A system, device, and method combining neuromodulation and pharmacological treatment for depression.

Abstract

A method is provided for treating depressive states and depressive-related conditions by combining the administration of pharmacological agents with neuromodulation induced by transcranial electrical stimulation.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority and benefits of U.S. Provisional Patent Application No. 63 / 381,235, filed on 27 October 2022, and U.S. Provisional Patent Application No. 63 / 515,823, filed on 26 July 2023, the contents of which are incorporated by reference in their entirety.

[0002] This specification describes systems, devices, and methods that combine neuromodulation and pharmacological treatment of depressive states by delivering transcranial electrical stimulation and administering pharmacological antidepressants to the target. [Background technology]

[0003] Depressive disorders are common in the population, and in affected individuals, they can relapse and become chronic, requiring treatment. Transcranial electrical stimulation (tES) is a form of non-invasive electrobrain stimulation that has been shown to act as a versatile tool for modulating neuronal function in healthy individuals and those in pathological conditions, including those with depressive disorders. Neuronal function can be modulated by tES to alter neuronal plasticity, to induce behavioral effects by increasing or decreasing neuronal excitability, to improve cognitive function, or to modulate network connectivity within the brain. tES utilizes low-intensity electrical stimulation of selected brain regions and has been shown to be a safe, efficient, and cost-effective means of inducing neuromodulation. Therefore, tES is proposed as a means of potentially restoring dysfunction within the nervous system and improving symptoms of various mood disorders. Pharmacological interventions for depressive disorders with the administration of antidepressants may be therapeutically effective in treating depressive states in some patients, and many drugs are well-tolerated. Many antidepressants can act to modulate neurotransmitter levels or the efficiency of neurotransmission across the brain. These antidepressant-induced modulations may improve neuronal function and enhance network connectivity deficiencies in individuals with depressive disorders. However, long-term treatment with antidepressants carries risks of adverse drug reactions, an increased risk of undesirable side effects, and difficulties in maintaining patient compliance with ongoing treatment. [Overview of the project]

[0004] Provided herein are methods combining neuromodulation with the administration of pharmacological antidepressants for the treatment of depressive states. Transcranial electrical stimulation (tES) is a safe and effective means of stimulating the brain to induce and maintain neuromodulation. Due to its non-invasive nature, low side effects, and cost-effectiveness, tES has been studied for its efficacy in the treatment of various depressive disorders. tES can be delivered to subjects through several different forms of electrical stimulation, including transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), or transcranial random noise stimulation (tRNS).

[0005] The methods disclosed herein describe administering pharmacological antidepressants to subjects in need to treat depressive states, and delivering them to subjects with tES. Existing methods of using pharmacological antidepressants to treat depressive states have several drawbacks. One of these drawbacks is achieving the desired treatment outcome in a sufficient number of subjects. In some earlier methods of treating depressive states by administering antidepressants to subjects, many individuals do not show significant improvement in depressive symptoms. In other earlier methods of treating depressive states by administering antidepressants to subjects, many patients never achieve remission of one or more depressive symptoms. In some earlier methods, the pharmacological treatment regimen must be maintained for a long period to evaluate efficacy, or the treatment regimen must be modified by changing the dosage, frequency, or type of pharmacological antidepressant. These modifications to existing methods may prolong the suffering a person endures and / or increase the risk of developing or exacerbating adverse drug reactions. In the methods described herein, combining the administration of pharmacological antidepressants to subjects with the delivery of tES to subjects mitigates many of the shortcomings of previous treatment methods, ultimately resulting in improved treatment of depression. The methods described herein can produce broader improvement in depressive symptoms than existing treatment methods. The methods described herein can produce more remissions in one or more depressive symptoms than existing treatment methods. The methods described herein can improve depressive symptoms in subjects more rapidly than previous methods and can also maintain those improvements for longer periods. This can reduce the distress burden on individuals enduring depressive episodes. This can also allow for a reduction in the therapeutically effective dose or frequency of administration of pharmacological antidepressants while still achieving the desired treatment outcome for the subject. In some of the methods described herein, certain classes of antidepressants show increased therapeutic efficacy when combined with tES.In some of the methods described herein, combining tES with the administration of specific pharmacological antidepressants surprisingly yields significantly improved results in the treatment of depressive states compared to combining tES with different pharmacological antidepressants of the same drug class. The unexpected synergistic effects of tES with specific antidepressants between and within drug classes provide improved treatment options for individuals with depressive states. Subjects with certain comorbidities to depression show significant improvement in one or more depressive symptoms with the use of the treatment methods described herein. In addition, certain comorbidities to depression show significant improvement in components of their overall symptoms with the use of the treatment methods described herein.

[0006] In one embodiment, disclosed herein is a method for treating a depressive state in a subject, comprising (a) administering a pharmacological antidepressant to the subject, and (b) delivering transcranial electrical stimulation (tES) to the subject. In some embodiments, the pharmacological antidepressant comprises one or more pharmacological antidepressants. In some embodiments, the pharmacological antidepressant is administered as part of a treatment regimen. In some embodiments, the pharmacological antidepressant is administered in a therapeutically effective dose. In some embodiments, delivery of tES to a subject includes delivery of tES before administration, delivery of tES concurrently with administration as part of a treatment regimen, delivery of tES after administration, delivery of tES concurrently with or after a change in the dosage of the administered pharmacological antidepressant, or delivery of tES after completion of the administration schedule. In some embodiments, delivery comprises one or more non-invasive brain stimulation sessions. In some embodiments, delivery in (b) includes delivery of tES via a tES device. In some embodiments, delivering tES via a tES device induces neuromodulation in the subject. In some embodiments, the method further includes evaluating the subject's response to a treatment regimen. In some embodiments, the method further includes evaluating the subject's response to one or more non-invasive brain stimulation sessions. In some embodiments, evaluating the subject's response includes determining the therapeutic efficacy. In some embodiments, the method further includes adjusting the parameters in (a) and (b) to achieve a desired therapeutic outcome.

[0007] In one embodiment, disclosed herein is a method for treating depression in a subject, comprising: (a) administering a therapeutically effective dose of a pharmacological antidepressant to the subject as part of a treatment regimen; (b) simultaneously delivering one or more non-invasive brain stimulation sessions to the subject via a transcranial electrical stimulation (tES) device to induce neuromodulation; (c) evaluating the subject's response to the treatment regimen and one or more non-invasive brain stimulation sessions to determine therapeutic efficacy; and (d) adjusting the parameters in (a) and (b) to achieve a desired therapeutic outcome.In some embodiments, pharmacological antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic antidepressants (NaSSAs), serotonin modulators and stimulators (SMSs), serotonin antagonists and reuptake inhibitors (SARIs), serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs), and norepinephrine reuptake inhibitors. This includes inhibitors (NRIs), norepinephrine-dopamine reuptake inhibitors (NDRIs), norepinephrine-dopamine releasing agents (NDRAs), serotonin-norepinephrine-dopamine releasing agents (SNDRAs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), monoamine oxidase inhibitors (MAOIs), NMDA receptor modulators, atypical antipsychotics, atypical antidepressants, benzodiazepines, or any combination thereof.In some embodiments, the SSRI includes fluoxetine, citalopram, escitalopram, paroxetine, sertraline, dapoxetine, fluvoxamine, or vortioxetine. In some embodiments, the SNRI includes desvenlafaxine, duloxetine, levomirnacipran, milnacipran, immediate-release venlafaxine (venlafaxine IR), or sustained-release venlafaxine (venlafaxine XR). In some embodiments, the NaSSA includes aptazapine, esmirtazapine, mianserin, mirtazapine, or setiptiline. In some embodiments, the SMS includes bilazodone or vortioxetine. In some embodiments, the SARI includes nefazodone or trazodone. In some embodiments, the SNDRI includes tordesvenlafaxine, OPC-64005, or anthafoxine. In some embodiments, NRI comprises atomoxetine, reboxetine, teniloxazine, or biloxazine. In some embodiments, NDRI comprises bupropion, amineptin, methylphenidate, or AXS-05. In some embodiments, NDRA comprises lisdexamfetamine, phenethylamine, tyramine, amphetamine, methamphetamine, cathinone, methcathinone, propylhexedrine, fenmetrazine, pemoline, 4-methylaminolex, or benzylpiperazine. In some embodiments, SNDRA comprises midmafetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, naphthylisopropylamine, mephedrone, methylone, α-methyltryptamine, or α-ethyltryptamine. In some embodiments, TCA includes amitriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine, lofepramine, nortriptyline, protriptyline, or trimipramine. In some embodiments, TeCA includes amoxapine, maprotiline, mianserin, mirtazapine, or setiptiline. In some embodiments, MAOI includes selegiline, tranylcypromine, phenelzine, or isocarboxazide.In some embodiments, the NMDA receptor modulator includes 4-chloroquinurenin, apimostinel, alketamine, esketamine, esmethadone, ketamine, risrenemdaz, or rapastinel. In some embodiments, the atypical antipsychotic includes brillaloxazine, caliprazine, lumateperone, lurasidone, pimavanserin, aripiprazole, brexpiprazole, olanzapine, quetiapine, ziprasidone, SEP-4199, or NRX-101. In some embodiments, the atypical antidepressant includes allopregnanolone, agomelatine, trazodone, mirtazapine, vortioxetine, bilazodone, psilocybin, DMT, zulanolone, certrexant, XEN1101, erteberel, NV-5138, TS-121, or ALKS 5461. In some embodiments, the benzodiazepine includes diazepam, alprazolam, triazolam, clonazepam, chlordiazepoxide, nitrazepam, or loprazolam. In some embodiments, the pharmacological antidepressant is administered in formulations including tablets, capsules, delayed-release capsules, or liquids. In some embodiments, the pharmacological antidepressant is administered orally, sublingually, orally, nasally, rectally, vaginally, intravenously, intramuscularly, subcutaneously, or by inhalation.In some embodiments, the therapeutically effective dose is at least about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.30 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.50 mg, 0.55 mg, 0.6 mg mg, 0.7mg, 0.8mg, 0.9mg, 1mg, 1.25mg, 1.5mg, 1.75mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg , 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 32mg, 34m g, 35mg, 36mg, 37.5mg, 38mg, 40mg, 42mg, 44mg, 46mg, 48mg, 50mg, 52mg, 54mg, 56mg, 58mg, 60mg, 6 Includes doses of pharmacological antidepressants of 5 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 600 mg.In some embodiments, the therapeutically effective dose is approximately 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.30 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.50 mg, 0.55 mg, 0.6 mg. 0.7mg, 0.8mg, 0.9mg, 1mg, 1.25mg, 1.5mg, 1.75mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 5. 5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 32mg, 34m g, 35mg, 36mg, 37.5mg, 38mg, 40mg, 42mg, 44mg, 46mg, 48mg, 50mg, 52mg, 54mg, 56mg, 58mg, 60mg This includes doses of pharmacological antidepressants of 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg, 300 mg, or less than 400 mg. In some embodiments, the treatment regimen includes a drug administration regime in which a dose of a pharmacological antidepressant is administered up to approximately every hour, every two hours, every three hours, every four hours, every five hours, every six hours, every seven hours, every eight hours, every nine hours, every ten hours, every eleven hours, every twelve hours, every thirteen hours, every fourteen hours, every fifteen hours, every sixteen hours, every seventeen hours, every eighteen hours, every nineteen hours, every twenty hours, every twenty-one hours, every twenty-one hours, every twenty-two hours, every twenty-three hours, every twenty-four hours, every twenty-eight hours, every thirty-two hours, every thirty-four hours, every twenty-one hours, every twenty-eight hours, every twenty-eight hours, every twenty-eight hours, every twenty-eight hours, every twenty-eight hours, every twenty-eight hours, every twenty-eight hours, every twenty-eight days, every twenty-eight days, every twenty-eight days, every twenty-eight days, every twenty-eight days, every twenty-eight days, every twenty-eight days, every twenty-eight days, every twenty-eight days, every twenty-eight days.In some embodiments, the treatment regimen includes a drug administration regime in which the dose of a pharmacological antidepressant is administered approximately once a month, once every three weeks, once every two weeks, once every ten days, once a week, once every six days, once every five days, once every four days, once every three days, once every two days, once daily, twice daily, three times daily, four times daily, five times daily, six times daily, seven times daily, eight times daily, nine times daily, ten times daily, eleven times daily, or twelve times daily. In some embodiments, the drug administration regime continues for a period of at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, or 2 years. In some embodiments, the treatment regime includes a multi-dose drug administration regime. In some embodiments, the tES device includes a transcranial direct current stimulation (tDCS) device, a transcranial alternating current stimulation (tACS) device, or a transcranial random noise stimulation (tRNS) device. In some embodiments, the tES device includes a transcranial direct current stimulation (tDCS) device. In some embodiments, the tES device is configured as a headset comprising a circuit including a first electrode, a second electrode, and a power supply configured to supply power to the circuit. In some embodiments, the tES device further comprises a wireless transceiver configured to wirelessly communicate with an electronic device having processing power so that transcranial brain stimulation is performed according to a schedule for performing transcranial brain stimulation, and a controller configured to control the power supply to the circuit according to a control signal of the headset. In some embodiments, the headset further comprises a memory configured to store a schedule for performing transcranial brain stimulation.In some embodiments, a processing-capable electronic device includes a non-temporary computer-readable recording medium on which a program executable on the electronic device is recorded, and the program includes a portion of program code configured, when executed on the electronic device, to store in computer memory a schedule for performing transcranial brain stimulation, generate and maintain control signals according to the schedule for performing transcranial brain stimulation, and display information on the electronic device's display according to a schedule for displaying information, the schedule for displaying information being related to the schedule for performing transcranial brain stimulation. The headset further comprises a frontal frame defined by an elongated arch, a first electrode positioned at a first end of the elongated arched frontal frame, a second electrode positioned at a second end of the elongated arched frontal frame, and a bracket fixed to the central portion of the elongated arched frontal frame, configured to support the bracket. In some embodiments, the method further includes, when using the headset to simultaneously deliver one or more non-invasive brain stimulation sessions to a subject, the elongated arched frontal frame being configured such that the first electrode is positioned on the left side of the subject's forehead and the second electrode is positioned on the right side of the subject's forehead, and the bracket being configured to extend from the elongated arched frontal frame across the subject's skull toward the subject's neck. In some embodiments, the program further includes a portion of program code configured, when executed on an electronic device, to prompt the subject to input information about the subject's state, the information about the subject's state including information about the subject's current health status. In some embodiments, the program further includes a portion of program code configured to store information about transcranial brain stimulation performed in computer memory when executed on an electronic device. In some embodiments, the program further includes a portion of program code configured to remind the subject to use the headset according to a schedule for performing transcranial brain stimulation when executed on an electronic device. In some embodiments, the program further includes a portion of program code configured to update the schedule for performing transcranial brain stimulation when executed on an electronic device. In some embodiments, the headset further comprises a first electrode and a second electrode that are pivotable so as to be able to conform to the shape of the subject's forehead. In some embodiments, the headset further comprises a first electrode and a second electrode having an adhesive layer configured such that the adhesive layer adheres to the subject's forehead.In some embodiments, the bracket has a longitudinal extension that extends from the forehead to the back of the head when the headset is used, and the bracket has a variable extension from the forehead frame. In some embodiments, the bracket further comprises a support cushion positioned at the end of the bracket opposite to where the bracket is fixed to the forehead frame, and the forehead frame is a single member molded as an elongated arch. In some embodiments, subjects are diagnosed with one or more conditions or disorders selected from the group consisting of depression, mild depression, moderate depression, severe depression, major depression, major depressive disorder, depression with anxiety-induced distress, melancholy, melancholic depression, agitation, persistent depressive disorder, type I bipolar disorder, type II bipolar disorder, bipolar disorder not otherwise specified, cyclothymic disorder, seasonal affective disorder, psychotic depression, psychotic major depression, postpartum depression, premenstrual dysphoric disorder, situational depression, sudden onset depression, atypical depression, treatment-resistant depression, catatonic depression, dysthymia, double depression, unspecified depressive disorder, depressive personality disorder, recurrent short-term depression, mild depressive disorder, alcohol-induced depression, substance-induced depression, benzodiazepine-induced depression, and mixed anxiety-depressive disorder. In some embodiments, subjects are at risk of developing a condition or disorder selected from the group consisting of depression, mild depression, moderate depression, severe depression, major depression, major depressive disorder, depression with anxiety-induced distress, melancholy, melancholic depression, agitation, persistent depressive disorder, type 1 bipolar disorder, type 2 bipolar disorder, bipolar disorder not otherwise specified, cyclothymic disorder, seasonal affective disorder, psychotic depression, psychotic major depression, postpartum depression, premenstrual dysphoric disorder, situational depression, sudden onset depression, atypical depression, treatment-resistant depression, catatonic depression, dysthymia, double depression, unspecified depressive disorder, depressive personality disorder, recurrent short-term depression, mild depressive disorder, alcohol-induced depression, substance-induced depression, benzodiazepine-induced depression, and mixed anxiety-depressive disorder.In some embodiments, subjects have achieved remission from symptoms associated with a condition or disorder selected from the group consisting of depression, mild depression, moderate depression, severe depression, major depression, major depressive disorder, depression with anxiety-induced distress, melancholy, melancholic depression, agitation, persistent depressive disorder, type I bipolar disorder, type II bipolar disorder, bipolar disorder not otherwise specified, cyclothymic disorder, seasonal affective disorder, psychotic depression, psychotic major depression, postpartum depression, premenstrual dysphoric disorder, situational depression, sudden onset depression, atypical depression, treatment-resistant depression, catatonic depression, dysthymia, double depression, unspecified depressive disorder, depressive personality disorder, recurrent short-term depression, mild depressive disorder, alcohol-induced depression, substance-induced depression, benzodiazepine-induced depression, and mixed anxiety-depressive disorder. In some embodiments, the subjects demonstrate improvement in one or more symptoms associated with a condition or disorder selected from the group consisting of depressive state, mild depression, moderate depression, severe depression, major depression, major depressive disorder, depression with anxiety distress, melancholy, melancholic depression, agitation, persistent depressive disorder, type I bipolar disorder, type II bipolar disorder, bipolar disorder not otherwise specified, cyclothymic disorder, seasonal affective disorder, psychotic depression, psychotic major depression, postpartum depression, premenstrual dysphoric disorder, situational depression, sudden onset depression, atypical depression, treatment-resistant depression, catatonic depression, dysthymia, double depression, unspecified depressive disorder, depressive personality disorder, recurrent short-term depression, mild depressive disorder, alcohol-induced depression, substance-induced depression, benzodiazepine-induced depression, and mixed anxiety-depressive disorder.In some embodiments, the subject is diagnosed with one or more conditions or disorders with a risk of comorbidity of depression, selected from the group consisting of Alzheimer's disease, cancer, coronary heart disease, acute coronary syndrome, diabetes, epilepsy, HIV / AIDS, hypothyroidism, multiple sclerosis, Parkinson's disease, stroke, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, dementia, substance abuse disorder, psychiatric disorders, anorexia nervosa, bulimia nervosa, muscular dysplasia, bulimia nervosa, compulsive eating disorder, polycystic ovary syndrome, Prader-Willi syndrome, diabetic bulimia, autoimmune disorders, and inflammatory disorders. In some embodiments, one or more non-invasive brain stimulation sessions include using a tES device with first and second electrodes in close proximity to or in contact with the subject's frontal lobe. In some embodiments, the frontal lobe of the subject's brain is stimulated to induce neuromodulation. In some embodiments, the parietal lobe of the subject brain is stimulated to induce neuromodulation. In some embodiments, the temporal lobe of the subject brain is stimulated to induce neuromodulation. In some embodiments, the prefrontal cortex of the subject is stimulated to induce neuromodulation. In some embodiments, the dorsolateral prefrontal cortex (DLPFC) of the subject is stimulated to induce neuromodulation. The DLPFC is a brain region that helps regulate mood and concentration and can influence sleep and appetite. When activity associated with this region of the brain is low, these functions may be affected. In some embodiments, the left dorsolateral prefrontal cortex of the subject is stimulated to induce neuromodulation. In some embodiments, the method further includes pyramidal cells of the cerebral cortex exhibiting depolarized cell bodies and axons. In some embodiments, the method further includes pyramidal cells of the cerebral cortex exhibiting hyperpolarized cell bodies and axons. In some embodiments, the method further includes pyramidal cells of the cerebral cortex exhibiting depolarized apical dendrites. In some embodiments, the method further includes pyramidal cells of the cerebral cortex exhibiting hyperpolarized pointed dendrites. In some embodiments, the method further includes depolarization of interneurons in the cerebral cortex. In some embodiments, the method further includes hyperpolarization of interneurons in the cerebral cortex.In some embodiments, the method further includes an increase in neural activity in the DLPFC at a time point following one or more non-invasive brain stimulation sessions. In some embodiments, the method further includes an increase in functional connectivity between the DLPFC and one or more primary association areas of the orbitofrontal cortex, thalamus, dorsal caudate nucleus, hippocampus, neocortex, or one or more secondary association areas of the neocortex, or any combination thereof. In some embodiments, the method further includes an increase in neural plasticity in the subject's brain. In some embodiments, the method further includes a significant improvement in cognitive function in the subject. In some embodiments, the method further includes a significant improvement in one or more executive functions of the brain in the subject. In some embodiments, the method further includes a significant improvement in attention in the subject. In some embodiments, cognitive inhibition is significantly improved in the subject. In some embodiments, the method further includes a significant improvement in inhibitory control in the subject. In some embodiments, the method further includes a significant improvement in cognitive planning in the subject. In some embodiments, the method further includes a significant improvement in working memory in the subject. In some embodiments, the method further includes a significant improvement in depressed mood in the subject. In some embodiments, the method further includes significantly improving one or more symptoms of depression in the subject. In some embodiments, the method further includes significantly restoring a sense of well-being in the subject. In some embodiments, each of one or more non-invasive brain stimulation sessions delivers tES to the subject for a duration of at least about 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 28 minutes, 29 minutes, 30 minutes, 31 minutes, 32 minutes, 33 minutes, 34 minutes, 35 minutes, 40 minutes, 45 minutes, or 50 minutes.In some embodiments, each of one or more non-invasive brain stimulation sessions delivers tES to the subject for a duration of approximately 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 28 minutes, 29 minutes, 30 minutes, 31 minutes, 32 minutes, 33 minutes, 34 minutes, 35 minutes, 40 minutes, 45 minutes, or less than 50 minutes. In some embodiments, subjects receive one or more non-invasive brain stimulation sessions at frequencies of approximately twice daily, once every 18 hours, once daily, once every 36 hours, once every other day, six times a week, five times a week, four times a week, three times a week, twice a week, once a week, or once every two weeks. In some embodiments, subjects receive one or more non-invasive brain stimulation sessions according to an initial activation phase schedule at frequencies of approximately twice daily, once every 18 hours, once daily, once every 36 hours, once every other day, six times a week, five times a week, four times a week, three times a week, twice a week, once a week, or once every two weeks. In some embodiments, subjects receive one or more non-invasive brain stimulation sessions according to the schedule of the secondary reinforcement phase, at frequencies of approximately twice daily, once every 18 hours, once daily, once every 36 hours, once every other day, six times a week, five times a week, four times a week, three times a week, twice a week, once a week, or once every two weeks. In some embodiments, the initial activation phase lasts approximately 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, and 15 weeks. The process lasts for a period of 16, 17, 18, 19, or 20 weeks. In some embodiments, the secondary strengthening phase begins approximately 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or 25 weeks after the completion of the initial activation phase. In some embodiments, tDCS provides approximately + / -0.5mA, + / -0.6mA, + / -0.7mA, + / -0.8mA, + / -0.9mA, + / -1.0mA, + / -1.1mA, + / -1.2mA, + / -1.3mA, + / -1.4mA, + / -1.5mA, + / -1.6mA, + / -1.7mA, + / -1.8mA, + / -1.9mA, + / -2.0mA, + / -2.1mA, + / -2 The system delivers currents of 0.2mA, + / -2.3mA, + / -2.4mA, + / -2.5mA, + / -2.6mA, + / -2.7mA, + / -2.8mA, + / -2.9mA, + / -3.0mA, + / -3.1mA, + / -3.2mA, + / -3.3mA, + / -3.4mA, + / -3.5mA, + / -3.6mA, + / -3.7mA, + / -3.8mA, + / -3.9mA, + / -4.0mA, + / -4.5mA, or + / -5.0mA. In some embodiments, the current is delivered continuously for the duration of one or more non-invasive brain stimulation sessions. In some embodiments, the subject completes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 non-invasive brain stimulation sessions.In some embodiments, subjects demonstrate a decrease of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, or 54 points in the MADRS-S, compared to the MADRS-S obtained before the start of treatment or at an earlier point in treatment, during or after treatment. In some embodiments, MADRS-S measurements are used in part to evaluate the treatment regimen and the subject's response to one or more stimulation sessions in order to determine the therapeutic efficacy in (c). In some embodiments, prompting the subject to input information about the subject's current health status includes displaying the subject a self-assessment MADRS-S questionnaire, allowing the subject to complete the questionnaire, and storing the results from the completed questionnaire in the computer memory of an electronic device. In some embodiments, the electronic device is a handheld device. In some embodiments, the desired therapeutic outcome is improvement of the subject's symptoms. In some embodiments, the subject's symptoms are symptoms of depression. In some embodiments, improvement includes a decrease in the subject's MADRS-S. In some embodiments, the reduction in the subject's MADRS-S persists over a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 weeks. In some embodiments, the method further includes a subject with moderate depression showing a significant reduction in MADRS-S after at least 6 weeks of tES treatment, including at least 21 non-invasive brain stimulation sessions.In some embodiments, the method further includes a subject with moderate depression showing a significant reduction in MADRS-S after at least 10 weeks of tES treatment including at least 21 non-invasive brain stimulation sessions. In some embodiments, the method further includes a subject with severe depression showing a significant reduction in MADRS-S after at least 6 weeks of tES treatment including at least 21 non-invasive brain stimulation sessions. In some embodiments, the method further includes a subject with severe depression showing a significant reduction in MADRS-S after at least 10 weeks of tES treatment including at least 21 non-invasive brain stimulation sessions. In some embodiments, the method further includes a subject with depression being administered sertraline as part of a treatment regimen and showing a significant reduction in MADRS-S after at least 6 weeks of tES treatment including at least 21 non-invasive brain stimulation sessions. In some embodiments, a significant reduction in MADRS-S is greater than the reduction in MADRS-S in a second subject after at least six weeks of tES treatment, which includes fluoxetine as part of a treatment regimen and at least 21 non-invasive brain stimulation sessions. In some embodiments, adjusting the parameters in (a) and (b) to achieve the desired treatment outcome includes reducing the ongoing dosage of pharmacological antidepressants administered to the subject as needed to maintain improvement in one or more symptoms of depression. In some embodiments, adjusting the parameters in (a) and (b) to achieve the desired treatment outcome includes reducing the ongoing frequency of administration of pharmacological antidepressants to the subject as needed to maintain improvement in one or more symptoms of depression. In some embodiments, adjusting the parameters in (a) and (b) to achieve the desired treatment outcome includes reducing the frequency of tES sessions required for the subject to maintain improvement in one or more symptoms of depression. In some embodiments, adjusting the parameters in (a) and (b) to achieve the desired treatment outcome includes reducing the duration of tES sessions required for the subject to maintain improvement in one or more symptoms of depression.In some embodiments, adjusting the parameters in (a) and (b) to achieve a desired therapeutic outcome includes reducing the current applied to the subject in an ongoing tES session as needed to maintain improvement in one or more symptoms of the depressive state. In some embodiments, the method further includes the subject receiving focused meditation exercises or focused relaxation exercises during one or more non-invasive brain stimulation sessions.

