, no more than 20 pg / kg, no more than 21 pg / kg, no more than 22 pg / kg, no more than 23 pg / kg, no more than 24 pg / kg, no more than 25 pg / kg, no more than 26 pg / kg, no more than 27 pg / kg, no more than 28 pg / kg, no more than 29 pg / kg, or no more than 30 pg / kg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of about 3.125 pg / kg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of about 9.375 pg / kg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of about 24.2 pg / kg.

[0091] In some embodiments, the therapeutically effective amount of the RAAD is at a dose of about 0.005 mg / kg to about 120 mg / kg. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of 0.005 mg / kg, 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, 6.0 mg / kg, 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, or 120 mg / kg. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of at least 0.005 mg / kg, at least 0.01 mg / kg, at least 0.05 mg / kg, at least 0.1 mg / kg, at least 0.5 mg / kg, at least 1.0 mg / kg, at least 2.0 mg / kg, at least 3.0 mg / kg, at least 4.0 mg / kg, at least 5.0 mg / kg, at least 6.0 mg / kg, at least 7.0 mg / kg, at least 8.0 mg / kg, at least 9.0 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, at least 30 mg / kg, at least 35 mg / kg, at least 40 mg / kg, at least 45 mg / kg, at least 50 mg / kg, at least 55 mg / kg, at least 60 mg / kg, at least 65 mg / kg, at least 70 mg / kg, at least 75 mg / kg, at least 80 mg / kg, at least 85 mg / kg, at least 90 mg / kg, at least 95 mg / kg, at least 100 mg / kg, or at least 120 mg / kg. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of at most 0.005 mg / kg, at most 0.01 mg / kg, at most 0.05 mg / kg, at most 0.1 mg / kg, at most 0.5 mg / kg, at most 1.0 mg / kg, at most 2.0 mg / kg, at most 3.0 mg / kg, at most 4.0 mg / kg, at most 5.0 mg / kg, at most 6.0 mg / kg, at most 7.0 mg / kg, at most 8.0 mg / kg, at most 9.0 mg / kg, at most 10 mg / kg, at most 15 mg / kg, at most 20 mg / kg, at most 25 mg / kg, at most 30 mg / kg, at most 35 mg / kg, at most 40 mg / kg, at most 45 mg / kg, at most 50 mg / kg, at most 55 mg / kg, at most 60 mg / kg, at most 65 mg / kg, at most 70 mg / kg, at most 75 mg / kg, at most 80 mg / kg, at most 85 mg / kg, at most 90 mg / kg, at most 95 mg / kg, at most 100 mg / kg, or at most 120 mg / kg. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, or about 120 mg / kg.

[0092] In some embodiments, the therapeutically effective amount of the RAAD is at a dose of about 0.5 milligrams (mg) to about 10 g. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of 0.5 mg, 0.8 mg, 1.0 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg,5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 g, 1.5 g, 2 g, 2.5 g, 3 g, 3.5 g, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of at least 0.5 mg, at least 0.8 mg, at least 1.0 mg, at least 1.5 mg, at least 2 mg, at least 2.5 mg, at least 3 mg, at least3.5 mg, at least 4 mg, at least 4.5 mg, at least 5 mg, at least 5,5 mg, at least 6 mg, at least 6.5 mg, at least 7 mg, at least 7.5 mg, at least 8 mg, at least 8.5 mg, at least 9 mg, at least 9.5 mg, at least 10 mg, at least 20 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1 g, at least 1.5 g, at least 2 g, at least 2.5 g, at least 3 g, at least 3.5 g, at least 4 g, at least 4.5 g, at least 5 g, at least 5.5 g, at least 6 g, at least 6.5 g, at least 7 g, at least 7.5 g, at least 8 g, at least 8.5 g, at least 9 g, at least 9.5 g, or at least 10 g. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of at most 0.5 mg, at most 0.8 mg, at most 1.0 mg, at most 1.5 mg, at most 2 mg, at most 2.5 mg, at most 3 mg, at most 3.5 mg, at most 4 mg, at most 4.5 mg, at most 5 mg, at most 5,5 mg, at most 6 mg, at most 6.5 mg, at most 7 mg, at most 7.5 mg, at most 8 mg, at most 8.5 mg, at most 9 mg, at most 9.5 mg, at most 10 mg, at most 20 mg, at most 30 mg, at most 40 mg, at most 50 mg, at most 60 mg, at most 70 mg, at most 80 mg, at most 90 mg, at most 100 mg, at most 200 mg, at most 300 mg, at most 400 mg, at most 500 mg, at most 600 mg, at most 700 mg, at most 800 mg, at most 900 mg, at most 1 g, at most 1.5 g, at most 2 g, at most 2.5 g, at most 3 g, at most 3.5 g, at most 4 g, at most 4.5 g, at most 5 g, at most 5.5 g, at most 6 g, at most 6.5 g, at most 7 g, at most 7.5 g, at most 8 g, at most 8.5 g, at most 9 g, at most 9.5 g, or at most 10 g. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of about 0.5 mg, about 0.8 mg, about 1.0 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about4.5 mg, about 5 mg, about 5,5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, about 5 g, about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g, about 8.5 g, about 9 g, about 9.5 g, or about 10 g.

[0093] In yet another aspect of the present disclosure, the method comprises administering to the human subject multiple doses of a pharmaceutical composition comprising a therapeutically effective amount of an RAAD and a therapeutically effective amount of an mTOR inhibitor. In some embodiments, the multiple doses comprise (i) one or more acute doses; and (ii) one or more maintenance doses after theone or more acute doses. In some embodiments, the multiple doses comprise one or more acute doses. In some embodiments, the multiple doses comprise one or more maintenance doses. In some embodiments, the multiple doses comprise one or more acute doses and one or more maintenance doses. In some embodiments, the one or more maintenance doses may be administered after the one or more acute doses. In some embodiments, the multiple doses comprise one or more acute doses and one or more maintenance doses administered after the one or more acute doses. In some embodiments, the pharmaceutical composition may be administered to the human subject through more than one dose. In some embodiments, the pharmaceutical composition may be administered to the human subject through one or more doses.

[0094] A further aspect of the present disclosure relates to a dosing regimen for administering to a human subject a pharmaceutical composition comprising (a) a therapeutically effective amount of an RAAD and (b) a therapeutically effective amount of an mTOR inhibitor, wherein the dosing regimen comprises: administering to the human subject one or more acute doses; and administering to the human subject one or more maintenance doses after the administration of the one or more acute doses.

[0095] In some cases, the human subject may be administered the one or more acute doses every week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, seven weeks, every eight weeks, every night weeks or every ten weeks. In some cases, the human subject may be administered the one or more acute doses every week. In some cases, the human subject may be administered the one or more acute doses every two weeks. In some cases, the human subject may be administered the one or more acute doses every three weeks. In some cases, the human subject may be administered the one or more acute doses every four weeks. In some cases, the human subject may be administered the one or more acute doses every five weeks. In some cases, the human subject may be administered the one or more acute doses every six weeks. In some cases, the human subject may be administered the one or more acute doses every seven weeks. In some cases, the human subject may be administered the one or more acute doses every eight weeks. In some cases, the human subject may be administered the one or more acute doses every nine weeks. In some cases, the human subject may be administered the one or more acute doses every ten weeks. In some cases, the human subject may be administered the one or more acute doses every twelve weeks. In some cases, the human subject may be administered the one or more acute doses repeatedly at an interval longer than twelve weeks.

[0096] In some cases, the human subject may be administered the one or more acute doses for one week, for two weeks, for three weeks, for four weeks, for a month, for two months or for three months. In some cases, the human subject may be administered the one or more acute doses for one week. In some cases, the human subject may be administered the one or more acute doses for two weeks. In some cases, the human subject may be administered the one or more acute doses for three weeks. In some cases, the human subject may be administered the one or more acute doses for four weeks. In some cases, the human subject may be administered the one or more acute doses for five weeks. In some cases, the human subject may be administered the one or more acute doses for six weeks. In some cases, the human subject may be administered the one or more acute doses for seven weeks. In some cases, the humansubject may be administered the one or more acute doses for eight weeks. In some cases, the human subject may be administered the one or more acute doses for a month. In some cases, the human subject may be administered the one or more acute doses for two months. In some cases, the human subject may be administered the one or more acute doses for three months. In some cases, the human subject may be administered the one or more acute doses for four months. In some cases, the human subject may be administered the one or more acute doses for five months. In some cases, the human subject may be administered the one or more acute doses for six months. In some cases, the human subject may be administered the one or more acute doses for a year. In some cases, the human subject may be administered the one or more acute doses more than a year.

[0097] In some cases, the human subject may be administered the one or more maintenance doses every week, every two weeks, every three weeks, every four weeks, every five weeks, or every ten weeks. In some cases, the human subject may be administered the one or more maintenance doses every week. In some cases, the human subject may be administered the one or more maintenance doses every two weeks. In some cases, the human subject may be administered the one or more maintenance doses every three weeks. In some cases, the human subject may be administered the one or more maintenance doses every four weeks. In some cases, the human subject may be administered the one or more maintenance doses every five weeks. In some cases, the human subject may be administered the one or more maintenance doses every six weeks. In some cases, the human subject may be administered the one or more maintenance doses every seven weeks. In some cases, the human subject may be administered the one or more maintenance doses every eight weeks. In some cases, the human subject may be administered the one or more maintenance doses every nine weeks. In some cases, the human subject may be administered the one or more maintenance doses every ten weeks. In some cases, the human subject may be administered the one or more maintenance doses every twelve weeks. In some cases, the human subject may be administered the one or more maintenance doses repeatedly at an interval longer than twelve weeks.

[0098] In some cases, the human subject may be administered the one or more maintenance doses for one week, for two weeks, for three weeks, for four weeks, for five weeks, for eight weeks, for a month, for two months, for three months, or for five months. In some cases, the human subject may be administered the one or more maintenance doses for one week. In some cases, the human subject may be administered the one or more maintenance doses for two weeks. In some cases, the human subject may be administered the one or more maintenance doses for three weeks. In some cases, the human subject may be administered the one or more maintenance doses for four weeks. In some cases, the human subject may be administered the one or more maintenance doses for five weeks. In some cases, the human subject may be administered the one or more maintenance doses for six weeks. In some cases, the human subject may be administered the one or more maintenance doses for seven weeks. In some cases, the human subject may be administered the one or more maintenance doses for eight weeks. In some cases, the human subject may be administered the one or more maintenance doses for a month. In some cases, the human subject may be administered the one or more maintenance doses for two months. Insome cases, the human subject may be administered the one or more maintenance doses for three months. In some cases, the human subject may be administered the one or more maintenance doses for four months. In some cases, the human subject may be administered the one or more maintenance doses for five months. In some cases, the human subject may be administered the one or more maintenance doses for six months. In some cases, the human subject may be administered the one or more maintenance doses for a year. In some cases, the human subject may be administered the one or more maintenance doses for more than a year. In some cases, the human subject may be administered the one or more maintenance doses periodically as clinically needed.

[0099] In some cases, the human subject may be administered an antidepressant before the administration of the RAAD or the mTOR inhibitor. In some cases, the human subject may be administered an antidepressant during the administration of the RAAD or the mTOR inhibitor. In some cases, the human subject may be administered an antidepressant after the administration of the RAAD or the mTOR inhibitor.

[0100] In some cases, the human subject may have an inadequate response to the antidepressant. In some cases, the human subject may have an inadequate response to two or more antidepressant treatments. The two or more antidepressant treatments may include the administration of the antidepressant. The two or more antidepressant treatments may not include the administration of the antidepressant.

[0101] In certain aspects, the present disclosure provides a method for administering a drug solution to a patient in need thereof. In some embodiments, the method comprises: (i) connecting a primary intravenous (IV) bag to a pump through a primary tubing, wherein the primary IV bag contains a saline solution, (ii) closing a roller clamp on a secondary tubing, (iii) connecting a secondary IV bag to a Y -site port on the primary tubing through a secondary tubing, wherein the secondary IV bag contains the drug solution, wherein the drug solution comprises a rapid-acting antidepressant (RAAD) and a mechanistic target of rapamycin (mTOR) inhibitor, (iv) hanging the secondary IV bag below the primary IV bag, (v) opening the roller clamp on the secondary tubing, (vi) allowing the saline solution in the primary IV bag to fill the secondary tubing and remove air in the secondary tubing, (vii) closing the roller clamp on the secondary tubing, and (viii) hanging the secondary IV bag above the primary IV bag, opening the roller clamp on the secondary tubing, and administering the drug solution in the secondary IV bag to the patient.

[0102] In some embodiments, the secondary IV bag comprises a CSTD port and wherein the secondary tubing is connected to the secondary IV bag through the CSTD port. In some embodiments, the CSTD port is closed before allowing the saline solution in the primary IV bag to fill the secondary tubing. In some embodiments, the primary tubing comprises a check valve.

[0103] In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.05 mg / ml to about 1 mg / ml. In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.1 mg / ml to about 1 mg / ml. In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.2 to about 0.5 mg / ml. In some embodiments, the drug solutioncomprises the RAAD at a concentration of about 0.2425 mg / ml. In some embodiments, a concentration of RAAD in the drug solution ranges from about 0.01 mg / mL to about 2 mg / mL. In some embodiments, a concentration of RAAD in the drug solution ranges from about 0.05 mg / mL to about 1 mg / mL. In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.1 mg / mL to about 1 mg / mL. In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.2 mg / mL to about 0.5 mg / mL. In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.2425 mg / mL. In some embodiments, a concentration of RAAD in the drug solution is 0.01 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.15 mg / mL, 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.35 mg / mL, 0.4 mg / mL, 0.45 mg / mL, 0.5 mg / mL, 0.55 mg / mL, 0.6 mg / mL, 0.65 mg / mL, 0.7 mg / mL, 0.75 mg / mL, 0.8 mg / mL, 0.85 mg / mL, 0.9 mg / mL, 0.95 mg / mL, 1 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, or 2 mg / mL. In some embodiments, a concentration of RAAD in the drug solution is about 0.01 mg / mL, about 0.05 mg / mL, about 0.1 mg / mL, about 0.15 mg / mL, about 0.2 mg / mL, about 0.25 mg / mL, about 0.3 mg / mL, about 0.35 mg / mL, about 0.4 mg / mL, about 0.45 mg / mL, about 0.5 mg / mL, about 0.55 mg / mL, about 0.6 mg / mL, about 0.65 mg / mL, about 0.7 mg / mL, about 0.75 mg / mL, about 0.8 mg / mL, about 0.85 mg / mL, about 0.9 mg / mL, about 0.95 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, or about 2 mg / mL. In some embodiments, a concentration of RAAD in the drug solution is at least 0.01 mg / mL, at least 0.05 mg / mL, at least 0.1 mg / mL, at least 0.15 mg / mL, at least 0.2 mg / mL, at least 0.25 mg / mL, at least 0.3 mg / mL, at least 0.35 mg / mL, at least 0.4 mg / mL, at least 0.45 mg / mL, at least 0.5 mg / mL, at least 0.55 mg / mL, at least 0.6 mg / mL, at least 0.65 mg / mL, at least 0.7 mg / mL, at least 0.75 mg / mL, at least 0.8 mg / mL, at least 0.85 mg / mL, at least 0.9 mg / mL, at least 0.95 mg / mL, at least 1 mg / mL, at least 1.1 mg / mL, at least 1.2 mg / mL, at least 1.3 mg / mL, at least 1.4 mg / mL, at least 1.5 mg / mL, at least 1.6 mg / mL, at least 1.7 mg / mL, at least 1.8 mg / mL, at least 1.9 mg / mL, or at least 2 mg / mL. In some embodiments, a concentration of RAAD in the drug solution is no more than 0.01 mg / mL, no more than 0.05 mg / mL, no more than 0.1 mg / mL, no more than 0.15 mg / mL, no more than 0.2 mg / mL, no more than 0.25 mg / mL, no more than 0.3 mg / mL, no more than 0.35 mg / mL, no more than 0.4 mg / mL, no more than 0.45 mg / mL, no more than 0.5 mg / mL, no more than 0.55 mg / mL, no more than 0.6 mg / mL, no more than 0.65 mg / mL, no more than 0.7 mg / mL, no more than 0.75 mg / mL, no more than 0.8 mg / mL, no more than 0.85 mg / mL, no more than 0.9 mg / mL, no more than 0.95 mg / mL, no more than 1 mg / mL, no more than 1.1 mg / mL, no more than 1.2 mg / mL, no more than 1.3 mg / mL, no more than 1.4 mg / mL, no more than 1.5 mg / mL, no more than 1.6 mg / mL, no more than 1.7 mg / mL, no more than 1.8 mg / mL, no more than 1.9 mg / mL, or no more than 2 mg / mL.

[0104] In some embodiments, the drug solution comprises the mTOR inhibitor at a concentration of about 0.11 to about 100 pg / ml. In some embodiments, the drug solution comprises the mTOR inhibitor at a concentration of about 1 to about 50 pg / ml. In some embodiments, the drug solution comprises the mTOR inhibitor at a concentration of about 1.5 pg / ml, about 4.5 pg / ml, about 11.6 pg / ml or about 30 pg / ml. In some embodiments, a concentration of mTOR inhibitor in the drug solution is 1.5 pg / mL. Insome embodiments, a concentration of mTOR inhibitor in the drug solution is 4.5 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is 11.6 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution ranges from about 0.1 pg / mL to about 100 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution ranges from about 1 pg / mL to about 50 pg / mL. In some embodiments, a concentration of mTOR inhibitor in drug the solution is about 1.5 pg / mL, about 4.5 pg / mL, about 11.6 pg / mL or about 30 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is about 1.5 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is about 4.5 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is about 11.6 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is about 30 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is 0.1 pg / mL, 0.5 pg / mL, 1 pg / mL, 2 pg / mL, 3 pg / mL, 4 pg / mL, 5 pg / mL, 6 pg / mL, 7 pg / mL, 8 pg / mL, 9 pg / mL, 10 pg / mL, 15 pg / mL, 20 pg / mL, 25 pg / mL, 30 pg / mL, 35 pg / mL, 40 pg / mL, 45 pg / mL, 50 pg / mL, 55 pg / mL, 60 pg / mL, 65 pg / mL, 70 pg / mL, 75 pg / mL, 80 pg / mL, 85 pg / mL, 90 pg / mL, 95 pg / mL, or 100 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is about 0.1 pg / mL, about 0.5 pg / mL, about 1 pg / mL, about 2 pg / mL, about 3 pg / mL, about 4 pg / mL, about 5 pg / mL, about 6 pg / mL, about 7 pg / mL, about 8 pg / mL, about 9 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, about 80 pg / mL, about 85 pg / mL, about 90 pg / mL, about 95 pg / mL, or about 100 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is at least 0.1 pg / mL, at least 0.5 pg / mL, at least 1 pg / mL, at least 2 pg / mL, at least 3 pg / mL, at least 4 pg / mL, at least 5 pg / mL, at least 6 pg / mL, at least 7 pg / mL, at least 8 pg / mL, at least 9 pg / mL, at least 10 pg / mL, at least 15 pg / mL, at least 20 pg / mL, at least 25 pg / mL, at least 30 pg / mL, at least 35 pg / mL, at least 40 pg / mL, at least 45 pg / mL, at least 50 pg / mL, at least 55 pg / mL, at least 60 pg / mL, at least 65 pg / mL, at least 70 pg / mL, at least 75 pg / mL, at least 80 pg / mL, at least 85 pg / mL, at least 90 pg / mL, at least 95 pg / mL, or at least 100 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is no more than 0.1 pg / mL, no more than 0.5 pg / mL, no more than 1 pg / mL, no more than 2 pg / mL, no more than 3 pg / mL, no more than 4 pg / mL, no more than 5 pg / mL, no more than 6 pg / mL, no more than 7 pg / mL, no more than 8 pg / mL, no more than 9 pg / mL, no more than 10 pg / mL, no more than 15 pg / mL, no more than 20 pg / mL, no more than 25 pg / mL, no more than 30 pg / mL, no more than 35 pg / mL, no more than 40 pg / mL, no more than 45 pg / mL, no more than 50 pg / mL, no more than 55 pg / mL, no more than 60 pg / mL, no more than 65 pg / mL, no more than 70 pg / mL, no more than 75 pg / mL, no more than 80 pg / mL, no more than 85 pg / mL, no more than 90 pg / mL, no more than 95 pg / mL, or no more than 100 pg / mL.

[0105] In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of 2.0 mg / mL to 4 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of 2.8 mg / mL to 3.2 mg / mL. In some embodiments, the drug solution comprisesdehydrated ethanol at a concentration of 3.00785 mg / mL or 3.01222 mg / mL. drug In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of 3.01222 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of about 2.0 mg / mL to about 4 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of about 2.8 mg / mL to about 3.2 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of about 3.00785 mg / mL or about 3.01222 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of about 3.00785 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of about 3.01222 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of 2.0 mg / mL, 2.1 mg / mL, 2.2 mg / mL, 2.3 mg / mL, 2.4 mg / mL, 2.5 mg / mL, 2.6 mg / mL, 2.7 mg / mL, 2.8 mg / mL, 2.9 mg / mL, 3 mg / mL, 3.1 mg / mL, 3.2 mg / mL, 3.3 mg / mL, 3.4 mg / mL, 3.5 mg / mL, 3.6 mg / mL, 3.7 mg / mL, 3.8 mg / mL, 3.9 mg / mL, or 4 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of about 2.0 mg / mL, about 2. 1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, about 3 mg / mL, about 3.1 mg / mL, about 3.2 mg / mL, about 3.3 mg / mL, about 3.4 mg / mL, about 3.5 mg / mL, about 3.6 mg / mL, about 3.7 mg / mL, about 3.8 mg / mL, about 3.9 mg / mL, or about 4 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of at least 2.0 mg / mL, at least 2.1 mg / mL, at least 2.2 mg / mL, at least 2.3 mg / mL, at least 2.4 mg / mL, at least 2.5 mg / mL, at least 2.6 mg / mL, at least 2.7 mg / mL, at least 2.8 mg / mL, at least 2.9 mg / mL, at least 3 mg / mL, at least 3.1 mg / mL, at least 3.2 mg / mL, at least 3.3 mg / mL, at least 3.4 mg / mL, at least 3.5 mg / mL, at least 3.6 mg / mL, at least 3.7 mg / mL, at least 3.8 mg / mL, at least 3.9 mg / mL, or at least 4 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of no more than 2.0 mg / mL, no more than 2. 1 mg / mL, no more than 2.2 mg / mL, no more than 2.3 mg / mL, no more than 2.4 mg / mL, no more than 2.5 mg / mL, no more than 2.6 mg / mL, no more than 2.7 mg / mL, no more than 2.8 mg / mL, no more than 2.9 mg / mL, no more than 3 mg / mL, no more than 3.1 mg / mL, no more than 3.2 mg / mL, no more than 3.3 mg / mL, no more than 3.4 mg / mL, no more than 3.5 mg / mL, no more than 3.6 mg / mL, no more than 3.7 mg / mL, no more than 3.8 mg / mL, no more than 3.9 mg / mL, or no more than 4 mg / mL.

[0106] In some embodiments, the drug solution comprises polysorbate 80 at a concentration of 0.5 mg / mL to 1.5 mg / mL. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of 0.8 mg / mL to 1.2 mg / mL. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of 1.0608 mg / ml. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of about 0.5 mg / mL to about 1.5 mg / mL. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of about 0.8 mg / mL to about 1.2 mg / mL. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of about 1.0608 mg / ml. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, or 1.5 mg / mL. In some embodiments, the drug solution comprises polysorbate 80 at aconcentration of about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, or about 1.5 mg / mL. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of at least 0.5 mg / mL, at least 0.6 mg / mL, at least 0.7 mg / mL, at least 0.8 mg / mL, at least 0.9 mg / mL, at least 1 mg / mL, at least 1.1 mg / mL, at least 1.2 mg / mL, at least 1.3 mg / mL, at least 1.4 mg / mL, or at least 1.5 mg / mL. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of no more than 0.5 mg / mL, no more than 0.6 mg / mL, no more than 0.7 mg / mL, no more than 0.8 mg / mL, no more than 0.9 mg / mL, no more than 1 mg / mL, no more than 1.1 mg / mL, no more than 1.2 mg / mL, no more than 1.3 mg / mL, no more than 1.4 mg / mL, or no more than 1.5 mg / mL.

[0107] In some embodiments, the drug solution comprises PEG 400 at a concentration of 0.2 mg / mL to 0.8 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of 0.5 mg / mL to 0.6 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of 0.54479 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of about 0.2 mg / mL to about 0.8 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of about 0.5 mg / mL to about 0.6 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of about 0.54479 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, or 0.8 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, or about 0.8 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of at least 0.2 mg / mL, at least 0.3 mg / mL, at least 0.4 mg / mL, at least 0.5 mg / mL, at least 0.6 mg / mL, at least 0.7 mg / mL, or at least 0.8 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of no more than 0.2 mg / mL, no more than 0.3 mg / mL, no more than 0.4 mg / mL, no more than 0.5 mg / mL, no more than 0.6 mg / mL, no more than 0.7 mg / mL, or no more than 0.8 mg / mL.

[0108] In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of 1 pg / mL to 4 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of 2 pg / mL to 3 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of 2.44 pg / mL or 2.448 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of 2.44 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of 2.448 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of about 1 pg / mL to about 4 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of about 2 pg / mL to about 3 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of about 2.44 pg / mL or about 2.448 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of about 2.44 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of about 2.448 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of 1 pg / mL, 2 pg / mL, 2.1 pg / mL, 2.2 pg / mL, 2.3 pg / mL, 2.4 pg / mL,2.5 pg / mL, 2.6 pg / mL, 2.7 pg / mL, 2.8 pg / mL, 2.9 pg / mL, 3 pg / mL, or 4 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of about 1 pg / mL, about 2 pg / mL, about 2.1 pg / mL, about 2.2 pg / mL, about 2.3 pg / mL, about 2.4 pg / mL, about 2.5 pg / mL, about 2.6 pg / mL, about 2.7 pg / mL, about 2.8 pg / mL, about 2.9 pg / mL, about 3 pg / mL, or about 4 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of at least 1 pg / mL, at least 2 pg / mL, at least 2.1 pg / mL, at least 2.2 pg / mL, at least 2.3 pg / mL, at least 2.4 pg / mL, at least 2.5 pg / mL, at least 2.6 pg / mL, at least 2.7 pg / mL, at least 2.8 pg / mL, at least 2.9 pg / mL, at least 3 pg / mL, or at least 4 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of no more thanl pg / mL, no more than 2 pg / mL, no more than 2.1 pg / mL, no more than 2.2 pg / mL, no more than 2.3 pg / mL, no more than 2.4 pg / mL, no more than 2.5 pg / mL, no more than 2.6 pg / mL, no more than 2.7 pg / mL, no more than 2.8 pg / mL, no more than 2.9 pg / mL, no more than 3 pg / mL, or no more than 4 pg / mL.

[0109] In some embodiments, the drug solution comprises citric acid at a concentration of 0.07 pg / mL to 0.1 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of 0.08 pg / mL to 0.09 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of 0.0882 pg / mL or 0.0885 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of 0.0882 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of 0.0885 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of about 0.07 pg / mL to about 0.1 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of about 0.08 pg / mL to about 0.09 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of about 0.0882 pg / mL or about 0.0885 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of about 0.0882 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of about 0.0885 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of 0.07 pg / mL, 0.08 pg / mL, 0.081 pg / mL, 0.082 pg / mL, 0.083 pg / mL, 0.084 pg / mL, 0.085 pg / mL, 0.086 pg / mL, 0.087 pg / mL, 0.088 pg / mL, 0.089 pg / mL, 0.09 pg / mL, or 0.1 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of about 0.07 pg / mL, about 0.08 pg / mL, about 0.081 pg / mL, about 0.082 pg / mL, about 0.083 pg / mL, about 0.084 pg / mL, about 0.085 pg / mL, about 0.086 pg / mL, about 0.087 pg / mL, about 0.088 pg / mL, about 0.089 pg / mL, about 0.09 pg / mL, or about 0.1 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of at least 0.07 pg / mL, at least 0.08 pg / mL, at least 0.081 pg / mL, at least 0.082 pg / mL, at least 0.083 pg / mL, at least 0.084 pg / mL, at least 0.085 pg / mL, at least 0.086 pg / mL, at least 0.087 pg / mL, at least 0.088 pg / mL, at least 0.089 pg / mL, at least 0.09 pg / mL, or at least 0.1 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of no more than 0.07 pg / mL, no more than 0.08 pg / mL, no more than 0.081 pg / mL, no more than 0.082 pg / mL, no more than 0.083 pg / mL, no more than 0.084 pg / mL, no more than 0.085 pg / mL, no more than 0.086 pg / mL, no more than 0.087 pg / mL, no more than 0.088 pg / mL, no more than 0.089 pg / mL, no more than 0.09 pg / mL, or no more than 0.1 pg / mL.