[0008] In one embodiment, the method disclosed herein is a method for neuromodulatory intervention in a subject, comprising: (a) administering a therapeutically effective dose of a pharmacological antidepressant to the subject as part of a treatment regimen; (b) simultaneously delivering one or more non-invasive brain stimulation sessions to the subject via a transcranial electrical stimulation (tES) device; (c) evaluating the subject's response to the treatment regimen and one or more non-invasive brain stimulation sessions to determine therapeutic efficacy; and (d) adjusting the parameters in (a) and (b) to achieve a desired therapeutic outcome.

[0009] In one embodiment, the method disclosed herein for preventing sudden depressive episodes in a subject is a method comprising: (a) administering a therapeutically effective dose of a pharmacological antidepressant to the subject as part of a treatment regimen; (b) simultaneously delivering one or more non-invasive brain stimulation sessions to the subject via a transcranial electrical stimulation (tES) device; (c) evaluating the subject's response to the treatment regimen and one or more non-invasive brain stimulation sessions to determine therapeutic efficacy; and (d) adjusting the parameters in (a) and (b) to achieve a desired therapeutic outcome.

[0010] In one aspect, disclosed herein is a method of maintaining remission of a depressive state in a subject, comprising: (a) administering to the subject a therapeutically effective amount of a pharmacological antidepressant as part of a treatment regimen; (b) simultaneously delivering to the subject one or more non-invasive brain stimulation sessions via a transcranial electrical stimulation (tES) device; (c) evaluating the subject's response to the treatment regimen and the one or more non-invasive brain stimulation sessions to determine treatment effectiveness; and (d) adjusting the parameters in (a) and (b) to achieve a desired treatment outcome.

[0011] In one aspect, disclosed herein is the use of a pharmaceutical composition comprising a pharmacological antidepressant for the manufacture of a medicament for use in treating a subject having a need for treatment of a depressive state, wherein the pharmaceutical composition is administered to the subject and transcranial electrical stimulation (tES) is applied to the subject.

[0012] Incorporation by reference All publications, patents, and patent applications mentioned herein are incorporated herein by reference as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict between an incorporated publication and patent or patent application and the disclosure included herein, this specification is intended to supersede and / or prevail over any such conflicting material. Brief Description of the Drawings

[0013] The novel features of the invention are set forth with particularity in the appended claims. The features and advantages of the invention will be better understood from the following detailed description of exemplary embodiments that utilize the principles of the invention, and from the accompanying drawings.

[0014] [Figure 1] Graph showing the improvement outcome score of the depressive state over 3 weeks after the start of nerve stimulation. Subjects were grouped by symptom severity and graphed according to the number of nerve stimulation sessions. [Figure 2] A graph showing the outcome of the improvement in the score of the depressive state over 6 weeks after the start of nerve stimulation is presented. The subjects were grouped according to the severity of the symptoms and graphed according to the number of nerve stimulation sessions. [Figure 3] A graph showing the outcome of the improvement in the score of the depressive state over 10 weeks after the start of nerve stimulation is presented. The subjects were grouped according to the severity of the symptoms and graphed according to the number of nerve stimulation sessions. [Figure 4] A graph showing the outcome of the improvement in the score of the depressive state over 25 weeks after the start of nerve stimulation is presented. The subjects were grouped according to the severity of the symptoms and graphed according to the number of nerve stimulation sessions. [Figure 5] A graph showing the outcome of the improvement in the score of the depressive state over 10 weeks after the start of nerve stimulation is presented. The subjects were not distinguished according to either the severity of the symptoms of the depressive state or the adherence to the nerve stimulation protocol. The subjects were graphed according to the category of antidepressant drugs used during the treatment. [Figure 6] A graph showing the outcome of the improvement in the score of the depressive state over 10 weeks after the start of nerve stimulation is presented. The subjects were not distinguished according to the severity of the symptoms of the depressive state, but were distinguished based on the degree of adherence to the nerve stimulation protocol. The subjects were graphed according to the category of antidepressant drugs used during the treatment. [Figure 7] A graph showing the outcome of the improvement in the score of the depressive state over 10 weeks after the start of nerve stimulation is presented. The subjects were not distinguished according to either the severity of the symptoms of the depressive state or the adherence to the nerve stimulation protocol. The subjects were graphed according to the category of selective serotonin reuptake inhibitor (SSRI) drugs used during the treatment. [Figure 8] A graph showing the outcome of the improvement in the score of the depressive state over 8 weeks after the start of nerve stimulation is presented. The subjects were graphed according to the adherence to nerve stimulation during the first 3 weeks. [Figure 9] A device 100 for delivering tES according to an embodiment is schematically shown. [Figure 10]This shows the differences in remission rates and response rates, as measured by HDRS-17 scores, between patients with different levels of adherence to the prescribed medication protocol for the clinical trial described in Example 3. The number of stimulations in parentheses indicates the number of tCDS stimulation sessions administered to patients over the course of the 10-week blinded portion of the trial. Data are shown for patients in the active group who were also receiving additional concomitant antidepressant therapy. For each group, the remission rate is shown in the left bar and the response rate is shown in the right bar. [Figure 11] Figure 10 shows the number of patients in each subgroup. [Figure 12A] Figure 10 shows the number of patients in each subgroup, further classified by the severity of depression at baseline, as measured by HDRS-17. Figure 12A shows the absolute number of patients in each adherence group, with the numbers, from top to bottom, indicating the number of patients with severe, moderate, and mild depression in each group. Figure 12B shows the disease severity for each adherence group as a percentage of the total, with the percentage of patients in that adherence group with severe, moderate, and mild depression from top to bottom. [Figure 12B] Figure 10 shows the number of patients in each subgroup, further classified by the severity of depression at baseline, as measured by HDRS-17. Figure 12A shows the absolute number of patients in each adherence group, with the numbers, from top to bottom, indicating the number of patients with severe, moderate, and mild depression in each group. Figure 12B shows the disease severity for each adherence group as a percentage of the total, with the percentage of patients in that adherence group with severe, moderate, and mild depression from top to bottom. [Modes for carrying out the invention]

[0015] Many potential benefits associated with the use of transcranial electrical stimulation (tES) for neuromodulation in the treatment of depressive disorders have been explored. Furthermore, pharmacological interventions and treatments involving the administration of pharmacological antidepressants remain effective therapeutic tools for many individuals suffering from depressive disorders. Numerous neurological conditions, including those classified as depressive disorders or those containing depressive behavioral elements, are resistant to current treatments in a significant portion of the population, resulting in widespread socioeconomic burdens and personal distress. Several challenges remain in adapting tES treatment as an effective therapy for depressive states. Among these challenges is a lack of complete understanding of how variability associated with tES delivery (e.g., form, stimulation intensity, duration, repetition, location) induces and maintains the degree of neuromodulation within a given population. tES has been demonstrated to be neuromodulatory in healthy subjects and those with pathological conditions. The type and degree of neuromodulation that may be therapeutic may vary depending on the specific neurological condition and state of a given subject. As a non-limiting example, individuals diagnosed with mild depression may benefit more from moderate neuromodulation than individuals diagnosed with a more severe form of major depressive disorder (MDD). Another non-limiting example is that individuals with depression showing improvement in one or more depressive symptoms may benefit more from moderate neuromodulation than individuals with refractory or chronic forms of depression. Yet another non-limiting example is that individuals with severe forms of depression, such as catatonic depression, may benefit more from a greater degree of neuromodulation than individuals diagnosed with milder forms of depression, such as mild depressive disorder. While pharmacological interventions and treatments for depression are often effective, they face some of the same types of efficacy problems as tES in improving depressive symptoms in specific individuals.As a non-limiting example, the estimated 12-month prevalence of treatment-resistant depression (TRD) among individuals with MDD treated with pharmacotherapy was recently calculated to be 30.9% of this population (Zhdanava M. et al. The Prevalence and National Burden of Treatment-Resistant Depression and Major Depressive Disorder in the United States. J Clin Psychiatry. 2021 Mar 16;82(2):20m13699). Given the prevalence of depressive states, the profound impact on the health and well-being of individuals affected, the degree of unmanageable or untreated depression, and the burden of side effects and patient non-adherence to depressive state treatment protocols, there is clearly a need to develop more effective treatments for depressive disorders.

[0016] This specification provides a method for treating depressive states by combining neuromodulation with the administration of pharmacological antidepressants. tES provides a safe and effective means of inducing neuromodulation in subjects. By varying the parameters of the tES delivery protocol, neuronal stimulation can be delivered to a degree tailored to a given subject based on a number of subject criteria. These subject criteria may include the diagnosis of a specific depressive disorder, medical history, assessment of depressive symptoms, regulation of depressive symptoms, and duration of depressive symptoms. tES also provides a safe and effective means of maintaining neuromodulation in subjects. All variations of the parameters of the tES delivery protocol, including the form, intensity, duration, repetition, and location of stimulation, contribute to the induction (activation) and maintenance or enhancement of neuromodulation.

[0017] I. Method In one embodiment, disclosed herein is a method for treating a depressive state in a subject, comprising administering a pharmacological antidepressant to the subject and delivering transcranial electrical stimulation (tES) to the subject. In some embodiments, the method comprises administering a pharmacological antidepressant comprising one or more pharmacological antidepressants. In some embodiments, the method comprises administering a pharmacological antidepressant as part of a treatment regimen. In some embodiments, the method comprises administering a pharmacological antidepressant in a therapeutically effective dose. In some embodiments, the method comprises delivering tES to the subject at a specific time in response to the administration of a pharmacological antidepressant. In some embodiments, the method comprises delivering tES through one or more non-invasive brain stimulation sessions. In some embodiments, the method comprises delivering tES via a tES device. In some embodiments, the method comprises evaluating the subject's response to a treatment regimen administering a pharmacological antidepressant. In some embodiments, the method comprises evaluating the subject's response to one or more non-invasive brain stimulation sessions. In some embodiments, evaluating the subject's response comprises determining therapeutic efficacy. In some embodiments, the method includes adjusting the parameters administered to a target pharmacological antidepressant to achieve a desired therapeutic outcome. In some embodiments, the method includes adjusting the parameters delivered to a target tES to achieve a desired therapeutic outcome.