[0110] In some embodiments, the drug solution comprises propylene glycol at a concentration of 0.5 mg / mL to 2.5 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of 1 mg / mL to 2 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of 1.6454 mg / mL or 1.6509 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of 1.6454 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of 1.6509 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of about 0.5 mg / mL to about 2.5 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of about 1 mg / mL to about 2 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of about 1.6454 mg / mL or about 1.6509 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of about 1.6454 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of about 1.6509 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of 0.5 mg / mL, 1 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.65 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2 mg / mL, or 2.5 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of about 0.5 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 1.6 mg / mL, about 1.65 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2 mg / mL, or about 2.5 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of at least 0.5 mg / mL, at least 1 mg / mL, at least 1.1 mg / mL, at least 1.2 mg / mL, at least 1.3 mg / mL, at least 1.4 mg / mL, at least 1.5 mg / mL, at least 1.6 mg / mL, at least 1.65 mg / mL, at least 1.7 mg / mL, at least 1.8 mg / mL, at least 1.9 mg / mL, at least 2 mg / mL, or at least 2.5 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of no more than 0.5 mg / mL, no more than 1 mg / mL, no more than 1.1 mg / mL, no more than 1.2 mg / mL, no more than 1.3 mg / mL, no more than 1.4 mg / mL, no more than 1.5 mg / mL, no more than 1.6 mg / mL, no more than 1.65 mg / mL, no more than 1.7 mg / mL, no more than 1.8 mg / mL, no more than 1.9 mg / mL, no more than 2 mg / mL, or no more than 2.5 mg / mL.[oni] In some embodiments, the RAAD is selected from the group consisting of ketamine, (R)- ketamine, (S)-ketamine, R, S-ketamine, S-Norketamine, R-Norketamine, 2R,6R-hydroxynorketamine, 2S,6S-hydroxynorketamine, nitrous oxide, memantine, amantadine, racemic dextromethorphan, a fixed dose combination of dextromethorphan and quinidine, dextromethorphan, a fixed dose combination of dextromethophane and bupropion, dextromethadone (d-methadone), D-CCPene, UBP141, UBP145, HA966 ((±)-3-amino-l-hydroxy-pyrrolidin-2-one), NVPAAM077, Ro-25-26981, TCN 201, QNZ46, Neu2000, GM-1020, besonprodil, eliprodil, rislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, traxoprodil (CP-101,606), BMT-108908, onfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1- aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L- Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7- dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-20I, MPX-004, MPX-007, NAB-14, EVT-IOI, QNZ-46, DQP-1105, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof. In some embodiments, the RAAD comprises aN-methyl-D-aspartate (NMD A) receptor modulator. In some embodiments, the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixture thereof. In some embodiments, the ketamine is ketamine HC1.

[0112] In some embodiments, the mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), umirolimus (Biolimus), KU-0063794, PI-103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI-103 - CAS 371935-74-9), torkinib (PP242), tacrolimus (FK-506, fujimycin,), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, sapanisertib), voxtalisib (XL- 765, SAR245409), torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), gedatolisib (PF-05212384, PKI-587), AZD- 2014 (Vistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP- BGT226), palomid-529 (P529, SG 00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC-0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC 223), clemastine (HS-592) fumarate, nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, astragaloside IV, samotolisib (LY3023414), chrysophanic acid, zotarolimus (ABT-578), and any salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, and geometric isomer thereof, and any mixtures thereof. In some embodiments, the mTOR inhibitor comprises rapamycin (sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779).ANTIDEPRESSANT

[0113] In some embodiments, the antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRs), serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs), serotonin modulators and stimulators (SMSs), serotonin antagonist and reuptake inhibitors (SARIs), norepinephrine reuptake inhibitors (NRIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), monoamine oxidase inhibitors(MAOIs), norepinephrine and dopamine reuptake inhibitors (NDRIs), atypical antipsychotics, typical antipsychotics, and allowable antidepressants used as sleep medications.

[0114] In some embodiments, the antidepressant may be SSRIs. In some embodiments, the antidepressant may be SNRs. In some embodiments, the antidepressant may be SNDRIs. In some embodiments, the antidepressant may be SMSs. In some embodiments, the antidepressant may be SARIs. In some embodiments, the antidepressant may be NRIs. In some embodiments, the antidepressant may be TCAs. In some embodiments, the antidepressant may be TeCAs. In some embodiments, the antidepressant may be MAOIs. In some embodiments, the antidepressant may be NDRIs. In some embodiments, the antidepressant may be atypical antipsychotics. In some embodiments, the antidepressant may be typical antipsychotics. In some embodiments, the antidepressant may be allowable antidepressants used as sleep medications.

[0115] In some embodiments, the antidepressant may be a combination thereof described above. In some embodiments, the antidepressant may be a combination of TCA and benzodiazepine. In some embodiments, the antidepressant may be a combination of TCA and typical antipsychotic. In some embodiments, the antidepressant may be a combination of SSRI and atypical antipsychotic. In some embodiments, the antidepressant may be a combination of MAOI and typical antipsychotic.

[0116] In some embodiments, the SSRIs comprise fluoxetine, fluvoxamine, citalopram, sertraline, paroxetine, or escitalopram.

[0117] In some embodiments, the SNRIs comprise duloxetine, levomilnacipran, milnacipran, venlafaxine, or desvenlafaxine.

[0118] In some embodiments, the SNDRIs comprise toludesvenlafaxine or nefazodone.

[0119] In some embodiments, the SMSs comprise vilazodone or vortioxetine.

[0120] In some embodiments, the SARIs comprise nefazodone or trazodone.

[0121] In some embodiments, the NRIs comprise reboxetine, teniloxazine, 5-HT2A receptor antagonist, atomoxetine, viloxazine, 5-HT2B receptor antagonist, or 5-HT2C receptor agonist.

[0122] In some embodiments, the NDRIs comprise bupropion, amphetamines, methylphenidate, modafinil, or non-competitive antagonist of nicotinic acetylcholine receptors.

[0123] In some embodiments, the TACs comprise amitriptyline, amitriptylinoxide, clomipramine, desipramine, dibenzepin, dimetacrine, dosulepin, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, nortriptyline, noxiptiline, pipofezine, protriptyline, trimipramine, opipramol, or tianeptine.

[0124] In some embodiments, the TeCAs comprise amoxapine, maprotiline, mianserin, mirtazapine, setiptiline, mianserin, mirtazapine, or setiptiline.

[0125] In some embodiments, the MAOIs comprise isocarboxazid, phenelzine, tranylcypromine, selegiline, metralindole, moclobemide, pirlindole, or bifemelane.

[0126] In some embodiments, the atypical antipsychotics comprise amisulpride, lumateperone, lurasidone, aripiprazole, brexpiprazole, quetiapine, risperidone, or olanzapine.

[0127] In some embodiments, the typical antipsychotics comprise trifluoperazine, buspirone, lithium, or thyroxine.

[0128] In some embodiments, the allowable antidepressants used as sleep medications comprise trazodone or mirtazapine.

[0129] In some embodiments, the antidepressant comprises a traditional antidepressant (TAD). In some embodiments, the antidepressant comprises a the rapid-acting antidepressant (RAAD).

[0130] In some cases, the antidepressant is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route. In some cases, the antidepressant is administered through an intramuscular route. In some cases, the antidepressant is administered through an intravenous route. In some cases, the antidepressant is administered through a subcutaneous route. In some cases, the antidepressant is administered through an oral route. In some cases, the antidepressant is administered through an inhalation route. In some cases, the antidepressant is administered through an intranasal route.RAPID-ACTING ANTIDEPRESSANT (RAAD)

[0131] In certain aspects, the present disclosure provides a formulation or a pharmaceutical composition comprising a rapid-acting antidepressant (RAAD). In some embodiments, the rapid-acting antidepressant (RAAD) is selected from the group consisting of ketamine, (R) -ketamine, (S)-ketamine, R, S-ketamine, S- Norketamine, / ?-Norkctaminc. 2R, 6 / ?-hydroxynorkctaminc. 2.S'. 6S'-hydroxynorkctaminc. nitrous oxide, memantine, amantadine, racemic dextromethorphan, a fixed dose combination of dextromethorphan and quinidine, dextromethorphan, a fixed dose combination of dextromethophane and bupropion, dextromethadone (d-methadone), D-CCPene, UBP141, UBP145, HA966 ((±)-3-amino-l-hydroxy- pyrrolidin-2-one), NVPAAM077, Ro-25-26981, TCN 201, QNZ46, Neu2000, GM-1020, besonprodil, eliprodil, rislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, traxoprodil (CP-101,606), BMT-108908, onfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1-aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7-dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN- 201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof. In some embodiments, the RAAD comprises a N-methyl-D-aspartate (NMD A) receptor modulator. In some embodiments, the NMDA receptor modulator may be ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixture thereof. In some embodiments, the ketamine may be ketamine HC1. The term “ketamine” used herein may represent ketamine and its metabolites.

[0132] In some embodiments, the therapeutically effective amount of the RAAD is at a dose of (i) about 0.01 milligrams per kilograms (mg / kg) to about 100 mg / kg, (ii) about 0.8 mg to about 8 g, or (iii) about 1.2 mg to about 12 g. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of (i) about 0.1 mg / kg to about 10 mg / kg, (ii) about 8 mg to about 800 mg, or (iii) about 12 mg to about 1200 mg. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of (i) about 0.5 mg / kg to about 2 mg / kg, (ii) about 4 mg to about 160 mg, or (iii) about 6 mg to about 240 mg.

[0133] In some embodiments, the therapeutically effective amount of the RAAD is at a dose of about 0.005 mg / kg to about 120 mg / kg. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of 0.005 mg / kg, 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, 6.0 mg / kg, 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, or 120 mg / kg. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of at least 0.005 mg / kg, at least 0.01 mg / kg, at least 0.05 mg / kg, at least 0.1 mg / kg, at least 0.5 mg / kg, at least 1.0 mg / kg, at least 2.0 mg / kg, at least 3.0 mg / kg, at least 4.0 mg / kg, at least 5.0 mg / kg, at least 6.0 mg / kg, at least 7.0 mg / kg, at least 8.0 mg / kg, at least 9.0 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, at least 30 mg / kg, at least 35 mg / kg, at least 40 mg / kg, at least 45 mg / kg, at least 50 mg / kg, at least 55 mg / kg, at least 60 mg / kg, at least 65 mg / kg, at least 70 mg / kg, at least 75 mg / kg, at least 80 mg / kg, at least 85 mg / kg, at least 90 mg / kg, at least 95 mg / kg, at least 100 mg / kg, or at least 120 mg / kg. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of at most 0.005 mg / kg, at most 0.01 mg / kg, at most 0.05 mg / kg, at most 0.1 mg / kg, at most 0.5 mg / kg, at most 1.0 mg / kg, at most 2.0 mg / kg, at most 3.0 mg / kg, at most 4.0 mg / kg, at most 5.0 mg / kg, at most 6.0 mg / kg, at most 7.0 mg / kg, at most 8.0 mg / kg, at most 9.0 mg / kg, at most 10 mg / kg, at most 15 mg / kg, at most 20 mg / kg, at most 25 mg / kg, at most 30 mg / kg, at most 35 mg / kg, at most 40 mg / kg, at most 45 mg / kg, at most 50 mg / kg, at most 55 mg / kg, at most 60 mg / kg, at most 65 mg / kg, at most 70 mg / kg, at most 75 mg / kg, at most 80 mg / kg, at most 85 mg / kg, at most 90 mg / kg, at most 95 mg / kg, at most 100 mg / kg, or at most 120 mg / kg. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, or about 120 mg / kg. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of 0.01 mg / kg to 100 mg / kg, 0.05 mg / kg to 95 mg / kg, 0.1 mg / kg to 90 mg / kg, 0.5 mg / kg to 85 mg / kg, 1.0 mg / kg to 80 mg / kg, 2.0 mg / kg to 75 mg / kg, 3.0 mg / kg to 70 mg / kg, 4.0 mg / kg to 65 mg / kg, 5.0 mg / kg to 60 mg / kg, 6.0 mg / kg to 55 mg / kg, 7.0 mg / kg to 50 mg / kg, 8.0 mg / kg to 45 mg / kg, or all values and sub ranges in between.

[0134] In some embodiments, the therapeutically effective amount of the RAAD is at a dose of about 0.5 milligrams (mg) to about 15 g. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of 0.5 mg, 0.8 mg, 1.0 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg,5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 g, 1.5 g, 2 g, 2.5 g, 3 g, 3.5 g, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, 10 g,10.5 g, 11 g, 11.5 g, 12 g, 12.5 g, 13 g, 13.5 g, 14 g, 14.5 g, or 15 g. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of at least 0.5 mg, at least 0.8 mg, at least 1.0 mg, at least 1.5 mg, at least 2 mg, at least 2.5 mg, at least 3 mg, at least 3.5 mg, at least 4 mg, at least 4.5 mg, at least 5 mg, at least 5,5 mg, at least 6 mg, at least 6.5 mg, at least 7 mg, at least 7.5 mg, at least 8 mg, at least 8.5 mg, at least 9 mg, at least 9.5 mg, at least 10 mg, at least 20 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1 g, at least 1.5 g, at least 2 g, at least 2.5 g, at least 3 g, at least 3.5 g, at least 4 g, at least 4.5 g, at least 5 g, at least 5.5 g, at least 6 g, at least 6.5 g, at least 7 g, at least 7.5 g, at least 8 g, at least 8.5 g, at least 9 g, at least 9.5 g, at least 10 g, at least 10.5 g, at least 11 g, at least 11.5 g, at least 12 g, at least 12.5 g, at least 13 g, at least 13.5 g, at least 14 g, at least 14.5 g, or at least 15 g. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of at most 0.5 mg, at most 0.8 mg, at most 1.0 mg, at most 1.5 mg, at most 2 mg, at most 2.5 mg, at most 3 mg, at most 3.5 mg, at most 4 mg, at most 4.5 mg, at most 5 mg, at most 5,5 mg, at most 6 mg, at most 6.5 mg, at most 7 mg, at most 7.5 mg, at most 8 mg, at most 8.5 mg, at most 9 mg, at most 9.5 mg, at most 10 mg, at most 20 mg, at most 30 mg, at most 40 mg, at most 50 mg, at most 60 mg, at most 70 mg, at most 80 mg, at most 90 mg, at most 100 mg, at most 200 mg, at most 300 mg, at most 400 mg, at most 500 mg, at most 600 mg, at most 700 mg, at most 800 mg, at most 900 mg, at most 1 g, at most 1.5 g, at most 2 g, at most2.5 g, at most 3 g, at most 3.5 g, at most 4 g, at most 4.5 g, at most 5 g, at most 5.5 g, at most 6 g, at most6.5 g, at most 7 g, at most 7.5 g, at most 8 g, at most 8.5 g, at most 9 g, at most 9.5 g, at most 10 g, at most 10.5 g, at most 11 g, at most 11 .5 g, at most 12 g, at most 12.5 g, at most 13 g, at most 13.5 g, at most 14 g, at most 14.5 g, or at most 15 g. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of about 0.5 mg, about 0.8 mg, about 1.0 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5,5 mg, about 6 mg, about6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, about 5 g, about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g, about 8.5 g, about 9 g, about 9.5 g, about 10 g, about 10.5 g, about 11 g, about 11.5 g, about 12 g, about12.5 g, about 13 g, about 13.5 g, about 14 g, about 14.5 g, or about 15 g. In some embodiments, the therapeutically effective amount of the RAAD is at a dose of 0.5 mg to 8 g, 0.8 mg to 7.5 g, 1.0 mg to 7g, 1.5 mg to 6.5 g, 2 mg to 6 g, 2.5 mg to 5.5 g, 3 mg to 5 g, 3.5 mg to 4.5 g, 4 mg to 4 g, 4.5 mg to 3.5 g, 5 mg to 3 g, 5,5 mg to 2.5 g, 6 mg to 2 g, 6.5 mg to 1.5 g, 7 mg to 1 g, or all values and sub ranges in between.

[0135] In some embodiments, the RAAD may be ketamine. In some embodiments, the ketamine comprises ketamine free base, ketamine metabolite, or ketamine HC1. In some embodiments, the therapeutically effective amount of ketamine is at a dose of (i) about 0.01 milligrams per kilograms (mg / kg) to about 100 mg / kg, (ii) about 0.8 mg to about 8 g, or (iii) about 1.2 mg to about 12 g. In some embodiments, the therapeutically effective amount of ketamine is at a dose of (i) about 0.1 mg / kg to about 10 mg / kg, (ii) about 8 mg to about 800 mg, or (iii) about 12 mg to about 1200 mg. In some embodiments, the therapeutically effective amount of ketamine is at a dose of (i) about 0.5 mg / kg to about 2 mg / kg, (ii) about 4 mg to about 160 mg, or (iii) about 6 mg to about 240 mg.

[0136] In some embodiments, the therapeutically effective amount of ketamine is at a dose of about 0.005 mg / kg to about 120 mg / kg. In some embodiments, the therapeutically effective amount of ketamine is at a dose of 0.005 mg / kg, 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, 6.0 mg / kg, 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, or 120 mg / kg. In some embodiments, the therapeutically effective amount of ketamine is at a dose of at least 0.005 mg / kg, at least 0.01 mg / kg, at least 0.05 mg / kg, at least 0.1 mg / kg, at least 0.5 mg / kg, at least 1.0 mg / kg, at least 2.0 mg / kg, at least 3.0 mg / kg, at least 4.0 mg / kg, at least 5.0 mg / kg, at least 6.0 mg / kg, at least 7.0 mg / kg, at least 8.0 mg / kg, at least 9.0 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, at least 30 mg / kg, at least 35 mg / kg, at least 40 mg / kg, at least 45 mg / kg, at least 50 mg / kg, at least 55 mg / kg, at least 60 mg / kg, at least 65 mg / kg, at least 70 mg / kg, at least 75 mg / kg, at least 80 mg / kg, at least 85 mg / kg, at least 90 mg / kg, at least 95 mg / kg, at least 100 mg / kg, or at least 120 mg / kg. In some embodiments, the therapeutically effective amount of ketamine is at a dose of at most 0.005 mg / kg, at most 0.01 mg / kg, at most 0.05 mg / kg, at most 0.1 mg / kg, at most 0.5 mg / kg, at most 1.0 mg / kg, at most 2.0 mg / kg, at most 3.0 mg / kg, at most 4.0 mg / kg, at most 5.0 mg / kg, at most 6.0 mg / kg, at most 7.0 mg / kg, at most 8.0 mg / kg, at most 9.0 mg / kg, at most 10 mg / kg, at most 15 mg / kg, at most 20 mg / kg, at most 25 mg / kg, at most 30 mg / kg, at most 35 mg / kg, at most 40 mg / kg, at most 45 mg / kg, at most 50 mg / kg, at most 55 mg / kg, at most 60 mg / kg, at most 65 mg / kg, at most 70 mg / kg, at most 75 mg / kg, at most 80 mg / kg, at most 85 mg / kg, at most 90 mg / kg, at most 95 mg / kg, at most 100 mg / kg, or at most 120 mg / kg. In some embodiments, the therapeutically effective amount of ketamine is at a dose of about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, or about 120 mg / kg. In some embodiments,the therapeutically effective amount of ketamine is at a dose of 0.01 mg / kg to 100 mg / kg, 0.05 mg / kg to 95 mg / kg, 0. 1 mg / kg to 90 mg / kg, 0.5 mg / kg to 85 mg / kg, 1.0 mg / kg to 80 mg / kg, 2.0 mg / kg to 75 mg / kg, 3.0 mg / kg to 70 mg / kg, 4.0 mg / kg to 65 mg / kg, 5.0 mg / kg to 60 mg / kg, 6.0 mg / kg to 55 mg / kg, 7.0 mg / kg to 50 mg / kg, 8.0 mg / kg to 45 mg / kg, or all values and sub ranges in between.

[0137] In some embodiments, the therapeutically effective amount of ketamine is at a dose of about 0.5 milligrams (mg) to about 10 g. In some embodiments, the therapeutically effective amount of ketamine is at a dose of 0.5 mg, 0.8 mg, 1.0 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5,5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 g,1.5 g, 2 g, 2.5 g, 3 g, 3.5 g, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, 10 g, 10.5 g, 11 g, 11.5 g, 12 g, 12.5 g, 13 g, 13.5 g, 14 g, 14.5 g, or 15 g. In some embodiments, the therapeutically effective amount of ketamine is at a dose of at least 0.5 mg, at least 0.8 mg, at least 1.0 mg, at least 1.5 mg, at least 2 mg, at least 2.5 mg, at least 3 mg, at least 3.5 mg, at least 4 mg, at least 4.5 mg, at least 5 mg, at least 5,5 mg, at least 6 mg, at least 6.5 mg, at least 7 mg, at least 7.5 mg, at least 8 mg, at least 8.5 mg, at least 9 mg, at least 9.5 mg, at least 10 mg, at least 20 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1 g, at least 1.5 g, at least 2 g, at least 2.5 g, at least 3 g, at least 3.5 g, at least 4 g, at least 4.5 g, at least 5 g, at least 5.5 g, at least 6 g, at least 6.5 g, at least 7 g, at least 7.5 g, at least 8 g, at least 8.5 g, at least 9 g, at least 9.5 g, at least 10 g, at least 10.5 g, at least 11 g, at least 11.5 g, at least 12 g, at least12.5 g, at least 13 g, at least 13.5 g, at least 14 g, at least 14.5 g, or at least 15 g. In some embodiments, the therapeutically effective amount of ketamine is at a dose of at most 0.5 mg, at most 0.8 mg, at most 1.0 mg, at most 1.5 mg, at most 2 mg, at most 2.5 mg, at most 3 mg, at most 3.5 mg, at most 4 mg, at most 4.5 mg, at most 5 mg, at most 5,5 mg, at most 6 mg, at most 6.5 mg, at most 7 mg, at most 7.5 mg, at most 8 mg, at most 8.5 mg, at most 9 mg, at most 9.5 mg, at most 10 mg, at most 20 mg, at most 30 mg, at most 40 mg, at most 50 mg, at most 60 mg, at most 70 mg, at most 80 mg, at most 90 mg, at most 100 mg, at most 200 mg, at most 300 mg, at most 400 mg, at most 500 mg, at most 600 mg, at most 700 mg, at most 800 mg, at most 900 mg, at most 1 g, at most 1.5 g, at most 2 g, at most 2.5 g, at most 3 g, at most 3.5 g, at most 4 g, at most 4.5 g, at most 5 g, at most 5.5 g, at most 6 g, at most 6.5 g, at most 7 g, at most 7.5 g, at most 8 g, at most 8.5 g, at most 9 g, at most 9.5 g, at most 10 g, at most 10.5 g, at most 11 g, at most 11.5 g, at most 12 g, at most 12.5 g, at most 13 g, at most 13.5 g, at most 14 g, at most 14.5 g, or at most 15 g. In some embodiments, the therapeutically effective amount of ketamine is at a dose of about 0.5 mg, about 0.8 mg, about 1.0 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5,5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5g, about 5 g, about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g, about 8.5 g, about 9 g, about 9.5 g, about 10 g, about 10.5 g, about 11 g, about 11.5 g, about 12 g, about 12.5 g, about 13 g, about 13.5 g, about 14 g, about 14.5 g, or about 15 g. In some embodiments, the therapeutically effective amount of ketamine is at a dose of 0.5 mg to 8 g, 0.8 mg to 7.5 g, 1.0 mg to 7 g, 1.5 mg to 6.5 g, 2 mg to 6 g, 2.5 mg to 5.5 g, 3 mg to 5 g, 3.5 mg to 4.5 g, 4 mg to 4 g, 4.5 mg to 3.5 g, 5 mg to 3 g, 5,5 mg to 2.5 g, 6 mg to 2 g, 6.5 mg to 1.5 g, 7 mg to 1 g, or all values and sub ranges in between.

[0138] In some embodiments, a concentration of ketamine in an IV bag ranges from 0.01 mg / mL to 0.5 mg / mL. In some embodiments, a concentration of ketamine in an IV bag ranges from about 0.01 mg / mL to about 0.5 mg / mL. In some embodiments, a concentration of ketamine in an IV bag is 0.01 mg / mL, 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / mL, 0.05 mg / mL, 0.06 mg / mL, 0.07 mg / mL, 0.08 mg / mL, 0.09 mg / mL, 0.1 mg / mL, 0.15 mg / mL, 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.35 mg / mL, 0.4 mg / mL, 0.45 mg / mL, or 0.5 mg / mL. In some embodiments, a concentration of ketamine in an IV bag is about 0.01 mg / mL, about 0.02 mg / mL, about 0.03 mg / mL, about 0.04 mg / mL, about 0.05 mg / mL, about 0.06 mg / mL, about 0.07 mg / mL, about 0.08 mg / mL, about 0.09 mg / mL, about 0.1 mg / mL, about 0.15 mg / mL, about 0.2 mg / mL, about 0.25 mg / mL, about 0.3 mg / mL, about 0.35 mg / mL, about 0.4 mg / mL, about 0.45 mg / mL, or about 0.5 mg / mL. In some embodiments, a concentration of ketamine in an IV bag is at least 0.01 mg / mL, at least 0.02 mg / mL, at least 0.03 mg / mL, at least 0.04 mg / mL, at least 0.05 mg / mL, at least 0.06 mg / mL, at least 0.07 mg / mL, at least 0.08 mg / mL, at least 0.09 mg / mL, at least 0.1 mg / mL, at least 0.15 mg / mL, at least 0.2 mg / mL, at least 0.25 mg / mL, at least 0.3 mg / mL, at least 0.35 mg / mL, at least 0.4 mg / mL, at least 0.45 mg / mL, or at least 0.5 mg / mL. In some embodiments, a concentration of ketamine in an IV bag is no more than 0.01 mg / mL, no more than 0.02 mg / mL, no more than 0.03 mg / mL, no more than 0.04 mg / mL, no more than 0.05 mg / mL, no more than 0.06 mg / mL, no more than 0.07 mg / mL, no more than 0.08 mg / mL, no more than 0.09 mg / mL, no more than 0. 1 mg / mL, no more than 0.15 mg / mL, no more than 0.2 mg / mL, no more than 0.25 mg / mL, no more than 0.3 mg / mL, no more than 0.35 mg / mL, no more than 0.4 mg / mL, no more than 0.45 mg / mL, or no more than 0.5 mg / mL.