[0018] Pharmacological antidepressants In some embodiments, the methods disclosed herein further include administering a pharmacological antidepressant known to modulate neurotransmission to a target. In some embodiments, the pharmacological antidepressant known to modulate neurotransmission includes selective serotonin reuptake inhibitors (SSRIs). In some embodiments, the pharmacological antidepressant known to modulate neurotransmission includes serotonin-norepinephrine reuptake inhibitors (SNRIs). In some embodiments, the pharmacological antidepressant known to modulate neurotransmission includes noradrenergic and specific serotonergic antidepressants (NaSSAs). In some embodiments, the pharmacological antidepressant known to modulate neurotransmission includes serotonin modulators and stimulators (SMSs). In some embodiments, the pharmacological antidepressant known to modulate neurotransmission includes serotonin antagonists and reuptake inhibitors (SARIs). In some embodiments, the pharmacological antidepressant known to modulate neurotransmission includes serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs). In some embodiments, pharmacological antidepressants known to modulate neurotransmission include norepinephrine reuptake inhibitors (NRIs). In some embodiments, pharmacological antidepressants known to modulate neurotransmission include norepinephrine-dopamine reuptake inhibitors (NDRIs). In some embodiments, pharmacological antidepressants known to modulate neurotransmission include norepinephrine-dopamine-releasing agents (NDRAs). In some embodiments, pharmacological antidepressants known to modulate neurotransmission include serotonin-norepinephrine-dopamine-releasing agents (SNDRAs). In some embodiments, pharmacological antidepressants known to modulate neurotransmission include tricyclic antidepressants (TCAs). In some embodiments, pharmacological antidepressants known to modulate neurotransmission include tetracyclic antidepressants (TeCAs). In some embodiments, pharmacological antidepressants known to modulate neurotransmission include monoamine oxidase inhibitors (MAOIs).In some embodiments, the pharmacological antidepressant known to modulate neurotransmission includes an NMDA receptor modulator. In some embodiments, the pharmacological antidepressant known to modulate neurotransmission includes an atypical antipsychotic. In some embodiments, the pharmacological antidepressant known to modulate neurotransmission includes an atypical antidepressant. In some embodiments, the pharmacological antidepressant known to modulate neurotransmission includes a benzodiazepine. In some embodiments, the pharmacological antidepressant known to modulate neurotransmission includes one or more pharmacological antidepressants. In some embodiments, the pharmacological antidepressant known to modulate neurotransmission includes two pharmacological antidepressants. In some embodiments, the pharmacological antidepressant known to modulate neurotransmission includes three pharmacological antidepressants. In some embodiments, one or more pharmacological antidepressants include one or more drugs classified as SSRIs, SNRIs, NaSSAs, SMSs, SARIs, SNDRIs, NRIs, NDRIs, NDRAs, SNDRAs, TCAs, TeCAs, MAOIs, NMDA receptor modulators, atypical antipsychotics, atypical antidepressants, or benzodiazepines, or any combination thereof.

[0019] SSRIs are a class of drugs commonly prescribed to function as antidepressants in individuals who need them. SSRIs have been shown to work by increasing extracellular levels of the neurotransmitter serotonin (5-HT) by limiting its reuptake into presynaptic cells. Neurotransmission in the brain occurs via signaling from one neuron to another through chemical synapses. Chemical synapses involve a small physical space between neurons. Presynaptic cells involved in the propagation of neuronal signals release neurotransmitters into the space near the chemical synapse. Following the processes of presynaptic release of neurotransmitters and postsynaptic binding of the released neurotransmitters to postsynaptic receptors, neuronal signal propagation begins, with approximately 90% of the neurotransmitters initially released from the synapse of the presynaptic neuron remaining in the synaptic space or being released into the synaptic space from the receptors. These free neurotransmitters can then be taken up by monoamine transporters into the presynaptic cell in a process called reuptake, and subsequently recycled for reuse in neurotransmission. In serotonergic neurons, action potentials stimulate calcium-dependent release of 5-HT from presynaptic vesicles into the synaptic space, where 5-HT interacts with both presynaptic and postsynaptic receptors. A feedback loop modulates 5-HT concentration in the synaptic space and, therefore, the degree of stimulation of various serotonergic receptors in the postsynaptic membrane. By selectively inhibiting 5-HT reuptake in presynaptic cells, SSRI treatment results in increased extracellular 5-HT levels near chemical synapses involved in serotonergic neurotransmission. This has an acute net effect of lowering the threshold for presynaptic 5-HT release required to initiate serotonin-mediated neuronal signaling in postsynaptic neurons connected via these affected chemical synapses. This effect of longer-lasting 5-HT molecules in the synaptic cleft in SSRI-treated subjects compared to untreated subjects can also translate to repeated stimulation of postsynaptic serotonergic receptors that induce neurotransmission.Therefore, acute SSRI treatment tends to increase neurotransmission from nerve cells that utilize 5-HT as a neurotransmitter. This acute response to SSRI treatment can be seen in the elevation of synaptic 5-HT levels within one hour of administration of the SSRI drug therapy dose. Decreased serotonergic activity is involved in various depressive disorders, and therefore, increased serotonergic neurotransmission is considered beneficial in the treatment of depressive disorders. Chronic administration of SSRIs increases the occupancy of postsynaptic serotonin receptors, which signals presynaptic neurons to decrease the production and release of 5-HT. This ultimately leads to a desensitized 5-HT and serotonin receptor feedback loop, as well as downregulation of postsynaptic serotonin receptors.

[0020] Despite the acute effects of SSRIs on presynaptic and postsynaptic serotonergic neurons described above, subjects responding to SSRI therapy often require a much longer period than the duration of the acute effects of SSRI therapy at the synapse to manifest as improvement in one or more depressive symptoms. Continuous SSRI treatment as monotherapy may take 2–4 weeks for subjects to experience improvement in one or more depressive symptoms. Continuous SSRI treatment as monotherapy may take up to 12 weeks before the maximum benefit of subjects manifesting as improvement in one or more depressive symptoms can be achieved. The nature of the delay from the initiation of SSRI therapy to measurable improvement in depressive symptoms in SSRI-responsive subjects is unclear, but the proportion of subjects who experienced symptom improvement with SSRI treatment remains significant. Approximately 50% of depressive subjects respond to an initial SSRI treatment regimen with significant improvement in depressive symptoms. Approximately 35–40% of patients with depressive disorders achieve remission in initial SSRI treatment regimens, with remission defined as recovery from depressive symptoms (Rush AJ et al., Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006 Nov;163(11):1905-17.). Due to the prevalence of depressive disorders and the widely held view within the clinical community that SSRI therapy is a viable first-line treatment strategy, several problems arise after initiating SSRI therapy in patients with depressive disorders. One such problem is that a significant proportion of patients do not respond to SSRI therapy and do not achieve any significant improvement in depressive symptoms. In line with this problem, common treatment strategies when patients do not respond to initial SSRI treatment regimens are any of the following: changing the dosage of SSRI administered, changing the frequency of SSRI dosage administration, changing to the administration of a different antidepressant, or any combination thereof.The effects of SSRIs and other antidepressant therapies may take several weeks to materialize, and the need to extend the evaluation of the effectiveness of these types of changes to treatment regimens and newly formulated regimens can result in prolonged symptoms and distress in affected subjects. Therefore, many subjects may not achieve measurable improvement in depressive symptoms even after receiving several different long-term treatment regimens using SSRIs or other antidepressants. Even subjects who experience significant improvement in depressive symptoms may still have impaired mood, psychosocial, and work functioning if remission is not achieved. Methods that increase the proportion of affected subjects who achieve improvement in depressive symptoms, increase the degree of improvement, increase the proportion of affected subjects who achieve remission of depressive states, increase the rate at which improvement in depressive symptoms is achieved, or allow for a reduction in the effective dose and / or effective frequency of pharmacological antidepressants would substantially reduce the degree of distress in subjects with depression and improve the overall burden resulting from the depression.

[0021] As shown, the nature of the delay from the initiation of SSRI therapy to a measurable improvement in depressive symptoms in SSRI-responsive subjects is unclear. The length of time required for functional neural network and network connectivity changes after long-term SSRI therapy may contribute to this delay in improvement of depressive symptoms. In addition, and / or alternatively, widespread changes in the nervous system, including changes in gene expression, protein synthesis, and cellular protein localization, may contribute to this delay in drug response. As a non-limiting example, subjects with depression have often been observed to have a higher percentage of G proteins in neurons and glial cells associated with lipid raft features of the cell membrane, which tend not to aggregate near chemical synapses as microdomains present in the plasma membrane. SSRI treatment of glial cells results in the eventual accumulation of SSRI within lipid rafts and the simultaneous redistribution of G proteins from the lipid rafts to cellular regions away from the lipid rafts, which may further facilitate the induction of functional G protein signaling events within a timeframe that can contribute to the delayed drug response to SSRI treatment (Erb SJ et al. Antidepressants Accumulate in Lipid Rafts Independent of Monoamine Transporters to Modulate Redistribution of the G Protein, Gαs. J Biol Chem. 2016 Sep 16;291(38):19725-19733). SSRIs have also been noted for exerting other effects on cells, including anti-inflammatory effects. As described herein, methods of treating depressive states by combining tES with the administration of pharmacological antidepressants, including SSRIs in non-limiting examples, result in improvement of one or more symptoms of the depressive state to a greater extent than either method alone. In some embodiments described herein, combining tES with the administration of pharmacological antidepressants results in synergistic effects on changes in functional neural networks and network connectivity in the brains of subjects with depression.In some embodiments described herein, combining tES with the administration of pharmacological antidepressants results in synergistic effects on changes in gene expression in the brains of subjects with depression. In some embodiments described herein, combining tES with the administration of pharmacological antidepressants results in synergistic effects on changes in protein synthesis in the brains of subjects with depression. In some embodiments described herein, combining tES with the administration of pharmacological antidepressants results in synergistic effects on changes in protein localization in the brains of subjects with depression. In some embodiments described herein, combining tES with the administration of pharmacological antidepressants results in synergistic effects on reducing inflammation in the brains of subjects with depression.

[0022] Individual members of the class of drugs classified as SSRIs may have different effects on the target population being treated for depressive disorders due to differences in the chemical structure or composition of a particular SSRI. SSRIs with different chemical compositions each have specific pharmacokinetic properties. Some SSRIs can be distinguished from one another based on their specific pharmacokinetic properties. In some cases, a particular SSRI may have specific pharmacokinetic properties that contribute more effectively to the treatment of a particular type of depressive disorder, or distinct symptoms that manifest as a particular type of depressive disorder. SSRIs have been shown to have different selectivity for different monoamine transporters. There are three main classes of monoamine transporters: serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET). SERT is responsible for the reuptake of extracellular 5-HT in a Na+ / Cl-- dependent process. DAT is responsible for the reuptake of extracellular dopamine (dopamine, DA) in a Na+ / Cl-dependent process. NET is responsible for the Na+ / Cl-dependent reuptake of extracellular norepinephrine (norepinephrine, NE). It has been noted that DAT can also transport extracellular NE, and NET can also transport extracellular DA. As mentioned above, SSRI-monoamine transporter selectivity varies among SSRI drugs, but all drugs classified as SSRIs exhibit a robust pharmacokinetic effect of inhibiting presynaptic 5-HT reuptake, with less inhibition of presynaptic reuptake of other monoamines. In addition to affecting 5-HT reuptake, various SSRIs have been observed to function as ligands for sigma receptors. The SSRIs fluvoxamine, fluoxetine, escitalopram, and citalopram can each function as agonists of the sigma-1 receptor. The SSRI sertraline can function as a sigma-1 receptor antagonist.In some embodiments described herein, combining tES with the administration of a pharmacological antidepressant that functions as a sigma-1 receptor agonist results in a synergistic effect on improving cognitive impairment, a symptom of depressive disorders.

[0023] Treatment with SSRIs is known to carry a risk of potential undesirable side effects. Generally, SSRIs are better tolerated than many other types of pharmacological antidepressants, and the majority of patients taking SSRIs experience only mild side effects. Treatment with SSRIs can induce undesirable side effects including dyspepsia, diarrhea, constipation, weight loss, loss of appetite, blurred vision, dizziness, dry mouth, excessive sweating, insomnia, headache, excessive sleepiness, sexual dysfunction, anxiety, anxiety, abnormal thoughts, agitated behavior, tremors, increased risk of hemorrhagic adverse events, confusion, urinary retention, hallucinations, hypoglycemia, hyponatremia, nausea, rash, and serotonin syndrome. The occurrence of these unpleasant potential side effects can prevent patients from maintaining a long-term treatment regimen of a given SSRI. The ability to reduce the dosage of SSRIs taken by a patient while maintaining therapeutic benefits in one or more symptoms of depression would be beneficial in mitigating the risk of undesirable side effects.

[0024] Described herein are methods for treating depressive states, comprising, in some embodiments, administering an SSRI and delivering a tES. In some embodiments, administering an SSRI and delivering a tES alleviates symptoms of mild depression. In some embodiments, administering an SSRI and delivering a tES alleviates symptoms of moderate depression. In some embodiments, administering an SSRI and delivering a tES alleviates symptoms of severe depression. In some embodiments, administering an SSRI includes administering two or more SSRIs. In some embodiments, administering an SSRI includes administering an SSRI and a second pharmacological antidepressant belonging to the drug category of SNRI, NaSSA, SMS, SARI, SNDRI, NRI, NDRI, NDRA, SNDRA, TCA, TeCA, MAOI, NMDA receptor modulator, atypical antipsychotic, atypical antidepressant, or benzodiazepine. In some embodiments, the SSRI is fluoxetine. In some embodiments, the SSRI is citalopram. In some embodiments, the SSRI is escitalopram. In some embodiments, the SSRI is paroxetine. In some embodiments, the SSRI is sertraline. In some embodiments, the SSRI is dapoxetine. In some embodiments, the SSRI is fluvoxamine. In some embodiments, the SSRI is vortioxetine.

[0025] SNRIs are a class of drugs commonly prescribed to function as antidepressants in individuals who require them. SNRIs are a class of monoamine inhibitors that have been shown to increase extracellular levels of the neurotransmitters 5-HT and norepinephrine by restricting their reuptake into presynaptic cells. SNRIs are less selective in their role in 5-HT uptake than SSRIs, which primarily act on 5-HT levels. While SNRIs are defined by their common characteristic of inhibiting the reuptake of 5-HT and norepinephrine, each member of this class has a different chemical structure and different pharmacological properties. As a non-limiting example, duloxetine and desvenlafaxine exhibit 10-fold higher selectivity for serotonin reuptake inhibition than for norepinephrine reuptake inhibition. Venlafaxine has been shown to exhibit 30-fold higher selectivity for serotonin reuptake inhibition than for norepinephrine reuptake inhibition, thus exhibiting higher relative selectivity for serotonin reuptake inhibition. Venlafaxine and duloxetine inhibit serotonin and norepinephrine reuptake in a sequential manner, with serotonin reuptake inhibition occurring first, followed by norepinephrine reuptake inhibition. Levomilnacipran is twice as potent in inhibiting norepinephrine reuptake as it is in inhibiting serotonin reuptake. Milnacipran is three times more potent in inhibiting norepinephrine reuptake than it is in inhibiting serotonin reuptake. Unlike venlafaxine and duloxetine, milnacipran acts simultaneously on the reuptake of both 5-TH and norepinephrine.

[0026] Treatment with SNRIs is known to carry a risk of potential undesirable side effects. All SNRIs inhibit 5-HT reuptake in human platelets, which is associated with an increased risk of hemorrhagic adverse events. High doses of duloxetine and venlafaxine weakly inhibit dopamine reuptake, which may contribute to their effect on blood pressure. Treatment with venlafaxine may result in an increased risk of undesirable side effects, including hypoglycemia, hyponatremia, rash, constipation, diarrhea, weight loss, sweating, headache, nausea, fatigue, sexual dysfunction, activating effects (including disinhibition, impulsivity, insomnia, restlessness, hyperactivity, irritability, and abnormal thinking), dry mouth, and night sweats. These are not limiting examples of potential undesirable side effects of SNRI use. The sequential effects of duloxetine and venlafaxine on reuptake inhibition may also result in a sequential side effect profile, with serotonergic side effects beginning first, followed by noradrenergic side effects. The occurrence of these unpleasant potential side effects may prevent the subject from maintaining a long-term treatment regimen of a given SNRI. The ability to reduce the dosage of SNRIs taken by the subject while maintaining the therapeutic benefit in one or more symptoms of depression would be beneficial in reducing the risk of undesirable side effects such as an increased risk of abnormal bleeding, an increased risk of coagulation disorders, elevated blood pressure, or other side effects described herein.

[0027] Described herein are methods for treating depressive states, comprising, in some embodiments, administering an SNRI and delivering a tES. In some embodiments, administering an SNRI and delivering a tES alleviates symptoms of mild depression. In some embodiments, administering an SNRI and delivering a tES alleviates symptoms of moderate depression. In some embodiments, administering an SNRI and delivering a tES alleviates symptoms of severe depression. In some embodiments, administering an SNRI includes administering two or more SNRIs. In some embodiments, administering an SNRI includes administering an SNRI and a second pharmacological antidepressant belonging to the drug category of SSRI, NaSSA, SMS, SARI, SNDRI, NRI, NDRI, NDRA, SNDRA, TCA, TeCA, MAOI, NMDA receptor modulator, atypical antipsychotic, atypical antidepressant, or benzodiazepine. In some embodiments, the SNRI is desvenlafaxine. In some embodiments, the SNRI is duloxetine. In some embodiments, the SNRI is levomilunacipran. In some embodiments, the SNRI is milnacipran. In some embodiments, the SNRI is venlafaxine IR. In some embodiments, the SNRI is venlafaxine XR.

[0028] NaSSAs are a class of drugs commonly prescribed to function as antidepressants in individuals who require them. NaSSAs act by antagonizing α2-adrenergic receptors and certain 5-HT receptors, thereby increasing the concentrations of norepinephrine and 5-HT at synapses. NaSSAs bind to and inhibit α2-adrenergic autoreceptors and α2-adrenergic heteroreceptors. This prevents the negative feedback loop of synaptic norepinephrine for 5-HT and noradrenergic neurotransmission, thereby sustaining neurotransmission across these synapses. Blocking of 5-HT2 and 5-HT3 receptors on the postsynaptic membrane by NaSSAs can also lead to an enhancement of 5-HT1 receptor-mediated neurotransmission.

[0029] Treatment with NaSSAs is known to carry a risk of potential undesirable side effects. Many of the side effects associated with NaSSAs overlap with those of SSRIs. Some non-exclusive examples of undesirable side effects shared between SSRI and NaSSA use include dizziness, drowsiness, dry mouth, constipation, tremors, confusion, syncope, agitation, nausea, diarrhea, blurred vision, and serotonin syndrome. However, differences in the incidence and severity of undesirable side effects between NaSSAs and SSRIs have also been demonstrated. Non-exclusive examples include a lower incidence of sexual dysfunction side effects with NaSSAs than with SSRIs, and a higher incidence and greater degree of drowsiness with NaSSAs than with SSRIs. This drowsiness side effect is particularly evident in many subjects during the initial stages of treatment with NaSSAs. NaSSA treatment has also been associated with weight gain, increased appetite, swelling of the hands and / or feet, eye pain, pupil dilation, loss of coordination, and muscle spasms. The occurrence of these unpleasant potential side effects may prevent the subject from maintaining a given long-term NaSSA treatment regimen. The ability to reduce the amount of NaSSA the subject takes while maintaining the therapeutic benefit in one or more symptoms of depression would be beneficial in mitigating the risk of undesirable side effects.