[0139] In some embodiments, the formulation or a pharmaceutical composition comprising RAAD may be a solution. In some embodiments, a concentration of RAAD in the solution ranges from 0.01 mg / mL to 2 mg / mL. In some embodiments, a concentration of RAAD in the solution ranges from 0.05 mg / mL to 1 mg / mL. In some embodiments, the solution comprises the RAAD at a concentration of 0.1 mg / mL to 1 mg / mL. In some embodiments, the solution comprises the RAAD at a concentration of 0.2 mg / mL to 0.5 mg / mL. In some embodiments, the solution comprises the RAAD at a concentration of 0.2425 mg / mL. In some embodiments, a concentration of RAAD in the solution ranges from about 0.01 mg / mL to about 2 mg / mL. In some embodiments, a concentration of RAAD in the solution ranges from about 0.05 mg / mL to about 1 mg / mL. In some embodiments, the solution comprises the RAAD at a concentration of about 0.1 mg / mL to about 1 mg / mL. In some embodiments, the solution comprises the RAAD at a concentration of about 0.2 mg / mL to about 0.5 mg / mL. In some embodiments, the solution comprises the RAAD at a concentration of about 0.2425 mg / mL. In some embodiments, a concentration of RAAD inthe solution is 0.01 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.15 mg / mL, 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.35 mg / mL, 0.4 mg / mL, 0.45 mg / mL, 0.5 mg / mL, 0.55 mg / mL, 0.6 mg / mL, 0.65 mg / mL, 0.7 mg / mL, 0.75 mg / mL, 0.8 mg / mL, 0.85 mg / mL, 0.9 mg / mL, 0.95 mg / mL, 1 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, or 2 mg / mL. In some embodiments, a concentration of RAAD in the solution is about 0.01 mg / mL, about 0.05 mg / mL, about 0.1 mg / mL, about 0.15 mg / mL, about 0.2 mg / mL, about 0.25 mg / mL, about 0.3 mg / mL, about 0.35 mg / mL, about 0.4 mg / mL, about 0.45 mg / mL, about 0.5 mg / mL, about 0.55 mg / mL, about 0.6 mg / mL, about 0.65 mg / mL, about 0.7 mg / mL, about 0.75 mg / mL, about 0.8 mg / mL, about 0.85 mg / mL, about 0.9 mg / mL, about 0.95 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, or about 2 mg / mL. In some embodiments, a concentration of RAAD in the solution is at least 0.01 mg / mL, at least 0.05 mg / mL, at least 0.1 mg / mL, at least 0.15 mg / mL, at least 0.2 mg / mL, at least 0.25 mg / mL, at least 0.3 mg / mL, at least 0.35 mg / mL, at least 0.4 mg / mL, at least 0.45 mg / mL, at least 0.5 mg / mL, at least 0.55 mg / mL, at least 0.6 mg / mL, at least 0.65 mg / mL, at least 0.7 mg / mL, at least 0.75 mg / mL, at least 0.8 mg / mL, at least 0.85 mg / mL, at least 0.9 mg / mL, at least 0.95 mg / mL, at least 1 mg / mL, at least 1.1 mg / mL, at least 1.2 mg / mL, at least 1.3 mg / mL, at least 1.4 mg / mL, at least 1.5 mg / mL, at least 1.6 mg / mL, at least 1.7 mg / mL, at least 1.8 mg / mL, at least 1.9 mg / mL, or at least 2 mg / mL. In some embodiments, a concentration of RAAD in the solution is no more than 0.01 mg / mL, no more than 0.05 mg / mL, no more than 0. 1 mg / mL, no more than 0.15 mg / mL, no more than 0.2 mg / mL, no more than 0.25 mg / mL, no more than 0.3 mg / mL, no more than 0.35 mg / mL, no more than 0.4 mg / mL, no more than 0.45 mg / mL, no more than 0.5 mg / mL, no more than 0.55 mg / mL, no more than 0.6 mg / mL, no more than 0.65 mg / mL, no more than 0.7 mg / mL, no more than 0.75 mg / mL, no more than 0.8 mg / mL, no more than 0.85 mg / mL, no more than 0.9 mg / mL, no more than 0.95 mg / mL, no more than 1 mg / mL, no more than 1.1 mg / mL, no more than 1.2 mg / mL, no more than 1.3 mg / mL, no more than 1.4 mg / mL, no more than 1.5 mg / mL, no more than 1.6 mg / mL, no more than 1.7 mg / mL, no more than 1.8 mg / mL, no more than 1.9 mg / mL, or no more than 2 mg / mL.

[0140] In some embodiments, the formulation or a pharmaceutical composition comprising RAAD may be a solution. In some embodiments, the RAAD may be ketamine. In some embodiments, the ketamine comprises ketamine free base, ketamine metabolite, or ketamine HC1. In some embodiments, a concentration of ketamine in the solution ranges from 0.01 mg / mL to 2 mg / mL. In some embodiments, a concentration of ketamine in the solution ranges from 0.05 mg / mL to 1 mg / mL. In some embodiments, the solution comprises the ketamine at a concentration of 0.1 mg / mL to 1 mg / mL. In some embodiments, the solution comprises the ketamine at a concentration of 0.2 mg / mL to 0.5 mg / mL. In some embodiments, the solution comprises the ketamine at a concentration of 0.2425 mg / mL. In some embodiments, a concentration of ketamine in the solution ranges from about 0.01 mg / mL to about 2 mg / mL. In some embodiments, a concentration of ketamine in the solution ranges from about 0.05 mg / mL to about 1 mg / mL. In some embodiments, the solution comprises ketamine at a concentration of about 0.1 mg / mL to about 1 mg / mL. In some embodiments, the solution comprises the ketamine at aconcentration of about 0.2 mg / mL to about 0.5 mg / mL. In some embodiments, the solution comprises ketamine at a concentration of about 0.2425 mg / mL. In some embodiments, a concentration of ketamine in the solution is 0.01 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.15 mg / mL, 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.35 mg / mL, 0.4 mg / mL, 0.45 mg / mL, 0.5 mg / mL, 0.55 mg / mL, 0.6 mg / mL, 0.65 mg / mL, 0.7 mg / mL, 0.75 mg / mL, 0.8 mg / mL, 0.85 mg / mL, 0.9 mg / mL, 0.95 mg / mL, 1 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, or 2 mg / mL. In some embodiments, a concentration of ketamine in the solution is about 0.01 mg / mL, about 0.05 mg / mL, about 0.1 mg / mL, about 0.15 mg / mL, about 0.2 mg / mL, about 0.25 mg / mL, about 0.3 mg / mL, about 0.35 mg / mL, about 0.4 mg / mL, about 0.45 mg / mL, about 0.5 mg / mL, about 0.55 mg / mL, about 0.6 mg / mL, about 0.65 mg / mL, about 0.7 mg / mL, about 0.75 mg / mL, about 0.8 mg / mL, about 0.85 mg / mL, about 0.9 mg / mL, about 0.95 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, or about 2 mg / mL. In some embodiments, a concentration of ketamine in the solution is at least 0.01 mg / mL, at least 0.05 mg / mL, at least 0.1 mg / mL, at least 0.15 mg / mL, at least 0.2 mg / mL, at least 0.25 mg / mL, at least 0.3 mg / mL, at least 0.35 mg / mL, at least 0.4 mg / mL, at least 0.45 mg / mL, at least 0.5 mg / mL, at least 0.55 mg / mL, at least 0.6 mg / mL, at least 0.65 mg / mL, at least 0.7 mg / mL, at least 0.75 mg / mL, at least 0.8 mg / mL, at least 0.85 mg / mL, at least 0.9 mg / mL, at least 0.95 mg / mL, at least 1 mg / mL, at least 1.1 mg / mL, at least 1.2 mg / mL, at least 1.3 mg / mL, at least 1.4 mg / mL, at least 1.5 mg / mL, at least 1.6 mg / mL, at least 1.7 mg / mL, at least 1.8 mg / mL, at least 1.9 mg / mL, or at least 2 mg / mL. In some embodiments, a concentration of ketamine in the solution is no more than 0.01 mg / mL, no more than 0.05 mg / mL, no more than 0.1 mg / mL, no more than 0.15 mg / mL, no more than 0.2 mg / mL, no more than 0.25 mg / mL, no more than 0.3 mg / mL, no more than 0.35 mg / mL, no more than 0.4 mg / mL, no more than 0.45 mg / mL, no more than 0.5 mg / mL, no more than 0.55 mg / mL, no more than 0.6 mg / mL, no more than 0.65 mg / mL, no more than 0.7 mg / mL, no more than 0.75 mg / mL, no more than 0.8 mg / mL, no more than 0.85 mg / mL, no more than 0.9 mg / mL, no more than 0.95 mg / mL, no more than 1 mg / mL, no more than 1.1 mg / mL, no more than 1.2 mg / mL, no more than 1.3 mg / mL, no more than 1.4 mg / mL, no more than 1.5 mg / mL, no more than 1.6 mg / mL, no more than 1.7 mg / mL, no more than 1.8 mg / mL, no more than 1.9 mg / mL, or no more than 2 mg / mL.

[0141] In some embodiments, the therapeutically effective amount of the RAAD may be administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route. In some embodiments, the therapeutically effective amount of the RAAD may be administered through an intramuscular route. In some embodiments, the therapeutically effective amount of the RAAD may be administered through an intravenous route. In some embodiments, the therapeutically effective amount of the RAAD may be administered through a subcutaneous route. In some embodiments, the therapeutically effective amount of the RAAD may be administered through an oral route. In some embodiments, the therapeutically effective amount of the RAAD may be administered through an inhalation route. In some embodiments, the therapeutically effective amount of the RAAD may be administered through an intranasal route.

[0142] In some embodiments, the therapeutically effective amount of the RAAD may be administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or seven times per week. In some embodiments, the therapeutically effective amount of the RAAD may be administered once per week. In some embodiments, the therapeutically effective amount of the RAAD may be administered twice per week. In some embodiments, the therapeutically effective amount of the RAAD may be administered three times per week. In some embodiments, the therapeutically effective amount of the RAAD may be administered four times per week. In some embodiments, the therapeutically effective amount of the RAAD may be administered five times per week. In some embodiments, the therapeutically effective amount of the RAAD may be administered six times per week. In some embodiments, the therapeutically effective amount of the RAAD may be administered seven times per week.

[0143] In some embodiments, the therapeutically effective amount of the RAAD may be administered once per week, once per two weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per month, or ten times per month. In some embodiments, the therapeutically effective amount of the RAAD may be administered once per week. In some embodiments, the therapeutically effective amount of the RAAD may be administered once per two weeks. In some embodiments, the therapeutically effective amount of the RAAD may be administered once per month. In some embodiments, the therapeutically effective amount of the RAAD may be administered twice per month. In some embodiments, the therapeutically effective amount of the RAAD may be administered three times per month, four times per month. In some embodiments, the therapeutically effective amount of the RAAD may be administered four times per month. In some embodiments, the therapeutically effective amount of the RAAD may be administered five times per month. In some embodiments, the therapeutically effective amount of the RAAD may be administered six times per month. In some embodiments, the therapeutically effective amount of the RAAD may be administered seven times per month. In some embodiments, the therapeutically effective amount of the RAAD may be administered eight times per month. In some embodiments, the therapeutically effective amount of the RAAD may be administered nine times per month. In some embodiments, the therapeutically effective amount of the RAAD may be administered ten times per month.MECHANISTIC TARGET OF RAPAMYCIN (MTOR) INHIBITOR

[0144] In certain aspects, the present disclosure provides a formulation or a pharmaceutical composition comprising a mechanistic target of rapamycin (mTOR) inhibitor. In some embodiments, the mechanistic target of rapamycin (mTOR) inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTBIOI), rapamycin (sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), umirolimus (Biolimus), KU-0063794, PI-103 (mTOR Inhibitor V, PI 3-K Inhibitor y, PI-103 - CAS 371935-74-9), torkinib (PP242), tacrolimus (FK-506, fujimycin,), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, sapanisertib), voxtalisib (XL- 765, SAR245409), torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1),omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), gedatolisib (PF-05212384, PKI-587), AZD- 2014 (Vistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP- BGT226), palomid-529 (P529, SG 00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC-0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC 223), clemastine (HS-592) fumarate, nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, astragaloside IV, samotolisib (LY3023414), chrysophanic acid, zotarolimus (ABT-578), and any salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, and geometric isomer thereof, and any mixtures thereof. In some embodiments, the mTOR inhibitor comprises rapamycin (sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779).

[0145] In some embodiments, the mTOR inhibitor may be rapamycin (sirolimus, AY 22989, ABI-009). In some embodiments, the mTOR inhibitor may be temsirolimus (CCI-779).

[0146] In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 1 micrograms per kilograms (pg / kg) to about 100 pg / kg, (ii) about 0.08 mg to about 8 mg, or (iii) about 0.12 mg to about 12 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 1 pg / kg to about 50 pg / kg, (ii) about 0.08 mg to about 5.6 mg, or (iii) about 0.12 mg to about 8.4 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 3.125 pg / kg, about 9.375 pg / kg, about 24.2 pg / kg, or about 62.5 pg / kg, (ii) about 0.25 mg, about 0.75 mg, about 1.93 mg, or about 5 mg, or (iii) about 0.375 mg, about 1.125 mg, about 2.9 mg, or about 7.5 mg.

[0147] In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of about 0.5 pg / kg to about 120 pg / kg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of 0.5 pg / kg, 1 pg / kg, 2 pg / kg, 3 pg / kg, 3.125 pg / kg, 4 pg / kg, 5 pg / kg, 6 pg / kg, 7 pg / kg, 8 pg / kg, 9 pg / kg, 9.375 pg / kg, 10 pg / kg, 20 pg / kg, 24.2 pg / kg, 30 pg / kg, 40 pg / kg, 50 pg / kg, 60 pg / kg, 70 pg / kg, 80 pg / kg, 90 pg / kg, 100 pg / kg, 110 pg / kg, or 120 pg / kg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of at least 0.5 pg / kg, at least 1 pg / kg, at least 2 pg / kg, at least 3 pg / kg, at least 4 pg / kg, at least 5 pg / kg, at least 6 pg / kg, at least 7 pg / kg, at least 8 pg / kg, at least 9 pg / kg, at least 10 pg / kg, at least 20 pg / kg, at least 30 pg / kg, at least 40 pg / kg, at least 50 pg / kg, at least 60 pg / kg, at least 70 pg / kg, at least 80 pg / kg, at least 90 pg / kg, at least 100 pg / kg, at least 110 pg / kg, or at least 120 pg / kg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of at most 0.5 pg / kg, at most 1 pg / kg, at most 2 pg / kg, at most 3 pg / kg, at most 4 pg / kg, at most 5 pg / kg, at most 6 pg / kg, at most 7 pg / kg, at most 8 pg / kg, at most 9 pg / kg, at most 10 pg / kg, at most 20 pg / kg, at most 30 pg / kg, at most 40 pg / kg, at most 50 pg / kg, at most 60 pg / kg, at most 70 pg / kg, at most 80 pg / kg, at most 90 pg / kg, at most 100pg / kg, at most 110 pg / kg, or at most 120 pg / kg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of about 0.5 pg / kg, about 1 pg / kg. about 2 pg / kg, about 3 pg / kg, about 4 pg / kg, about 5 pg / kg, about 6 pg / kg, about 7 pg / kg, about 8 pg / kg, about 9 pg / kg, about 10 pg / kg, about 20 pg / kg, about 30 pg / kg, about 40 pg / kg, about 50 pg / kg, about 60 pg / kg, about 70 pg / kg, about 80 pg / kg, about 90 pg / kg, about 100 pg / kg, about 110 pg / kg, or about 120 pg / kg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of 0.5 pg / kg to 120 pg / kg, 1 pg / kg to 100 pg / kg, 2 pg / kg to 80 pg / kg, 3 pg / kg to 50 pg / kg, 4 pg / kg to 40 pg / kg, 5 pg / kg to 90 pg / kg, 6 pg / kg to 30 pg / kg, 7 pg / kg to 60 pg / kg, 8 pg / kg to 20 pg / kg, 9 pg / kg to 70 pg / kg, or all values and sub ranges in between.

[0148] In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of about 0.01 mg to about 15 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 1.93 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14,5 mg, or 15 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of at least 0.01 mg, at least 0.05 mg, at least 0. 1 mg, at least 0.15 mg, at least 0.2 mg, at least 0.25 mg, at least 0.3 mg, at least 0.35 mg, at least 0.4 mg, at least 0.45 mg, at least 0.5 mg, at least 0.55 mg, at least 0.6 mg, at least 0.65 mg, at least 0.7 mg, at least 0.75 mg, at least 0.8 mg, at least 0.85 mg, at least 0.9 mg, at least 0.95 mg, at least 1 mg, at least 1.25 mg, at least 1.5 mg, at least 1.75 mg, at least 2 mg, at least 2.25 mg, at least 2.5 mg, at least 2.75 mg, at least 3 mg, at least 3.25 mg, at least 3.5 mg, at least 3.75 mg, at least 4 mg, at least 4.5 mg, at least 5 mg, at least 5.5 mg, at least 6 mg, at least 6.5 mg, at least 7 mg, at least 7.5 mg, at least 8 mg, at least 8.5 mg, at least 9 mg, at least 9.5 mg, at least 10 mg, at least 10.5 mg, at least 11 mg, at least 11.5 mg, at least 12 mg, at least 12.5 mg, at least 13 mg, at least 13.5 mg, at least 14 mg, at least 14,5 mg, or at least 15 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of at most 0.01 mg, at most 0.05 mg, at most 0.1 mg, at most 0.15 mg, at most 0.2 mg, at most 0.25 mg, at most 0.3 mg, at most 0.35 mg, at most 0.4 mg, at most 0.45 mg, at most 0.5 mg, at most 0.55 mg, at most 0.6 mg, at most 0.65 mg, at most 0.7 mg, at most 0.75 mg, at most 0.8 mg, at most 0.85 mg, at most 0.9 mg, at most 0.95 mg, at most 1 mg, at most 1.25 mg, at most 1.5 mg, at most 1.75 mg, at most 2 mg, at most 2.25 mg, at most 2.5 mg, at most 2.75 mg, at most 3 mg, at most 3.25 mg, at most 3.5 mg, at most 3.75 mg, at most 4 mg, at most 4.5 mg, at most 5 mg, at most 5.5 mg, at most 6 mg, at most 6.5 mg, at most 7 mg, at most 7.5 mg, at most 8 mg, at most 8.5 mg, at most 9 mg, at most 9.5 mg, at most 10 mg, at most 10.5 mg, at most 11 mg, at most 11.5 mg, at most 12 mg, at most 12.5 mg, at most 13 mg, at most 13.5 mg, at most 14 mg, at most 14,5 mg, or at most 15 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg,about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14,5 mg, or about 15 mg. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is at a dose of 0.01 mg to 9.5 mg, 0.05 mg to 7.5 mg, 0.1 mg to 7 mg, 0.15 mg to 10 mg, 0.2 mg to 8 mg, 0.25 mg to 6 mg, 0.3 mg to 9 mg, 0.35 mg to 6.5 mg, 0.4 mg to 3 mg, or all values and sub ranges in between.

[0149] In some embodiments, mTOR inhibitor may be temsirolimus (TEM). In some embodiments, the therapeutically effective amount of the TEM is at a dose of (i) about 1 micrograms per kilograms (pg / kg) to about 100 pg / kg, (ii) about 0.08 mg to about 8 mg, or (iii) about 0.12 mg to about 12 mg. In some embodiments, the therapeutically effective amount of TEM is at a dose of (i) about 1 pg / kg to about 50 pg / kg, (ii) about 0.08 mg to about 5.6 mg, or (iii) about 0. 12 mg to about 8.4 mg. In some embodiments, the therapeutically effective amount of TEM is at a dose of (i) about 3.125 pg / kg, about 9.375 pg / kg, about 24.2 pg / kg, or about 62.5 pg / kg, (ii) about 0.25 mg, about 0.75 mg, about 1.93 mg, or about 5 mg, or (iii) about 0.375 mg, about 1.125 mg, about 2.9 mg, or about 7.5 mg.

[0150] In some embodiments, mTOR inhibitor may be temsirolimus (TEM). In some embodiments, a therapeutically effective amount of TEM is at a dose of 3.125 pg / kg, 9.375 pg / kg, 24.2 pg / kg, or 62.5 pg / kg. In some embodiments, a therapeutically effective amount of TEM is at a dose of 3.125 pg / kg. In some embodiments, a therapeutically effective amount of TEM is at a dose of 9.375 pg / kg. In some embodiments, a therapeutically effective amount of TEM is at a dose of 24.2 pg / kg. In some embodiments, a therapeutically effective amount of TEM is at a dose of 62.5 pg / kg. In some embodiments, a therapeutically effective amount of TEM is at a dose of about 3.125 pg / kg, about 9.375 pg / kg, about 24.2 pg / kg, or about 62.5 pg / kg. In some embodiments, a therapeutically effective amount of TEM is at a dose of about 3.125 pg / kg. In some embodiments, a therapeutically effective amount of TEM is at a dose of about 9.375 pg / kg. In some embodiments, a therapeutically effective amount of TEM is at a dose of about 24.2 pg / kg. In some embodiments, a therapeutically effective amount of TEM is at a dose of about 62.5 pg / kg.

[0151] In some embodiments, a therapeutically effective amount of TEM is at a dose of about 0.5 pg / kg to about 120 pg / kg. In some embodiments, the therapeutically effective amount of the TEM is at a dose of 0.5 pg / kg, 1 pg / kg, 2 pg / kg, 3 pg / kg, 3.125 pg / kg, 4 pg / kg, 5 pg / kg, 6 pg / kg, 7 pg / kg, 8 pg / kg, 9 pg / kg, 9.375 pg / kg, 10 pg / kg, 20 pg / kg, 24.2 pg / kg, 30 pg / kg, 40 pg / kg, 50 pg / kg, 60 pg / kg, 62.5 pg / kg, 70 pg / kg, 80 pg / kg, 90 pg / kg, 100 pg / kg, 110 pg / kg, or 120 pg / kg. In some embodiments, the therapeutically effective amount of the TEM is at a dose of about 0.5 pg / kg, about 1 pg / kg, about 2 pg / kg, about 3 pg / kg, about 3.125 pg / kg, about 4 pg / kg, about 5 pg / kg, about 6 pg / kg, about 7 pg / kg, about 8 pg / kg, about 9 pg / kg, about 9.375 pg / kg, about 10 pg / kg, about 20 pg / kg, about 24.2 pg / kg,about 30 pg / kg. about 40 pg / kg, about 50 pg / kg. about 60 pg / kg. about 62.5 gg / kg, about 70 gg / kg, about 80 gg / kg, about 90 gg / kg, about 100 gg / kg, about 110 gg / kg, or about 120 gg / kg. In some embodiments, the therapeutically effective amount of the TEM is at a dose of at least 0.5 gg / kg, at least 1 gg / kg, at least 2 gg / kg, at least 3 gg / kg, at least 3.125 gg / kg, at least 4 gg / kg, at least 5 gg / kg, at least 6 gg / kg, at least 7 gg / kg, at least 8 gg / kg, at least 9 gg / kg, at least 9.375 gg / kg, at least 10 gg / kg, at least 20 gg / kg, at least 24.2 gg / kg, at least 30 gg / kg, at least 40 gg / kg, at least 50 gg / kg, at least 60 gg / kg, at least 62.5 gg / kg, at least 70 gg / kg, at least 80 gg / kg, at least 90 gg / kg, at least 100 gg / kg, at least 110 gg / kg, or at least 120 gg / kg. In some embodiments, the therapeutically effective amount of the TEM is at a dose of no more than 0.5 gg / kg, no more than 1 gg / kg, no more than 2 gg / kg, no more than 3 gg / kg, no more than 3.125 gg / kg, no more than 4 gg / kg, no more than 5 gg / kg, no more than 6 gg / kg, no more than 7 gg / kg, no more than 8 gg / kg, no more than 9 gg / kg, no more than 9.375 gg / kg, no more than 10 gg / kg, no more than 20 gg / kg, no more than 24.2 gg / kg, no more than 30 gg / kg, no more than 40 gg / kg, no more than 50 gg / kg, no more than 60 gg / kg, no more than 62.5 gg / kg, no more than 70 gg / kg, no more than 80 gg / kg, no more than 90 gg / kg, no more than 100 gg / kg, no more than 110 gg / kg, or no more than 120 gg / kg.

[0152] In some embodiments, the therapeutically effective amount of TEM is at a dose of about 0.01 mg to about 15 mg. In some embodiments, the therapeutically effective amount of TEM is at a dose of 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 1.93 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14,5 mg, or 15 mg. In some embodiments, the therapeutically effective amount of TEM is at a dose of at least 0.01 mg, at least 0.05 mg, at least 0.1 mg, at least 0.15 mg, at least 0.2 mg, at least 0.25 mg, at least 0.3 mg, at least 0.35 mg, at least 0.4 mg, at least 0.45 mg, at least 0.5 mg, at least 0.55 mg, at least 0.6 mg, at least 0.65 mg, at least 0.7 mg, at least 0.75 mg, at least 0.8 mg, at least 0.85 mg, at least 0.9 mg, at least 0.95 mg, at least 1 mg, at least 1.25 mg, at least 1.5 mg, at least 1.75 mg, at least 2 mg, at least 2.25 mg, at least 2.5 mg, at least 2.75 mg, at least 3 mg, at least 3.25 mg, at least 3.5 mg, at least 3.75 mg, at least 4 mg, at least 4.5 mg, at least 5 mg, at least 5.5 mg, at least 6 mg, at least 6.5 mg, at least 7 mg, at least 7.5 mg, at least 8 mg, at least 8.5 mg, at least 9 mg, at least 9.5 mg, at least 10 mg, at least 10.5 mg, at least 11 mg, at least 11.5 mg, at least 12 mg, at least 12.5 mg, at least 13 mg, at least 13.5 mg, at least 14 mg, at least 14,5 mg, or at least 15 mg. In some embodiments, the therapeutically effective amount of TEM is at a dose of at most 0.01 mg, at most 0.05 mg, at most 0.1 mg, at most 0.15 mg, at most 0.2 mg, at most 0.25 mg, at most 0.3 mg, at most 0.35 mg, at most 0.4 mg, at most 0.45 mg, at most 0.5 mg, at most 0.55 mg, at most 0.6 mg, at most 0.65 mg, at most 0.7 mg, at most 0.75 mg, at most 0.8 mg, at most 0.85 mg, at most 0.9 mg, at most 0.95 mg, at most 1 mg, at most 1.25 mg, at most 1.5 mg, at most 1.75 mg, at most 2 mg, at most 2.25 mg, at most 2.5 mg, at most 2.75 mg, at most 3 mg, at most 3.25 mg, at most 3.5 mg, at most 3.75 mg, at most 4 mg, at most 4.5 mg, atmost 5 mg, at most 5.5 mg, at most 6 mg, at most 6.5 mg, at most 7 mg, at most 7.5 mg, at most 8 mg, at most 8.5 mg, at most 9 mg, at most 9.5 mg, at most 10 mg, at most 10.5 mg, at most 11 mg, at most 11.5 mg, at most 12 mg, at most 12.5 mg, at most 13 mg, at most 13.5 mg, at most 14 mg, at most 14,5 mg, or at most 15 mg. In some embodiments, the therapeutically effective amount of TEM is at a dose of about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14,5 mg, or about 15 mg. In some embodiments, the therapeutically effective amount of TEM is at a dose of 0.01 mg to 9.5 mg, 0.05 mg to 7.5 mg, 0.1 mg to 7 mg, 0.15 mg to 10 mg, 0.2 mg to 8 mg, 0.25 mg to 6 mg, 0.3 mg to 9 mg, 0.35 mg to 6.5 mg, 0.4 mg to 3 mg, or all values and sub ranges in between.

[0153] In some embodiments, a concentration of TEM in an IV bag is 0.030 mg / mL, 0.0116 mg / mL, 0.0045 mg / mL, or 0.0015 mg / mL. In some embodiments, a concentration of TEM in an IV bag is 0.030 mg / mL. In some embodiments, a concentration of TEM in an IV bag is 0.0116 mg / mL. In some embodiments, a concentration of TEM in an IV bag is 0.0015 mg / mL. In some embodiments, a concentration of TEM in an IV bag is 0.0045 mg / mL. In some embodiments, a concentration of TEM in an IV bag is about 0.030 mg / mL, about 0.0116 mg / mL, about 0.0015 mg / mL, or about 0.0045 mg / mL. In some embodiments, a concentration of TEM in an IV bag is about 0.030 mg / mL. In some embodiments, a concentration of TEM in an IV bag is about 0.0116 mg / mL. In some embodiments, a concentration of TEM in an IV bag is about 0.0015 mg / mL. In some embodiments, a concentration of TEM in an IV bag is about 0.0045 mg / mL.

[0154] In some embodiments, a concentration of TEM in an IV bag ranges from 0.0005 mg / mL to 0.090 mg / mL. In some embodiments, a concentration of TEM in an IV bag ranges from about 0.0005 mg / mL to about 0.090 mg / mL. In some embodiments, a concentration of TEM in an IV bag is 0.0005 mg / mL, 0.0010 mg / mL, 0.0015 mg / mL, 0.0020 mg / mL, 0.0025 mg / mL, 0.0030 mg / mL, 0.0040 mg / mL, 0.0050 mg / mL, 0.0060 mg / mL, 0.0070 mg / mL, 0.0080 mg / mL, 0.0090 mg / mL, 0.010 mg / mL, 0.020 mg / mL, 0.030 mg / mL, 0.040 mg / mL, 0.050 mg / mL, 0.060 mg / mL, 0.070 mg / mL, 0.080 mg / mL, or 0.090 mg / mL. In some embodiments, a concentration of TEM in an IV bag is about 0.0005 mg / mL, about 0.0010 mg / mL, about 0.0015 mg / mL, about 0.0020 mg / mL, about 0.0025 mg / mL, about 0.0030 mg / mL, about 0.0040 mg / mL, about 0.0050 mg / mL, about 0.0060 mg / mL, about 0.0070 mg / mL, about 0.0080 mg / mL, about 0.0090 mg / mL, about 0.010 mg / mL, about 0.020 mg / mL, about 0.030 mg / mL, about 0.040 mg / mL, about 0.050 mg / mL, about 0.060 mg / mL, about 0.070 mg / mL, about 0.080 mg / mL, or about 0.090 mg / mL. In some embodiments, a concentration of TEM in an IV bag is at least 0.0005 mg / mL, at least 0.0010 mg / mL, at least 0.0015 mg / mL, at least 0.0020 mg / mL, at least 0.0025 mg / mL, at least0.0030 mg / mL, at least 0.0040 mg / mL, at least 0.0050 mg / mL, at least 0.0060 mg / mL, at least 0.0070 mg / mL, at least 0.0080 mg / mL, at least 0.0090 mg / mL, at least 0.010 mg / mL, at least 0.020 mg / mL, at least 0.030 mg / mL, at least 0.040 mg / mL, at least 0.050 mg / mL, at least 0.060 mg / mL, at least 0.070 mg / mL, at least 0.080 mg / mL, or at least 0.090 mg / mL. In some embodiments, a concentration of TEM in an IV bag is no more than 0.0005 mg / mL, no more than 0.0010 mg / mL, no more than 0.0015 mg / mL, no more than 0.0020 mg / mL, no more than 0.0025 mg / mL, no more than 0.0030 mg / mL, no more than 0.0040 mg / mL, no more than 0.0050 mg / mL, no more than 0.0060 mg / mL, no more than 0.0070 mg / mL, no more than 0.0080 mg / mL, no more than 0.0090 mg / mL, no more than 0.010 mg / mL, no more than 0.020 mg / mL, no more than 0.030 mg / mL, no more than 0.040 mg / mL, no more than 0.050 mg / mL, no more than 0.060 mg / mL, no more than 0.070 mg / mL, no more than 0.080 mg / mL, or no more than 0.090 mg / mL.