[0030] Described herein are methods for treating depressive states, comprising, in some embodiments, administering NaSSA and delivering tES. In some embodiments, administering NaSSA and delivering tES alleviates symptoms of mild depression. In some embodiments, administering NaSSA and delivering tES alleviates symptoms of moderate depression. In some embodiments, administering NaSSA and delivering tES alleviates symptoms of severe depression. In some embodiments, administering NaSSA comprises administering two or more SNRIs. In some embodiments, administering NaSSA comprises administering NaSSA and a second pharmacological antidepressant belonging to the drug category of SSRI, SNRI, SMS, SARI, SNDRI, NRI, NDRI, NDRA, SNDRA, TCA, TeCA, MAOI, NMDA receptor modulator, atypical antipsychotic, atypical antidepressant, or benzodiazepine. In some embodiments, NaSSA is aptazapine. In some embodiments, NaSSA is esmirtazapine. In some embodiments, NaSSA is mianserin. In some embodiments, NaSSA is mirtazapine. In some embodiments, NaSSA is setiptiline. Treatment with NaSSA is known to carry a risk of developing potential undesirable side effects. Treatment with NaSSA may result in an increased risk of undesirable side effects, including constipation, dry mouth, weight gain, drowsiness, sedation, blurred vision, and dizziness. More serious adverse reactions to NaSSA include seizures, leukopenia, syncope, and allergic reactions. The ability to reduce the dosage of NaSSA taken by a subject while maintaining therapeutic benefits in one or more symptoms of depression would be beneficial in mitigating the risk of undesirable side effects.

[0031] SMS is a class of drugs prescribed to function as antidepressants in subjects who need it. SMS acts by simultaneously modulating one or more serotonin receptors, thereby inhibiting serotonin reuptake. Described herein are methods for treating depressive states, in some embodiments, comprising administering SMS to a subject and delivering it to a tES. In some embodiments, administering SMS and delivering it to a tES alleviates symptoms of mild depression. In some embodiments, administering SMS and delivering it to a tES alleviates symptoms of moderate depression. In some embodiments, administering SMS and delivering it to a tES alleviates symptoms of severe depression. In some embodiments, administering SMS includes administering two or more SMSs. In some embodiments, administering SMS involves administering SMS and a second pharmacological antidepressant belonging to the drug category of SSRI, SNRI, NaSSA, SARI, SNDRI, NRI, NDRI, NDRA, SNDRA, TCA, TeCA, MAOI, NMDA receptor modulator, atypical antipsychotic, atypical antidepressant, or benzodiazepine. In some embodiments, SMS is virazodone. Virazodone is known to function as a serotonin reuptake inhibitor and a partial agonist of the serotonin receptor. In some embodiments, SMS is vortioxetine. Vortioxetine is a serotonin reuptake inhibitor, 5-HT 1A It is known to function as a partial agonist of receptors, as well as an antagonist of 5-HT3 and 5-HT7 receptors.

[0032] SARIs are a class of medications prescribed to function as antidepressants in individuals who need them. SARIs are 5-HT 2AThey act by antagonizing serotonin receptors such as receptors, and by inhibiting postsynaptic reuptake of serotonin, norepinephrine, and / or dopamine. Some members of the SARI class of drugs also function as α1-adrenergic receptor antagonists. Described herein are methods for treating depressive states, in some embodiments, comprising administering SARIs to a target and delivering them to a target tES. In some embodiments, administering SARIs and delivering them to a target tES alleviates symptoms of mild depression. In some embodiments, administering SARIs and delivering them to a target tES alleviates symptoms of moderate depression. In some embodiments, administering SARIs and delivering them to a target tES alleviates symptoms of severe depression. In some embodiments, administering SARIs comprises administering two or more SARIs. In some embodiments, administering a SARI involves administering a SARI and a second pharmacological antidepressant belonging to the drug category of SSRI, SNRI, NaSSA, SMS, SNDRI, NRI, NDRI, NDRA, SNDRA, TCA, TeCA, MAOI, NMDA receptor modulator, atypical antipsychotic, atypical antidepressant, or benzodiazepine. In some embodiments, the SARI is nefazodone. In some embodiments, the SARI is trazodone.

[0033] SNDRIs are a class of drugs prescribed to function as antidepressants in subjects who need them. SNDRIs are known as triple reuptake inhibitors because they act as combined reuptake inhibitors of serotonin, norepinephrine, and dopamine. SNDRIs work by simultaneously inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations near synapses, thus resulting in increased serotonergic, adrenergic, and dopaminergic neurotransmission. Compared to MAOIs, SNDRIs share similar results in their activity after administration, in that each class of drugs increases the effects of serotonin, norepinephrine, and dopamine on neurotransmission. Described herein are methods for treating depressive states, in some embodiments, including administering SNDRIs to a subject and delivering them to a subject with tES. In some embodiments, administering an SNDRI and delivering it to tES alleviates symptoms of mild depression. In some embodiments, administering an SNDRI and delivering it to tES alleviates symptoms of moderate depression. In some embodiments, administering an SNDRI and delivering it to tES alleviates symptoms of severe depression. In some embodiments, administering an SNDRI includes administering two or more SNDRIs. In some embodiments, administering an SNDRI includes administering an SNDRI and a second pharmacological antidepressant belonging to the drug category of SSRI, SNRI, NaSSA, SMS, SARI, NRI, NDRI, NDRA, SNDRA, TCA, TeCA, MAOI, NMDA receptor modulator, atypical antipsychotic, atypical antidepressant, or benzodiazepine. In some embodiments, the SNDRI is tordesvenlafaxine. In some embodiments, the SNDRI is OPC-64005. In some embodiments, SNDRI is an anthophyxin.

[0034] NRIs are a class of drugs prescribed to function as antidepressants in subjects who need them. NRIs are known to function as neurotransmitter norepinephrine and epinephrine reuptake inhibitors, which can increase extracellular concentrations of norepinephrine and epinephrine by inhibiting the action of norepinephrine transporters, thereby increasing adrenergic neurotransmission. Described herein are methods for treating depressive states, in some embodiments, comprising administering an NRI to a subject and delivering it to a tES. In some embodiments, administering an NRI and delivering it to a tES alleviates symptoms of mild depression. In some embodiments, administering an NRI and delivering it to a tES alleviates symptoms of moderate depression. In some embodiments, administering an NRI and delivering it to a tES alleviates symptoms of severe depression. In some embodiments, administering an NRI includes administering two or more NRIs. In some embodiments, the step of administering an NRI includes administering the NRI and a second pharmacological antidepressant belonging to the drug category of SSRI, SNRI, NaSSA, SMS, SARI, SNDRI, NDRI, NDRA, SNDRA, TCA, TeCA, MAOI, NMDA receptor modulator, atypical antipsychotic, atypical antidepressant, or benzodiazepine. In some embodiments, the NRI is atomoxetine. In some embodiments, the NRI is reboxetine. In some embodiments, the NRI is teniroxazine. In some embodiments, the NRI is biloxazine.

[0035] NDRIs are a class of drugs prescribed to function as antidepressants in subjects who need them. NDRIs are known to function as neurotransmitter norepinephrine and dopamine reuptake inhibitors, which can inhibit the function of NETs and DATs, resulting in increased extracellular concentrations of norepinephrine and dopamine, thereby increasing adrenergic and dopaminergic neurotransmission. Described herein are methods for treating depressive states, in some embodiments, comprising administering an NDRI to a subject and delivering it to a tES. In some embodiments, administering an NDRI and delivering it to a tES alleviates symptoms of mild depression. In some embodiments, administering an NDRI and delivering it to a tES alleviates symptoms of moderate depression. In some embodiments, administering an NDRI and delivering it to a tES alleviates symptoms of severe depression. In some embodiments, administering an NDRI includes administering two or more NDRIs. In some embodiments, administering an NDRI involves administering an NDRI and a second pharmacological antidepressant belonging to the drug category of SSRI, SNRI, NaSSA, SMS, SARI, SNDRI, NRI, NDRA, SNDRA, TCA, TeCA, MAOI, NMDA receptor modulator, atypical antipsychotic, atypical antidepressant, or benzodiazepine. In some embodiments, the NDRI is combined with dextromethorphan. In some embodiments, bupropion is combined with dextromethorphan. The dextromethorphan component of AXS-05 is an NMDA receptor antagonist, an ion channel glutamate receptor, and a sigma-1 receptor agonist, all of which are thought to function in modulating glutamatergic neurotransmission. The bupropion component of AXS-05 functions as a norepinephrine and dopamine reuptake inhibitor, increasing the bioavailability of dextromethorphan. In some embodiments, NDRI is bupropion. In some embodiments, NDRI is amineptin. In some embodiments, NDRI is methylphenidate.In some embodiments, NDRI is AXS-05, a pharmaceutical formulation containing dextromethorphan and bupropion.

[0036] NDRAs are a class of drugs prescribed to function as antidepressants in subjects who need them. NDRAs are known to function by inducing the release of norepinephrine and dopamine. Described herein are methods for treating depressive states, in some embodiments, including administering an NDRA to a subject and delivering a tES to a subject. In some embodiments, administering an NDRA and delivering a tES to a subject alleviates symptoms of mild depression. In some embodiments, administering an NDRA and delivering a tES to a subject alleviates symptoms of moderate depression. In some embodiments, administering an NDRA and delivering a tES to a subject alleviates symptoms of severe depression. In some embodiments, administering an NDRA includes administering two or more NDRAs. In some embodiments, administering NDRA involves administering NDRA and a second pharmacological antidepressant belonging to the drug category of SSRI, SNRI, NaSSA, SMS, SARI, SNDRI, NRI, NDRI, SNDRA, TCA, TeCA, MAOI, NMDA receptor modulator, atypical antipsychotic, atypical antidepressant, or benzodiazepine. In some embodiments, NDRA is lisdexamfetamine. In some embodiments, NDRA is phenethylamine. In some embodiments, NDRA is tyramine. In some embodiments, NDRA is amphetamine. In some embodiments, NDRA is methamphetamine. In some embodiments, NDRA is cathinone. In some embodiments, NDRA is methcathinone. In some embodiments, NDRA is propylhexedrine. In some embodiments, NDRA is fenmetrazine. In some embodiments, NDRA is pemoline. In some embodiments, NDRA is 4-methylaminorex. In some embodiments, NDRA is benzylpiperazine.

[0037] SNDRAs are a class of drugs prescribed to function as antidepressants in subjects who need them. SNDRAs are known to function by inducing the release of serotonin, norepinephrine, and dopamine. Described herein are methods for treating depressive states, in some embodiments, including administering SNDRAs to a subject and delivering them to a tES (therapeutic esophageal stimuli). In some embodiments, administering SNDRAs and delivering them to a tES alleviates symptoms of mild depression. In some embodiments, administering SNDRAs and delivering them to a tES alleviates symptoms of moderate depression. In some embodiments, administering SNDRAs and delivering them to a tES alleviates symptoms of severe depression. In some embodiments, administering SNDRAs includes administering two or more SNDRAs. In some embodiments, administering SNDRA involves administering SNDRA and a second pharmacological antidepressant belonging to the drug category of SSRI, SNRI, NaSSA, SMS, SARI, SNDRI, NRI, NDRI, NDRA, TCA, TeCA, MAOI, NMDA receptor modulator, atypical antipsychotic, atypical antidepressant, or benzodiazepine. In some embodiments, SNDRA is midmafetamine. In some embodiments, SNDRA is 3,4-methylenedioxymethamphetamine. In some embodiments, SNDRA is 3,4-methylenedioxyamphetamine. In some embodiments, SNDRA is naphthylisopropylamine. In some embodiments, SNDRA is mephedrone. In some embodiments, SNDRA is methylone. In some embodiments, SNDRA is α-methyltryptamine. In some embodiments, SNDRA is α-ethyltryptamine.

[0038] TCAs are a class of drugs prescribed to function as antidepressants in subjects who need them. TCAs are known to act on at least four different neurotransmitter pathways. TCAs have been shown to block the reuptake of serotonin and norepinephrine at presynaptic terminals, thereby resulting in increased concentrations of these neurotransmitters in the extracellular synaptic cleft. TCAs also act as competitive antagonists to postsynaptic alpha-cholinergic, muscarinic, and histaminergic receptors. Through these means, TCAs affect the extracellular levels of serotonin, norepinephrine, acetylcholine, and histamine. Described herein are methods for treating depressive states, in some embodiments, comprising administering TCAs to a subject and delivering them to a tES (transient receptor system). In some embodiments, administering TCAs and delivering them to a tES alleviates symptoms of mild depression. In some embodiments, administering TCAs and delivering them to a tES alleviates symptoms of moderate depression. In some embodiments, administering a TCA and delivering it to tES alleviates symptoms of severe depression. In some embodiments, administering a TCA includes administering two or more TCAs. In some embodiments, administering a TCA includes administering a TCA and a second pharmacological antidepressant belonging to the drug category of SSRI, SNRI, NaSSA, SMS, SARI, SNDRI, NRI, NDRI, NDRA, SNDRA, TeCA, MAOI, NMDA receptor modulator, atypical antipsychotic, atypical antidepressant, or benzodiazepine. In some embodiments, the TCA is amitriptyline. In some embodiments, the TCA is clomipramine. In some embodiments, the TCA is desipramine. In some embodiments, the TCA is dosulepin. In some embodiments, the TCA is doxepin. In some embodiments, the TCA is imipramine. In some embodiments, the TCA is lofepramine. In some embodiments, TCA is nortriptyline. In some embodiments, TCA is protriptyline.In some embodiments, the TCA is trimipramine.

[0039] Treatment with TCAs is known to carry a risk of potential undesirable side effects. TCA treatment can lead to an increased risk of undesirable side effects, including seizures, insomnia, anxiety, arrhythmias, hypertension, rash, nausea, vomiting, abdominal cramps, weight loss, constipation, urinary retention, elevated intraocular pressure, and sexual dysfunction. The ability to reduce the dosage of TCAs taken by a patient while maintaining therapeutic benefits in one or more symptoms of depression would be beneficial in mitigating the risk of undesirable side effects.

[0040] TeCAs are a class of drugs prescribed to function as antidepressants in subjects who need them. TeCAs do not inhibit 5-HT reuptake, with amoxapine being a notable exception. TeCAs, apart from mirtazapine, inhibit norepinephrine reuptake. TeCAs have been demonstrated to block 5-HT2 receptors, similar to TCAs. TeCAs also function to block the action of α1-adrenergic receptors and histamine H1 receptors. TeCAs have a low affinity for muscarinic acetylcholine receptors and, therefore, unlike TCAs, are associated with little to very mild anticholinergic side effects. Described herein are methods for treating depressive states, in some embodiments, comprising administering TeCA to a subject and delivering it to a subject tES. In some embodiments, administering TeCA and delivering it to a subject alleviates symptoms of mild depression. In some embodiments, administering TeCA and delivering it to a subject alleviates symptoms of moderate depression. In some embodiments, administering TeCA and delivering it to tES alleviates symptoms of severe depression. In some embodiments, administering TeCA includes administering two or more TeCAs. In some embodiments, administering TeCA includes administering TeCA and a second pharmacological antidepressant belonging to the drug category of SSRI, SNRI, NaSSA, SMS, SARI, SNDRI, NRI, NDRI, NDRA, SNDRA, TCA, MAOI, NMDA receptor modulator, atypical antipsychotic, atypical antidepressant, or benzodiazepine. In some embodiments, TeCA is amoxapine. In some embodiments, TeCA is maprotiline. In some embodiments, TeCA is mianserin. In some embodiments, TeCA is mirtazapine. In some embodiments, TeCA is setiptiline.

[0041] MAOIs are a class of drugs prescribed to function as antidepressants in subjects who need them. MAOIs are known to inhibit the activity of one or both of the monoamine oxidases (MAO-A and MAO-B). A subset of MAOIs are known as reversible inhibitors of monoamine oxidase A (RIMAs), which selectively and reversibly inhibit MAO-A. By inhibiting the activity of monoamine oxidases, the breakdown of monoamine neurotransmitters is reduced, which has the effect of increasing the availability of these neurotransmitters (e.g., 5-HT, norepinephrine, and dopamine). Described herein are methods for treating depressive states, comprising, in some embodiments, administering MAOIs to a subject and delivering them to a tES. In some embodiments, administering MAOIs and delivering them to a tES alleviates symptoms of mild depression. In some embodiments, administering MAOIs and delivering them to a tES alleviates symptoms of moderate depression. In some embodiments, administering an MAOI and delivering it to tES alleviates symptoms of severe depression. In some embodiments, administering an MAOI includes administering two or more MAOIs. In some embodiments, administering an MAOI includes administering an MAOI and a second pharmacological antidepressant belonging to the drug category of SSRI, SNRI, NaSSA, SMS, SARI, SNDRI, NRI, NDRI, NDRA, SNDRA, TCA, TeCA, NMDA receptor modulator, atypical antipsychotic, atypical antidepressant, or benzodiazepine. In some embodiments, the MAOI is selegiline. In some embodiments, the MAOI is tranylcypromine. In some embodiments, the MAOI is phenelzine. In some embodiments, the MAOI is isocarboxazide. Treatment with MAOIs is known to carry a risk of potential undesirable side effects.Treatment with MAOs may carry an increased risk of undesirable side effects, including blurred vision, rash, seizures, edema, weight loss, sexual dysfunction, diarrhea, nausea, constipation, anxiety, insomnia, drowsiness, headache, dizziness, arrhythmia, syncope, and hypertension. The ability to reduce the dosage of MAOIs taken by a patient while maintaining therapeutic benefits in one or more symptoms of depression would be beneficial in mitigating the risk of undesirable side effects.

[0042] NMDA receptor modulators are a class of drugs prescribed to function as antidepressants in subjects who require them. NMDA receptor modulators are known to induce NMDA receptor function by either inhibiting or enhancing NMDA receptor activation. Thus, NMDA receptor modulators influence the relative effect of glutamate on neurotransmission. In some embodiments, NMDA receptor modulators may also function as agonists for glycine receptors. Described herein are methods for treating depressive states, in some embodiments, comprising administering NMDA receptor modulators to a subject and delivering them to a tES (thermally inflammatory steroid). In some embodiments, administering NMDA receptor modulators and delivering them to a tES alleviates symptoms of mild depression. In some embodiments, administering NMDA receptor modulators and delivering them to a tES alleviates symptoms of moderate depression. In some embodiments, administering NMDA receptor modulators and delivering them to a tES alleviates symptoms of severe depression. In some embodiments, administering NMDA receptor modulators includes administering two or more NMDA receptor modulators. In some embodiments, administering an NMDA receptor modulator involves administering the NMDA receptor modulator and a second pharmacological antidepressant belonging to the drug category of SSRI, SNRI, NaSSA, SMS, SARI, SNDRI, NRI, NDRI, NDRA, SNDRA, TCA, TeCA, MAOI, atypical antipsychotic, atypical antidepressant, or benzodiazepine. In some embodiments, the NMDA receptor modulator is 4-chlorokynurenine. In some embodiments, the NMDA receptor modulator is apimostinel. In some embodiments, the NMDA receptor modulator is a ketamine-containing drug for treating depressive states. In some embodiments, the NMDA receptor modulator is alketamine. In some embodiments, the NMDA receptor modulator is esketamine. In some embodiments, the NMDA receptor modulator is esmethadone. In some embodiments, the NMDA receptor modulator is ketamine.In some embodiments, the NMDA receptor modulator is risrenemudaz. In some embodiments, the NMDA receptor modulator is lapastinel.