[0155] In some embodiments, the formulation or a pharmaceutical composition comprising mTOR inhibitor may be a solution. In some embodiments, a concentration of mTOR inhibitor in the solution ranges from 0.1 pg / mL to 100 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution ranges from 1 pg / mL to 50 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution is 1.5 pg / mL, 4.5 pg / mL, 11.6 pg / mL or 30 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution is 1.5 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution is 4.5 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution is 11.6 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution ranges from about 0.1 pg / mL to about 100 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution ranges from about 1 pg / mL to about 50 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution is about 1.5 pg / mL, about 4.5 pg / mL, about 11.6 pg / mL or about 30 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution is about 1.5 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution is about 4.5 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution is about 11.6 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution is about 30 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution is 0.1 pg / mL, 0.5 pg / mL, 1 pg / mL, 2 pg / mL, 3 pg / mL, 4 pg / mL, 5 pg / mL, 6 pg / mL, 7 pg / mL, 8 pg / mL, 9 pg / mL, 10 pg / mL, 15 pg / mL, 20 pg / mL, 25 pg / mL, 30 pg / mL, 35 pg / mL, 40 pg / mL, 45 pg / mL, 50 pg / mL, 55 pg / mL, 60 pg / mL, 65 pg / mL, 70 pg / mL, 75 pg / mL, 80 pg / mL, 85 pg / mL, 90 pg / mL, 95 pg / mL, or 100 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution is about 0.1 pg / mL, about 0.5 pg / mL, about 1 pg / mL, about 2 pg / mL, about 3 pg / mL, about 4 pg / mL, about 5 pg / mL, about 6 pg / mL, about 7 pg / mL, about 8 pg / mL, about 9 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, about 80 pg / mL, about 85 pg / mL, about 90 pg / mL, about 95 pg / mL, or about 100 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution is at least 0.1 pg / mL, at least 0.5 pg / mL, at least 1 pg / mL, at least 2 pg / mL, at least 3 pg / mL, at least 4 pg / mL, at least 5 pg / mL, at least 6 pg / mL, at least 7 pg / mL, at least 8pg / mL, at least 9 pg / mL, at least 10 pg / mL, at least 15 pg / mL, at least 20 pg / mL, at least 25 pg / mL, at least 30 pg / mL, at least 35 pg / mL, at least 40 pg / mL, at least 45 pg / mL, at least 50 pg / mL, at least 55 pg / mL, at least 60 pg / mL, at least 65 pg / mL, at least 70 pg / mL, at least 75 pg / mL, at least 80 pg / mL, at least 85 pg / mL, at least 90 pg / mL, at least 95 pg / mL, or at least 100 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution is no more than 0.1 pg / mL, no more than 0.5 pg / mL, no more than 1 pg / mL, no more than 2 pg / mL, no more than 3 pg / mL, no more than 4 pg / mL, no more than 5 pg / mL, no more than 6 pg / mL, no more than 7 pg / mL, no more than 8 pg / mL, no more than 9 pg / mL, no more than 10 pg / mL, no more than 15 pg / mL, no more than 20 pg / mL, no more than 25 pg / mL, no more than 30 pg / mL, no more than 35 pg / mL, no more than 40 pg / mL, no more than 45 pg / mL, no more than 50 pg / mL, no more than 55 pg / mL, no more than 60 pg / mL, no more than 65 pg / mL, no more than 70 pg / mL, no more than 75 pg / mL, no more than 80 pg / mL, no more than 85 pg / mL, no more than 90 pg / mL, no more than 95 pg / mL, or no more than 100 pg / mL.

[0156] In some embodiments, the formulation or a pharmaceutical composition comprising mTOR inhibitor may be a solution. In some embodiments, mTOR inhibitor may be temsirolimus (TEM). In some embodiments, a concentration of TEM in the solution ranges from 0.1 pg / mL to 100 pg / mL. In some embodiments, a concentration of TEM in the solution ranges from 1 pg / mL to 50 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution is 1.5 pg / mL, 4.5 pg / mL, 11.6 pg / mL or 30 pg / mL. In some embodiments, a concentration of TEM in the solution is 1.5 pg / mL. In some embodiments, a concentration of TEM in the solution is 4.5 pg / mL. In some embodiments, a concentration of TEM in the solution is 11.6 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution ranges from about 0.1 pg / mL to about 100 pg / mL. In some embodiments, a concentration of TEM in the solution ranges from about 1 pg / mL to about 50 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the solution is about 1.5 pg / mL, about 4.5 pg / mL, about 11.6 pg / mL or about 30 pg / mL. In some embodiments, a concentration of TEM in the solution is about 1.5 pg / mL. In some embodiments, a concentration of TEM in the solution is about 4.5 pg / mL. In some embodiments, a concentration of TEM in the solution is about 11.6 pg / mL.In some embodiments, a concentration of TEM in the solution is about 30 pg / mL. In some embodiments, a concentration of TEM in the solution is 0.1 pg / mL, 0.5 pg / mL, 1 pg / mL, 2 pg / mL, 3 pg / mL, 4 pg / mL, 5 pg / mL, 6 pg / mL, 7 pg / mL, 8 pg / mL, 9 pg / mL, 10 pg / mL, 15 pg / mL, 20 pg / mL, 25 pg / mL, 30 pg / mL, 35 pg / mL, 40 pg / mL, 45 pg / mL, 50 pg / mL, 55 pg / mL, 60 pg / mL, 65 pg / mL, 70 pg / mL, 75 pg / mL, 80 pg / mL, 85 pg / mL, 90 pg / mL, 95 pg / mL, or 100 pg / mL. In some embodiments, a concentration of TEM in the solution is about 0.1 pg / mL, about 0.5 pg / mL, about 1 pg / mL, about 2 pg / mL, about 3 pg / mL, about 4 pg / mL, about 5 pg / mL, about 6 pg / mL, about 7 pg / mL, about 8 pg / mL, about 9 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, about 80 pg / mL, about 85 pg / mL, about 90 pg / mL, about 95 pg / mL, or about 100 pg / mL. In some embodiments, a concentration of TEM in the solution is at least 0.1 pg / mL, at least 0.5 pg / mL, at least 1 pg / mL, at least 2 pg / mL, at least 3 pg / mL, at least 4 pg / mL, at least 5 pg / mL, at least 6pg / mL, at least 7 pg / mL, at least 8 pg / mL, at least 9 pg / mL, at least 10 pg / mL, at least 15 pg / mL, at least 20 pg / mL, at least 25 pg / mL, at least 30 pg / mL, at least 35 pg / mL, at least 40 pg / mL, at least 45 pg / mL, at least 50 pg / mL, at least 55 pg / mL, at least 60 pg / mL, at least 65 pg / mL, at least 70 pg / mL, at least 75 pg / mL, at least 80 pg / mL, at least 85 pg / mL, at least 90 pg / mL, at least 95 pg / mL, or at least 100 pg / mL. In some embodiments, a concentration of TEM in the solution is no more than 0.1 pg / mL, no more than 0.5 pg / mL, no more than 1 pg / mL, no more than 2 pg / mL, no more than 3 pg / mL, no more than 4 pg / mL, no more than 5 pg / mL, no more than 6 pg / mL, no more than 7 pg / mL, no more than 8 pg / mL, no more than 9 pg / mL, no more than 10 pg / mL, no more than 15 pg / mL, no more than 20 pg / mL, no more than 25 pg / mL, no more than 30 pg / mL, no more than 35 pg / mL, no more than 40 pg / mL, no more than 45 pg / mL, no more than 50 pg / mL, no more than 55 pg / mL, no more than 60 pg / mL, no more than 65 pg / mL, no more than 70 pg / mL, no more than 75 pg / mL, no more than 80 pg / mL, no more than 85 pg / mL, no more than 90 pg / mL, no more than 95 pg / mL, or no more than 100 pg / mL.

[0157] In some embodiments, the mTOR inhibitor may be administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route. In some embodiments, the mTOR inhibitor may be administered through an intramuscular route. In some embodiments, the mTOR inhibitor may be administered through an intravenous route. In some embodiments, the mTOR inhibitor may be administered through a subcutaneous route. In some embodiments, the mTOR inhibitor may be administered through an oral route. In some embodiments, the mTOR inhibitor may be administered through an inhalation route. In some embodiments, the mTOR inhibitor may be administered through an intranasal route.

[0158] In some embodiments, the mTOR inhibitor may be administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or seven times per week. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered once per week. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered twice per week. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered three times per week. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered four times per week. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered five times per week. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered six times per week. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered seven times per week.

[0159] In some embodiments, the mTOR inhibitor is administered once per week, once per two weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per month, or ten times per month. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered once per week. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered once per two weeks. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered once per month. In some embodiments, thetherapeutically effective amount of the mTOR inhibitor may be administered twice per month. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered three times per month, four times per month. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered four times per month. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered five times per month. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered six times per month. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered seven times per month. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered eight times per month. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered nine times per month. In some embodiments, the therapeutically effective amount of the mTOR inhibitor may be administered ten times per month.COMPOSITION

[0160] In some embodiments, the RAAD and the mTOR inhibitor may be formulated into a pharmaceutical composition. In some embodiments, the RAAD and the mTOR inhibitor may be formulated into a pharmaceutical composition prior to administering to the human subject. In some embodiments, the RAAD may be ketamine. In some embodiments, the mTOR inhibitor may be temsirolimus. In some embodiments, ketamine and temsirolimus may be formulated into a pharmaceutical composition. In some embodiments, ketamine and temsirolimus may be formulated into a pharmaceutical composition prior to administering to the human subject.

[0161] In some embodiments, the pharmaceutical composition may be administered to the human subject through one dose. In some embodiments, the pharmaceutical composition may be administered to the human subject through more than one dose. In some embodiments, the pharmaceutical composition may be administered to the human subject through one or more doses. In some embodiments, the pharmaceutical composition may be administered to the human subject through at least two doses. In some embodiments, the pharmaceutical composition may be administered to the human subject through at least three doses. In some embodiments, the pharmaceutical composition may be administered to the human subject through at least four doses. In some embodiments, the pharmaceutical composition may be administered to the human subject through at least five doses. In some embodiments, the pharmaceutical composition may be administered to the human subject through at least six doses. In some embodiments, the pharmaceutical composition may be administered to the human subject through at most two doses. In some embodiments, the pharmaceutical composition may be administered to the human subject through at most three doses. In some embodiments, the pharmaceutical composition may be administered to the human subject through at most four doses. In some embodiments, the pharmaceutical composition may be administered to the human subject through at most five doses. In some embodiments, the pharmaceutical composition may be administered to the human subject through at most six doses.

[0162] In some embodiments, the pharmaceutical composition may be administered to the human subject through multiple doses. In some embodiments, the multiple doses comprise one or more acute doses. In some embodiments, the multiple doses comprise one or more maintenance doses. In some embodiments, the multiple doses comprise one or more acute doses and one or more maintenance doses. In some embodiments, the one or more maintenance doses may be administered after the one or more acute doses. In some embodiments, the multiple doses comprise one or more acute doses and one or more maintenance doses administered after the one or more acute doses.

[0163] In some embodiments, the pharmaceutical composition may be administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route. In some embodiments, the pharmaceutical composition may be administered through an intravenous route. In some embodiments, the pharmaceutical composition may be administered through an intramuscular route. In some embodiments, the pharmaceutical composition may be administered through a subcutaneous route. In some embodiments, the pharmaceutical composition may be administered through an oral route. In some embodiments, the pharmaceutical composition may be administered through an inhalation route. In some embodiments, the pharmaceutical composition may be administered through an intranasal route.

[0164] In some cases, the pharmaceutical composition may be formulated as a solution. In some embodiments, the solution comprises water, ethanol, polyethylene glycol (PEG), polysorbate, or any combinations thereof. In some embodiments, the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the polysorbate may be polysorbate 80. In some embodiments, the PEG has an average molecular weight between about 300 and about 600. In some embodiments, the PEG may be PEG 400.

[0165] In some embodiments, the solution comprises dehydrated ethanol, DL-alpha-tocopherol, propylene glycol, anhydrous citric acid, polysorbate 80, PEG 400, sodium chloride, or any combinations thereof.

[0166] In some embodiments, the solution comprises dehydrated ethanol at a concentration of 2.0 mg / mL to 4 mg / mL. In some embodiments, the solution comprises dehydrated ethanol at a concentration of 2.8 mg / mL to 3.2 mg / mL. In some embodiments, the solution comprises dehydrated ethanol at a concentration of 3.00785 mg / mL or 3.01222 mg / mL. In some embodiments, the solution comprises dehydrated ethanol at a concentration of 3.00785 mg / mL. In some embodiments, the solution comprises dehydrated ethanol at a concentration of 3.01222 mg / mL. In some embodiments, the solution comprises dehydrated ethanol at a concentration of about 2.0 mg / mL to about 4 mg / mL. In some embodiments, the solution comprises dehydrated ethanol at a concentration of about 2.8 mg / mL to about 3.2 mg / mL. In some embodiments, the solution comprises dehydrated ethanol at a concentration of about 3.00785 mg / mL or about 3.01222 mg / mL. In some embodiments, the solution comprises dehydrated ethanol at a concentration of about 3.00785 mg / mL. In some embodiments, the solution comprises dehydrated ethanol at a concentration of about 3.01222 mg / mL. In some embodiments, the solution comprises dehydrated ethanol at a concentration of 2.0 mg / mL, 2.1 mg / mL, 2.2 mg / mL, 2.3 mg / mL, 2.4 mg / mL, 2.5mg / mL, 2.6 mg / mL, 2.7 mg / mL, 2.8 mg / mL, 2.9 mg / mL, 3 mg / mL, 3.1 mg / mL, 3.2 mg / mL, 3.3 mg / mL,3.4 mg / mL, 3.5 mg / mL, 3.6 mg / mL, 3.7 mg / mL, 3.8 mg / mL, 3.9 mg / mL, or 4 mg / mL. In some embodiments, the solution comprises dehydrated ethanol at a concentration of about 2.0 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, about 3 mg / mL, about 3.1 mg / mL, about 3.2 mg / mL, about 3.3 mg / mL, about 3.4 mg / mL, about 3.5 mg / mL, about 3.6 mg / mL, about 3.7 mg / mL, about 3.8 mg / mL, about 3.9 mg / mL, or about 4 mg / mL. In some embodiments, the solution comprises dehydrated ethanol at a concentration of at least 2.0 mg / mL, at least 2.1 mg / mL, at least 2.2 mg / mL, at least 2.3 mg / mL, at least 2.4 mg / mL, at least 2.5 mg / mL, at least 2.6 mg / mL, at least 2.7 mg / mL, at least 2.8 mg / mL, at least 2.9 mg / mL, at least 3 mg / mL, at least 3.1 mg / mL, at least 3.2 mg / mL, at least 3.3 mg / mL, at least 3.4 mg / mL, at least 3.5 mg / mL, at least 3.6 mg / mL, at least 3.7 mg / mL, at least 3.8 mg / mL, at least 3.9 mg / mL, or at least 4 mg / mL. In some embodiments, the solution comprises dehydrated ethanol at a concentration of no more than 2.0 mg / mL, no more than 2.1 mg / mL, no more than 2.2 mg / mL, no more than 2.3 mg / mL, no more than 2.4 mg / mL, no more than 2.5 mg / mL, no more than 2.6 mg / mL, no more than 2.7 mg / mL, no more than 2.8 mg / mL, no more than 2.9 mg / mL, no more than 3 mg / mL, no more than 3.1 mg / mL, no more than 3.2 mg / mL, no more than 3.3 mg / mL, no more than 3.4 mg / mL, no more than 3.5 mg / mL, no more than 3.6 mg / mL, no more than 3.7 mg / mL, no more than 3.8 mg / mL, no more than 3.9 mg / mL, or no more than 4 mg / mL.

[0167] In some embodiments, the solution comprises polysorbate 80 at a concentration of 0.5 mg / mL to1.5 mg / mL. In some embodiments, the solution comprises polysorbate 80 at a concentration of 0.8 mg / mL to 1.2 mg / mL. In some embodiments, the solution comprises polysorbate 80 at a concentration of 1.0608 mg / ml. In some embodiments, the solution comprises polysorbate 80 at a concentration of about 0.5 mg / mL to about 1.5 mg / mL. In some embodiments, the solution comprises polysorbate 80 at a concentration of about 0.8 mg / mL to about 1.2 mg / mL. In some embodiments, the solution comprises polysorbate 80 at a concentration of about 1.0608 mg / ml. In some embodiments, the solution comprises polysorbate 80 at a concentration of 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, or 1.5 mg / mL. In some embodiments, the solution comprises polysorbate 80 at a concentration of about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, or about 1.5 mg / mL. In some embodiments, the solution comprises polysorbate 80 at a concentration of at least 0.5 mg / mL, at least 0.6 mg / mL, at least 0.7 mg / mL, at least 0.8 mg / mL, at least 0.9 mg / mL, at least 1 mg / mL, at least 1.1 mg / mL, at least 1.2 mg / mL, at least 1.3 mg / mL, at least 1.4 mg / mL, or at least 1.5 mg / mL. In some embodiments, the solution comprises polysorbate 80 at a concentration of no more than 0.5 mg / mL, no more than 0.6 mg / mL, no more than 0.7 mg / mL, no more than 0.8 mg / mL, no more than 0.9 mg / mL, no more than 1 mg / mL, no more than 1.1 mg / mL, no more than 1.2 mg / mL, no more than 1.3 mg / mL, no more than 1.4 mg / mL, or no more than1.5 mg / mL.

[0168] In some embodiments, the solution comprises PEG 400 at a concentration of 0.2 mg / mL to 0.8 mg / mL. In some embodiments, the solution comprises PEG 400 at a concentration of 0.5 mg / mL to 0.6 mg / mL. In some embodiments, the solution comprises PEG 400 at a concentration of 0.54479 mg / mL. In some embodiments, the solution comprises PEG 400 at a concentration of about 0.2 mg / mL to about 0.8 mg / mL. In some embodiments, the solution comprises PEG 400 at a concentration of about 0.5 mg / mL to about 0.6 mg / mL. In some embodiments, the solution comprises PEG 400 at a concentration of about 0.54479 mg / mL. In some embodiments, the solution comprises PEG 400 at a concentration of 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, or 0.8 mg / mL. In some embodiments, the solution comprises PEG 400 at a concentration of about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, or about 0.8 mg / mL. In some embodiments, the solution comprises PEG 400 at a concentration of at least 0.2 mg / mL, at least 0.3 mg / mL, at least 0.4 mg / mL, at least 0.5 mg / mL, at least 0.6 mg / mL, at least 0.7 mg / mL, or at least 0.8 mg / mL. In some embodiments, the solution comprises PEG 400 at a concentration of no more than 0.2 mg / mL, no more than 0.3 mg / mL, no more than 0.4 mg / mL, no more than 0.5 mg / mL, no more than 0.6 mg / mL, no more than 0.7 mg / mL, or no more than 0.8 mg / mL.

[0169] In some embodiments, the solution comprises DL-a tocopherol at a concentration of 1 pg / mL to 4 pg / mL. In some embodiments, the solution comprises DL-a tocopherol at a concentration of 2 pg / mL to 3 pg / mL. In some embodiments, the solution comprises DL-a tocopherol at a concentration of 2.44 pg / mL or 2.448 pg / mL. In some embodiments, the solution comprises DL-a tocopherol at a concentration of 2.44 pg / mL. In some embodiments, the solution comprises DL-a tocopherol at a concentration of 2.448 pg / mL. In some embodiments, the solution comprises DL-a tocopherol at a concentration of about 1 pg / mL to about 4 pg / mL. In some embodiments, the solution comprises DL-a tocopherol at a concentration of about 2 pg / mL to about 3 pg / mL. In some embodiments, the solution comprises DL-a tocopherol at a concentration of about 2.44 pg / mL or about 2.448 pg / mL. In some embodiments, the solution comprises DL-a tocopherol at a concentration of about 2.44 pg / mL. In some embodiments, the solution comprises DL-a tocopherol at a concentration of about 2.448 pg / mL. In some embodiments, the solution comprises DL-a tocopherol at a concentration of 1 pg / mL, 2 pg / mL, 2.1 pg / mL, 2.2 pg / mL, 2.3 pg / mL, 2.4 pg / mL, 2.5 pg / mL, 2.6 pg / mL, 2.7 pg / mL, 2.8 pg / mL, 2.9 pg / mL, 3 pg / mL, or 4 pg / mL. In some embodiments, the solution comprises DL-a tocopherol at a concentration of about 1 pg / mL, about 2 pg / mL, about 2.1 pg / mL, about 2.2 pg / mL, about 2.3 pg / mL, about 2.4 pg / mL, about 2.5 pg / mL, about 2.6 pg / mL, about 2.7 pg / mL, about 2.8 pg / mL, about 2.9 pg / mL, about 3 pg / mL, or about 4 pg / mL. In some embodiments, the solution comprises DL-a tocopherol at a concentration of at least 1 pg / mL, at least 2 pg / mL, at least 2. 1 pg / mL, at least 2.2 pg / mL, at least 2.3 pg / mL, at least 2.4 pg / mL, at least 2.5 pg / mL, at least 2.6 pg / mL, at least 2.7 pg / mL, at least 2.8 pg / mL, at least 2.9 pg / mL, at least 3 pg / mL, or at least 4 pg / mL. In some embodiments, the solution comprises DL-a tocopherol at a concentration of no more thanl pg / mL, no more than 2 pg / mL, no more than 2.1 pg / mL, no more than 2.2 pg / mL, no more than 2.3 pg / mL, no more than 2.4 pg / mL, no more than 2.5 pg / mL, no more than 2.6pg / mL, no more than 2.7 pg / mL, no more than 2.8 pg / mL, no more than 2.9 pg / mL, no more than 3 pg / mL, or no more than 4 pg / mL.

[0170] In some embodiments, the solution comprises citric acid at a concentration of 0.07 pg / mL to 0.1 pg / mL. In some embodiments, the solution comprises citric acid at a concentration of 0.08 pg / mL to 0.09 pg / mL. In some embodiments, the solution comprises citric acid at a concentration of 0.0882 pg / mL or 0.0885 pg / mL. In some embodiments, the solution comprises citric acid at a concentration of 0.0882 pg / mL. In some embodiments, the solution comprises citric acid at a concentration of 0.0885 pg / mL. In some embodiments, the solution comprises citric acid at a concentration of about 0.07 pg / mL to about 0.1 pg / mL. In some embodiments, the solution comprises citric acid at a concentration of about 0.08 pg / mL to about 0.09 pg / mL. In some embodiments, the solution comprises citric acid at a concentration of about 0.0882 pg / mL or about 0.0885 pg / mL. In some embodiments, the solution comprises citric acid at a concentration of about 0.0882 pg / mL. In some embodiments, the solution comprises citric acid at a concentration of about 0.0885 pg / mL. In some embodiments, the solution comprises citric acid at a concentration of 0.07 pg / mL, 0.08 pg / mL, 0.081 pg / mL, 0.082 pg / mL, 0.083 pg / mL, 0.084 pg / mL, 0.085 pg / mL, 0.086 pg / mL, 0.087 pg / mL, 0.088 pg / mL, 0.089 pg / mL, 0.09 pg / mL, or 0.1 pg / mL. In some embodiments, the solution comprises citric acid at a concentration of about 0.07 pg / mL, about 0.08 pg / mL, about 0.081 pg / mL, about 0.082 pg / mL, about 0.083 pg / mL, about 0.084 pg / mL, about 0.085 pg / mL, about 0.086 pg / mL, about 0.087 pg / mL, about 0.088 pg / mL, about 0.089 pg / mL, about 0.09 pg / mL, or about 0. 1 pg / mL. In some embodiments, the solution comprises citric acid at a concentration of at least 0.07 pg / mL, at least 0.08 pg / mL, at least 0.081 pg / mL, at least 0.082 pg / mL, at least 0.083 pg / mL, at least 0.084 pg / mL, at least 0.085 pg / mL, at least 0.086 pg / mL, at least 0.087 pg / mL, at least 0.088 pg / mL, at least 0.089 pg / mL, at least 0.09 pg / mL, or at least 0.1 pg / mL. In some embodiments, the solution comprises citric acid at a concentration of no more than 0.07 pg / mL, no more than 0.08 pg / mL, no more than 0.081 pg / mL, no more than 0.082 pg / mL, no more than 0.083 pg / mL, no more than 0.084 pg / mL, no more than 0.085 pg / mL, no more than 0.086 pg / mL, no more than 0.087 pg / mL, no more than 0.088 pg / mL, no more than 0.089 pg / mL, no more than 0.09 pg / mL, or no more than 0.1 pg / mL.

[0171] In some embodiments, the solution comprises propylene glycol at a concentration of 0.5 mg / mL to 2.5 mg / mL. In some embodiments, the solution comprises propylene glycol at a concentration of 1 mg / mL to 2 mg / mL. In some embodiments, the solution comprises propylene glycol at a concentration of 1.6454 mg / mL or 1.6509 mg / mL. In some embodiments, the solution comprises propylene glycol at a concentration of 1.6454 mg / mL. In some embodiments, the solution comprises propylene glycol at a concentration of 1.6509 mg / mL. In some embodiments, the solution comprises propylene glycol at a concentration of about 0.5 mg / mL to about 2.5 mg / mL. In some embodiments, the solution comprises propylene glycol at a concentration of about 1 mg / mL to about 2 mg / mL. In some embodiments, the solution comprises propylene glycol at a concentration of about 1.6454 mg / mL or about 1.6509 mg / mL. In some embodiments, the solution comprises propylene glycol at a concentration of about 1.6454 mg / mL. In some embodiments, the solution comprises propylene glycol at a concentration of about 1.6509 mg / mL. In some embodiments, the solution comprises propylene glycol at a concentration of 0.5mg / mL, 1 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.65 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2 mg / mL, or 2.5 mg / mL. In some embodiments, the solution comprises propylene glycol at a concentration of about 0.5 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 1.6 mg / mL, about 1.65 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2 mg / mL, or about 2.5 mg / mL. In some embodiments, the solution comprises propylene glycol at a concentration of at least 0.5 mg / mL, at least 1 mg / mL, at least 1.1 mg / mL, at least 1.2 mg / mL, at least 1.3 mg / mL, at least 1.4 mg / mL, at least 1.5 mg / mL, at least 1.6 mg / mL, at least 1.65 mg / mL, at least 1.7 mg / mL, at least 1.8 mg / mL, at least 1.9 mg / mL, at least 2 mg / mL, or at least 2.5 mg / mL. In some embodiments, the solution comprises propylene glycol at a concentration of no more than 0.5 mg / mL, no more than 1 mg / mL, no more than 1.1 mg / mL, no more than 1.2 mg / mL, no more than 1.3 mg / mL, no more than 1.4 mg / mL, no more than 1.5 mg / mL, no more than 1.6 mg / mL, no more than 1.65 mg / mL, no more than 1.7 mg / mL, no more than 1.8 mg / mL, no more than 1.9 mg / mL, no more than 2 mg / mL, or no more than 2.5 mg / mL.

[0172] In some embodiments, the solution comprises about 0.9% (w / v) sodium chloride in water. In some embodiments, the solution comprises 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.8%, or 2.0% (w / v) sodium chloride in water. In some embodiments, the solution comprises at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1.0%, at least 1.1%, at least 1.2%, at least 1.3%, at least 1.4%, at least 1.5%, at least 1.6%, at least 1.8%, or 2.0% (w / v) sodium chloride in water. In some embodiments, the solution comprises at most 0.5%, at most 0.6%, at most 0.7%, at most 0.8%, at most 0.9%, at most 1.0%, at most 1.1%, at most 1.2%, at most 1.3%, at most 1.4%, at most 1.5%, at most 1.6%, at most 1.8%, or at most 2.0% (w / v) sodium chloride in water. In some embodiments, the solution comprises about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.8%, or about 2.0% (w / v) sodium chloride in water. In some embodiments, the solution comprises 0.5% to 2.0%, 0.6% to 1.6%, 0.7% to 1.8%, 0.8% to 1.4% (w / v) sodium chloride in water, or all values and sub ranges in between.

[0173] In some embodiments, the solution further comprises about 5% (w / v) dextrose in water. In some embodiments, the solution comprises 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (w / v) dextrose in water. In some embodiments, the solution comprises at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% (w / v) dextrose in water. In some embodiments, the solution comprises at most 1%, at most 2%, at most 3%, at most 4%, at most 5%, at most 6%, at most 7%, at most 8%, at most 9%, or at most 10% (w / v) dextrose in water. In some embodiments, the solution comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% (w / v) dextrose in water. In some embodiments, the solution comprises 1% to 10%, 2% to 9% , 3% to 8% , 4% to 7% (w / v) dextrose in water, or all values and sub ranges in between.

[0174] In some embodiments, the solution is stable for at least about one week, two weeks, three weeks, a month, two months, six months, eight months, ten months, twelve months, or two years at atemperature of at most about 60°C. In some embodiments, the solution is stable for from about one week to about two years, two weeks to twelve months, three weeks to ten months, a month to ten months, two months to eight months, or six months to two years at a temperature of at most about 60°C. In some embodiments, the solution is stable at a temperature of about 10, 20, 30, 40, 50, or 60°C. In some embodiments, the solution is stable at a temperature of from about 10°C to 60°C, 20°C to 50°C, or 30°C to 40°C.

[0175] In some embodiments, the solution comprises (i) ketamine hydrochloride, wherein a concentration of an equivalent ketamine free base is about 0.2425 mg / ml, and (ii) temsirolimus, wherein a concentration of the temsirolimus is about 1.5 pg / ml, about 4.5 pg / ml, about 11.6 pg / ml or about 30 pg / ml. In some embodiments, the solution further comprises dehydrated ethanol at a concentration of about 2.8 mg / ml to about 3.2 mg / ml. In some embodiments, the solution comprises the dehydrated ethanol at a concentration of about 3.00785 mg / ml or about 3.01222 mg / ml. In some embodiments, the solution comprises polysorbate 80 at a concentration of about 0.8 mg / ml to about 1.2 mg / ml. In some embodiments, the solution comprises the polysorbate 80 at a concentration of about 1.0608 mg / ml. In some embodiments, the solution comprises PEG 400 at a concentration of about 0.5 mg / ml to about 0.6 mg / ml. In some embodiments, the solution comprises the PEG 400 at a concentration of about 0.54479 mg / ml. In some embodiments, the solution comprises DL-a tocopherol at a concentration of about 2 to about 3 pg / ml. In some embodiments, the solution comprises the DL-a tocopherol at a concentration of about 2.44 pg / ml or about 2.448 pg / ml. In some embodiments, the solution comprises citric acid at a concentration of about 0.08 pg / ml to about 0.09 pg / ml. In some embodiments, the solution comprises the citric acid at a concentration of about 0.0882 pg / ml or about 0.0885 pg / ml. In some embodiments, the solution comprises propylene glycol at a concentration of about 1 mg / ml to about 2 mg / ml. In some embodiments, the solution comprises the propylene glycol at a concentration of about 1.6454 mg / ml or about 1.6509 mg / ml.

[0176] In some embodiments, the solution is in an IV bag. In some embodiments, the IV bag has one or more closed system transfer device (CSTD) ports. In some embodiments, the IV bag has one closed system transfer device (CSTD) port. In some embodiments, the IV bag has two CSTD ports. In some embodiments, the IV bag has three CSTD ports. In some embodiments, the IV bag has four CSTD ports. In some embodiments, the IV bag has more than two CSTD ports. In some embodiments, the CSTD ports can allow passage of the solution without leak or aerosolization.SYSTEM

[0177] In certain aspects, the present disclosure provides a system for administering a drug solution to a patient in need thereof. In some embodiments, the system comprises a primary intravenous (IV) bag containing a saline solution and a secondary IV bag containing the drug solution. In some embodiments, the drug solution comprises a rapid-acting antidepressant (RAAD) and a mechanistic target of rapamycin (mTOR) inhibitor. In some embodiments, the secondary IV bag comprises a CSTD port.

[0178] In some embodiments, the system further comprises a primary tubing that connects to the primary IV bag. In some embodiments, the system further comprises a secondary tubing that connects tothe secondary IV bag. In some embodiments, the secondary tubing is connected to the primary tubing through a Y -site port.

[0179] In some embodiments, the system further comprises a pump. In some embodiments, the system further comprises a roller clamp on the secondary tubing.

[0180] In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.05 mg / ml to about 1 mg / ml. In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.1 mg / ml to about 1 mg / ml. In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.2 to about 0.5 mg / ml. In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.2425 mg / ml. In some embodiments, a concentration of RAAD in the drug solution ranges from about 0.01 mg / mL to about 2 mg / mL. In some embodiments, a concentration of RAAD in the drug solution ranges from about 0.05 mg / mL to about 1 mg / mL. In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.1 mg / mL to about 1 mg / mL. In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.2 mg / mL to about 0.5 mg / mL. In some embodiments, the drug solution comprises the RAAD at a concentration of about 0.2425 mg / mL. In some embodiments, a concentration of RAAD in the drug solution is 0.01 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.15 mg / mL, 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.35 mg / mL, 0.4 mg / mL, 0.45 mg / mL, 0.5 mg / mL, 0.55 mg / mL, 0.6 mg / mL, 0.65 mg / mL, 0.7 mg / mL, 0.75 mg / mL, 0.8 mg / mL, 0.85 mg / mL, 0.9 mg / mL, 0.95 mg / mL, 1 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, or 2 mg / mL. In some embodiments, a concentration of RAAD in the drug solution is about 0.01 mg / mL, about 0.05 mg / mL, about 0.1 mg / mL, about 0.15 mg / mL, about 0.2 mg / mL, about 0.25 mg / mL, about 0.3 mg / mL, about 0.35 mg / mL, about 0.4 mg / mL, about 0.45 mg / mL, about 0.5 mg / mL, about 0.55 mg / mL, about 0.6 mg / mL, about 0.65 mg / mL, about 0.7 mg / mL, about 0.75 mg / mL, about 0.8 mg / mL, about 0.85 mg / mL, about 0.9 mg / mL, about 0.95 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, or about 2 mg / mL. In some embodiments, a concentration of RAAD in the drug solution is at least 0.01 mg / mL, at least 0.05 mg / mL, at least 0.1 mg / mL, at least 0.15 mg / mL, at least 0.2 mg / mL, at least 0.25 mg / mL, at least 0.3 mg / mL, at least 0.35 mg / mL, at least 0.4 mg / mL, at least 0.45 mg / mL, at least 0.5 mg / mL, at least 0.55 mg / mL, at least 0.6 mg / mL, at least 0.65 mg / mL, at least 0.7 mg / mL, at least 0.75 mg / mL, at least 0.8 mg / mL, at least 0.85 mg / mL, at least 0.9 mg / mL, at least 0.95 mg / mL, at least 1 mg / mL, at least 1.1 mg / mL, at least 1.2 mg / mL, at least 1.3 mg / mL, at least 1.4 mg / mL, at least 1.5 mg / mL, at least 1.6 mg / mL, at least 1.7 mg / mL, at least 1.8 mg / mL, at least 1.9 mg / mL, or at least 2 mg / mL. In some embodiments, a concentration of RAAD in the drug solution is no more than 0.01 mg / mL, no more than 0.05 mg / mL, no more than 0.1 mg / mL, no more than 0.15 mg / mL, no more than 0.2 mg / mL, no more than 0.25 mg / mL, no more than 0.3 mg / mL, no more than 0.35 mg / mL, no more than 0.4 mg / mL, no more than 0.45 mg / mL, no more than 0.5 mg / mL, no more than 0.55 mg / mL, no more than 0.6 mg / mL, no more than 0.65 mg / mL, no more than 0.7 mg / mL, no more than 0.75 mg / mL, no more than 0.8 mg / mL, no more than 0.85 mg / mL, no more than 0.9 mg / mL, no more than 0.95mg / mL, no more than 1 mg / mL, no more than 1.1 mg / mL, no more than 1.2 mg / mL, no more than 1.3 mg / mL, no more than 1.4 mg / mL, no more than 1.5 mg / mL, no more than 1.6 mg / mL, no more than 1.7 mg / mL, no more than 1.8 mg / mL, no more than 1.9 mg / mL, or no more than 2 mg / mL.

[0181] In some embodiments, the drug solution comprises the mTOR inhibitor at a concentration of about 0.11 to about 100 pg / ml. In some embodiments, the drug solution comprises the mTOR inhibitor at a concentration of about 1 to about 50 pg / ml. In some embodiments, the drug solution comprises the mTOR inhibitor at a concentration of about 1.5 pg / ml, about 4.5 pg / ml, about 11.6 pg / ml or about 30 pg / ml. In some embodiments, a concentration of mTOR inhibitor in the drug solution is 1.5 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is 4.5 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is 11.6 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution ranges from about 0.1 pg / mL to about 100 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution ranges from about 1 pg / mL to about 50 pg / mL. In some embodiments, a concentration of mTOR inhibitor in drug the solution is about 1.5 pg / mL, about 4.5 pg / mL, about 11.6 pg / mL or about 30 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is about 1.5 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is about 4.5 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is about 11.6 pg / mL.In some embodiments, a concentration of mTOR inhibitor in the drug solution is about 30 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is 0.1 pg / mL, 0.5 pg / mL, 1 pg / mL,2 pg / mL, 3 pg / mL, 4 pg / mL, 5 pg / mL, 6 pg / mL, 7 pg / mL, 8 pg / mL, 9 pg / mL, 10 pg / mL, 15 pg / mL, 20 pg / mL, 25 pg / mL, 30 pg / mL, 35 pg / mL, 40 pg / mL, 45 pg / mL, 50 pg / mL, 55 pg / mL, 60 pg / mL, 65 pg / mL, 70 pg / mL, 75 pg / mL, 80 pg / mL, 85 pg / mL, 90 pg / mL, 95 pg / mL, or 100 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is about 0.1 pg / mL, about 0.5 pg / mL, about 1 pg / mL, about 2 pg / mL, about 3 pg / mL, about 4 pg / mL, about 5 pg / mL, about 6 pg / mL, about 7 pg / mL, about 8 pg / mL, about 9 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, about 80 pg / mL, about 85 pg / mL, about 90 pg / mL, about 95 pg / mL, or about 100 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is at least 0.1 pg / mL, at least 0.5 pg / mL, at least 1 pg / mL, at least 2 pg / mL, at least 3 pg / mL, at least 4 pg / mL, at least 5 pg / mL, at least 6 pg / mL, at least 7 pg / mL, at least 8 pg / mL, at least 9 pg / mL, at least 10 pg / mL, at least 15 pg / mL, at least 20 pg / mL, at least 25 pg / mL, at least 30 pg / mL, at least 35 pg / mL, at least 40 pg / mL, at least 45 pg / mL, at least 50 pg / mL, at least 55 pg / mL, at least 60 pg / mL, at least 65 pg / mL, at least 70 pg / mL, at least 75 pg / mL, at least 80 pg / mL, at least 85 pg / mL, at least 90 pg / mL, at least 95 pg / mL, or at least 100 pg / mL. In some embodiments, a concentration of mTOR inhibitor in the drug solution is no more than 0.1 pg / mL, no more than 0.5 pg / mL, no more than 1 pg / mL, no more than 2 pg / mL, no more than 3 pg / mL, no more than 4 pg / mL, no more than 5 pg / mL, no more than 6 pg / mL, no more than 7 pg / mL, no more than 8 pg / mL, no more than 9 pg / mL, no more than 10 pg / mL, no more than 15 pg / mL, no more than 20pg / mL, no more than 25 pg / mL, no more than 30 pg / mL, no more than 35 pg / mL, no more than 40 pg / mL, no more than 45 pg / mL, no more than 50 pg / mL, no more than 55 pg / mL, no more than 60 pg / mL, no more than 65 pg / mL, no more than 70 pg / mL, no more than 75 pg / mL, no more than 80 pg / mL, no more than 85 pg / mL, no more than 90 pg / mL, no more than 95 pg / mL, or no more than 100 pg / mL.

[0182] In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of 2.0 mg / mL to 4 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of 2.8 mg / mL to 3.2 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of 3.00785 mg / mL or 3.01222 mg / mL. drug In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of 3.01222 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of about 2.0 mg / mL to about 4 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of about 2.8 mg / mL to about 3.2 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of about 3.00785 mg / mL or about 3.01222 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of about 3.00785 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of about 3.01222 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of 2.0 mg / mL, 2.1 mg / mL, 2.2 mg / mL, 2.3 mg / mL, 2.4 mg / mL, 2.5 mg / mL, 2.6 mg / mL, 2.7 mg / mL, 2.8 mg / mL, 2.9 mg / mL, 3 mg / mL, 3.1 mg / mL, 3.2 mg / mL, 3.3 mg / mL, 3.4 mg / mL, 3.5 mg / mL, 3.6 mg / mL, 3.7 mg / mL, 3.8 mg / mL, 3.9 mg / mL, or 4 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of about 2.0 mg / mL, about 2. 1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, about 3 mg / mL, about 3.1 mg / mL, about 3.2 mg / mL, about 3.3 mg / mL, about 3.4 mg / mL, about 3.5 mg / mL, about 3.6 mg / mL, about 3.7 mg / mL, about 3.8 mg / mL, about 3.9 mg / mL, or about 4 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of at least 2.0 mg / mL, at least 2.1 mg / mL, at least 2.2 mg / mL, at least 2.3 mg / mL, at least 2.4 mg / mL, at least 2.5 mg / mL, at least 2.6 mg / mL, at least 2.7 mg / mL, at least 2.8 mg / mL, at least 2.9 mg / mL, at least 3 mg / mL, at least 3.1 mg / mL, at least 3.2 mg / mL, at least 3.3 mg / mL, at least 3.4 mg / mL, at least 3.5 mg / mL, at least 3.6 mg / mL, at least 3.7 mg / mL, at least 3.8 mg / mL, at least 3.9 mg / mL, or at least 4 mg / mL. In some embodiments, the drug solution comprises dehydrated ethanol at a concentration of no more than 2.0 mg / mL, no more than 2. 1 mg / mL, no more than 2.2 mg / mL, no more than 2.3 mg / mL, no more than 2.4 mg / mL, no more than 2.5 mg / mL, no more than 2.6 mg / mL, no more than 2.7 mg / mL, no more than 2.8 mg / mL, no more than 2.9 mg / mL, no more than 3 mg / mL, no more than 3.1 mg / mL, no more than 3.2 mg / mL, no more than 3.3 mg / mL, no more than 3.4 mg / mL, no more than 3.5 mg / mL, no more than 3.6 mg / mL, no more than 3.7 mg / mL, no more than 3.8 mg / mL, no more than 3.9 mg / mL, or no more than 4 mg / mL.

[0183] In some embodiments, the drug solution comprises polysorbate 80 at a concentration of 0.5 mg / mL to 1.5 mg / mL. In some embodiments, the drug solution comprises polysorbate 80 at aconcentration of 0.8 mg / mL to 1.2 mg / mL. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of 1.0608 mg / ml. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of about 0.5 mg / mL to about 1.5 mg / mL. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of about 0.8 mg / mL to about 1.2 mg / mL. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of about 1.0608 mg / ml. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL,1.4 mg / mL, or 1.5 mg / mL. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, or about 1.5 mg / mL. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of at least 0.5 mg / mL, at least 0.6 mg / mL, at least 0.7 mg / mL, at least 0.8 mg / mL, at least 0.9 mg / mL, at least 1 mg / mL, at least 1.1 mg / mL, at least 1.2 mg / mL, at least 1.3 mg / mL, at least 1.4 mg / mL, or at least1.5 mg / mL. In some embodiments, the drug solution comprises polysorbate 80 at a concentration of no more than 0.5 mg / mL, no more than 0.6 mg / mL, no more than 0.7 mg / mL, no more than 0.8 mg / mL, no more than 0.9 mg / mL, no more than 1 mg / mL, no more than 1.1 mg / mL, no more than 1.2 mg / mL, no more than 1.3 mg / mL, no more than 1.4 mg / mL, or no more than 1.5 mg / mL.

[0184] In some embodiments, the drug solution comprises PEG 400 at a concentration of 0.2 mg / mL to 0.8 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of 0.5 mg / mL to 0.6 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of 0.54479 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of about 0.2 mg / mL to about 0.8 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of about 0.5 mg / mL to about 0.6 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of about 0.54479 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, or 0.8 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, or about 0.8 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of at least 0.2 mg / mL, at least 0.3 mg / mL, at least 0.4 mg / mL, at least 0.5 mg / mL, at least 0.6 mg / mL, at least 0.7 mg / mL, or at least 0.8 mg / mL. In some embodiments, the drug solution comprises PEG 400 at a concentration of no more than 0.2 mg / mL, no more than 0.3 mg / mL, no more than 0.4 mg / mL, no more than 0.5 mg / mL, no more than 0.6 mg / mL, no more than 0.7 mg / mL, or no more than 0.8 mg / mL.

[0185] In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of 1 pg / mL to 4 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of 2 pg / mL to 3 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of 2.44 pg / mL or 2.448 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of 2.44 pg / mL. In some embodiments, the drug solutioncomprises DL-a tocopherol at a concentration of 2.448 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of about 1 pg / mL to about 4 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of about 2 pg / mL to about 3 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of about 2.44 pg / mL or about 2.448 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of about 2.44 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of about 2.448 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of 1 pg / mL, 2 pg / mL, 2.1 pg / mL, 2.2 pg / mL, 2.3 pg / mL, 2.4 pg / mL, 2.5 pg / mL, 2.6 pg / mL, 2.7 pg / mL, 2.8 pg / mL, 2.9 pg / mL, 3 pg / mL, or 4 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of about 1 pg / mL, about 2 pg / mL, about 2.1 pg / mL, about 2.2 pg / mL, about 2.3 pg / mL, about 2.4 pg / mL, about 2.5 pg / mL, about 2.6 pg / mL, about 2.7 pg / mL, about 2.8 pg / mL, about 2.9 pg / mL, about 3 pg / mL, or about 4 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of at least 1 pg / mL, at least 2 pg / mL, at least 2.1 pg / mL, at least 2.2 pg / mL, at least 2.3 pg / mL, at least 2.4 pg / mL, at least 2.5 pg / mL, at least 2.6 pg / mL, at least 2.7 pg / mL, at least 2.8 pg / mL, at least 2.9 pg / mL, at least 3 pg / mL, or at least 4 pg / mL. In some embodiments, the drug solution comprises DL-a tocopherol at a concentration of no more than I pg / mL, no more than 2 pg / mL, no more than 2.1 pg / mL, no more than 2.2 pg / mL, no more than 2.3 pg / mL, no more than 2.4 pg / mL, no more than 2.5 pg / mL, no more than 2.6 pg / mL, no more than 2.7 pg / mL, no more than 2.8 pg / mL, no more than 2.9 pg / mL, no more than 3 pg / mL, or no more than 4 pg / mL.

[0186] In some embodiments, the drug solution comprises citric acid at a concentration of 0.07 pg / mL to 0.1 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of 0.08 pg / mL to 0.09 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of 0.0882 pg / mL or 0.0885 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of 0.0882 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of 0.0885 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of about 0.07 pg / mL to about 0.1 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of about 0.08 pg / mL to about 0.09 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of about 0.0882 pg / mL or about 0.0885 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of about 0.0882 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of about 0.0885 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of 0.07 pg / mL, 0.08 pg / mL, 0.081 pg / mL, 0.082 pg / mL, 0.083 pg / mL, 0.084 pg / mL, 0.085 pg / mL, 0.086 pg / mL, 0.087 pg / mL, 0.088 pg / mL, 0.089 pg / mL, 0.09 pg / mL, or 0.1 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of about 0.07 pg / mL, about 0.08 pg / mL, about 0.081 pg / mL, about 0.082 pg / mL, about 0.083 pg / mL, about 0.084 pg / mL, about 0.085 pg / mL, about 0.086 pg / mL, about 0.087 pg / mL, about 0.088 pg / mL, about 0.089 pg / mL, about 0.09 pg / mL, or about 0.1 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of at least 0.07 pg / mL, atleast 0.08 pg / mL, at least 0.081 pg / mL. at least 0.082 pg / mL, at least 0.083 pg / mL, at least 0.084 pg / mL, at least 0.085 pg / mL, at least 0.086 pg / mL, at least 0.087 pg / mL, at least 0.088 pg / mL, at least 0.089 pg / mL, at least 0.09 pg / mL, or at least 0.1 pg / mL. In some embodiments, the drug solution comprises citric acid at a concentration of no more than 0.07 pg / mL, no more than 0.08 pg / mL, no more than 0.081 pg / mL, no more than 0.082 pg / mL, no more than 0.083 pg / mL, no more than 0.084 pg / mL, no more than 0.085 pg / mL, no more than 0.086 pg / mL, no more than 0.087 pg / mL, no more than 0.088 pg / mL, no more than 0.089 pg / mL, no more than 0.09 pg / mL, or no more than 0. 1 pg / mL.

[0187] In some embodiments, the drug solution comprises propylene glycol at a concentration of 0.5 mg / mL to 2.5 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of 1 mg / mL to 2 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of 1.6454 mg / mL or 1.6509 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of 1.6454 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of 1.6509 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of about 0.5 mg / mL to about 2.5 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of about 1 mg / mL to about 2 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of about 1.6454 mg / mL or about 1.6509 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of about 1.6454 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of about 1.6509 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of 0.5 mg / mL, 1 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.65 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2 mg / mL, or 2.5 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of about 0.5 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 1.6 mg / mL, about 1.65 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2 mg / mL, or about 2.5 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of at least 0.5 mg / mL, at least 1 mg / mL, at least 1.1 mg / mL, at least 1.2 mg / mL, at least 1.3 mg / mL, at least 1.4 mg / mL, at least 1.5 mg / mL, at least 1.6 mg / mL, at least 1.65 mg / mL, at least 1.7 mg / mL, at least 1.8 mg / mL, at least 1.9 mg / mL, at least 2 mg / mL, or at least 2.5 mg / mL. In some embodiments, the drug solution comprises propylene glycol at a concentration of no more than 0.5 mg / mL, no more than 1 mg / mL, no more than 1.1 mg / mL, no more than 1.2 mg / mL, no more than 1.3 mg / mL, no more than 1.4 mg / mL, no more than 1.5 mg / mL, no more than 1.6 mg / mL, no more than 1.65 mg / mL, no more than 1.7 mg / mL, no more than 1.8 mg / mL, no more than 1.9 mg / mL, no more than 2 mg / mL, or no more than 2.5 mg / mL.

[0188] In some embodiments, the RAAD is selected from the group consisting of ketamine, (R)- ketamine, (S)-ketamine, R, S-ketamine, S-Norketamine, R-Norketamine, 2R,6R-hydroxynorketamine, 2S,6S-hydroxynorketamine, nitrous oxide, memantine, amantadine, racemic dextromethorphan, a fixed dose combination of dextromethorphan and quinidine, dextromethorphan, a fixed dose combination of dextromethophane and bupropion, dextromethadone (d-methadone), D-CCPene, UBP141, UBP145,HA966 ((±)-3-amino-l-hydroxy-pyrrolidin-2-one), NVPAAM077, Ro-25-26981, TCN 201, QNZ46, Neu2000, GM-1020, besonprodil, eliprodil, rislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, traxoprodil (CP-101,606), BMT-108908, onfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1- aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO- PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L- Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7- dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof. In some embodiments, the RAAD comprises aN-methyl-D-aspartate (NMD A) receptor modulator. In some embodiments, the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixture thereof. In some embodiments, the ketamine is ketamine HC1.

[0189] In some embodiments, the mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), umirolimus (Biolimus), KU-0063794, PI-103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI-103 - CAS 371935-74-9), torkinib (PP242), tacrolimus (FK-506, fujimycin,), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, sapanisertib), voxtalisib (XL- 765, SAR245409), torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), gedatolisib (PF-05212384, PKI-587), AZD- 2014 (Vistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP- BGT226), palomid-529 (P529, SG 00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC-0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC 223), clemastine (HS-592) fumarate, nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, astragaloside IV, samotolisib (LY3023414), chrysophanic acid, zotarolimus (ABT-578), and any salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, and geometric isomer thereof, and any mixtures thereof. In some embodiments, the mTOR inhibitor comprises rapamycin (sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779).DEFINITIONS

[0190] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

[0191] Throughout this disclosure, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0192] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[0193] As used herein, the term “about” a number refers to that number plus or minus 10% of that number. The term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.

[0194] Whenever the term “at least,” “greater than,” or “greater than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “at least,” “greater than” or “greater than or equal to” applies to each of the numerical values in that series of numerical values. For example, greater than or equal to 1, 2, or 3 is equivalent to greater than or equal to 1, greater than or equal to 2, or greater than or equal to 3.

[0195] Whenever the term “no more than,” “less than,” or “less than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “no more than,” “less than,” or “less than or equal to” applies to each of the numerical values in that series of numerical values. For example, less than or equal to 3, 2, or 1 is equivalent to less than or equal to 3, less than or equal to 2, or less than or equal to 1.

[0196] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of’ can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.

[0197] The terms “subject,” “individual,” or “patient” are often used interchangeably herein. A “subject” can be a biological entity containing expressed genetic materials. The biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa. The subject can be tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro. The subject can be a mammal. The mammal can be a human. The subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease.

[0198] The term “in vivo " is used to describe an event that takes place in a subject’s body.

[0199] The term in vitro is used to describe an event that takes places contained in a container for holding laboratory reagent such that it is separated from the biological source from which the material is obtained. In vitro assays can encompass cell-based assays in which living or dead cells are employed. In vitro assays can also encompass a cell-free assay in which no intact cells are employed.

[0200] As used herein, the terms “treatment” or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.

[0201] As used herein, the term “antidepressant” refers to a category of pharmaceutical drugs designed primarily to alleviate symptoms and treat conditions associated with major depressive disorder and anxiety disorders. These medications function by adjusting the brain's chemical environment, typically affecting the activity and balance of neurotransmitters, which in turn impact mood and emotions. Apart from their central role in mental health treatment, antidepressants have also shown efficacy in managing chronic pain and helping in the treatment of addiction, demonstrating their versatile therapeutic applications.

[0202] As used herein, the term "traditional antidepressant (TAD)" is used to denote the class of antidepressants as defined herein, excluding those categorized as rapid-acting antidepressants (RAADs) as defined in subsequent paragraph.

[0203] As used herein, the term “rapid acting antidepressant (RAAD)” refers to a class of therapeutic agents used in the treatment of depressive disorders that exhibit faster onset of therapeutic effects compared to traditional antidepressants. These medications are designed to alleviate depressivesymptoms within hours to a few days of administration, rather than the usual two to six weeks onset period seen with conventional antidepressants.

[0204] As used herein, the term “mechanistic target of rapamycin (mTOR) inhibitor” refers to a class of drugs designed to inhibit the action of the mTOR protein, a central regulator of cell growth, proliferation, metabolism, and survival. By inhibiting mTOR, these drugs disrupt these cellular processes, effectively reducing abnormal cell growth and proliferation. This mechanism of action is particularly important in disease states characterized by unchecked cell growth or regulation, with mTOR inhibitors often used in the treatment of cancers and in transplant medicine to prevent organ rejection. In the context of neuroscience, mTOR inhibitors have the potential to modulate neural plasticity and memory, holding potential therapeutic value for certain neurological and mental health disorders.

[0205] As used herein, the term "inadequate response" refers to a condition wherein a patient exhibits insufficient therapeutic improvement or exhibits no discernible effects after undergoing antidepressant treatment(s) of appropriate dosage and duration. This scenario may encompass situations where the patient shows no response, minimal alleviation of symptoms, or an inability to maintain response over time. It implies that despite treatment, the patient continues to experience significant symptoms of depression, thereby failing to reach the desired clinical outcome. This highlights the critical need for alternative therapeutic interventions or modifications to existing treatment strategies.