[0043] Atypical antipsychotics, also known as second-generation antipsychotics (SGAs) and serotonin-dopamine antagonists (SDAs), are a class of drugs prescribed to function as antidepressants in individuals who require them. Typical antipsychotics function almost exclusively by modulating the dopamine system. Atypical antipsychotics generally function as neuroleptics, and most members of this class of drugs block receptors in the dopamine pathway. In some embodiments, atypical antipsychotics selectively bind to and block the function of dopamine D2 and D3 receptors, with little or no affinity for dopamine D1, D4, or D5 receptors. In addition, various representative examples of atypical antipsychotics can modulate 5-HT, norepinephrine, and / or histamine neurotransmission, in addition to the effects recorded in the dopaminergic system. In some embodiments, 5-HT 2AAtypical antipsychotics that modulate receptors are combined with NMDA receptor antagonists. Described herein are methods for treating depressive states, in some embodiments, comprising administering an atypical antipsychotic to a target and delivering it to a target tES. In some embodiments, administering an atypical antipsychotic and delivering it to a target tES alleviates symptoms of mild depression. In some embodiments, administering an atypical antipsychotic and delivering it to a target tES alleviates symptoms of moderate depression. In some embodiments, administering an atypical antipsychotic and delivering it to a target tES alleviates symptoms of severe depression. In some embodiments, administering an atypical antipsychotic includes administering two or more atypical antipsychotics. In some embodiments, administering an atypical antipsychotic involves administering an atypical antipsychotic and a second pharmacological antidepressant belonging to the drug category of SSRI, SNRI, NaSSA, SMS, SARI, SNDRI, NRI, NDRI, NDRA, SNDRA, TCA, TeCA, MAOI, NMDA receptor modulator, atypical antidepressant, or benzodiazepine. In some embodiments, the atypical antipsychotic is brillaroxazine. In some embodiments, the atypical antipsychotic is caliprazine. In some embodiments, the atypical antipsychotic is lumateperone. In some embodiments, the atypical antipsychotic is lurasidone. In some embodiments, the atypical antipsychotic is pimavanserin. In some embodiments, the atypical antipsychotic is aripiprazole. In some embodiments, the atypical antipsychotic is brexpiprazole. In some embodiments, the atypical antipsychotic is olanzapine. In some embodiments, the atypical antipsychotic is quetiapine. In some embodiments, the atypical antipsychotic is ziprasidone. In some embodiments, the atypical antipsychotic is SEP-4199. In some embodiments, SEP-4199 contains a non-racemic ratio of amisulpride enantiomers with increased potency towards 5-HT7 receptors compared to dopamine D2 receptors. SEP-4199 contains an 85-15 ratio of R-amisulpride to S-amisulpride.In some embodiments, the atypical antipsychotic is NRX-101. NRX-101 is a pharmaceutical formulation of lurasidone and D-cycloserine. In some embodiments, NRX-101 is 5-HT. 2A It functions as a regulator of receptor function and an NMDA receptor antagonist. In some embodiments, olanzapine may be used in combination with an SSRI as an adjunctive treatment for MDD. In some embodiments, olanzapine may be used in combination with fluoxetine as an adjunctive treatment for MDD. In some embodiments, aripiprazole may be used in combination with an SSRI as an adjunctive treatment for MDD. In some embodiments, brexpiprazole may be used in combination with an SSRI as an adjunctive treatment for MDD. In some embodiments, quetiapine may be administered as part of pharmacological monotherapy, or quetiapine may be used in combination with an SSRI as an adjunctive treatment for MDD.

[0044] Treatment with atypical antipsychotics is known to carry a risk of potential undesirable side effects. Treatment with atypical antipsychotics may result in an increased risk of undesirable side effects, including weight gain, motor impairment, dizziness, fatigue, constipation, dry mouth, allergic reactions, hypotension, neuroleptic malignant syndrome, hyperglycemia, seizures, tardive dyskinesia, vomiting, excessive drowsiness, nasopharyngitis, and / or upper respiratory tract infections. These are not limiting examples of potential undesirable side effects of atypical antipsychotic use. The occurrence of these unpleasant potential side effects may prevent a patient from maintaining a long-term treatment regimen of a given atypical antipsychotic. The ability to reduce the dosage or frequency of atypical antipsychotics taken by a patient while maintaining therapeutic benefits in one or more symptoms of depression would be beneficial in mitigating the risk of the undesirable side effects described herein.

[0045] Atypical antidepressants are a class of drugs prescribed to function as antidepressants in individuals who need them. Atypical antidepressants are often classified as having biochemical mechanisms of action that fall outside the known mechanisms of action of typical antidepressants such as SSRIs, SNRIs, MAOIs, and TCAs, all of which typically induce an increase in extracellular postsynaptic levels of serotonin and / or norepinephrine. In some embodiments, atypical antidepressants may function as agonists of 5-HT receptors. In some embodiments, atypical antidepressants may function as agonists of the 5-HT1 receptor subtype. In some embodiments, atypical antidepressants may function as agonists of the 5-HT1 receptor subtype. 1A They can function as receptor agonists. In some embodiments, atypical antidepressants can function as agonists of the 5-HT2 receptor subtype. In some embodiments, atypical antidepressants can function as agonists of the 5-HT2 receptor subtype. 2AThey can function as receptor agonists. In some embodiments, atypical antidepressants can function as selective estrogen receptor beta (NR3A2) agonists. In some embodiments, atypical antidepressants can function as partial opioid receptor modulators. In some embodiments, atypical antidepressants can function as partial opioid receptor antagonists. In some embodiments, atypical antidepressants can function as peripherally selective aromatic L-amino acid decarboxylase inhibitors and can be combined with serotonin precursors. In some embodiments, atypical antidepressants can function as sigma-1 receptor agonists, NMDA receptor antagonists, serotonin and norepinephrine reuptake inhibitors, and CYP2D6 inhibitors. Described herein are methods for treating depressive states, in some embodiments, including administering an atypical antidepressant to a target and delivering it to a target tES. In some embodiments, administering an atypical antidepressant and delivering it to tES alleviates symptoms of mild depression. In some embodiments, administering an atypical antidepressant and delivering it to tES alleviates symptoms of moderate depression. In some embodiments, administering an atypical antidepressant and delivering it to tES alleviates symptoms of severe depression. In some embodiments, administering an atypical antidepressant includes administering two or more atypical antidepressants. In some embodiments, administering an atypical antidepressant includes administering an atypical antidepressant and a second pharmacological antidepressant belonging to the drug category of SSRI, SNRI, NaSSA, SMS, SARI, SNDRI, NRI, NDRI, NDRA, SNDRA, TCA, TeCA, MAOI, NMDA receptor modulator, atypical antipsychotic, or benzodiazepine. In some embodiments, the atypical antidepressant is allopregnanolone. In some embodiments, the atypical antidepressant is agomelatine. In some embodiments, the atypical antidepressant is trazodone. In some embodiments, the atypical antidepressant is mirtazapine. In some embodiments, the atypical antidepressant is vortioxetine. In some embodiments, the atypical antidepressant is bilazodone.In some embodiments, the atypical antidepressant is psilocybin. In some embodiments, the atypical antidepressant is a psilocybin-containing drug for treating depressive states. In some embodiments, the atypical antidepressant is DMT. In some embodiments, the atypical antidepressant is zulanolone. In some embodiments, the atypical antidepressant is certrexant. In some embodiments, the atypical antidepressant is XEN1101. In some embodiments, the atypical antidepressant is erteverel. In some embodiments, the atypical antidepressant is NV-5138. In some embodiments, the atypical antidepressant is TS-121. In some embodiments, the atypical antidepressant is ALKS 5461. ALKS 5461 is a pharmaceutical formulation containing buprenorphine and samidorphan. In some embodiments, the atypical antidepressant is a pharmaceutical formulation containing carbidopa and oxytriptan. In some embodiments, the atypical antidepressant is a pharmaceutical formulation comprising dudextromethorphan and quinidine. In some embodiments, the pharmaceutical formulation comprising dudextromethorphan and quinidine functions as a sigma-1 receptor agonist, an NMDA receptor antagonist, a serotonin and norepinephrine reuptake inhibitor, an antiarrhythmic agent, and a CYP2D6 inhibitor.

[0046] Allopregnanolone is GABA AIt is known to function as a positive allosteric modulator of the action of γ-aminobutyric acid (GABA) in receptors. Agometaline is known to function as an agonist for both melatonin MT1 and MT2 receptors. Trazodone is known to inhibit the reuptake of serotonin and block both histamine receptors and α1-adrenergic receptors. Mirtazapine is classified as a NaSSA, TeCA, and atypical antidepressant, and although the mechanism of action of mirtazapine is not fully understood, it is known that both noradrenergic and serotonergic activities increase after mirtazapine administration. Mirtazapine is also a potent antagonist of serotonin 5-HT2 and 5-HT3 receptors. Mirtazapine is a peripheral α1-adrenergic antagonist and a potent histamine (H1) receptor antagonist. Vortioxetine has been shown to have a dual mechanism of action on the serotonin neurotransmitter system, thereby regulating one or more serotonin receptors simultaneously and also inhibiting 5-HT reuptake. Vortioxetine is also a partial agonist of the 5-HT 1B receptor, an agonist of 5-HT 1A , and functions as an antagonist of 5-HT3, 5-HT 1D , and 5-HT7 receptors. Vilazodone acts to selectively inhibit 5-HT reuptake and also acts as a partial agonist of the 5HT 1A receptor. Psilocybin and DMT are both known to function as agonists of various 5-HT receptors. Zuranolone is a GABA AIt is known to act as a positive allosteric modulator of the receptor. Certrexant is known to function as an orexin antagonist. In some embodiments, certrexant is a selective agonist of the orexin OX2 receptor (2-SORA). XEN1101 is known to function as a modulator of voltage-gated potassium channels. XEN1101 is known to function as a modulator of the Kv7 potassium channel. XEN1101 is known to function as an agonist of the KCNQ2 / 3 channel. Erteverel is a nonsteroidal estrogen drug known to act as a selective estrogen receptor beta agonist. In some embodiments, erteverel may function as an agonist of the estrogen receptor alpha. NV-5138 is a small molecule drug known to directly and selectively activate the mTORC1 signaling pathway by binding to and modulating the activity of sestrin 2. TS-121 is known to function as a vasopressin V1B receptor antagonist.

[0047] Benzodiazepines are a class of drugs prescribed to function as antidepressants for those who need them. Benzodiazepines may be used to treat one or more symptoms of depression. Benzodiazepines may be used to treat one or more symptoms that occur concurrently with symptoms of depression. In some embodiments, the one or more symptoms that occur concurrently with symptoms of depression include anxiety, insomnia, parasomnias, muscle rigidity, muscle spasms, seizures, and / or alcohol withdrawal symptoms. Benzodiazepines are gamma-aminobutyric acid (GABA)- A It is known to function as an allosteric modulator of receptors. Benzodiazepines are known to enhance the function of the inhibitory neurotransmitter GABA. Certain benzodiazepines are known to interact with further neurotransmitter systems. As a non-limiting example, clonazepam interacts with GABA in a very potent and long-lasting manner. ABenzodiazepines function not only as receptor agonists but also as serotonin agonists. Benzodiazepines tend to be fast-acting, and therefore, subjects taking benzodiazepines may experience rapid symptom relief. Benzodiazepines are generally not considered safe for continuous use because they may increase the risk of physical dependence. Benzodiazepines, as part of a treatment regimen, may reduce the intensity of physiological symptoms of generalized anxiety disorder, such as panic attacks, sweating, headache, muscle tension, insomnia, and restlessness. Benzodiazepines, as part of a treatment regimen, may reduce cognitive symptoms of anxiety disorder, such as excessive worry or rumination. Possible side effects associated with benzodiazepine use include excessive sleepiness, confusion, dizziness, depression, motor coordination problems, and visual disturbances. Benzodiazepine use may not be indicated for subjects exhibiting suicidal ideation or suicidal thoughts, or those with addictive tendencies or a family history of addiction. Described herein are methods for treating depressive states, which in some embodiments include administering benzodiazepines to a target and delivering tES to a target.

[0048] In some embodiments, administering a benzodiazepine involves administering a benzodiazepine and a second pharmacological antidepressant belonging to the drug category of SSRIs, SNRIs, NaSSAs, SMSs, SARIs, SNDRIs, NRIs, NDRIs, NDRAs, SNDRAs, TCAs, TeCAs, MAOIs, NMDA receptor modulators, atypical antipsychotics, or atypical antidepressants. In some embodiments, the benzodiazepine is diazepam. In some embodiments, the benzodiazepine is alprazolam. In some embodiments, the benzodiazepine is triazolam. In some embodiments, the benzodiazepine is lorazepam. In some embodiments, the benzodiazepine is clonazepam. In some embodiments, the benzodiazepine is chlordiazepoxide. In some embodiments, the benzodiazepine is nitrazepam. In some embodiments, the benzodiazepine is loprazolam.

[0049] Administration of pharmacological antidepressants In some embodiments, a method for treating depression includes administering a pharmacological antidepressant to a target and delivering it to a target tES. In some embodiments, the pharmacological antidepressant is administered orally. In some embodiments, the pharmacological antidepressant is administered sublingually. In some embodiments, the pharmacological antidepressant is administered orally. In some embodiments, the pharmacological antidepressant is administered nasally. In some embodiments, the pharmacological antidepressant is administered rectally. In some embodiments, the pharmacological antidepressant is administered vaginally. In some embodiments, the pharmacological antidepressant is administered intravenously. In some embodiments, the pharmacological antidepressant is administered intramuscularly. In some embodiments, the pharmacological antidepressant is administered subcutaneously. In some embodiments, the pharmacological antidepressant is administered transdermally. In some embodiments, the pharmacological antidepressant is administered by inhalation. In some preferred embodiments, the pharmacological antidepressant is administered orally or intravenously. In some embodiments, the pharmacological antidepressant may be administered orally and intravenously.

[0050] Solid dosage forms for oral administration of pharmacological antidepressants may include capsules, tablets, caplets, pills, lozenges, powders, and granules. A capsule may include a core material containing a nutritional protein or composition, and a shell wall enclosing the core material. In some embodiments, the core material may be at least one of a solid, a liquid, and an emulsion. In some embodiments, the shell wall material may be at least one of soft gelatin, hard gelatin, and a polymer. Suitable polymers include, but are not limited to, cellulose polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose (HPMC), methylcellulose, ethylcellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, and sodium carboxymethylcellulose; vinyl polymers and copolymers such as polyvinylpyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate, vinyl acetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer; and shellac (purified lac). In some embodiments, at least one polymer can function as a taste masking agent. In some embodiments, the pharmacological antidepressant may be formulated as a gel. In some embodiments, the pharmacological antidepressant may be formulated as a cream. In some embodiments, the pharmacological antidepressant may be formulated as an ointment. In some embodiments, the pharmacological antidepressant may be formulated as a solution. In some embodiments, the pharmacological antidepressant may be formulated as a powder. In some embodiments, the pharmacological antidepressant may be formulated as a paste. In some embodiments, the pharmacological antidepressant may be formulated as a foam. In some embodiments, the pharmacological antidepressant may be formulated as an emulsion.

[0051] Tablets, pills, etc., may be compressed, multi-compressed, multilayered, and / or coated. The coating may be single or multiple. In some embodiments, the coating material may include at least one of sugars, polysaccharides, and glycoproteins extracted from at least one of plants, fungi, and microorganisms. Non-limiting examples include corn starch, wheat starch, potato starch, tapioca starch, cellulose, hemicellulose, dextran, maltodextrin, cyclodextrin, inulin, pectin, mannan, gum arabic, locust bean gum, mesquite gum, guar gum, karaya gum, tragacanth gum, seaweed, carrageenan, agar, alginate, chitosan, or gellan gum. In some embodiments, the coating material may include proteins. In some embodiments, the coating material may include at least one of fats and / or oils. In some embodiments, at least one of the fats and / or oils may be high-temperature meltable. In some embodiments, at least one of the fats and / or oils may be hydrogenated or partially hydrogenated. In some embodiments, at least one of the fats and / or oils may be derived from plants. In some embodiments, at least one of the fats and / or oils may include at least one of glycerides, free fatty acids, and fatty acid esters. In some embodiments, the coating material may include at least one edible wax. The edible wax may be derived from animals, insects, or plants. Non-limiting examples include beeswax, lanolin, bayberry wax, carnauba wax, and rice bran wax. Tablets and pills may further be prepared using enteric coatings.

[0052] Liquid formulations may include syrups (e.g., oral formulations), intravenous formulations, intranasal formulations, ointments, creams, aerosols, and the like. In some embodiments, various combinations of formulations can be administered. In some embodiments, pharmacological antidepressants may be administered orally in solid formulations and intravenously in liquid formulations.

[0053] In some embodiments, tablets, pills, capsules, etc., may be formulated for an extended-release profile. In some embodiments, tablets, pills, capsules, etc., may be formulated for a delayed-release profile. In some embodiments, tablets, pills, capsules, etc., may be formulated for a sustained-release profile. In some embodiments, tablets, pills, capsules, etc., may be formulated for a prolonged-release profile. In some embodiments, tablets, pills, capsules, etc., may be formulated for a slow-acting profile. In some embodiments, tablets, pills, capsules, etc., may be formulated to be pharmacological antidepressants.

[0054] In some embodiments, tablets, pills, capsules, etc., may be formulated to contain two or more pharmacological antidepressants. In some embodiments, two or more pharmacological antidepressants may be formulated to be released in the subject according to different release profiles. In some embodiments, the first pharmacological antidepressant may be formulated for immediate or rapid release, and the second pharmacological antidepressant may be formulated for sustained release. In some embodiments, the first pharmacological antidepressant may be formulated for immediate or rapid release, and the second pharmacological antidepressant may be formulated for delayed release. In some embodiments, the pharmacological antidepressant formulation includes liposomes. In some embodiments, the pharmacological antidepressant formulation includes liposomes. In some embodiments, the pharmacological antidepressant loaded into liposomes results in a superior pharmacokinetic profile after administration due to the low solubility of the pharmacological antidepressant in aqueous solution. In some embodiments, the pharmacological antidepressant formulation includes nanoparticles. In some embodiments, the pharmacological antidepressant formulation includes nanoparticles. In some embodiments, the nanoparticles include magnetic nanoparticles, zinc oxide nanoparticles, selenium-coated nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, chitosan-coated nanoparticles, polymer micelles, cyclodextrins, or dendrimers. In some embodiments, the formulation includes a release of a pharmacological antidepressant that is slower than that of conventional oral formulations. In some embodiments, the formulation includes a release of a pharmacological antidepressant that is slower than that of conventional liquid formulations. In some embodiments, the pharmacological antidepressant formulation includes a matrix. In some embodiments, the matrix includes a bioabsorbable polymer. In some embodiments, the bioabsorbable polymer is poly(lactic-co-glycolic acid) (PLGA), poly(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA), or poly(glycolic acid) (PGA). In some embodiments, the matrix includes a bioinert polymer.In some embodiments, the bioinert polymer is ethylene vinyl acetate, cellulose acetate, or low-density polyethylene (LDPE). In some embodiments, the matrix may release one active ingredient containing a pharmacological antidepressant. In some embodiments, the matrix may release two or more active ingredients containing pharmacological antidepressants. In some embodiments, the matrix may release two or more active ingredients containing multiple pharmacological antidepressants. In some embodiments, the matrix may enable delayed release of a pharmacological antidepressant. In some embodiments, the matrix may enable sustained release of a pharmacological antidepressant. In some embodiments, the matrix may enable prolonged release of a pharmacological antidepressant. In some embodiments, the matrix may enable slow-release of a pharmacological antidepressant. In some embodiments, the matrix may enable prolonged release of a pharmacological antidepressant. In some embodiments, the matrix may enable prolonged release of a pharmacological antidepressant. In some embodiments, the matrix may be contained within a patch and formulated for administration by patch. In some embodiments, the pharmacological antidepressant is administered via the patch. In some embodiments, the pharmacological antidepressant administered via the patch is administered transdermally.