[0206] As used herein, Treatment Resistant Depression (TRD) is characterized by inadequate response to at least two or more antidepressant treatments of adequate dose and duration in the current mood episode.

[0207] As used herein, the term “mg / kg” refers to the weight of a drug in milligrams (mg) per subject's body weight in kilogram (kg). Similarly, the term “pg / kg” refers to the weight of a drug in micrograms (pg) per subject's body weight in kilogram (kg).

[0208] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.EXAMPLES

[0209] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.Example 1: Administration and Dosing Regimen for Phase 2a Clinical Study (I)

[0210] The pharmaceutical composition is provided as a two-vial kit, with one vial containing temsirolimus and the second vial containing ketamine hydrochloride. For administration of ketamine only, the ketamine injection commercial drug product is used. For clinical study, there are 3 dose strengths for the vial of temsirolimus (470 pg / mL; 1,410 pg / mL; 3,630 pg / mL) in 1.2 mL of a solution consisting of the following: propylene glycol, dehydrated ethanol, DL-alpha-tocopherol and anhydrous citric acid. For clinical study, there is one dose strength for the vial of ketamine hydrochloride (57.67 mg / mL ketamine hydrochloride, which is equivalent to 50 mg / mL ketamine free base) in 2.2 mL of a solution consisting of the following: dehydrated ethanol, water, polysorbate 80, and polyethylene glycol 400.

[0211] Prior to administration, 1.8 mL from the vial containing ketamine hydrochloride is added to the vial containing temsirolimus, and the mixed solution is mixed via inversion. This generates a mixed solution containing temsirolimus (188 pg / mL; 564 pg / mL; 1,452 pg / mL for the low, middle and high dose, respectively), and ketamine hydrochloride (34.6 mg / mL ketamine hydrochloride, which is equivalent to 30.0 mg / mL ketamine free base). The appropriate volume of the mixed solution based on the patient’s weight is added to 270 mL of sterile 0.9% sodium chloride in an IV bag, and then 250 mL of that solution in saline is administered by IV infusion to the patient.

[0212] Route of administration is IV infusion over 40 minutes.

[0213] Proposed dosing regimen: Every 2 weeks for the first 4 weeks, followed by every 2 to 4 weeks for the next 2 months and longer.Example 2: Administration and Dosing Regimen for Phase 2a Clinical Study (II)

[0214] This study is a Phase 2a, triple-blind (patient, site, and rater), randomized, parallel-design trial that serves as an active-comparator control for evaluating the safety, pharmacokinetics (PK), and efficacy of the study drug as an adjunctive treatment for adult patients with Treatment- Resistant Depression (TRD). Participants are defined as those who have demonstrated an inadequate response to two or more antidepressants administered at adequate doses and durations during the current mood episode. This inadequate response will be validated in the study using the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (ATRQ).

[0215] All participants will be randomized in a 1 : 1 : 1 ratio to one of three dosing arms: study drug (medium strength), study drug (high strength), and placebo (ketamine (KET) only).

[0216] The dose arms to be studied are as follows:• Study Drug (medium strength): KET 0.5 mg / kg (maximum single dose is 60 mg) plus temsirolimus (TEM) 9.38 pg / kg (e.g., 0.75 mg TEM for an 80-kg participant)• Study Drug (high strength): KET 0.5 mg / kg (maximum single dose is 60 mg) plus TEM 24.2 pg / kg (e.g., 1.9 mg TEM for an 80-kg participant)• KET only (KETALAR or generic ketamine hydrochloride): KET 0.5 mg / kg (maximum single dose is 60 mg)

[0217] The study design consists of three distinct phases: an up to 4-week (28-day) screening phase, a 4- week triple-blind treatment phase, and a 2-week follow-up phase as shown in FIG. 1.

[0218] During the baseline visit on Day 1, participants will receive the study medication, undergo safety and efficacy assessments, and have safety and pharmacokinetic (PK) blood samples collected. The second administration of the study drug will take place on Day 15, which corresponds to Week 2 of the treatment phase. Following the completion of the triple-blind treatment phase on Day 29 (Week 4), all participants will transition into the follow-up phase, which lasts for an additional 2 weeks.

[0219] The primary objective of the study is to evaluate the safety and tolerability of study drug (combination of KET and TEM) administered adjunctively to adult TRD patients who are taking other antidepressant treatments. PK, safety, and tolerability assessments will be conducted according to the Schedule of Activities (SOA) (Table 1 and Table 2) throughout the study from screening through Week6. Efficacy will be a secondary objective of the study, with the primary efficacy endpoint evaluated at Week 4. Exploratory efficacy assessments will be measured from Week 2 through Week 6Table 1. Time and Events Schedule (Screening through Day 10 / 11)a Time from the Screening Visit to baseline (Day 1) of admittance to the CRU may be up to 28 days. b Initial participant eligibility will be confirmed at screening. Continuing eligibility will be confirmed for all participants on Day 1 (baseline). Visit windows on Day 1 for PK samples, ECG, and vital signs are ±15 minutes. c The Day 10 / 11 visit will be conducted by telephone and does not require an in-person visit by the patient to the clinical site. d Complete physical examination at screening only. An abbreviated, symptom-based exam at other visits. Additional unscheduled physical examinations may be performed as needed. Assess for symptoms of interstitial lung disease, bowel perforation, infection, glucose intolerance, and hypersensitivity reaction. e Only weight and BMI (not height) are required after the Screening Visit. f The 12-lead ECG will be obtained with the participant remaining in a supine position following at least 5 minutes of rest. If other procedures are scheduled at the same timepoint, the ECG should be obtained after vital signs measurements and / or before the scheduled blood draw. g Vital signs measurements will include resting pulse, resting systolic and diastolic blood pressure, respiratory rate, and body temperature. Resting blood pressure and pulse rate will be measured after the participant has been resting in a seated or supine position in a quiet environment for at least 5 minutes. If other procedures are scheduled at the same timepoint, vital signs will be obtained first, before an ECG and / or blood draw. At time of discharge, blood pressure must be below 140 / 90, pulse must be <10 bpm above baseline rate.h Urine drug screen to include amphetamines, barbiturates, benzodiazepines, cocaine, marijuana [THC], MDMA, opiates, oxycodone, and phencyclidine. i Serum pregnancy test performed for female participants of childbearing potential at Screening and Day 43 only; all other pregnancy tests will be urine pregnancy tests. FSH levels for female participants of non-childbearing potential will be conducted at screening only. j Serology screening will include tests for HbsAg, HCV, and HIV 1 and 2 antibodies. k Clinical laboratory evaluations will include hematology, liver enzymes, serum chemistry including glucose, lipid panel, and urinalysis. Measures will include estimated glomerular fdtration rate (eGFR), urine protein creatinine ratio (UPCR), and urine albumin creatinine ratio (UACR). Coagulation tests (PT and INR) will be performed only at the Screening Visit. Testosterone should be drawn at baseline, Days 29 and 43 from male participants. Clinical labs should be drawn when the participant has been fasting for at least 8 hours (overnight) in the morning prior to 11 AM. Screening clinical labs do not require fasting. Appropriate clinical laboratory tests may be performed at any time to assess an adverse event.1 Child-Pugh score will be assessed at screening. Participants with a total score of 7 or higher or any score >1 for encephalopathy, ascites, or bilirubin will be excluded. mAdministration of the C-SSRS will be performed by a trained clinician. Any indication of newly emergent or worsening suicidal ideation or behavior will be reported as an adverse event. n The site staff will explain the dosing, study procedures and assessments to be performed during the visit. o Participants should not eat at least 1 hour prior to the dosing since they may experience nausea or vomiting. During dosing, safety monitoring is required (e.g., periodic BP and pulse). p Participant will be discharged after all assessments have been completed and they are assessed as clinically stable for discharge. q Remote and site-based raters will perform HDRS at screening. HDRS ratings will be assessed by the Sponsor at screening for consistency. Only the site-based rater will perform HDRS at baseline and Week 4. r At baseline and Week 2, samples of whole blood for TEM and its metabolite SIR and plasma samples for KET and its metabolite NORKET will be collected. Predose samples will be within 30 minutes of the start of the infusion. The 40-minute sample will be taken within ±15 minutes of the end of the infusion. The exact date and time of collection must be documented.Table 2. Time and Events Schedule (Day 15 through Day 43)a Initial participant eligibility will be confirmed at screening. Continuing eligibility will be confirmed for all participants on Day 15 (Predose). Visit windows on Day 15 for PK samples, ECG, and vital signs are ±15 minutes.b An abbreviated, symptom -based physical examination. Additional unscheduled physical examinations may be performed as needed. Assess symptoms of interstitial lung disease, bowel perforation, infection, glucose intolerance, and hypersensitivity reaction. c Only weight and BMI (not height) are required after the Screening Visit. dThe 12-lead ECG will be obtained with the participant remaining in a supine position following at least 5 minutes of rest. If other procedures are scheduled at the same timepoint, the ECG should be obtained after vital signs measurements and / or before the scheduled blood draw. e Vital signs measurements will include resting pulse, resting systolic and diastolic blood pressure, respiratory rate, and body temperature. Resting blood pressure and pulse rate will be measured after the participant has been resting in a seated or supine position in a quiet environment for at least 5 minutes. If other procedures are scheduled at the same timepoint, vital signs will be obtained first, before an ECG and / or blood draw. f Urine drug screen to include amphetamines, barbiturates, benzodiazepines, cocaine, marijuana [THC], MDMA, opiates, oxycodone, and phencyclidine. g Serum pregnancy test performed for female participants of childbearing potential at Screening and Day 43 only; all other pregnancy tests will be urine pregnancy tests. h Clinical laboratory evaluations will include hematology, liver enzymes, serum chemistry including glucose, lipid panel, and urinalysis. Measures include eGFR, UPCR, and UACR. Coagulation tests (PT and INR) will be performed only at the Screening Visit. Testosterone should be drawn at baseline, Days 29 and 43 from male participants. Clinical labs should be drawn in the morning before 11 AM when the participant has been fasting for at least 8 hours (overnight). Screening clinical labs do not require fasting. Appropriate clinical laboratory tests may be performed at any time to assess an adverse event. i Administration of the C-SSRS will be performed by a trained and certified clinician. Any indication of newly emergent or worsening suicidal ideation will be reported as an adverse event. j Participants should not eat for at least 1 hour prior to dosing as the study drug may cause nausea or vomiting. During dosing, safety monitoring is required (e.g., periodic BP and pulse). k Participant will be discharged after all assessments have been completed and they are assessed as clinically stable for discharge.1 Only the site-based rater will perform HDRS at Week 4. mAt baseline and Week 2, samples of whole blood for TEM and its metabolite SIR and plasma samples for KET and its metabolite NORKET will be collected. Predose samples will be within 30 minutes of the start of the infusion. The 40-minute sample will be taken within ±15 minutes of the end of the infusion. The exact date and time of collection must be documented.Table 3. PK Sample Collection ScheduleAbbreviations: hr, hour(s); KET, ketamine; min, minutes; NORKET, norketamine; PK, pharmacokinetic;SIR, sirolimus; TEM, temsirolimus

[0220] Screening phase: The screening phase will be up to 4 weeks (28 days). Following completion of baseline procedures, participants will enter a 4-week triple-blind phase.

[0221] Triple-Blind treatment phase: The baseline (Day 1) visit will include dose administration, safety, and efficacy assessments, as well as collection of safety and PK blood samples. Testosterone levels will be measured in male participants at baseline and other timepoints according to the SOA (Table 1 and Table 2). Study medication will be administered at baseline (Day 1) and Week 2 (Day 15). Each patient will receive IV diphenhydramine 25 to 50 mg approximately 30 minutes before the start of each dose of blinded study drug.

[0222] Follow-up phase: After completion of the triple-blind phase on Day 29 (Week 4), to ensure participant safety, all participants will enter the follow-up phase for an additional 2 weeks (until Week 6). The total duration of the study will be up to 10 weeks, including a <4-week screening phase, a 4 week triple-blind treatment phase, and a 2-week follow-up phase.

[0223] Additional trial design features: This is a multicenter study which will be conducted at approximately 15 sites in the US. A Safety Review Committee (SRC) will be composed of external clinical and statistical experts to review the safety and tolerability data in a blinded fashion.

[0224] Inclusion Criteria: Participants must meet all inclusion criteria to be eligible for study participation.• Males or females aged 18 to 65 years, inclusive.• Participants must meet the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision (DSM-5-TR) criteria for recurrent major depressive disorder (MDD) or single-episode MDD (with a minimum episode duration of >2 years), without psychotic features, as determined by clinical assessment and confirmed through the M I N I. International Neuropsychiatric Interview (MINI).• The Hamilton Depression Rating Scale (HDRS) total score must be > 18 at both screening and baseline, with a change between screening and baseline not exceeding 25% to confirm eligibility.• Participants must meet the criteria for treatment-resistant depression (TRD), defined as having an inadequate response to two or more antidepressants administered at adequate doses and durations during the current mood episode. A diagnosis of TRD must be validated using the Antidepressant Treatment Response Questionnaire (ATRQ).• Stable doses of oral antidepressant treatment for a period of 4 weeks or longer at the time of enrollment, except for monoamine oxidase inhibitors (MAOIs), which are prohibited (see Table 5). No new antidepressant therapies may be initiated, and no dose increases of concomitant antidepressant treatments are allowed after the Screening Visit or at any time during the study. If a participant has stopped their oral antidepressant treatment prior to screening, they may be enrolled in the study without an oral antidepressant treatment.• Stable frequency of psychotherapy (if participating) for a period of 4 weeks or longer at the time of randomization. No new psychotherapy may be started during the study and the frequency of therapy sessions should remain stable.• Participants must be medically stable as determined by their medical history, physical examination, psychological examination, electrocardiogram (ECG), vital signs, and laboratory tests (including complete blood count, liver enzymes, serum chemistry, and urinalysis). A participant with a clinical abnormality may be included only if the Investigator considers that the abnormality will not introduce additional risk factors for the participant's health nor interfere with the study objectives.• Females of childbearing potential must agree to use a highly effective method of contraception from the time of consent through at least 3 months after the last dose of study medication. Highly effective methods of contraception: intrauterine device, intrauterine system, contraceptive implant, combined injectable contraceptives, hormonal oral contraceptives when used in combination with male condoms with spermicide.• Menopausal females do not require highly effective methods of contraception. Female menopause is defined as amenorrhea >12 consecutive months without another cause and documented serum follicle stimulating hormone (FSH) levels >35 mIU / mL, or women with irregular menstrual periods and a documented FSH level >35 mIU / mL. Follicle stimulating hormone (FSH) testing is not required for women >62 years old with amenorrhea of at least 1 year and women on hormone replacement therapy.• Males who are sexually active and whose partners are females of childbearing potential must agree to use condoms from the time of consent through 3 months after administration of the last dose of study drug, and their partners must be willing to use a highly effective method of contraception from screening through 1 month after administration of the last dose of study drug. Males must agree not to donate sperm from screening through 3 months after administration of the last dose of study drug.• Participants must avoid any prescription or over-the-counter medications, herbal remedies, or food supplements during the study unless prescribed or otherwise approved by the study Investigators.• All participants must be able to provide written, personally signed, and dated informed consent to participate in the study before completing any study-related procedures.• All participants must be fluent in English and have a degree of understanding sufficient to communicate suitably with the primary Investigator and the study coordinator.

[0225] Exclusion Criteria: Participants will not be eligible for study participation if they meet any of the exclusion criteria or will be discontinued at the discretion of the Investigator if they develop any of the exclusion criteria during the study.• All of the following medical conditions are exclusionary: a. Any active or severe medical condition which could interfere with the participant’s safety during the trial, expose them to undue risk, or which could interfere with the study objectives b. Known positive tests for human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus (HCV) c. History of organ transplantationd. History of seizure disorder other than infantile febrile seizures e. Previous malignant disease except basal cell carcinoma of skin and cervical carcinoma in situ / dysplasia f. Contraindications for use of KET including aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage, uncontrolled hypertension g. Body mass index (BMI) >35 or weight >120 kg h. History of hepatic impairment, unstable diabetes, immunosuppression due to any cause, interstitial lung disease, bowl perforation, central nervous system (CNS) tumors, recent or upcoming surgery (due to risk of abnormal wound healing), nephrotic syndrome, aneurysmal vascular disease, or intracerebral hemorrhage• Any evidence of renal injury or disease including: a. Acute renal injury within 12 weeks prior to screening. b. Use of nephrotoxic medications, including continuous daily use of NSAIDs (>21 days or more). c. Participants with planned procedures that require contrast dye during the study. d. Signs or symptoms of hypotension or volume depletion / dehydration. e. Evidence of severe renal disease or diminished renal function.• Patients taking any of the prohibited or restricted medications in Table 5 and Table 6• Participants must not exceed the following resting vital sign parameters at baseline and at the time of study drug dosing: systolic blood pressure (SBP) <85 mmHg or >145 mmHg, diastolic blood pressure (DBP) <55 mmHg or >95 mmHg; pulse lower than 45 bpm or higher than 95 bpm. May be repeated once after resting for 10 minutes if the participant does not meet one of the required vital sign criteria.• Any previous diagnoses of psychosis, schizophrenia, schizophreniform disorder, schizoaffective disorder, bipolar disorder, neurodegenerative disorder, traumatic brain injury, dementia, mild cognitive impairment, or personality disorder based on Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision (DSM-5-TR) criteria and as confirmed by the MINI• Psychiatric hospitalization within 6 months of enrollment date• Participant must not have homicidal ideation / intent or suicidal ideation with intent to act within the past 6 months based on the CSSR-S assessment and the Investigator’s clinical assessment. Current, ongoing serious suicidal risk as assessed by the CSSR-S, or by the Investigator assessment.• Participants must not have a history of moderate to severe substance use disorder according to DSM- 5-TR criteria currently or within 6 months prior to enrollment (excluding nicotine and caffeine) or a lifetime history of KET or other psychedelic use disorder.• Participants must not have a positive urine drug screen for any illicit substance at screening, baseline, or Week 2. Positive urine drug screens are allowed for prescribed medicines (e.g., benzodiazepines, opiates). Retests will not be allowed for a positive test of an illicit drug, except for marijuana (THC).Those positive at Screening Visit for marijuana may retest once after at least 30 days. Those with a positive urine drug screen for an illicit drug (including marijuana) at Days 1 or 15 must be withdrawn from the study.• Self-reported use of psychedelics in the last 3 months (psilocybin, lysergic acid diethylamide [LSD], dimethyltryptamine [DMT], Ayahuasca, 5-methoxy DMT, mescaline, ibogaine, 3, 4- methylenedioxy-methamphetamine [MDMA], and ketamine).• Previous nonresponse (as verified by the Investigator) to treatment with esketamine or ketamine. Treatment with ketamine or esketamine for any neuropsychiatric disorder in the last 6 months.• Treatment with an mTOR inhibitor such as rapamycin, TEM, SIR, or everolimus in the last 6 months• Positive pregnancy test at screening, baseline, or prior to Week 2 dosing or currently lactating• Hypersensitivity or known intolerance to TEM, SIR, everolimus, polysorbate 80 (Tween 80), KET, esketamine, or any of the excipients; sensitivity to antihistamines or unable to receive an antihistamine for other medical reasons.• Sensitivity to heparin or heparin-induced thrombocytopenia• Current systemic infection. Participants with influenza or a positive test for COVID-19 may isolate and be re screened for the study.• Participants must not have received any vaccination within 2 weeks of screening and may not receive a live vaccine during the study or have close contact with someone who recently received or plans to receive a live vaccine.• Participants must not have taken other investigational drug or device within 6 months prior to the first dose of study drug in this study or be currently participating in another clinical study.• Clinically significant abnormality on ECG or QT interval corrected using Fridericia's formula (QTCF) at screening and baseline of >460 ms in males and >470 ms in females.• Clinically significant laboratory assessment of blood or urine at screening, including the following: a. Markers of impaired liver function, including >2x upper limit of normal (ULN) aspartate aminotransferase (AST) or alanine aminotransferase (ALT) and / or >1.5x ULN bilirubin, or participants with a Child-Pugh total score of 7 or higher (indicating at least mild hepatic impairment) or any score >1 for encephalopathy, ascites, or bilirubin will be excluded. b. Markers of impaired renal function, based on an estimated glomerular filtration rate (eGFR) <60 mL / min / 1.73 m2, urine protein creatinine ratio (UPCR) >0.2 or urine albumin creatinine ratio (UACR) >0.3. c. Markers of dyslipidemia, including total cholesterol >210 mg / dL and / or triglycerides >200 mg / dL d. Hemoglobin A1C >7.0 e. Proteinuria (>1+ protein in urine) or hematuria >5 Red Blood Cells / High Powered Field (RBC / HPF)f. Neutropenia (absolute neutrophil count <1.5x 103 / mm3) g . Platelet count <125x 103 / mm3 h. Any abnormal values deemed clinically significant by the Investigator

[0226] For the KET only arm, KET commercial product (KETALAR - ketamine hydrochloride injection or generic ketamine hydrochloride) will be supplied. Study medications will be administered as a 40-minute IV infusion every 2 weeks (baseline [Day 1] and Week 2 [Day 15]). All doses (IV infusions) are prepared by the site unblinded pharmacist. Dosage is calculated per body weight measured on the day of dose administration.Table 4. TEM Dose Levels Compared with Torisel® (TEM) US Product LabelAbbreviations: TEM, temsirolimus; USPI, United States Prescribing Information.

[0227] Concomitant therapy:

[0228] Concomitant medications, treatments, and therapies that are prohibited or permitted with restrictions are listed in Table 5 and Table 6, respectively. Any new medications or therapies are permitted only at the discretion of the investigator after careful review of current concomitant medications, prohibitions, and restrictions in this protocol.

[0229] Participants may take concomitant oral antidepressants including all of the following medications:• Selective serotonin reuptake inhibitors (SSRIs): fluoxetine, citalopram, sertraline, paroxetine, and escitalopram• Serotonin and norepinephrine reuptake inhibitors (SNRIs): duloxetine, venlafaxine, and desvenlafaxine• Norepinephrine and dopamine reuptake inhibitor (NDRI): bupropion• Serotonin modulators: vilazodone and vortioxetine• Atypical antipsychotics: aripiprazole, brexpiprazole, quetiapine, and olanzapine• Allowable antidepressants used as sleep medications: trazodone (up to 100 mg) and mirtazapine (up to 15 mg)

[0230] Patients must be on stable doses of antidepressants (if prescribed) for a period of 4 weeks or longer at the time of enrollment, and doses should remain stable for the entire study. Any dose changes should be discussed with the study Medical Monitor. Adjunctive oral antidepressants are not required. No new antidepressant therapies may be initiated during the study.Table 5. Concomitant Treatments that are ProhibitedAbbreviations: ACE, angiotensin converting enzyme; BCG, Bacillus Calmette-Guerin; COVID, coronavirus disease; CYP3A4, cytochrome P450 3A4; DBS, deep brain stimulation; ECT, electroconvulsive therapy; MAOI, monoamine oxidase inhibitor; P-gp, P-glycoprotein; RSV, respiratory syncytial virus; VNS, vagal nerve stimulation.

[0231] All treatments that the Investigator considers necessary for a participant’s welfare may be administered at the discretion of the Investigator in keeping with the community standards of medicalcare (i.e., supportive care). Additionally, use of the concomitant therapies shown in Table 6 is permitted with restrictions.Table 6. Concomitant Treatments that are Permitted with RestrictionsAbbreviations: CYP3A4, cytochrome P450 3A4; P-gp, P-glycoprotein; SIR, sirolimus.Notes: Sedatives, hypnotics, benzodiazepines, sedating antihistamines, or other psychotropic medications were not permitted within 8 hours of treatment sessions; except - at the discretion of the Investigator - for medications that will results in discontinuation / withdrawal symptoms or that may alter the riskbenefit ratio.Example 3: Preparation of example formulations

[0232] High strength Temsirolimus ITEM) bulk solution (3,63 mg / ml TEM in excipients)

[0233] In the preparation of the formulation, a mixture was created by combining 1757.96 g of dehydrated ethanol, 3.32 g of DL-alpha-tocopherol, 2238.60 g of propylene glycol, and 0.12 g of anhydrous citric acid. Separately, 14.732 g of the TEM drug substance, with a potency of 98.56%, yielding an effective weight of 14.51986 g of TEM, was added to a container. To this, sufficient excipient solution was incorporated to achieve a total weight of 3652.4 g, resulting in the addition of 3637.668 g of the excipient solution. The final mixture, which was thoroughly mixed, yielded a total volume of 4000 mL, calculated based on the density of the excipient solution at 0.9131 g / mL. It is noted that not all of the excipient solution prepared was utilized in the formulation of the TEM bulk solution.Table 7. High strength TEM bulk solution

[0234] Medium strength TEM bulk solution (1,41 mg / mL TEM in excipients)

[0235] In the formulation process, a mixture was prepared by combining 1757.96 g of dehydrated ethanol, 3.32 g of DL-alpha-tocopherol, 2238.60 g of propylene glycol, and 0.12 g of anhydrous citric acid. In a separate container, 5.722 g of TEM. To achieve a total weight of 3655.6 g, an appropriate amount of excipient solution was added, specifically 3649.878 g, to the TEM drug substance. This mixture was thoroughly blended, yielding a final solution volume of 4000 mb, based on a density of 0.9139 g / mL. It is noted that not all of the excipient solution prepared was utilized in the formulation of the TEM solution.Table 8. Medium strength TEM bulk solution

[0236] Bulk Ketamine (KET) Solution: 50 mg / mL in ketamine free base (density 0,9709 g / mL)

[0237] In the formulation procedure, a mixture was created by combining 1796.25 g of polysorbate 80, 922.50 g of PEG 400, 2905.25 g of dehydrated ethanol, and 1875.00 g of water for injection. In a separate container, 403.690 g of ketamine hydrochloride was added, which had a potency of 100%. To achieve a total weight of 6796.3 g, an adequate amount of excipient solution was incorporated, specifically 6392.61 g, into the ketamine hydrochloride drug substance. This final mixture was thoroughly mixed, resulting in a solution volume of 7000 mL, calculated based on a density of 0.9709 g / mL. It is noted that not all of the excipient solution prepared was utilized in the formulation of the KET solution.Table 9. KET bulk solution

[0238] Bulk Solution with TEM and KET in Saline

[0239] The bulk solution containing TEM and KET in saline has been prepared for use in IV bags, adhering to the specified target fill volume of 270 mL for the IV bags.

[0240] High Dose Study Drug (High TEM, Standard KET): For the high dose study drug, the high TEM Solution, which contains 3.63 mg / mL of TEM, was mixed with the KET Solution at a concentration of 50 mg / mL of KET free base in a volume ratio of 1.2: 1.8 (or 2:3). This combination results in a solution with concentrations of 1.452 mg / mL of TEM and 30 mg / mL of KET free base. Subsequently, this solution was diluted with saline in a volume ratio of 2.2:270, yielding a final concentration of 0.0117 mg / mL of TEM and 0.242 mg / mL of KET free base, which is designated for filling the IV bags.

[0241] Medium Dose Study Drug (Medium TEM, Standard KET): For the medium dose study drug, the Medium TEM Solution, containing 1.41 mg / mL of TEM, was combined with the KET Solution (50 mg / mL KET free base) in the same volume ratio of 1.2: 1.8, resulting in a concentration of 0.564 mg / mL of TEM and 30 mg / mL of KET free base. This solution was also mixed with saline at a ratio of 2.2:270, producing a final concentration of 0.0046 mg / mL of TEM and 0.242 mg / mL of KET free base, intended for IV bag filling. Table 10 provides Study Drug ready-to-administered IV bag formulations in water (concentrations in water) -target concentrations in mg / mL for high and medium dose strengths.Table 10. Formulation in saline IV bag (mg / mL)*Dose Strength Based on TEMExample 4: IV bags with built-in Closed System Transfer Device (CSTDs) ports and Administration Process

[0242] This provides an exemplary method of the administration of the study drug. While custom-made IV bags with more than one built-in CSTD ports can be utilized, off-the-shelf IV bags with only one CSTD port are also suitable for use. In some embodiments, the off-the-shelf IV bags comprises a BD SmartSite Bag.

[0243] FIG. 2 illustrates an example of an IV bag equipped with a built-in CSTD port. The CSTD port functions as a valve that can be opened or closed, allowing for the passage of solution without leaks or aerosolization. The IV bag can contain the study drug solution, which includes all ingredients combined in one solution.