[0055] Methods for administering pharmacological antidepressants are described herein. In some embodiments, the pharmacological antidepressant is administered to a subject in need according to a treatment regimen. In some embodiments, the pharmacological antidepressant is administered to the subject in a therapeutically effective dose. In some embodiments, a therapeutically effective dose of the pharmacological antidepressant is sufficient to bring about improvement in the symptoms of a depressive state. In some embodiments, a therapeutically effective dose of the pharmacological antidepressant is sufficient to bring about improvement in two or more symptoms of a depressive state. In some embodiments, a therapeutically effective dose of the pharmacological antidepressant is sufficient to bring about improvement in the symptoms of a mild depressive state. In some embodiments, a therapeutically effective dose of the pharmacological antidepressant is sufficient to bring about improvement in the symptoms of a moderate depressive state. In some embodiments, a therapeutically effective dose of the pharmacological antidepressant is sufficient to bring about improvement in the symptoms of a severe depressive state.

[0056] In some embodiments, the treatment regimen comprises a single dose of a certain amount of pharmacological antidepressant. In some embodiments, the treatment regimen comprises at least one dose of a certain amount of pharmacological antidepressant. In some embodiments, the treatment regimen comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 or more doses of a certain amount of pharmacological antidepressant. In some embodiments, the administration of a certain amount of pharmacological antidepressant includes the administration of a therapeutically effective amount of pharmacological antidepressant. In some embodiments, the amount contained in a single dose is an effective amount that lasts for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 30, 36, 40, 44, or 48 hours. In some embodiments, the amount contained in a single dose is an effective dose for at least 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 35, 42, 49, 56, 60, 61, 62, or 90 days. In some embodiments, a single dose contains an effective dose for at least 1 week, at least 2 weeks, at least 4 weeks, at least 2 months, or at least 6 months. In some embodiments, a therapeutically effective dose of the pharmacological antidepressant is sufficient to improve the symptoms of a depressive state. In some embodiments, a therapeutically effective dose of the pharmacological antidepressant is sufficient to improve two or more symptoms of a depressive state. In some embodiments, the therapeutically effective dose of pharmacological antidepressant remains consistent throughout the duration of the treatment regimen.

[0057] In some embodiments, a consistent dose of therapeutically effective pharmacological antidepressant is sufficient to maintain a measure of one or more depressive symptoms. In some embodiments, a consistent dose of therapeutically effective pharmacological antidepressant is sufficient to improve a measure of one or more depressive symptoms. In some embodiments, a consistent dose of therapeutically effective pharmacological antidepressant is sufficient to prevent relapse of one or more depressive symptoms. In some embodiments, a therapeutically effective dose of pharmacological antidepressant may be reduced throughout the duration of the treatment regimen. In some embodiments, a reduced therapeutically effective dose of pharmacological antidepressant is sufficient to maintain a measure of one or more depressive symptoms. In some embodiments, a reduced therapeutically effective dose of pharmacological antidepressant is sufficient to improve a measure of one or more depressive symptoms. In some embodiments, a reduced therapeutically effective dose of pharmacological antidepressant is sufficient to prevent relapse of one or more depressive symptoms. In some embodiments, improvement in a measure of one or more depressive symptoms includes a reduction in one or more depressive symptoms. In some embodiments, improvement in a measure of one or more depressive symptoms includes a reduction in the MADRS score. In some embodiments, improvement in one or more depressive symptom measures includes a reduction in the MADRS-s score. In some embodiments, maintaining one or more depressive symptom measures includes preventing an increase in the MADRS score. In some embodiments, maintaining one or more depressive symptom measures includes preventing an increase in the MADRS-s score. In some embodiments, preventing a relapse of one or more depressive symptoms includes preventing an increase in the target MADRS score compared to the target MADRS score obtained at an earlier point in time. In some embodiments, preventing a relapse of one or more depressive symptoms includes preventing an increase in the target MADRS-s score compared to the target MADRS-s score obtained at an earlier point in time.

[0058] In some embodiments, the treatment regimen includes the administration of a pharmacological antidepressant according to recommendations. In some embodiments, the recommendations include recommendations for the frequency of administration. In some embodiments, the recommendations include recommendations for the dosage. In some embodiments, the recommendations include an assessment of one or more symptoms of depression. In some embodiments, the recommendations include a reduction in the frequency of administration after a certain number of doses of the pharmacological antidepressant. In some embodiments, the recommendations include a reduction in the dosage of the pharmacological antidepressant administered after a certain number of doses. In some embodiments, the recommendations are provided by a physician or healthcare professional. In some embodiments, the recommendations are a medical prescription for the treatment of depression. In some embodiments, the recommendations are provided by a system that analyzes one or more symptoms of depression in a subject. In some embodiments, the treatment regimen includes daily administration of a pharmacological antidepressant. In some embodiments, the treatment regimen includes twice-daily administration of a pharmacological antidepressant. In some embodiments, the treatment regimen includes three times-daily administration of a pharmacological antidepressant. In some embodiments, the treatment regimen includes four times-daily administration of a pharmacological antidepressant. In some embodiments, the treatment regimen includes administration of a pharmacological antidepressant every other day. In some embodiments, the treatment regimen includes administration of a pharmacological antidepressant every three days. In some embodiments, the treatment regimen includes administration of a pharmacological antidepressant every four days. In some embodiments, the treatment regimen includes administration of a pharmacological antidepressant every five days. In some embodiments, the treatment regimen includes administration of a pharmacological antidepressant every six days. In some embodiments, the treatment regimen includes administration of a pharmacological antidepressant every seven days. In some embodiments, the treatment regimen includes administration of a pharmacological antidepressant until improvement in depressive symptoms is indicated by the subject. In some embodiments, the treatment regimen includes administration of a pharmacological antidepressant until improvement in depressive symptoms is recorded by the subject in the study. In some embodiments, the treatment regimen includes administration of a pharmacological antidepressant until improvement in depressive symptoms in the subject is indicated by a physician or healthcare professional.In some embodiments, the treatment regimen includes the administration of a pharmacological antidepressant for a period following improvement in depressive symptoms demonstrated by the subject. In some embodiments, the treatment regimen includes the administration of a pharmacological antidepressant for a period following improvement in depressive symptoms recorded by the subject in a study. In some embodiments, the study is completed by the subject. In some embodiments, the study is completed by a physician or healthcare professional providing healthcare to the subject. In some embodiments, the treatment regimen includes the administration of a pharmacological antidepressant for a period following improvement in depressive symptoms in the subject demonstrated by a physician or healthcare professional.

[0059] In some embodiments, what is described herein is a method by which a pharmacological antidepressant is administered to a subject in a therapeutically effective dose. In some embodiments, the therapeutically effective dose increases during the course of treatment. In some embodiments, the therapeutically effective dose is maintained at the same amount during the course of treatment. In some embodiments, the therapeutically effective dose decreases during the course of treatment. In some embodiments, increasing the therapeutically effective dose prevents the need to replace a currently administered pharmacological antidepressant with a pharmacological antidepressant of the same drug class. In some embodiments, increasing the therapeutically effective dose prevents the need to replace a currently administered pharmacological antidepressant with a pharmacological antidepressant of a different antidepressant class. In some embodiments, maintaining the therapeutically effective dose prevents the need to replace a currently administered pharmacological antidepressant with a pharmacological antidepressant of the same drug class. In some embodiments, maintaining the therapeutically effective dose prevents the need to replace a currently administered pharmacological antidepressant with a pharmacological antidepressant of a different antidepressant class. In some embodiments, a decrease in the therapeutic dose prevents the need to replace a currently administered pharmacological antidepressant with a pharmacological antidepressant of the same drug class. In some embodiments, a decrease in the therapeutic dose prevents the need to replace a currently administered pharmacological antidepressant with a pharmacological antidepressant of a different antidepressant class. In some embodiments, an increase in the therapeutic dose includes an increase in the dosage of the pharmacological antidepressant. In some embodiments, an increase in the therapeutic dose includes an increase in the frequency of administration of the pharmacological antidepressant. In some embodiments, an increase in the therapeutic dose includes an increase in the dosage and an increase in the frequency of administration of the pharmacological antidepressant. In some embodiments, maintaining the therapeutic dose includes an increase in the dosage and a decrease in the frequency of administration of the pharmacological antidepressant. In some embodiments, maintaining the therapeutic dose includes a decrease in the dosage and an increase in the frequency of administration of the pharmacological antidepressant. In some embodiments, a decrease in the therapeutic dose includes a decrease in the frequency of administration of the pharmacological antidepressant. In some embodiments, a reduction in the therapeutic dose includes a reduction in the dosage of the pharmacological antidepressant. In some embodiments, a reduction in the therapeutic dose includes a reduction in the dosage of the pharmacological antidepressant and a reduction in the frequency of administration of the pharmacological antidepressant.In some embodiments, the therapeutically effective dose of the pharmacological antidepressant is gradually tapered, and one or more symptoms of the depressive state are evaluated. In some embodiments, the tapered therapeutically effective dose includes reducing the amount of the pharmacological antidepressant administered. In some embodiments, the tapered therapeutically effective dose includes reducing the frequency of administration of the pharmacological antidepressant. In some embodiments, the evaluation of one or more symptoms of the depressive state is completed at consecutive time points to determine the therapeutic effect.