[0244] In some embodiments, the administration can be conducted by employing a configuration referred to as a piggy-back configuration as shown in FIG. 3. This process is often referred to as secondary infusion (piggy-bag infusion). It is important to ensure IV lines are primed and free of air before administration. Using an IV bag incorporating a closed system transfer device (CSTD) helps to minimize exposure to hazardous drugs during administration. As illustrated in FIG. 3, the primary bag(301) contains only saline solution while the secondary bag (302) contains the study drug in saline solution. The secondary bag (302) is equipped with a CSTD port (307) to prevent the drug from leaking onto the medical practitioner and the environment. In some embodiments, a primary tubing (303) is equipped with a check valve. In some embodiments, the secondary tubing (304) is equipped with a roller clamp. Below is an exemplary procedure to perform the secondary infusion using the piggy-back configuration.

[0245] Preparation: 1) perform hand hygiene with soap and water; 2) gather supplies (PPE-two pairs of ASTM -D6978 gloves, impermeable gown, alcohol swabs, primary fluid bag and IV tubing, secondary medication bag, secondary IV tubing, and pump); 3) inspect secondary bag for clarity, leaks, particulates, and expiration date.

[0246] Tubing setup (primary): 1) spike primary tubing (301) into primary bag (301) and prime according to manufacturer guidelines; 2) load primary tubing (301) into pump (306) and connect to patient; 3) program primary fluid to run at keep-vein-open rate of lOml / hr.

[0247] Tubing setup (secondary): 1) ensure roller clamp is closed on secondary tubing (304); 2) connect secondary bag (302) to empty secondary tubing (304) through the CSTD port (307); 3) the top of the Y- site port (305) on the primary tubing (303) is swabbed with an appropriate antiseptic, followed by the attachment of the secondary tubing (304) to this Y-site port (305).

[0248] To prime the pump and tube with saline prior to connecting the drug bag, the back priming technique can be used to avoid contamination. Additionally, the back priming technique can minimize waste, prevent air embolism, and ensure that the patient receives the full dose of medication (drug) intended for them. The back priming involves the process of clearing the IV line of any air bubbles and ensuring that the medication or fluid is ready to be delivered to the patient without delay or contamination. Back priming process: 1) hang secondary bag (302) below the primary bag (301); 2) open roller clamp on the secondary tubing to allow primary fluid (saline) to backfill the secondary tubing (304); 3) ensure air is removed from tubing; 4) close the roller clamp on secondary tubing (304) once primed.

[0249] Infusion setup: 1) hang secondary bag (302) above primary bag (301); 2) open roller clamp on secondary tubing (304); 3) remove outer gloves before programing pump (306); 4) program pump with correct rate and volume (select secondary mode if applicable) and administer the drug to the patient.

[0250] Post-infusion: confirm pump switches back to primary bag; 2) lower to remove secondary bag(302) when complete.

[0251] Final steps: dispose of study drug into appropriate waste container; 2) remove inner gloves and gown and wash hands with soap and water; 3) document drug administration (time, drug, does, route,response, etc.). This systematic approach enhances the efficiency and safety of administration of the drug.

[0252] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WHAT IS CLAIMED IS:

1. A method of treating or preventing a disease, disorder, or condition in a human subject in need thereof comprising:(a) administering a therapeutically effective amount of a rapid-acting antidepressant (RAAD) to the human subject, and(b) administering a therapeutically effective amount of a mechanistic target of rapamycin (mTOR) inhibitor to the human subject, wherein the human subject is administered an antidepressant before, during, or after(i) the administration of the RAAD, or(ii) the administration of the mTOR inhibitor.

2. The method of claim 1, wherein the human subject has an inadequate response to the antidepressant.

3. The method of claim 1 or 2, wherein the human subject has an inadequate response to two or more antidepressant treatments.

4. The method of claim 3, wherein the two or more antidepressant treatments includes the administration of the antidepressant.

5. The method of claim 3, wherein the two or more antidepressant treatments does not include the administration of the antidepressant.

6. The method of any one of claims 1 to 5, wherein the antidepressant comprises a traditional antidepressant (TAD).

7. The method of any one of claims 1 to 5, wherein the antidepressant comprises a RAAD.

8. The method of any one of claims 1 to 7, wherein the human subject is administered the antidepressant before the administration of the RAAD or the administration of the mTOR inhibitor.

9. The method of any one of claims 1 to 7, wherein the human subject is administered the antidepressant during the administration of the RAAD or the administration of the mTOR inhibitor.

10. The method of any one of claims 1 to 7, wherein the human subject is administered the antidepressant after the administration of the RAAD or the administration of the mTOR inhibitor.

11. The method of any one of claims 1 to 10, wherein the antidepressant is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route.

12. The method of any one of claims 1 to 11, wherein the antidepressant is administered through the oral route.

13. The method of any one of claims 1 to 12, wherein the antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRs), serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs), serotonin modulators and stimulators (SMSs), serotonin antagonist and reuptake inhibitors (SARIs), norepinephrine reuptake inhibitors (NRIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants(TeCAs), monoamine oxidase inhibitors (MAOIs), norepinephrine and dopamine reuptake inhibitors (NDRIs), atypical antipsychotics, typical antipsychotics, and allowable antidepressants used as sleep medications.

14. The method of claim 13, wherein the SSRIs comprise fluoxetine, fluvoxamine, citalopram, sertraline, paroxetine, or escitalopram.

15. The method of claim 13, wherein the SNRIs comprise duloxetine, levomilnacipran, milnacipran, venlafaxine, or desvenlafaxine.

16. The method of claim 13, wherein the SNDRIs comprise toludesvenlafaxine or nefazodone.

17. The method of claim 13, wherein the SMSs comprise vilazodone or vortioxetine.

18. The method of claim 13, wherein the SARIs comprise nefazodone or trazodone.

19. The method of claim 13, wherein the NRIs comprise reboxetine, teniloxazine, 5-HT2A receptor antagonist, atomoxetine, viloxazine, 5-HT2B receptor antagonist, or 5-HT2C receptor agonist.

20. The method of claim 13, wherein the NDRIs comprise bupropion, amphetamines, methylphenidate, modafinil, or non-competitive antagonist of nicotinic acetylcholine receptors.

21. The method of claim 13, wherein the TACs comprise amitriptyline, amitriptylinoxide, clomipramine, desipramine, dibenzepin, dimetacrine, dosulepin, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, nortriptyline, noxiptiline, pipofezine, protriptyline, trimipramine, opipramol, or tianeptine.

22. The method of claim 13, wherein the TeCAs comprise amoxapine, maprotiline, mianserin, mirtazapine, setiptiline, mianserin, mirtazapine, or setiptiline.

23. The method of claim 13, wherein the MAOIs comprise isocarboxazid, phenelzine, tranylcypromine, selegiline, metralindole, moclobemide, pirlindole, or bifemelane.

24. The method of claim 13, wherein the atypical antipsychotics comprise amisulpride, lumateperone, lurasidone, aripiprazole, brexpiprazole, quetiapine, risperidone, or olanzapine.

25. The method of claim 13, wherein the typical antipsychotics comprise trifluoperazine, buspirone, lithium, or thyroxine.

26. The method of claim 13, wherein the allowable antidepressants used as sleep medications comprise trazodone or mirtazapine.

27. The method of any one of claims 1 to 26, wherein the therapeutically effective amount of the RAAD is at a dose of (i) about 0.01 mg / kg to about 100 mg / kg, (ii) about 0.8 mg to about 8 g, or (iii) about 1.2 mg to about 12 g.

28. The method of any one of claims 1 to 27, wherein the therapeutically effective amount of the RAAD is at a dose of (i) about 0. 1 mg / kg to about 10 mg / kg, (ii) about 8 mg to about 800 mg, or (iii) about 12 mg to about 1200 mg.

29. The method of any one of claims 1 to 28, wherein the therapeutically effective amount of the RAAD is at a dose of (i) about 0.5 mg / kg to about 2 mg / kg, (ii) about 4 mg to about 160 mg, or (iii) about 6 mg to about 240 mg.

30. The method of any one of claims 1 to 29, wherein the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 1 pg / kg to about 100 pg / kg, (ii) about 0.08 mg to about 8 mg, or (iii) about 0.12 mg to about 12 mg.

31. The method of any one of claims 1 to 30, wherein the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 1 pg / kg to about 50 pg / kg, (ii) about 0.08 mg to about 5.6 mg, or (iii) about 0.12 mg to about 8.4 mg.

32. The method of any one of claims 1 to 31, wherein the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 3.125 pg / kg, about 9.375 pg / kg, about 24.2 pg / kg, or about 62.5 pg / kg, (ii) about 0.25 mg, about 0.75 mg, about 1.93 mg, or about 5 mg, or (iii) about 0.375 mg, about 1.125 mg, about 2.9 mg, or about 7.5 mg.

33. The method of any one of claims 1 to 32, wherein the RAAD is selected from the group consisting of ketamine, (R) -ketamine, (S)-ketamine, R, S-ketamine, S-Norketamine, R-Norketamine,2R, 6 / ?-hydroxynorkctaminc. 2.S'. 6S'-hydroxynorkctaminc. nitrous oxide, memantine, amantadine, racemic dextromethorphan, a fixed dose combination of dextromethorphan and quinidine, dextromethorphan, a fixed dose combination of dextromethophane and bupropion, dextromethadone (d-methadone), D- CCPene, UBP141, UBP145, HA966 ((±)-3-amino-l-hydroxy-pyrrolidin-2-one), NVPAAM077, Ro-25- 26981, TCN 201, QNZ46, Neu2000, GM-1020, besonprodil, eliprodil, rislenemdaz (CERC-301 / MK- 0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, traxoprodil (CP-101,606), BMT-108908, onfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1-aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4- chlorokynurenine, 5,7-dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof.

34. The method of any one of claims 1 to 33, wherein the RAAD comprises a N-methyl-D-aspartate (NMD A) receptor modulator.

35. The method of claim 34, wherein the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixture thereof.

36. The method of claim 35, wherein the ketamine is ketamine HC1.

37. The method of any one of claims 1 to 36, wherein the mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY 22989, ABI-009), everolimus(RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), umirolimus (Biolimus), KU-0063794, PI- 103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI-103 - CAS 371935-74-9), torkinib (PP242), tacrolimus (FK-506, fujimycin,), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), gedatolisib (PF-05212384, PKI-587), AZD- 2014 (Vistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE- 132), BGT226 (NVP-BGT226), palomid-529 (P529, SG 00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC-0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound 401, GNE- 477, Bimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC 223), clemastine (HS-592) fumarate, nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, astragaloside IV, samotolisib (LY3023414), chrysophanic acid, zotarolimus (ABT-578), and any salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, and geometric isomer thereof, and any mixtures thereof.

38. The method of any one of claims 1 to 37, wherein the mTOR inhibitor comprises rapamycin (sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779).

39. The method of any one of claims 1 to 38, wherein the therapeutically effective amount of the RAAD is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route.

40. The method of any one of claims 1 to 39, wherein the therapeutically effective amount of the RAAD is administered through an intravenous route.

41. The method of any one of claims 1 to 40, wherein the therapeutically effective amount of the RAAD is administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, seven times per week, once per two weeks, once per three weeks, once per four weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten times per month.

42. The method of any one of claims 1 to 40, wherein the therapeutically effective amount of the RAAD is administered once per day, once per two days, once per three days, once per four days, once per five days, once per ten days or once per fifteen days.

43. The method of any one of claims 1 to 42, wherein the mTOR inhibitor is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route.

44. The method of any one of claims 1 to 43, wherein the mTOR inhibitor is administered through an intravenous route.

45. The method of any one of claims 1 to 44, wherein the mTOR inhibitor is administered once per week, twice per week, three times per week, four times per week, five times per week, six times perweek, seven times per week, once per two weeks, once per three weeks, once per four weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten times per month.

46. The method of any one of claims 1 to 44, wherein the mTOR inhibitor is administered once per day, once per two days, once per three days, once per four days, once per five days, once per ten days or once per fifteen days.

47. The method of any one of claims 1 to 46, wherein the disease, disorder, or condition is selected from the group consisting of a major depressive disorder (MDD), a major depressive episode in bipolar disorder (bipolar depression), a persistent depressive disorder (dysthymia), a disruptive mood dysregulation disorder, a major depressive disorder (including major depressive episode), a premenstrual dysphoric disorder, a substance / medication-induced depressive disorder, a depressive disorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, a posttraumatic stress disorder, an addictive disorder, bipolar I disorder, bipolar II disorder, generalized anxiety disorder, social anxiety disorder (social phobia), specific phobia, panic disorder, agoraphobia, separation anxiety disorder, selective mutism, substance-induced anxiety disorder, medication-induced anxiety disorder, anxiety disorder due to another medical condition, borderline personality disorder, treatment-resistant depression, unspecified anxiety disorder, chronic pain, and any combinations thereof.

48. The method of any one of claims 1 to 47, wherein the disease, disorder, or condition is a mood disorder, optionally a depressive disorder.

49. The method of any one of claims 1 to 47, wherein the disease, disorder, or condition is a treatment-resistant depression (TRD).

50. The method of any one of claims 1 to 49, wherein the RAAD and the mTOR inhibitor are formulated into a pharmaceutical composition prior to administering to the human subject.

51. The method of claim 50, wherein the pharmaceutical composition is administered to the human subject through multiple doses.

52. The method of claim 51, wherein the multiple doses comprise one or more acute doses and one or more maintenance doses administered after the one or more acute doses.

53. The method of any one of claims 50 to 52, wherein the pharmaceutical composition is formulated as a solution.

54. The method of claim 53, wherein the solution comprises dehydrated ethanol, DL-alpha- tocopherol, propylene glycol, anhydrous citric acid, polysorbate 80, or PEG 400.

55. The method of claim 54, wherein the solution further comprises about 0.9% (w / v) sodium chloride in water.

56. A method of treating or preventing a disease, disorder, or condition in a human subject in need thereof comprising:(a) administering a therapeutically effective amount of a rapid-acting antidepressant (RAAD) to the human subject, and(b) administering a therapeutically effective amount of a mechanistic target of rapamycin (mTOR) inhibitor to the human subject, wherein the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 0.25 mg, about 0.75 mg, about 1.93 mg, or about 5 mg, (ii) about 0.375 mg, about 1.125 mg, about 2.9 mg, or about 7.5 mg, or (iii) about 3.125 pg / kg, about 9.375 pg / kg, about 24.2 pg / kg, or about 62.5 tig / kg-57. The method of claim 56, wherein the therapeutically effective amount of the mTOR inhibitor is at a dose of about 0.25 mg, about 0.375 mg, or about 3.125 pg / kg.

58. The method of claim 56, wherein the therapeutically effective amount of the mTOR inhibitor is at a dose of about 0.75 mg, about 1.125 mg, or about 9.375 pg / kg.

59. The method of claim 56, wherein the therapeutically effective amount of the mTOR inhibitor is at a dose of about 1.93 mg, about 2.9 mg, or about 24.2 pg / kg.

60. The method of any one of claims 56 to 59, wherein the therapeutically effective amount of the RAAD is at a dose of (i) about 0.01 mg / kg to about 100 mg / kg, (ii) about 0.8 mg to about 8 g, or (iii) about 1.2 mg to about 12 mg.

61. The method of any one of claims 56 to 60, wherein the therapeutically effective amount of the RAAD is at a dose of (i) about 0. 1 mg / kg to about 10 mg / kg, (ii) about 8 mg to about 800 mg, or (iii) about 12 mg to about 1200 mg.

62. The method of any one of claims 56 to 61, wherein the therapeutically effective amount of the RAAD is at a dose of (i) about 0.5 mg / kg to about 2 mg / kg, (ii) about 4 mg to about 160 mg, or (iii) about 6 mg to about 240 mg.

63. The method of any one of claims 56 to 62, wherein the human subject is administered an antidepressant before, during, or after(i) the administration of the RAAD, or(ii) the administration of the mTOR inhibitor.

64. The method of claim 63, wherein the human subject has an inadequate response to the antidepressant.

65. The method of claim 63 or 64, wherein the human subject has an inadequate response to two or more antidepressant treatments.

66. The method of claim 65, wherein the two or more antidepressant treatments includes the administration of the antidepressant.

67. The method of claim 65, wherein the two or more antidepressant treatments does not include the administration of the antidepressant.

68. The method of any one of claims 63 to 67, wherein the human subject is administered the antidepressant before the administration of the RAAD or the administration of the mTOR inhibitor.

69. The method of any one of claims 63 to 67, wherein the human subject is administered the antidepressant during the administration of the RAAD or the administration of the mTOR inhibitor.

70. The method of any one of claims 63 to 67, wherein the human subject is administered the antidepressant after the administration of the RAAD or the administration of the mTOR inhibitor.

71. The method of any one of claims 63 to 70, wherein the antidepressant is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route.

72. The method of any one of claims 63 to 71, wherein the antidepressant is administered through the oral route.

73. The method of any one of claims 63 to 72, wherein the antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRs), serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs), serotonin modulators and stimulators (SMSs), serotonin antagonist and reuptake inhibitors (SARIs), norepinephrine reuptake inhibitors (NRIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), monoamine oxidase inhibitors (MAOIs), norepinephrine and dopamine reuptake inhibitors (NDRIs), atypical antipsychotics, typical antipsychotics, and allowable antidepressants used as sleep medications.

74. The method of claim 73, wherein the SSRIs comprise fluoxetine, fluvoxamine, citalopram, sertraline, paroxetine, or escitalopram.

75. The method of claim 73, wherein the SNRIs comprise duloxetine, levomilnacipran, milnacipran, venlafaxine, or desvenlafaxine.

76. The method of claim 73, wherein the SNDRIs comprise toludesvenlafaxine or nefazodone.

77. The method of claim 73, wherein the SMSs comprise vilazodone or vortioxetine.

78. The method of claim 73, wherein the SARIs comprise nefazodone or trazodone.

79. The method of claim 73, wherein the NRIs comprise reboxetine, teniloxazine, 5-HT2A receptor antagonist, atomoxetine, viloxazine, 5-HT2B receptor antagonist, or 5-HT2C receptor agonist.

80. The method of claim 73, wherein the NDRIs comprise bupropion, amphetamines, methylphenidate, modafinil, or non-competitive antagonist of nicotinic acetylcholine receptors.

81. The method of claim 73, wherein the TACs comprise amitriptyline, amitriptylinoxide, clomipramine, desipramine, dibenzepin, dimetacrine, dosulepin, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, nortriptyline, noxiptiline, pipofezine, protriptyline, trimipramine, opipramol, or tianeptine.

82. The method of claim 73, wherein the TeCAs comprise amoxapine, maprotiline, mianserin, mirtazapine, setiptiline, mianserin, mirtazapine, or setiptiline.

83. The method of claim 73, wherein the MAOIs comprise isocarboxazid, phenelzine, tranylcypromine, selegiline, metralindole, moclobemide, pirlindole, or bifemelane.

84. The method of claim 73, wherein the atypical antipsychotics comprise amisulpride, lumateperone, lurasidone, aripiprazole, brexpiprazole, quetiapine, risperidone, or olanzapine.

85. The method of claim 73, wherein the typical antipsychotics comprise trifluoperazine, buspirone, lithium, or thyroxine.

86. The method of claim 73, wherein the allowable antidepressants used as sleep medications comprise trazodone or mirtazapine.

87. The method of any one of claims 56 to 86, wherein the RAAD is selected from the group consisting of ketamine, (R) -ketamine, (S)-ketamine, R, S-ketamine, S-Norketamine, / ?-Norkctaminc.2R, 6 / ?-hydroxynorkctaminc. 2.S'.6S'-hydroxynorkctaminc. nitrous oxide, memantine, amantadine, racemic dextromethorphan, a fixed dose combination of dextromethorphan and quinidine, dextromethorphan, a fixed dose combination of dextromethophane and bupropion, dextromethadone (d-methadone), D- CCPene, UBP141, UBP145, HA966 ((±)-3-amino-l-hydroxy-pyrrolidin-2-one), NVPAAM077, Ro-25- 26981, TCN 201, QNZ46, Neu2000, GM-1020, besonprodil, eliprodil, rislenemdaz (CERC-301 / MK- 0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, traxoprodil (CP-101,606), BMT-108908, onfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1-aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4- chlorokynurenine, 5,7-dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof.

88. The method of any one of claims 56 to 87, wherein the RAAD comprises a N-methyl-D-aspartate (NMD A) receptor modulator.

89. The method of claim 88, wherein the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixture thereof.

90. The method of claim 89, wherein the ketamine is ketamine HC1.

91. The method of any one of claims 56 to 90, wherein the mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), umirolimus (Biolimus), KU- 0063794, PI-103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI-103 - CAS 371935-74-9), torkinib (PP242), tacrolimus (FK-506, fujimycin,), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), gedatolisib (PF- 05212384, PKI-587), AZD- 2014 (Vistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839,AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), palomid-529 (P529, SG 00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC- 0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI- 31, PQR620, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC 223), clemastine (HS-592) fumarate, nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, astragaloside IV, samotolisib (LY3023414), chrysophanic acid, zotarolimus (ABT-578), and any salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, and geometric isomer thereof, and any mixtures thereof.

92. The method of any one of claims 56 to 91, wherein the mTOR inhibitor comprises rapamycin (sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779).

93. The method of any one of claims 56 to 92, wherein the therapeutically effective amount of the RAAD is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route.

94. The method of any one of claims 56 to 93, wherein the therapeutically effective amount of the RAAD is administered through an intravenous route.

95. The method of any one of claims 56 to 94, wherein the therapeutically effective amount of the RAAD is administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, seven times per week, once per two weeks, once per three weeks, once per four weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten times per month.

96. The method of any one of claims 56 to 94, wherein the therapeutically effective amount of the RAAD is administered once per day, once per two days, once per three days, once per four days, once per five days, once per ten days or once per fifteen days.

97. The method of any one of claims 56 to 96, wherein the mTOR inhibitor is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route.

98. The method of any one of claims 56 to 97, wherein the mTOR inhibitor is administered through an intravenous route.

99. The method of any one of claims 56 to 98, wherein the mTOR inhibitor is administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, seven times per week, once per two weeks, once per three weeks, once per four weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten times per month.

100. The method of any one of claims 56 to 98, wherein the mTOR inhibitor is administered once per day, once per two days, once per three days, once per four days, once per five days, once per ten days or once per fifteen days.

101. The method of any one of claims 56 to 100, wherein the disease, disorder, or condition is selected from the group consisting of a major depressive disorder (MDD), a major depressive episode in bipolar disorder (bipolar depression), a persistent depressive disorder (dysthymia), a disruptive mood dysregulation disorder, a major depressive disorder (including major depressive episode), a premenstrual dysphoric disorder, a substance / medication-induced depressive disorder, a depressive disorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, a posttraumatic stress disorder, an addictive disorder, bipolar I disorder, bipolar II disorder, generalized anxiety disorder, social anxiety disorder (social phobia), specific phobia, panic disorder, agoraphobia, separation anxiety disorder, selective mutism, substance-induced anxiety disorder, medication-induced anxiety disorder, anxiety disorder due to another medical condition, borderline personality disorder, treatment-resistant depression, unspecified anxiety disorder, chronic pain, and any combinations thereof.

102. The method of any one of claims 56 to 101, wherein the disease, disorder, or condition is a mood disorder, optionally a depressive disorder.

103. The method of any one of claims 56 to 101, wherein the disease, disorder, or condition is a treatment-resistant depression (TRD).

104. The method of any one of claims 56 to 103, wherein the RAAD and the mTOR inhibitor are formulated into a pharmaceutical composition prior to administering to the human subject.

105. The method of claim 104, wherein the pharmaceutical composition is administered to the human subject through multiple doses.

106. The method of claim 105, wherein the multiple doses comprise one or more acute doses and one or more maintenance doses administered after the one or more acute doses.

107. The method of any one of claims 104 to 106, wherein the pharmaceutical composition is formulated as a solution.

108. The method of claim 107, wherein the solution comprises dehydrated ethanol, DL-alpha- tocopherol, propylene glycol, anhydrous citric acid, polysorbate 80, or PEG 400.

109. The method of claim 108, wherein the solution further comprises about 0.9% (w / v) sodium chloride in water.

110. A dosing regimen for administering to a human subject a pharmaceutical composition comprising (a) a therapeutically effective amount of a rapid-acting antidepressant (RAAD) and (b) a therapeutically effective amount of a mechanistic target of rapamycin (mTOR) inhibitor, wherein the dosing regimen comprises:(i) administering to the human subject one or more acute doses; and(ii) administering to the human subject one or more maintenance doses after the administration of the one or more acute doses.

111. The dosing regimen of claim 110, wherein the human subject is administered the one or more acute doses once per day, once per two days, once per three days, once per four days, once per five days, once per ten days, once per fifteen days, once per week, twice per week, three times per week, four timesper week, five times per week, six times per week, seven times per week, once per two weeks, once per three weeks, once per four weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten times per month.

112. The dosing regimen of claim 110 or 111, wherein the human subject is administered the one or more acute doses once per two weeks.

113. The dosing regimen of any one of claims 110 to 112, wherein the human subject is administered the one or more acute doses for one week, for two weeks, for three weeks, for four weeks, for a month, for two months or for three months.

114. The dosing regimen of any one of claims 110 to 113, wherein the human subject is administered the one or more acute doses for four weeks.

115. The dosing regimen of any one of claims 110 to 114, wherein the human subject is administered the one or more maintenance doses once per day, once per two days, once per three days, once per four days, once per five days, once per ten days, once per fifteen days, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, seven times per week, once per two weeks, once per three weeks, once per four weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten times per month.

116. The dosing regimen of any one of claims 110 to 115, wherein the human subject is administered the one or more maintenance doses for one week, for two weeks, for three weeks, for four weeks, for five weeks, for eight weeks, for a month, for two months, for three months or for five months.

117. The dosing regimen of any one of claims 110 to 116, wherein the human subject is administered the one or more maintenance doses for two months.

118. The dosing regimen of any one of claims 110 to 117, wherein the human subject is administered the one or more maintenance doses periodically as clinically needed.

119. The dosing regimen of any one of claims 110 to 118, wherein the therapeutically effective amount of the RAAD is at a dose of (i) about 0.01 mg / kg to about 100 mg / kg, (ii) about 0.8 mg to about 8 g, or (iii) about 1.2 mg to about 12 g.

120. The dosing regimen of any one of claims 110 to 119, wherein the therapeutically effective amount of the RAAD is at a dose of (i) about 0.1 mg / kg to about 10 mg / kg, (ii) about 8 mg to about 800 mg, or (iii) about 12 mg to about 1200 mg.

121. The dosing regimen of any one of claims 110 to 120, wherein the therapeutically effective amount of the RAAD is at a dose of (i) about 0.5 mg / kg to about 2 mg / kg, (ii) about 4 mg to about 160 mg, or (iii) about 6 mg to about 240 mg.

122. The dosing regimen of any one of claims 110 to 121, wherein the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 1 pg / kg to about 100 pg / kg, (ii) about 0.08 mg to about 8 mg, or (iii) about 0.12 mg to about 12 mg.

123. The dosing regimen of any one of claims 110 to 122, wherein the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 1 pg / kg to about 70 pg / kg, (ii) about 0.08 mg to about 5.6 mg, or (iii) about 0. 12 mg to about 8.4 mg.

124. The dosing regimen of any one of claims 110 to 123, wherein the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 3.125 pg / kg, about 9.375 pg / kg, about 24.2 pg / kg, or about 62.5 pg / kg, (ii) about 0.25 mg, about 0.75 mg, about 1.93 mg, or about 5 mg, or (iii) about 0.375 mg, about 1.125 mg, about 2.9 mg, or about 7.5 mg.

125. The dosing regimen of any one of claims 110 to 124, wherein the RAAD is selected from the group consisting of ketamine, (7? -ketamine, (S)-ketamine, R, S-ketamine, S-Norketamine, R- Norketamine, 2R, 6 / ?-hydroxynorkctaminc. 2S, 6.S'-hydroxynorkctaminc. nitrous oxide, memantine, amantadine, racemic dextromethorphan, a fixed dose combination of dextromethorphan and quinidine, dextromethorphan, a fixed dose combination of dextromethophane and bupropion, dextromethadone (d- methadone), D-CCPene, UBP141, UBP145, HA966 ((±)-3-amino-l-hydroxy-pyrrolidin-2-one), NVPAAM077, Ro-25-26981, TCN 201, QNZ46, Neu2000, GM-1020, besonprodil, eliprodil, rislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, traxoprodil (CP- 101,606), BMT- 108908, onfasprodil, radiprodil, NP 10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1-aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7-dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN- 201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof.

126. The dosing regimen of any one of claims 110 to 125, wherein the RAAD comprises a N-m ethyl - D-aspartate (NMD A) receptor modulator.

127. The dosing regimen of claim 126, wherein the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixture thereof.

128. The dosing regimen of claim 127, wherein the ketamine is ketamine HC1.

129. The dosing regimen of any one of claims 110 to 128, wherein the mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), umirolimus (Biolimus), KU- 0063794, PI-103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI-103 - CAS 371935-74-9), torkinib (PP242), tacrolimus (FK-506, fujimycin,), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128(MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), gedatolisib (PF- 05212384, PKI-587), AZD- 2014 (Vistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), palomid-529 (P529, SG 00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC- 0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI- 31, PQR620, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC 223), clemastine (HS-592) fumarate, nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, astragaloside IV, samotolisib (LY3023414), chrysophanic acid, zotarolimus (ABT-578), and any salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, and geometric isomer thereof, and any mixtures thereof.

130. The dosing regimen of any one of claims 110 to 129, wherein the mTOR inhibitor comprises rapamycin (sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779).

131. The dosing regimen of any one of claims 110 to 130, wherein the pharmaceutical composition is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route.

132. The dosing regimen of any one of claims 110 to 131, wherein the pharmaceutical composition is administered through an intravenous route.

133. The dosing regimen of any one of claims 110 to 132, wherein the pharmaceutical composition is formulated as a solution.

134. The dosing regimen of claim 133, wherein the solution comprises dehydrated ethanol, DL-alpha- tocopherol, propylene glycol, anhydrous citric acid, polysorbate 80, or PEG 400.

135. The dosing regimen of claim 134, wherein the solution further comprises about 0.9% (w / v) sodium chloride in water.

136. A method of treating or preventing a disease, disorder, or condition in a human subject in need thereof comprising administering to the human subject multiple doses of a pharmaceutical composition comprising:(a) a therapeutically effective amount of a rapid-acting antidepressant (RAAD) and(b) a therapeutically effective amount of a mechanistic target of rapamycin (mTOR) inhibitor, wherein the multiple doses comprise (i) one or more acute doses; and (ii) one or more maintenance doses after the one or more acute doses.

137. The method of claim 136, wherein the human subject is administered the one or more acute doses once per day, once per two days, once per three days, once per four days, once per five days, once per ten days, once per fifteen days, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, seven times per week, once per two weeks, once per three weeks, once per four weeks, once per month, twice per month, three times per month, four times permonth, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten times per month.

138. The method of claim 136 or 137, wherein the human subject is administered the one or more acute doses once per two weeks.

139. The method of any one of claims 136 to 138, wherein the human subject is administered the one or more acute doses for one week, for two weeks, for three weeks, for four weeks, for a month, for two months or for three months.

140. The method of any one of claims 136 to 139, wherein the human subject is administered the one or more acute doses for four weeks.

141. The method of any one of claims 136 to 140, wherein the human subject is administered the one or more maintenance doses once per day, once per two days, once per three days, once per four days, once per five days, once per ten days, once per fifteen days, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, seven times per week, once per two weeks, once per three weeks, once per four weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten times per month.

142. The method of any one of claims 136 to 141, wherein the human subject is administered the one or more maintenance doses for one week, for two weeks, for three weeks, for four weeks, for five weeks, for eight weeks, for a month, for two months, for three months, or for five months.

143. The method of any one of claims 136 to 142, wherein the human subject is administered the one or more maintenance doses for two months.

144. The method of any one of claims 136 to 143, wherein the human subject is administered the one or more maintenance doses periodically as clinically needed.

145. The method of any one of claims 136 to 144, wherein the therapeutically effective amount of the RAAD is at a dose of (i) about 0.01 mg / kg to about 100 mg / kg, (ii) about 0.8 mg to about 8 g, or (iii) about 1.2 mg to about 12 g.

146. The method of any one of claims 136 to 145, wherein the therapeutically effective amount of the RAAD is at a dose of (i) about 0. 1 mg / kg to about 10 mg / kg, (ii) about 8 mg to about 800 mg, or (iii) about 12 mg to about 1200 mg.

147. The method of any one of claims 136 to 146, wherein the therapeutically effective amount of the RAAD is at a dose of (i) about 0.5 mg / kg to about 2 mg / kg, (ii) about 4 mg to about 160 mg, or (iii) about 6 mg to about 240 mg.

148. The method of any one of claims 136 to 147, the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 1 pg / kg to about 100 pg / kg, (ii) about 0.08 mg to about 8 mg, or (iii) about 0.12 mg to about 12 mg.

149. The method of any one of claims 136 to 148, wherein the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 1 pg / kg to about 70 pg / kg, (ii) about 0.08 mg to about 5.6 mg, or (iii) about 0.12 mg to about 8.4 mg.

150. The method of any one of claims 136 to 149, wherein the therapeutically effective amount of the mTOR inhibitor is at a dose of (i) about 3.125 pg / kg, about 9.375 pg / kg, about 24.2 pg / kg, or about 62.5 pg / kg, (ii) about 0.25 mg, about 0.75 mg, about 1.93 mg, or about 5 mg, or (iii) about 0.375 mg, about 1.125 mg, about 2.9 mg, or about 7.5 mg.

151. The method of any one of claims 136 to 150, wherein the human subject is administered an antidepressant before, during, or after administration of the pharmaceutical composition.

152. The method of claim 151, wherein the human subject has an inadequate response to the antidepressant.

153. The method of any one of claims 150 to 152, wherein the human subject has an inadequate response to two or more antidepressant treatments.

154. The method of claim 153, wherein the two or more antidepressant treatments includes the administration of the antidepressant.

155. The method of claim 153, wherein the two or more antidepressant treatments does not include the administration of the antidepressant.

156. The method of any one of claims 151 to 155, wherein the human subject is administered the antidepressant before the administration of the RAAD or the administration of the mTOR inhibitor.

157. The method of any one of claims 151 to 155, wherein the human subject is administered the antidepressant during the administration of the RAAD or the administration of the mTOR inhibitor.

158. The method of any one of claims 151 to 155, wherein the human subject is administered the antidepressant after the administration of the RAAD or the administration of the mTOR inhibitor.

159. The method of any one of claims 151 to 158, wherein the antidepressant is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route.

160. The method of any one of claims 151 to 159, wherein the antidepressant is administered through the oral route.

161. The method of any one of claims 151 to 160, wherein the antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRs), serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs), serotonin modulators and stimulators (SMSs), serotonin antagonist and reuptake inhibitors (SARIs), norepinephrine reuptake inhibitors (NRIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), monoamine oxidase inhibitors (MAOIs), norepinephrine and dopamine reuptake inhibitors (NDRIs), atypical antipsychotics, typical antipsychotics, and allowable antidepressants used as sleep medications.

162. The method of claim 161, wherein the SSRIs comprise fluoxetine, fluvoxamine, citalopram, sertraline, paroxetine, or escitalopram.

163. The method of claim 161, wherein the SNRIs comprise duloxetine, levomilnacipran, milnacipran, venlafaxine, or desvenlafaxine.

164. The method of claim 161, wherein the SNDRIs comprise toludesvenlafaxine or nefazodone.

165. The method of claim 161, wherein the SMSs comprise vilazodone or vortioxetine.

166. The method of claim 161, wherein the SARIs comprise nefazodone or trazodone.

167. The method of claim 161, wherein the NRIs comprise reboxetine, teniloxazine, 5-HT2A receptor antagonist, atomoxetine, viloxazine, 5-HT2B receptor antagonist, or 5-HT2C receptor agonist.

168. The method of claim 161, wherein the NDRIs comprise bupropion, amphetamines, methylphenidate, modafinil, or non-competitive antagonist of nicotinic acetylcholine receptors.

169. The method of claim 161, wherein the TACs comprise amitriptyline, amitriptylinoxide, clomipramine, desipramine, dibenzepin, dimetacrine, dosulepin, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, nortriptyline, noxiptiline, pipofezine, protriptyline, trimipramine, opipramol, or tianeptine.

170. The method of claim 161, wherein the TeCAs comprise amoxapine, maprotiline, mianserin, mirtazapine, setiptiline, mianserin, mirtazapine, or setiptiline.

171. The method of claim 161, wherein the MAOIs comprise isocarboxazid, phenelzine, tranylcypromine, selegiline, metralindole, moclobemide, pirlindole, or bifemelane.

172. The method of claim 161, wherein the atypical antipsychotics comprise amisulpride, lumateperone, lurasidone, aripiprazole, brexpiprazole, quetiapine, risperidone, or olanzapine.

173. The method of claim 161, wherein the typical antipsychotics comprise trifluoperazine, buspirone, lithium, or thyroxine.

174. The method of claim 161, wherein the allowable antidepressants used as sleep medications comprise trazodone or mirtazapine.

175. The method of any one of claims 136 to 174, wherein the RAAD is selected from the group consisting of ketamine, (R)-ketamine, (S)-ketamine, R, S-ketamine, S-Norketamine, R-Norketamine,2R, 6 / ?-hydroxynorkctaminc. 2.S'.6.S'-hydroxynorkctaminc. nitrous oxide, memantine, amantadine, racemic dextromethorphan, a fixed dose combination of dextromethorphan and quinidine, dextromethorphan, a fixed dose combination of dextromethophane and bupropion, dextromethadone (d-methadone), D- CCPene, UBP141, UBP145, HA966 ((±)-3-amino-l-hydroxy-pyrrolidin-2-one), NVPAAM077, Ro-25- 26981, TCN 201, QNZ46, Neu2000, GM-1020, besonprodil, eliprodil, rislenemdaz (CERC-301 / MK- 0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, traxoprodil (CP-101,606), BMT-108908, onfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1-aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4- chlorokynurenine, 5,7-dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966,felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof.

176. The method of any one of claims 136 to 175, wherein the RAAD comprises a N-methyl-D- aspartate (NMD A) receptor modulator.

177. The method of claim 176, wherein the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixture thereof.

178. The method of claim 177, wherein the ketamine is ketamine HC1.

179. The method of any one of claims 136 to 178, wherein the mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), umirolimus (Biolimus), KU- 0063794, PI-103 (mTOR Inhibitor V, PI 3-K Inhibitor y, PI-103 - CAS 371935-74-9), torkinib (PP242), tacrolimus (FK-506, fujimycin,), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), gedatolisib (PF- 05212384, PKI-587), AZD- 2014 (Vistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), palomid-529 (P529, SG 00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC- 0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI- 31, PQR620, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC 223), clemastine (HS-592) fumarate, nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, astragaloside IV, samotolisib (LY3023414), chrysophanic acid, zotarolimus (ABT-578), and any salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, and geometric isomer thereof, and any mixtures thereof.

180. The method of any one of claims 136 to 179, wherein the mTOR inhibitor comprises rapamycin (sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779).

181. The method of any one of claims 136 to 180, wherein the pharmaceutical composition is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route.

182. The method of any one of claims 136 to 181, wherein the pharmaceutical composition is administered through an intravenous route.

183. The method of any one of claims 136 to 182, wherein the pharmaceutical composition is formulated as a solution.

184. The method of claim 183, wherein the solution comprises dehydrated ethanol, DL-alpha- tocopherol, propylene glycol, anhydrous citric acid, polysorbate 80, or PEG 400.

185. The method of claim 184, wherein the solution further comprises about 0.9% (w / v) sodium chloride in water.

186. The method of any one of claims 136 to 185, wherein the disease, disorder, or condition is selected from the group consisting of a major depressive disorder (MDD), a major depressive episode in bipolar disorder (bipolar depression), a persistent depressive disorder (dysthymia), a disruptive mood dysregulation disorder, a major depressive disorder (including major depressive episode), a premenstrual dysphoric disorder, a substance / medication-induced depressive disorder, a depressive disorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, a posttraumatic stress disorder, an addictive disorder, bipolar I disorder, bipolar II disorder, generalized anxiety disorder, social anxiety disorder (social phobia), specific phobia, panic disorder, agoraphobia, separation anxiety disorder, selective mutism, substance-induced anxiety disorder, medication-induced anxiety disorder, anxiety disorder due to another medical condition, borderline personality disorder, treatment-resistant depression, unspecified anxiety disorder, chronic pain, and any combinations thereof.

187. The method of any one of claims 136 to 186, wherein the disease, disorder, or condition is a mood disorder, optionally a depressive disorder.

188. The method of any one of claims 136 to 186, wherein the disease, disorder, or condition is a treatment-resistant depression (TRD).

189. The method of claim 53, 107 or 183, wherein the solution comprises the RAAD at a concentration of about 0.05 mg / ml to about 1 mg / ml.

190. The method of claim 189, wherein the solution comprises the RAAD at a concentration of about 0.1 mg / ml to about 1 mg / ml.

191. The method of claim 190, wherein the solution comprises the RAAD at a concentration of about 0.2 to about 0.5 mg / ml.

192. The method of claim 191, wherein the solution comprises the RAAD at a concentration of about 0.2425 mg / ml.

193. The method of any one of claims 53, 107 183, and 189-192, wherein the solution comprises the mTOR inhibitor at a concentration of about 1 to about 50 pg / ml.

194. The method of any one of claims 53, 107 183, and 189-193, wherein the solution comprises the mTOR inhibitor at a concentration of about 1.5 pg / ml, about 4.5 pg / ml, about 11.6 pg / ml or about 30 pg / ml.

195. The method of any one of claims 54, 108 and 184, wherein the solution comprises dehydrated ethanol at a concentration of about 2.8 mg / ml to about 3.2 mg / ml.

196. The method of claim 195, wherein the solution comprises dehydrated ethanol at a concentration of about 3.00785 mg / ml or about 3.01222 mg / ml.

197. The method of any one of claims 54, 108, 184 and 195, wherein the solution comprises polysorbate 80 at a concentration of about 0.8 mg / ml to about 1.2 mg / ml.

198. The method of claim 197, wherein the solution comprises polysorbate 80 at a concentration of about 1.0608 mg / ml.

199. The method of any one of claims 54, 108, 184 and 195-196, wherein the solution comprises PEG 400 at a concentration of about 0.5 mg / ml to about 0.6 mg / ml.

200. The method of claim 199, wherein the solution comprises PEG 400 at a concentration of about 0.54479 mg / ml.

201. The method of any one of claims 54, 108, 184 and 195-197, wherein the solution comprises DL- a tocopherol at a concentration of about 2 to about 3 pg / ml.

202. The method of claim 201, wherein the solution comprises DL-a tocopherol at a concentration of about 2.44 pg / ml or about 2.448 pg / ml.

203. The method of any one of claims 54, 108, 184 and 195-198, wherein the solution comprises citric acid at a concentration of about 0.08 pg / ml to about 0.09 pg / ml.

204. The method of claim 203, wherein the solution comprises citric acid at a concentration of about 0.0882 pg / ml or about 0.0885 pg / ml.

205. The method of any one of claims 54, 108, 184 and 195-199, wherein the solution comprises propylene glycol at a concentration of about 1 mg / ml to about 2 mg / ml.

206. The method of claim 205, wherein the solution comprises propylene glycol at a concentration of about 1.6454 mg / ml or about 1.6509 mg / ml.

207. The method of any one of claims 53-55, 107-109, 183-185 and 189-206, wherein the solution is in an IV bag.

208. The method of claim 207, wherein the IV bag has one or more closed system transfer device (CSTD) ports.

209. The method of claim 208, wherein the IV bag has two CSTD ports.

210. The method of claim 208 or 209, wherein the CSTD ports can allow passage of the solution without leak or aerosolization.

211. A solution comprising : i. ketamine hydrochloride, wherein a concentration of an equivalent ketamine free base is about 0.2425 mg / ml, and ii. temsirolimus, wherein a concentration of the temsirolimus is about 1.5 pg / ml, about 4.5 pg / ml, about 11.6 pg / ml or about 30 pg / ml.

212. The solution of claim 211, wherein the solution further comprises dehydrated ethanol at a concentration of about 2.8 mg / ml to about 3.2 mg / ml.

213. The solution of claim 212, wherein the solution comprises the dehydrated ethanol at a concentration of about 3.00785 mg / ml or about 3.01222 mg / ml.

214. The solution of any one of claims 211-213, wherein the solution comprises polysorbate 80 at a concentration of about 0.8 mg / ml to about 1.2 mg / ml.

215. The solution of claim 214, wherein the solution comprises the polysorbate 80 at a concentration of about 1.0608 mg / ml.

216. The solution of any one of claims 211-215, wherein the solution comprises PEG 400 at a concentration of about 0.5 mg / ml to about 0.6 mg / ml.

217. The solution of claim 216, wherein the solution comprises the PEG 400 at a concentration of about 0.54479 mg / ml.

218. The solution of any one of claims 211-217, wherein the solution comprises DL-a tocopherol at a concentration of about 2 to about 3 pg / ml.

219. The solution of claim 218, wherein the solution comprises the DL-a tocopherol at a concentration of about 2.44 pg / ml or about 2.448 pg / ml.

220. The solution of any one of claims 211-219, wherein the solution comprises citric acid at a concentration of about 0.08 pg / ml to about 0.09 pg / ml.

221. The solution of claim 220, wherein the solution comprises the citric acid at a concentration of about 0.0882 pg / ml or about 0.0885 pg / ml.

222. The solution of any one of claims 211-221, wherein the solution comprises propylene glycol at a concentration of about 1 mg / ml to about 2 mg / ml.

223. The solution of claim 222, wherein the solution comprises the propylene glycol at a concentration of about 1.6454 mg / ml or about 1.6509 mg / ml.

224. The solution of any one of claims 211-223, wherein the solution is in an IV bag.

225. The solution of claim 224, wherein the IV bag has one or more closed system transfer device (CSTD) ports.

226. The solution of claim 225, wherein the IV bag has two CSTD ports.

227. The solution of claim 225 or 226, wherein the CSTD ports can allow passage of the solution without leak or aerosolization.

228. A system for administering a drug solution to a patient in need thereof, wherein the system comprises a primary IV bag containing a saline solution and a secondaryIV bag containing the drug solution, and wherein the drug solution comprises a rapid-acting antidepressant (RAAD) and a mechanistic target of rapamycin (mTOR) inhibitor.

229. The system of claim 228, wherein the secondary IV bag comprises a CSTD port.

230. The system of claim 228 or 229, wherein the system further comprises a primary tubing that connects to the primary IV bag.

231. The system of any one of claims 228-230, wherein the system further comprises a secondary tubing that connects to the secondary IV bag.

232. The system of claim 231, wherein the secondary tubing is connected to the primary tubing through a Y-site port.

233. The system of any one of claims 228-232, wherein the system further comprises a pump.

234. The system of any one of claims 228-233, wherein the system further comprises a roller clamp on the secondary tubing.

235. The system of any one of claims 228 to 234, wherein the drug solution comprises the RAAD at a concentration of about 0.05 mg / ml to about 1 mg / ml.

236. The system of claim 235, wherein the drug solution comprises the RAAD at a concentration of about 0.1 mg / ml to about 1 mg / ml.

237. The system of claim 236, wherein the drug solution comprises the RAAD at a concentration of about 0.2 to about 0.5 mg / ml.

238. The system of claim 237, wherein the drug solution comprises the RAAD at a concentration of about 0.2425 mg / ml.

239. The system of any one of claims 228 to 238, wherein the drug solution comprises the mTOR inhibitor at a concentration of about 1 to about 50 pg / ml.

240. The system of claim 239, wherein the drug solution comprises the mTOR inhibitor at a concentration of about 1.5 pg / ml, about 4.5 pg / ml, about 11.6 pg / ml or about 30 pg / ml.

241. The system of any one of claims 228 to 240, wherein the drug solution comprises dehydrated ethanol at a concentration of about 2.8 mg / ml to about 3.2 mg / ml.

242. The system of claim 241, wherein the drug solution comprises dehydrated ethanol at a concentration of about 3.00785 mg / ml or about 3.01222 mg / ml.

243. The system of any one of claims 228 to 242, wherein the drug solution comprises polysorbate 80 at a concentration of about 0.8 mg / ml to about 1.2 mg / ml.

244. The system of claim 243, wherein the drug solution comprises polysorbate 80 at a concentration of about 1.0608 mg / ml.

245. The system of any one of claims 228 to 244, wherein the drug solution comprises PEG 400 at a concentration of about 0.5 mg / ml to about 0.6 mg / ml.

246. The system of claim 245, wherein the drug solution comprises PEG 400 at a concentration of about 0.54479 mg / ml.

247. The system of any one of claims 228 to 246, wherein the drug solution comprises DL-a tocopherol at a concentration of about 2 to about 3 pg / ml.

248. The system of claim 247, wherein the drug solution comprises DL-a tocopherol at a concentration of about 2.44 pg / ml or about 2.448 pg / ml.

249. The system of any one of claims 228 to 248, wherein the drug solution comprises citric acid at a concentration of about 0.08 pg / ml to about 0.09 pg / ml.

250. The system of claim 249, wherein the drug solution comprises citric acid at a concentration of about 0.0882 pg / ml or about 0.0885 pg / ml.

251. The system of any one of claims 228 to 250, wherein the drug solution comprises propylene glycol at a concentration of about 1 mg / ml to about 2 mg / ml.

252. The system of claim 251, wherein the drug solution comprises propylene glycol at a concentration of about 1.6454 mg / ml or about 1.6509 mg / ml.

253. The system of any one of claim 228 to 252, wherein the RAAD is selected from the group consisting of ketamine, (R)-ketamine, (S)-ketamine, R, S-ketamine, S-Norketamine, / / -Norkctaminc.2R, 6 / ?-hydroxynorkctaminc. 2S, 6.S'-hydroxynorkctaminc. nitrous oxide, memantine, amantadine, racemic dextromethorphan, a fixed dose combination of dextromethorphan and quinidine, dextromethorphan, a fixed dose combination of dextromethophane and bupropion, dextromethadone (d-methadone), D- CCPene, UBP141, UBP145, HA966 ((±)-3-amino-l-hydroxy-pyrrolidin-2-one), NVPAAM077, Ro-25- 26981, TCN 201, QNZ46, Neu2000, GM-1020, besonprodil, eliprodil, rislenemdaz (CERC-301 / MK- 0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, traxoprodil (CP-101,606), BMT-108908, onfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1-aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4- chlorokynurenine, 5,7-dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof.

254. The system of any one of claims 228-253, wherein the RAAD comprises a N-methyl-D-aspartate (NMD A) receptor modulator.

255. The system of claim 254, wherein the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixture thereof.

256. The system of claim 255, wherein the ketamine is ketamine HC1.

257. The system of any one of claims 228-256, wherein the mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), umirolimus (Biolimus), KU- 0063794, PI-103 (mTOR Inhibitor V, PI 3-K Inhibitor y, PI-103 - CAS 371935-74-9), torkinib (PP242), tacrolimus (FK-506, fujimycin,), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), gedatolisib (PF- 05212384, PKI-587), AZD- 2014 (Vistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), palomid-529 (P529, SG 00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC- 0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI- 31, PQR620, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084),CC-115, onatasertib (CC 223), clemastine (HS-592) fumarate, nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, astragaloside IV, samotolisib (LY3023414), chrysophanic acid, zotarolimus (ABT-578), and any salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, and geometric isomer thereof, and any mixtures thereof.

258. The system of claim 257, wherein the mTOR inhibitor comprises rapamycin (sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779).

259. A method for administration of a drug solution to a patient in need thereof, comprising:(a) connecting a primary IV bag to a pump through a primary tubing, wherein the primary IV bag contains a saline solution,(b) closing a roller clamp on a secondary tubing,(c) connecting a secondary IV bag to a Y -site port on the primary tubing through a secondary tubing, wherein the secondary IV bag contains the drug solution, wherein the drug solution comprises a rapid-acting antidepressant (RAAD) and a mechanistic target of rapamycin (mTOR) inhibitor,(d) hanging the secondary IV bag below the primary IV bag,(e) opening the roller clamp on the secondary tubing,(f) allowing the saline solution in the primary IV bag to fdl the secondary tubing and remove air in the secondary tubing,(g) closing the roller clamp on the secondary tubing, and(h) hanging the secondary IV bag above the primary IV bag, opening the roller clamp on the secondary tubing, and administering the drug solution in the secondary IV bag to the patient.

260. The method of claim 259, wherein the secondary IV bag comprises a CSTD port and wherein the secondary tubing is connected to the secondary IV bag through the CSTD port.

261. The method of claim 259, wherein the primary tubing comprises a check valve.

262. The method of any one of claims 259 to 261, wherein the drug solution comprises the RAAD at a concentration of about 0.05 mg / ml to about 1 mg / ml.

263. The method of claim 262, wherein the drug solution comprises the RAAD at a concentration of about 0.1 mg / ml to about 1 mg / ml.

264. The method of claim 263, wherein the drug solution comprises the RAAD at a concentration of about 0.2 to about 0.5 mg / ml.

265. The method of claim 264, wherein the drug solution comprises the RAAD at a concentration of about 0.2425 mg / ml.

266. The method of any one of claims 259 to 265, wherein the drug solution comprises the mTOR inhibitor at a concentration of about 1 to about 50 pg / ml.

267. The method of claim 266, wherein the drug solution comprises the mTOR inhibitor at a concentration of about 1.5 pg / ml, about 4.5 pg / ml, about 11.6 pg / ml or about 30 pg / ml.

268. The method of any one of claims 259 to 267, wherein the drug solution comprises dehydrated ethanol at a concentration of about 2.8 mg / ml to about 3.2 mg / ml.

269. The method of claim 268, wherein the drug solution comprises dehydrated ethanol at a concentration of about 3.00785 mg / ml or about 3.01222 mg / ml.

270. The method of any one of claims 259 to 269, wherein the drug solution comprises polysorbate 80 at a concentration of about 0.8 mg / ml to about 1.2 mg / ml.

271. The method of claim 270, wherein the drug solution comprises polysorbate 80 at a concentration of about 1.0608 mg / ml.

272. The method of any one of claims 259 to 271, wherein the drug solution comprises PEG 400 at a concentration of about 0.5 mg / ml to about 0.6 mg / ml.

273. The method of claim 272, wherein the drug solution comprises PEG 400 at a concentration of about 0.54479 mg / ml.

274. The method of any one of claims 259 to 273, wherein the drug solution comprises DL-a tocopherol at a concentration of about 2 to about 3 pg / ml.

275. The method of claim 274, wherein the drug solution comprises DL-a tocopherol at a concentration of about 2.44 pg / ml or about 2.448 pg / ml.

276. The method of any one of claims 259 to 275, wherein the drug solution comprises citric acid at a concentration of about 0.08 pg / ml to about 0.09 pg / ml.

277. The method of claim 276, wherein the drug solution comprises citric acid at a concentration of about 0.0882 pg / ml or about 0.0885 pg / ml.

278. The method of any one of claims 259 to 277, wherein the drug solution comprises propylene glycol at a concentration of about 1 mg / ml to about 2 mg / ml.

279. The method of claim 278, wherein the drug solution comprises propylene glycol at a concentration of about 1.6454 mg / ml or about 1.6509 mg / ml.

280. The method of any one of claim 259 to 279, wherein the RAAD is selected from the group consisting of ketamine, (R)-ketamine, (S)-ketamine, R, S-ketamine, S-Norketamine, R-Norketamine,2R, 6 / ?-hydroxynorkctaminc. 2.S'. 6.S'-hydroxynorkctaminc. nitrous oxide, memantine, amantadine, racemic dextromethorphan, a fixed dose combination of dextromethorphan and quinidine, dextromethorphan, a fixed dose combination of dextromethophane and bupropion, dextromethadone (d-methadone), D- CCPene, UBP141, UBP145, HA966 ((±)-3-amino-l-hydroxy-pyrrolidin-2-one), NVPAAM077, Ro-25- 26981, TCN 201, QNZ46, Neu2000, GM-1020, besonprodil, eliprodil, rislenemdaz (CERC-301 / MK- 0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, traxoprodil (CP-101,606), BMT-108908, onfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1-aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4- chlorokynurenine, 5,7-dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon,methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof.

281. The method of any one of claims 259-280, wherein the RAAD comprises a N-methyl-D- aspartate (NMD A) receptor modulator.

282. The method of claim 281, wherein the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixture thereof.

283. The method of claim 282, wherein the ketamine is ketamine HC1.

284. The method of any one of claims 259-283, wherein the mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), umirolimus (Biolimus), KU- 0063794, PI-103 (mTOR Inhibitor V, PI 3-K Inhibitor y, PI-103 - CAS 371935-74-9), torkinib (PP242), tacrolimus (FK-506, fujimycin,), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), gedatolisib (PF- 05212384, PKI-587), AZD- 2014 (Vistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), palomid-529 (P529, SG 00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC- 0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI- 31, PQR620, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC 223), clemastine (HS-592) fumarate, nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, astragaloside IV, samotolisib (LY3023414), chrysophanic acid, zotarolimus (ABT-578), and any salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, and geometric isomer thereof, and any mixtures thereof.

285. The method of claim 284, wherein the mTOR inhibitor comprises rapamycin (sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779).

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