[0060] In some embodiments, the therapeutically effective dose includes a dose of the pharmacological antidepressant. In some embodiments, the dose of the pharmacological antidepressant is 0.01 mg to 150 mg. In some embodiments, the dose of the pharmacological antidepressant is at least about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.30 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.50 mg, 0 .55mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1mg, 1.25mg, 1.5mg, 1.75mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg, 11mg, 12mg, 13mg, 14 mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 32mg, 34mg, 35mg, 36mg, 37.5mg, 38mg, 40mg, 42mg, 44mg, 46mg, 48mg, 50mg, 52mg, 54mg, 5 The dosages are 6mg, 58mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 250mg, 300mg, or 400mg.In some embodiments, the pharmacological dose of the antidepressant is approximately 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.30 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.50 mg, 0.55 mg , 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1mg, 1.25mg, 1.5mg, 1.75mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5m g, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg, 11mg, 12mg, 13mg, 14mg, 1 5mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30m g, 32mg, 34mg, 35mg, 36mg, 37.5mg, 38mg, 40mg, 42mg, 44mg, 46mg, 48mg, 50mg, 52mg, 54mg, 56mg , 58 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg, 300 mg, or less than 400 mg. In some embodiments, the dose of the pharmacological antidepressant is about 0.1 mg. In some embodiments, the dose of the pharmacological antidepressant is about 0.25 mg. In some embodiments, the dose of the pharmacological antidepressant is about 0.50 mg. In some embodiments, the dose of the pharmacological antidepressant is about 0.75 mg. In some embodiments, the dose of the pharmacological antidepressant is about 1 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 1.5 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 2 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 2.5 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 5 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 7.5 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 10 mg.In some embodiments, the dose of the pharmacological antidepressant is approximately 12.5 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 15 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 20 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 25 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 30 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 35 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 37.5 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 40 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 45 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 50 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 60 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 70 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 75 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 80 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 100 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 125 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 150 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 200 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 250 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 300 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 400 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 500 mg. In some embodiments, the dose of the pharmacological antidepressant is approximately 600 mg. In some embodiments, the dose of fluoxetine is approximately 10 mg. In some embodiments, the dose of fluoxetine is about 20 mg. In some embodiments, the dose of fluoxetine is about 20 mg taken once daily. In some embodiments, the dose of fluoxetine is about 20 mg taken once daily in the morning. In some embodiments, the dose of fluoxetine is about 20 mg taken once daily in the evening.In some embodiments, the dose of fluoxetine is about 40 mg. In some embodiments, the dose of fluoxetine is about 40 mg in the morning. In some embodiments, the dose of fluoxetine is about 50 mg. In some embodiments, the dose of fluoxetine is about 50 mg taken once daily in the evening. In some embodiments, the dose of fluoxetine is about 60 mg. In some embodiments, the dose of fluoxetine is about 60 mg once daily in the morning. In some embodiments, the dose of fluoxetine is about 80 mg once daily. In some embodiments, the dose of citalopram is about 10 mg. In some embodiments, the dose of citalopram is about 20 mg. In some embodiments, the dose of citalopram is about 30 mg. In some embodiments, the dose of citalopram is about 40 mg. In some embodiments, the dose of escitalopram is about 5 mg. In some embodiments, the dose of escitalopram is about 10 mg. In some embodiments, the dose of escitalopram is about 20 mg. In some embodiments, the dose of paroxetine is about 10 mg. In some embodiments, the dose of paroxetine is about 20 mg. In some embodiments, the dose of sertraline is about 25 mg taken once daily. In some embodiments, the dose of sertraline is about 50 mg taken once daily. In some embodiments, the dose of sertraline is about 75 mg taken once daily. In some embodiments, the dose of sertraline is about 100 mg taken once daily. In some embodiments, the dose of sertraline is about 125 mg taken once daily. In some embodiments, the dose of sertraline is about 150 mg taken once daily. In some embodiments, the dose of sertraline is about 175 mg taken once daily. In some embodiments, the dose of sertraline is approximately 200 mg, taken once daily. In some embodiments, the dose of dapoxetine is approximately 30 mg, taken once daily. In some embodiments, the dose of dapoxetine is approximately 60 mg. In some embodiments, the dose of fluvoxamine is approximately 25 mg.In some embodiments, the dose of fluvoxamine is approximately 25 mg, taken once daily in the evening. In some embodiments, the dose of fluvoxamine is approximately 50 mg. In some embodiments, the dose of fluvoxamine is approximately 50 mg, taken once daily in the evening. In some embodiments, the dose of fluvoxamine is approximately 50 mg, taken once daily at bedtime. In some embodiments, the dose of fluvoxamine is approximately 100 mg. In some embodiments, the dose of fluvoxamine is approximately 150 mg. In some embodiments, the dose of fluvoxamine is approximately 200 mg. In some embodiments, the dose of fluvoxamine is approximately 250 mg. In some embodiments, the dose of fluvoxamine is approximately 300 mg. In some embodiments, the dose of vortioxetine is approximately 5 mg. In some embodiments, the dose of vortioxetine is approximately 10 mg. In some embodiments, the dose of vortioxetine is about 10 mg once daily, regardless of meals. In some embodiments, the dose of vortioxetine is about 15 mg. In some embodiments, the dose of vortioxetine is about 20 mg. In some embodiments, the dose of desvenlafaxine is about 10 mg once daily. In some embodiments, the dose of desvenlafaxine is about 20 mg once daily. In some embodiments, the dose of desvenlafaxine is about 25 mg once daily. In some embodiments, the dose of desvenlafaxine is about 50 mg once daily. In some embodiments, the dose of desvenlafaxine is about 100 mg once daily. In some embodiments, the dose of desvenlafaxine is about 200 mg once daily. In some embodiments, the dose of desvenlafaxine is about 300 mg once daily. In some embodiments, the dose of desvenlafaxine is about 400 mg once daily. In some embodiments, the dose of duloxetine is about 20 mg once daily. In some embodiments, the dose of duloxetine is about 30 mg once daily. In some embodiments, the dose of duloxetine is about 40 mg once daily.In some embodiments, the dose of duloxetine is about 50 mg once daily. In some embodiments, the dose of duloxetine is about 60 mg once daily. In some embodiments, the dose of levomirnacipran is about 20 mg once daily. In some embodiments, the dose of levomirnacipran is about 40 mg. In some embodiments, the dose of levomirnacipran is about 60 mg. In some embodiments, the dose of levomirnacipran is about 80 mg. In some embodiments, the dose of milnacipran is about 12.5 mg. In some embodiments, the dose of milnacipran is about 25 mg. In some embodiments, the dose of milnacipran is about 37.5 mg. In some embodiments, the dose of milnacipran is about 50 mg. In some embodiments, the dose of milnacipran is about 50 mg twice daily. In some embodiments, the dose of milnacipran is about 75 mg. In some embodiments, the dose of milnacipran is about 100 mg. In some embodiments, the dose of venlafaxine IR is approximately 37.5 mg. In some embodiments, the dose of venlafaxine IR is approximately 37.5 mg once daily. In some embodiments, the dose of venlafaxine IR is approximately 75 mg. In some embodiments, the dose of venlafaxine IR is approximately 75 mg once daily. In some embodiments, the dose of venlafaxine IR is approximately 150 mg. In some embodiments, the dose of venlafaxine IR is approximately 225 mg. In some embodiments, the dose of venlafaxine XR is approximately 37.5 mg once daily. In some embodiments, the dose of venlafaxine XR is approximately 37.5 mg twice daily. In some embodiments, the dose of venlafaxine XR is approximately 75 mg. In some embodiments, the dose of venlafaxine XR is approximately 75 mg once daily. In some embodiments, the dose of venlafaxine XR is approximately 150 mg. In some embodiments, the dose of aptazapine is about 15 mg. In some embodiments, the dose of aptazapine is about 30 mg. In some embodiments, the dose of aptazapine is about 45 mg. In some embodiments, the dose of esmirtazapine is about 1.5 mg. In some embodiments, the dose of esmirtazapine is about 3 mg. In some embodiments, the dose of esmirtazapine is about 4.5 mg. In some embodiments, the dose of mianserin is about 30 mg. In some embodiments, the dose of mianserin is about 40 mg. In some embodiments, the dose of mianserin is about 60 mg. In some embodiments, the dose of mianserin is about 80 mg. In some embodiments, the dose of mianserin is about 90 mg. In some embodiments, the dose of mirtazapine is about 15 mg. In some embodiments, the dose of mirtazapine is about 30 mg. In some embodiments, the dose of mirtazapine is about 45 mg. In some embodiments, the dose of setiptiline is about 30 mg. In some embodiments, the dose of virazodone is about 10 mg. In some embodiments, the dose of virazodone is about 20 mg.In some embodiments, the dose of vortioxetine is about 5 mg. In some embodiments, the dose of vortioxetine is about 10 mg. In some embodiments, the dose of vortioxetine is about 15 mg. In some embodiments, the dose of vortioxetine is about 20 mg. In some embodiments, the dose of nefazodone is about 100 mg. In some embodiments, the dose of nefazodone is about 200 mg. In some embodiments, the dose of trazodone is about 50 mg. In some embodiments, the dose of trazodone is about 100 mg. In some embodiments, the dose of trazodone is about 150 mg. In some embodiments, the dose of trazodone is about 200 mg. In some embodiments, the dose of trazodone is about 250 mg. In some embodiments, the dose of trazodone is about 300 mg. In some embodiments, the dose of tordesvenlafaxine is about 50 mg. In some embodiments, the dose of tordesvenlafaxine is about 75 mg. In some embodiments, the dose of tordesvenlafaxine is about 100 mg. In some embodiments, the dose of OPC-64005 is about 20 mg. In some embodiments, the dose of ansofaxine is 40 mg. In some embodiments, the dose of ansofaxine is 80 mg. In some embodiments, the dose of ansofaxine is 120 mg. In some embodiments, the dose of ansofaxine is 160 mg. In some embodiments, the dose of atomoxetine is about 40 mg. In some embodiments, the dose of atomoxetine is about 80 mg. In some embodiments, the dose of reboxetine is about 4 mg. In some embodiments, the dose of reboxetine is about 8 mg. In some embodiments, the dose of reboxetine is about 10 mg. In some embodiments, the dose of teniroxazine is about 80 mg. In some embodiments, the dose of biloxazine is about 100 mg. In some embodiments, the dose of biloxazine is about 200 mg. In some embodiments, the dose of bupropion is about 100 mg. In some embodiments, the dose of bupropion is about 150 mg.In some embodiments, the dose of bupropion is about 200 mg. In some embodiments, the dose of bupropion is about 300 mg. In some embodiments, the dose of bupropion is about 400 mg. In some embodiments, the dose of bupropion is about 450 mg. In some embodiments, the dose of amineptin is about 100 mg. In some embodiments, the dose of amineptin is about 200 mg. In some embodiments, the dose of methylphenidate is about 5 mg. In some embodiments, the dose of methylphenidate is about 10 mg. In some embodiments, the dose of methylphenidate is about 15 mg. In some embodiments, the dose of methylphenidate is about 20 mg. In some embodiments, the dose of methylphenidate is about 25 mg. In some embodiments, the dose of methylphenidate is about 30 mg. In some embodiments, the dose of AXS-05 is about 45 mg of dextromethorphan and about 105 mg of bupropion. In some embodiments, the dose of AXS-05 is about 90 mg of dextromethorphan and about 210 mg of bupropion. In some embodiments, the dose of lisdexamfetamine is about 30 mg once daily in the morning. In some embodiments, the dose of lisdexamfetamine is about 40 mg once daily in the morning. In some embodiments, the dose of lisdexamfetamine is about 50 mg once daily in the morning. In some embodiments, the dose of lisdexamfetamine is about 60 mg once daily in the morning. In some embodiments, the dose of phenethylamine is about 10 mg. In some embodiments, the dose of phenethylamine is about 20 mg. In some embodiments, the dose of phenethylamine is about 30 mg. In some embodiments, the dose of phenethylamine is about 40 mg. In some embodiments, the dose of phenethylamine is about 50 mg. In some embodiments, the dose of phenethylamine is about 60 mg. In some embodiments, the dose of pemoline is about 37.5 mg. In some embodiments, the dose of pemoline is about 75 mg. In some embodiments, the dose of mephedrone is about 100 mg.In some embodiments, the dose of mephedrone is about 200 mg. In some embodiments, the dose of mephedrone is about 300 mg. In some embodiments, the dose of amitriptyline is about 25 mg. In some embodiments, the dose of amitriptyline is about 50 mg. In some embodiments, the dose of amitriptyline is about 75 mg. In some embodiments, the dose of amitriptyline is about 100 mg. In some embodiments, the dose of amitriptyline is about 125 mg. In some embodiments, the dose of amitriptyline is about 150 mg. In some embodiments, the dose of clomipramine is about 25 mg. In some embodiments, the dose of clomipramine is about 50 mg. In some embodiments, the dose of clomipramine is about 75 mg. In some embodiments, the dose of clomipramine is about 100 mg. In some embodiments, the dose of desipramine is about 100 mg. In some embodiments, the dose of desipramine is about 200 mg. In some embodiments, the dose of desipramine is about 300 mg. In some embodiments, the dose of dosulepin is about 75 mg. In some embodiments, the dose of dosulepin is about 150 mg. In some embodiments, the dose of dosulepin is about 225 mg. In some embodiments, the dose of doxepin is about 25 mg. In some embodiments, the dose of doxepin is about 50 mg. In some embodiments, the dose of doxepin is about 75 mg. In some embodiments, the dose of doxepin is about 100 mg. In some embodiments, the dose of doxepin is about 125 mg. In some embodiments, the dose of doxepin is about 150 mg. In some embodiments, the dose of imipramine is about 75 mg. In some embodiments, the dose of imipramine is about 100 mg. In some embodiments, the dose of imipramine is about 150 mg. In some embodiments, the dose of lofepramine is about 70 mg. In some embodiments, the dose of lofepramine is about 140 mg. In some embodiments, the dose of lofepramine is about 210 mg.In some embodiments, the dose of nortriptyline is about 25 mg, taken 3 to 4 times a day. In some embodiments, the dose of nortriptyline is about 50 mg. In some embodiments, the dose of nortriptyline is about 75 mg. In some embodiments, the dose of nortriptyline is about 75 mg, taken once a day. In some embodiments, the dose of nortriptyline is about 100 mg. In some embodiments, the dose of protriptyline is about 10 mg. In some embodiments, the dose of protriptyline is about 15 mg. In some embodiments, the dose of protriptyline is about 20 mg. In some embodiments, the dose of protriptyline is about 30 mg. In some embodiments, the dose of protriptyline is about 45 mg. In some embodiments, the dose of protriptyline is about 60 mg. In some embodiments, the dose of trimipramine is about 50 mg. In some embodiments, the dose of trimipramine is about 50 mg once daily. In some embodiments, the dose of trimipramine is about 75 mg. In some embodiments, the dose of trimipramine is about 100 mg. In some embodiments, the dose of trimipramine is about 150 mg. In some embodiments, the dose of amoxapine is about 25 mg two to three times daily. In some embodiments, the dose of amoxapine is about 50 mg two to three times daily. In some embodiments, the dose of amoxapine is about 75 mg two to three times daily. In some embodiments, the dose of maprotiline is about 25 mg two to three times daily. In some embodiments, the dose of maprotiline is about 50 mg two to three times daily. In some embodiments, the dose of maprotiline is about 75 mg two to three times daily. In some embodiments, the dose of mianserin is about 30 mg one to three times daily. In some embodiments, the dose of mirtazapine is about 15 mg, taken 1 to 3 times a day. In some embodiments, the dose of selegiline is about 1.25 mg. In some embodiments, the dose of selegiline is about 2.5 mg. In some embodiments, the dose of selegiline is about 3.75 mg. In some embodiments, the dose of selegiline is about 5 mg.In some embodiments, the dose of selegiline is approximately 6.25 mg. In some embodiments, the dose of selegiline is approximately 7.5 mg. In some embodiments, the dose of selegiline is approximately 10 mg. In some embodiments, the dose of selegiline is approximately 12 mg. In some embodiments, the dose of tranylcypromine is approximately 10 mg, 1 to 3 times a day. In some embodiments, the dose of tranylcypromine is about 15 mg, taken 1 to 3 times a day. In some embodiments, the dose of tranylcypromine is about 20 mg, taken 1 to 3 times a day. In some embodiments, the dose of phenelzine is about 10 mg. In some embodiments, the dose of phenelzine is about 10 mg, taken 3 times a day. In some embodiments, the dose of phenelzine is about 15 mg. In some embodiments, the dose of phenelzine is about 15 mg, taken 3 times a day. In some embodiments, the dose of phenelzine is about 20 mg. In some embodiments, the dose of phenelzine is about 20 mg, taken 3 times a day. In some embodiments, the dose of phenelzine is about 25 mg, taken 3 times a day. In some embodiments, the dose of phenelzine is about 30 mg, taken 3 times a day. In some embodiments, the dose of isocarboxazide is about 10 mg. In some embodiments, the dose of isocarboxazide is about 10 mg twice daily. In some embodiments, the dose of isocarboxazide is about 15 mg twice daily. In some embodiments, the dose of isocarboxazide is about 20 mg twice daily. In some embodiments, the dose of isocarboxazide is about 25 mg twice daily. In some embodiments, the dose of apimostinel is about 50 mg. In some embodiments, the dose of apimostinel is about 100 mg. In some embodiments, the dose of apimostinel is about 150 mg. In some embodiments, the dose of apimostinel is about 200 mg. In some embodiments, the dose of apimostinel is about 250 mg. In some embodiments, the dose of apimostinel is about 375 mg. In some embodiments, the dose of apimostinel is about 500 mg. In some embodiments, the dose of alketamine is about 25 mg. In some embodiments, the dose of alketamine is about 50 mg. In some embodiments, the dose of alketamine is about 75 mg. In some embodiments, the dose of alketamine is about 100 mg. In some embodiments, the dose of alketamine is about 150 mg. In some embodiments, the dose of esketamine is about 25 mg.In some embodiments, the dose of esketamine is about 50 mg. In some embodiments, the dose of esketamine is about 75 mg. In some embodiments, the dose of esketamine is about 100 mg. In some embodiments, the dose of esketamine is about 150 mg. In some embodiments, the dose of esketamine is about 28 mg. In some embodiments, the dose of esketamine is about 56 mg. In some embodiments, the dose of esketamine is about 84 mg. In some embodiments, the dose of esketamine is about 56 mg administered intranasally once a week. In some embodiments, the dose of esketamine is about 56 mg administered intranasally twice a week. In some embodiments, the dose of esketamine is about 84 mg once a week. In some embodiments, the dose of esketamine is about 84 mg twice a week. In some embodiments, the dose of esmethadone is about 25 mg. In some embodiments, the dose of risrenemdaz is about 8 mg. In some embodiments, the dose of risrenemdaz is about 12 mg. In some embodiments, the dose of risrenemdaz is about 20 mg. In some embodiments, lapastinel is administered by intravenous infusion. In some embodiments, lapastinel is administered by intravenous infusion at a dose of 1 mg / kg. In some embodiments, lapastinel is administered by intravenous infusion at a dose of 3 mg / kg. In some embodiments, lapastinel is administered by intravenous infusion at a dose of 5 mg / kg. In some embodiments, lapastinel is administered by intravenous infusion at a dose of 10 mg / kg. In some embodiments, lapastinel is administered by intravenous infusion at a dose of 30 mg / kg. In some embodiments, the dose of brilaloxazine is about 15 mg. In some embodiments, the dose of brilaloxazine is about 25 mg. In some embodiments, the dose of brillaroxazine is about 50 mg. In some embodiments, the dose of caliprazine is about 1 mg. In some embodiments, the dose of caliprazine is about 1.5 mg. In some embodiments, the dose of caliprazine is about 2 mg.In some embodiments, the dose of caliprazine is about 2.5 mg. In some embodiments, the dose of caliprazine is about 3 mg. In some embodiments, the dose of lumateperone is about 42 mg. In some embodiments, the dose of lurasidone is about 20 mg. In some embodiments, the dose of lurasidone is about 40 mg. In some embodiments, the dose of pimavanserin is about 17 mg. In some embodiments, the dose of pimavanserin is about 34 mg. In some embodiments, the dose of aripiprazole is about 2 mg once daily. In some embodiments, the dose of aripiprazole is about 3.5 mg once daily. In some embodiments, the dose of aripiprazole is about 5 mg once daily. In some embodiments, the dose of brexpiprazole is about 0.5 mg once daily. In some embodiments, the dose of brexpiprazole is about 1 mg once daily. In some embodiments, the dose of olanzapine is about 2.5 mg once daily. In some embodiments, the dose of olanzapine is about 5 mg once daily. In some embodiments, the dose of olanzapine is about 10 mg once daily. In some embodiments, the dose of quetiapine is about 50 mg once daily. In some embodiments, the dose of quetiapine is about 75 mg once daily. In some embodiments, the dose of quetiapine is about 100 mg once daily. In some embodiments, the dose of quetiapine is about 125 mg once daily. In some embodiments, the dose of quetiapine is about 150 mg once daily. In some embodiments, the dose of ziprasidone is about 40 mg twice daily. In some embodiments, the dose of ziprasidone is about 60 mg twice daily. In some embodiments, the dose of SEP-4199 is about 50 mg / day. In some embodiments, the dose of SEP-4199 is about 100 mg / day. In some embodiments, the dose of SEP-4199 is about 200 mg / day. In some embodiments, the dose of SEP-4199 is about 400 mg / day. In some embodiments, the dose of NRX-101 contains about 66 mg of lurasidone and about 950 mg of D-cycloserine.In some embodiments, the dose of allopregnanolone is approximately 30 mg once daily. In some embodiments, the dose of allopregnanolone is administered as a continuous intravenous infusion. In some embodiments, the dose of allopregnanolone is administered as a continuous intravenous infusion over a period of approximately 60 hours. In some embodiments, the dose of allopregnanolone is administered as a continuous intravenous infusion starting at a dose of approximately 30 mcg / kg / hour. In some embodiments, the dose of allopregnanolone is administered as a continuous intravenous infusion increasing up to a dose of 60 mcg / kg / hour. In some embodiments, the dose of allopregnanolone is administered as a continuous intravenous infusion increasing up to a dose of 90 mcg / kg / hour. In some embodiments, the dose of allopregnanolone is administered as a continuous intravenous infusion decreasing up to a dose of 60 mcg / kg / hour. In some embodiments, the dose of allopregnanolone is administered as a continuous intravenous infusion decreasing up to a dose of 30 mcg / kg / hour. In some embodiments, the dose of agomelatine is about 12.5 mg once daily at bedtime. In some embodiments, the dose of agomelatine is about 25 mg once daily at bedtime. In some embodiments, the dose of trazodone is about 150 mg. In some embodiments, the dose of mirtazapine is about 15 mg one to three times daily. In some embodiments, the dose of vortioxetine is about 2.5 mg. In some embodiments, the dose of vortioxetine is about 5 mg. In some embodiments, the dose of vortioxetine is about 10 mg. In some embodiments, the dose of bilazodone is about 10 mg. In some embodiments, the dose of bilazodone is about 20 mg. In some embodiments, the dose of bilazodone is about 40 mg. In some embodiments, the dose of psilocybin is about 10 mg. In some embodiments, the dose of psilocybin is about 20 mg. In some embodiments, the dose of psilocybin is about 25 mg. In some embodiments, the dose of psilocybin is about 35 mg. In some embodiments, the dose of psilocybin is about 40 mg. In some embodiments, the dose of psilocybin is about 50 mg.In some embodiments, the dose of DMT is approximately 6 mg. In some embodiments, the dose of DMT is approximately 8 mg. In some embodiments, the dose of DMT is approximately 18 mg. In some embodiments, the dose of DMT is approximately 24 mg. In some embodiments, the dose of DMT is approximately 30 mg. In some embodiments, the dose of zulanolone is approximately 20 mg. In some embodiments, the dose of zulanolone is approximately 30 mg. In some embodiments, the dose of zulanolone is approximately 50 mg. In some embodiments, the dose of certrexant is 10 mg. In some embodiments, the dose of certrexant is 20 mg. In some embodiments, the dose of certrexant is 40 mg. In some embodiments, the dose of XEN1101 is 10 mg. In some embodiments, the dose of XEN1101 is 20 mg. In some embodiments, the dose of erteverel is 25 mg. In some embodiments, the dose of erteverel is 50 mg. In some embodiments, the dose of erteberel is 75 mg. In some embodiments, the dose of NV-5138 is 200 mg. In some embodiments, the dose of NV-5138 is 400 mg. In some embodiments, the dose of NV-5138 is 800 mg. In some embodiments, the dose of NV-5138 is 1200 mg. In some embodiments, the dose of NV-5138 is 1600 mg. In some embodiments, the dose of TS-121 is 10 mg. In some embodiments, the dose of TS-121 is 25 mg. In some embodiments, the dose of TS-121 is 50 mg. In some embodiments, the dose of ALKS 5461 contains about 2 mg of buprenorphine and about 2 mg of samidorphan. In some embodiments, the dose of ALKS 5461 contains about 8 mg of buprenorphine and about 8 mg of samidorphan. In some embodiments, the dosage of a pharmaceutical formulation containing carbidopa and oxytriptan is approximately 25 mg of carbidopa and approximately 50 mg of oxytriptan.In some embodiments, the dosage of a pharmaceutical formulation containing carbidopa and oxytriptan is approximately 25 mg of carbidopa and approximately 75 mg of oxytriptan. In some embodiments, the dosage of a pharmaceutical formulation containing carbidopa and oxytriptan is approximately 10 mg of carbidopa and approximately 50 mg of oxytriptan. In some embodiments, the dosage of a pharmaceutical formulation containing dudextromethorphan hydrobromide (d6-DM) and quinidine is approximately 18 mg of d6-DM and approximately 4.9 mg of quinidine. Several embodiments. In some embodiments, the dosage of the pharmaceutical formulation containing d6-DM and quinidine is approximately 28 mg of d6-DM and approximately 4.9 mg of quinidine. In some embodiments, the dosage of diazepam is approximately 2 mg. In some embodiments, the dosage of diazepam is approximately 2.5 mg. In some embodiments, the dosage of diazepam is approximately 2 mg, taken 1 to 4 times a day. In some embodiments, the dosage of diazepam is approximately 2.5 mg, taken 1 to 4 times a day. In some embodiments, the dosage of alprazolam is approximately 0.25 mg. In some embodiments, the dosage of alprazolam is approximately 0.25 mg, taken 1 to 3 times a day. In some embodiments, the dosage of alprazolam is approximately 0.5 mg, taken 1 to 3 times a day. In some embodiments, the dosage of triazolam is approximately 0.125 mg. In some embodiments, the dose of triazolam is about 0.125 mg taken at bedtime. In some embodiments, the dose of triazolam is about 0.25 mg. In some embodiments, the dose of triazolam is about 0.25 mg taken at bedtime. In some embodiments, the dose of lorazepam is about 0.5 mg. In some embodiments, the dose of lorazepam is about 1 mg. In some embodiments, the dose of lorazepam is about 1 mg, taken 1 to 4 times a day. In some embodiments, the dose of lorazepam is about 2.5 mg. In some embodiments, the dose of lorazepam is about 2.5 mg, taken 1 to 4 times a day. In some embodiments, the dose of clonazepam is about 0.25 mg. In some embodiments, the dose of clonazepam is about 0.25 mg, taken twice a day. In some embodiments, the dose of clonazepam is about 0.5 mg. In some embodiments, the dose of clonazepam is about 1 mg. In some embodiments, the dose of clonazepam is about 2 mg. In some embodiments, the dose of clonazepam is about 2.5 mg. In some embodiments, the dose of chlordiazepoxide is about 5 mg. In some embodiments, the dose of chlordiazepoxide is about 5 mg three to four times a day. In some embodiments, the dose of chlordiazepoxide is about 10 mg.In some embodiments, the dose of chlordiazepoxide is about 10 mg, taken 3 to 4 times a day. In some embodiments, the dose of nitrazepam is about 5 mg. In some embodiments, the dose of nitrazepam is about 5 mg, taken at bedtime. In some embodiments, the dose of nitrazepam is about 10 mg. In some embodiments, the dose of nitrazepam is about 10 mg, taken at bedtime. In some embodiments, the dose of loprazolam is about 1 mg. In some embodiments, the dose of loprazolam is about 1 mg, taken at bedtime. In some embodiments, the dose of loprazolam is about 1.5 mg. In some embodiments, the dose of loprazolam is about 1.5 mg, taken at bedtime. In some embodiments, the dose of loprazolam is about 2 mg. In some embodiments, the dose of loprazolam is about 2 mg, taken at bedtime. In some embodiments, the dose of the pharmacological antidepressant is gradually increased until the desired improvement in one or more depressive symptoms is achieved. In some embodiments, the dose of the pharmacological antidepressant is titrated downward to determine the lowest effective dose. In some embodiments, the dose of the pharmacological antidepressant is titrated downward to determine the lowest effective dose that shows the desired improvement in one or more depressive symptoms in the subject. In some embodiments, the dose of the pharmacological antidepressant is titrated downward to determine the lowest effective dose that shows the desired improvement in one or more depressive symptoms in the subject and reduces the severity or occurrence of undesirable drug side effects. In some embodiments, the dose of the pharmacological antidepressant is titrated downward to determine the lowest effective dose that shows the desired improvement in one or more depressive symptoms in the subject and reduces the severity or occurrence of undesirable drug side effects in the subject. In some embodiments, the dose of the pharmacological antidepressant is titrated downward to reduce two or more undesirable drug side effects in the subject.In some embodiments, the dose of the pharmacological antidepressant is 0.25 mg, 0.50 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, Titrate upward in increments of 28 mg, 29 mg, 30 mg, 32 mg, 34 mg, 35 mg, 36 mg, 37.5 mg, 38 mg, 40 mg, 42 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 175 mg, 200 mg, 225 mg, or 250 mg. In some embodiments, the dose of the pharmacological antidepressant is 0.25 mg, 0.50 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, The drug is titrated downward in increments of 28 mg, 29 mg, 30 mg, 32 mg, 34 mg, 35 mg, 36 mg, 37.5 mg, 38 mg, 40 mg, 42 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 175 mg, 200 mg, 225 mg, or 250 mg. In some embodiments, the frequency of administration and the dose per administration of the pharmacological antidepressant are selected to treat the subject, which is an adult. In some embodiments, the frequency of administration and the dose per administration of the pharmacological antidepressant are selected to treat the subject, which is an elderly person.In some embodiments, the frequency and dosage of the pharmacological antidepressant are selected to treat a subject, which is an adolescent. In some embodiments, the frequency and dosage of the pharmacological antidepressant are selected to treat a subject, which is a child. In some embodiments, a child or adolescent is being treated for a depressive state during adolescence. In some embodiments, the frequency and dosage of the pharmacological antidepressant are selected to provide a therapeutic benefit for the treatment of a depressive state that responds partially to a separate antidepressant therapy. In some embodiments, the frequency and dosage of the pharmacological antidepressant are selected to provide an adjunctive treatment for a depressive state.

[0061] In some embodiments, the treatment regimen includes a drug administration regime. In some embodiments, the drug administration regime specifies the frequency of administration of a dose of a pharmacological antidepressant. In some embodiments, the administration frequency is up to approximately every hour, every two hours, every three hours, every four hours, every five hours, every six hours, every seven hours, every eight hours, every nine hours, every ten hours, every eleven hours, every twelve hours, every thirteen hours, every fourteen hours, every fifteen hours, every sixteen hours, every seventeen hours, every eighteen hours, every nineteen hours, every twenty hours, every twenty-one hours, every twenty-one hours, every twenty-two hours, every twenty-three hours, every twenty-four hours, every twenty-eight hours, every thirty-two hours, every thirty-four hours, every forty hours, every forty-four hours, every twenty-one hours, every twenty-eight days, every twenty-eight days, every twenty-eight days, every twenty-eight days, or every twenty-eight days. In some embodiments, the administration frequency is approximately once a month, once every three weeks, once every two weeks, once every ten days, once a week, once every six days, once every five days, once every four days, once every three days, once every two days, once daily, twice daily, three daily, four daily, five daily, six daily, seven daily, eight daily, nine daily, ten daily, eleven daily, or twelve daily. In some embodiments, the administration frequency is approximately every eight hours. In some embodiments, the administration frequency is three times a day. In some embodiments, the administration frequency is approximately every twelve hours. In some embodiments, the administration frequency is twice a day. In some embodiments, the administration frequency is approximately every 24 hours. In some embodiments, the administration frequency is once a day. In some embodiments, the administration frequency is once a day, in the morning. In some embodiments, the administration frequency is once a day, at night. In some embodiments, the administration frequency is once a day, at bedtime. In some embodiments, the administration frequency is once a day, regardless of food intake. In some embodiments, the administration frequency is once a day, coinciding with food intake. In some embodiments, the administration frequency is approximately every 36 hours. In some embodiments, the administration frequency is approximately every other day. In some embodiments, the administration frequency is once every 3 days. In some embodiments, the administration frequency is once every 4 days. In some embodiments, the administration frequency is approximately twice a week. In some embodiments, the administration frequency is approximately once a week.In some embodiments, the pharmacological antidepressant administered to the subject is a pharmaceutically acceptable salt of a pharmacological antidepressant as named herein.

[0062] In some embodiments, the drug administration regime continues for a period of time. In some embodiments, the duration is determined before the start of treatment. In some embodiments, the duration is determined approximately at the start of treatment. In some embodiments, the duration is determined after the start of treatment. In some embodiments, the duration is determined after the start of treatment according to the results from measurements of one or more symptoms of depression. In some embodiments, the duration is determined by the subject. In some embodiments, the duration is determined by the physician or healthcare professional providing medical treatment to the subject. In some embodiments, the duration is determined according to the subject achieving the desired treatment outcome. In some embodiments, the desired treatment outcome is a reduction in one or more symptoms of depression. In some embodiments, the desired treatment outcome is a significant change in the MADRS score. In some embodiments, the desired treatment outcome is a significant change in the MADRS-s score. In some embodiments, the desired treatment outcome is remission of one or more symptoms of depression. In some embodiments, the desired treatment outcome is complete remission of the symptoms of depression. In some embodiments, the drug administration regime continues for a period of time, is stopped for a second period, and resumed for a third period. In some embodiments, a drug regime is continued for a certain period, paused for a second period during which the subject maintains the desired therapeutic outcome, and resumed for a third period during which the subject strives to improve one or more symptoms of depression. In some embodiments, a drug regime is continued for a certain period, paused for a second period during which the subject maintains the desired therapeutic outcome, and resumed for a third period during which the subject strives to improve one or more symptoms of depression, as measured by achieving a significant reduction in the MADRS or MADRS-s score.In some embodiments, the drug administration regime continues for a period of at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, or 2 years. In some embodiments, the drug administration regime continues for a period of 6 weeks. In some embodiments, the drug administration regime continues for a period of 10 weeks. In some embodiments, the drug administration regime continues for a period of 12 weeks. In some embodiments, the drug administration regime continues for a period of 16 weeks. In some embodiments, the drug regime continues for a period of 20 weeks. In some embodiments, the drug regime continues for a period of 25 weeks. In some embodiments, the drug regime continues for a period of 52 weeks. In some embodiments, the treatment regimen includes a multi-dose drug regimen. In some embodiments, the dosage in the multi-dose drug regimen is adjusted during the treatment period, including the administration of pharmacological antidepressants.

[0063] Conditions to be treated In another embodiment, the Specified Provision is a method for carrying out treatment in a subject requiring treatment of a disease, disorder, or condition, comprising administering a pharmacological antidepressant to the subject and delivering a tES to the subject. In some embodiments, the disease, disorder, or condition is a depressive state or a disease, disorder, or condition associated with a depressive state. In some embodiments, the depressive state is mild depression, moderate depression, severe depression, major depressive disorder, MDD, melancholic depression, persistent depressive disorder, psychotic depression, psychotic major depressive disorder, postpartum depression, situational depression, sudden depression, atypical depression, treatment-resistant depression, catatonic depression, double depression, unspecified depressive disorder, recurrent short-term depression, mild depressive disorder, alcohol-induced depression, substance-induced depression, benzodiazepine-induced depression. In some embodiments, the disease, disorder, or condition associated with a depressive state is anxiety. In some embodiments, the disorders, conditions, or states associated with depression are depression with anxiety distress, melancholy, agitation, type 1 bipolar disorder, type 2 bipolar disorder, bipolar disorder not otherwise specified, cyclothymic disorder, seasonal affective disorder, premenstrual dysphoric disorder, dysthymia, depressive personality disorder, or mixed anxiety-depressive disorder. In some embodiments, the methods for treating a depressive state or a disorder, disorder, or state associated with depression include treating the symptoms associated with the depressive state or a disorder, disorder, or state associated with depression. In some embodiments, the subject matter is the Diagnostic and Statistical Manual of Mental Disorders - 5th Edition. thThe subject is diagnosed with MDD based on the diagnostic criteria of the DSM-V edition. In some embodiments, the subject diagnosed with MDD also undergoes a thorough diagnostic evaluation to identify other psychiatric or general medical conditions that may require attention. In some embodiments, the psychiatrist develops a comprehensive treatment plan for the subject's MDD and conducts an assessment that includes the history of the current illness and current symptoms that may induce or exacerbate depressive symptoms. In some embodiments, the psychiatrist uses one of several clinically validated standard scales available for assessing the severity of depressive symptoms and classifies the severity of the subject's MDD as mild, moderate, or severe depression based on cutoffs from these scales.

[0064] The methods described herein may be used to treat depressive states or depressive-related conditions in a variety of subjects. In some embodiments, the subjects are adults. In some embodiments, the subjects are elderly. In some embodiments, the subjects are adolescents. In some embodiments, the subjects are children. In some embodiments, the adolescents or children have a depressive state or depressive-related condition during adolescence. In some embodiments, the subjects had a previous episode of depression. In some embodiments, the previous episode of depression was partially responsive to treatment. In some embodiments, the previous episode of depression was partially responsive to treatment with an SSRI. In some embodiments, the previous episode of depression was partially responsive to treatment with an SNRI. In some embodiments, the previous episode of depression was partially responsive to treatment with a NaSSA. In some embodiments, the previous episode of depression was partially responsive to treatment with an SMS. In some embodiments, the previous episode of depression was partially responsive to treatment with a SARI. In some embodiments, the previous episode of depression was partially responsive to treatment with an SNDRI. In some embodiments, the previous episode of depression was partially responsive to treatment with an NRI. In some embodiments, previous depressive episodes were partially responsive to treatment with NDRIs. In some embodiments, previous depressive episodes were partially responsive to treatment with NDRAs. In some embodiments, previous depressive episodes were partially responsive to treatment with SNDRAs. In some embodiments, previous depressive episodes were partially responsive to treatment with TCAs. In some embodiments, previous depressive episodes were partially responsive to treatment with TeCAs. In some embodiments, previous depressive episodes were partially responsive to treatment with MAOIs. In some embodiments, previous depressive episodes were partially responsive to treatment with NMDA receptor modulators.In some embodiments, the previous depressive episode was partially responsive to treatment with atypical antipsychotics. In some embodiments, the previous depressive episode was partially responsive to treatment with atypical antidepressants. In some embodiments, the previous depressive episode was partially responsive to treatment with benzodiazepines. In some embodiments, subjects who have previously received treatment for a depressive episode determined to be partially responsive to treatment may be defined as subjects who have achieved a reduction in the assessment of depressive state of less than 50% symptom improvement. In some embodiments, subjects who have previously received treatment for a depressive episode determined to be partially responsive to treatment may be defined as subjects who have achieved a reduction in MADRS score of less than 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the baseline MADRS score. In some embodiments, a previously treated subject for a depressive state determined to be partially responsive to treatment may be defined as a subject who has achieved a reduction in MADRS-s score of 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or less than 5% of the baseline MADRS-s score. In some embodiments, the desired treatment outcome for a subject treated by the method described herein is improvement of one or more of the subject's symptoms. In some embodiments, the desired treatment outcome for a subject treated by the method described herein is remission of one or more of the subject's symptoms. In some embodiments, the one or more symptoms are symptoms of a depressive state or a depressive state-related condition. In some embodiments, the one or more symptoms are symptoms of a comorbidity of the subject. In some embodiments, the desired treatment outcome for a subject may be a reduction of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, or 54 points in the MADRS-s score compared to the subject's baseline MADRS-s score.In some embodiments, the desired treatment outcome for a subject may be the maintenance of an improvement of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, or 54 points in the subject's MADRS-s score compared to the subject's baseline MADRS-s score over a period of time. In some embodiments, the period is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks.

[0065] Symptoms This specification describes methods for treating depressive states in subjects, wherein one or more symptoms of a mood disorder are modified. In some embodiments, one or more symptoms indicating a depressive state or a disorder or condition associated with a depressive state are modified. In some embodiments, one or more symptoms that do not indicate a depressive state or a disorder or condition associated with a depressive state are modified. In some embodiments, mood disorders are selected from the group consisting of depressive states, clinical depressive states, depressive states-related states, MDD, MDD with suicide risk, bipolar I disorder, bipolar II disorder, seasonal affective disorder (SAD), cyclothymic disorder, premenstrual dysphoric disorder, perimenopause-related depression, persistent depressive disorder (dysthymia), severe mood dysregulation, medically-associated depression, post-traumatic stress disorder, substance use or pharmacotherapy-induced depression, postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, double depression, depressive personality disorder, recurrent short-term depression, mild depressive disorder, treatment-resistant depression, anxiety-associated depression, treatment-refractory depression, suicidal tendencies, and suicidal behavior. In some embodiments, one or more symptoms of the depressive state improve in the subject. In some embodiments, one or more symptoms that do not indicate depression or a depression-related disorder or condition improve in the subject. In some embodiments, one or more symptoms of depression decrease in the subject. In some embodiments, one or more symptoms that do not indicate depression or a depression-related disorder or condition decrease in the subject. In some embodiments, one or more symptoms of depression increase in the subject. In some embodiments, one or more symptoms that do not indicate depression or a depression-related disorder or condition increase in the subject. In some embodiments, one or more symptoms of depression are maintained in the subject. In some embodiments, one or more symptoms that do not indicate depression or a depression-related disorder or condition are maintained in the subject. In some embodiments, one or more symptoms of depression are evaluated by the subject. In some embodiments, one or more symptoms of depression are evaluated by a physician or medical professional.In some embodiments, one or more symptoms of depression are recorded on a questionnaire. In some embodiments, one or more symptoms that do not indicate depression or a depression-related disorder or condition are evaluated by the subject. In some embodiments, one or more symptoms that do not indicate depression or a depression-related disorder or condition are evaluated by a physician or medical professional. In some embodiments, one or more symptoms that do not indicate depression or a depression-related disorder or condition are recorded on a questionnaire. In some embodiments, one or more symptoms of depression are evaluated by the subject. In some embodiments, one or more do not indicate depression or a depression-related disorder or condition. In some embodiments, the frequency and dosage of pharmacological antidepressants are selected to provide a therapeutic benefit to the treatment of depressive states selected from depressive states, clinical depressive states, depressive states-related states, MDD, MDD with risk of suicide, bipolar I disorder, bipolar II disorder, SAD, cyclothymic disorder, premenstrual dysphoric disorder, perimenopause-related depression, dysthymia, severe mood dysregulation, depressive states associated with medical illness, post-traumatic stress disorder, depressive states induced by substance use or pharmacotherapy, postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, double depression, depressive personality disorder, recurrent short-term depression, mild depressive disorder, treatment-resistant depression, anxiety-associated depression, treatment-refractory depression, suicidal tendencies, or suicidal behavior.

[0066] In some embodiments, the methods described herein modulate one or more symptoms of the subject. In some embodiments, the one or more modulated symptoms are symptoms of depression. In some embodiments, the one or more modulated symptoms are symptoms associated with depression. In some embodiments, the one or more modulated symptoms are symptoms indicating depression. In some embodiments, the one or more modulated symptoms are symptoms for the diagnosis of depression. In some embodiments, the one or more modulated depressive symptoms are depressed mood, irritability, mood instability, mood changes, mood swings, hormone-related mood swings, short-term memory impairment, abstract thinking impairment, judgment impairment, speech impairment, persistent feelings of anxiety, persistent feelings of sadness, helplessness, hopelessness, pessimism, worthlessness, lack of energy, restlessness, insomnia, sleep disturbances, irritability, excessive fatigue, motor dysfunction, loss of interest in pleasure activities, loss of concentration, low self-esteem, lack of positive thinking, lack of positive planning, excessive sleepiness, overeating, loss of appetite, self-harm. The symptoms are selected from the group consisting of behavior, suicidal ideation, suicidal thoughts, suicide attempts, anxiety, apathy, general discontent, guilt, despair, agitation, excessive crying, social isolation, early arousal, light sleep, excessive hunger, slowness of activity, lethargy, weight gain, weight loss, loss of appetite, rumination, changes in daily behavior, outbursts of anger, slow speech, slowness of body movements, fixation on past failures, self-blame, difficulty thinking, difficulty making decisions, frequent or recurrent thoughts of death, headaches, back pain, excessive worry, misplaced attention, excessive anger, avoidance of social interaction, personality changes, loss of libido, and persistent emptiness. In some embodiments, one or more modulated symptoms are symptoms that do not indicate a depressive state or a disorder or condition associated with depression.In some embodiments, symptoms that do not manifest as depression or a depression-related disorder or condition may be due to long-term stress, long-term fatigue, anxiety syndrome, borderline personality disorder, chronic pain, insomnia, attention-deficit / hyperactivity disorder (ADHD), bipolar disorder, eating disorders, posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), autism spectrum disorder, alcohol addiction, drug addiction, pregnancy, or hormonal imbalance.

[0067] Improvement and evaluation of symptoms related to depression Changes in depressive symptoms in a subject with a depressive state can be determined in several ways, and these changes can inform the subject's treatment plan. In some embodiments, the subject's treatment plan is modified according to the subject's evaluation. In some embodiments, modification of the treatment plan may include reducing the dosage of pharmacological antidepressants the subject is receiving, reducing the frequency of administration of pharmacological antidepressants the subject is receiving, reducing the number of tES sessions delivered to the subject, reducing the duration of tES sessions delivered to the subject, and / or reducing the intensity of tES in the sessions delivered to the subject. In some embodiments, modification of the treatment plan may include increasing the dosage of pharmacological antidepressants the subject is receiving, increasing the frequency of administration of pharmacological antidepressants the subject is receiving, changing the number of tES sessions delivered to the subject (which may be an increase or decrease in the number of tES sessions), changing the duration of tES sessions delivered to the subject (which may be an increase or decrease in the tES sessions), and / or changing the intensity of tES in the sessions delivered to the subject (which may be an increase or decrease in the intensity of tES in the sessions). In some embodiments, the assessment may be performed to determine a change in symptoms associated with depression. In some embodiments, the assessment may be used to determine an improvement in symptoms associated with depression. In some embodiments, the assessment may be used to determine the persistence of symptoms associated with depression. In some embodiments, the assessment may be used to determine a worsening of symptoms associated with depression. In some embodiments, the assessment may be used to determine the onset of new symptoms associated with depression. In some embodiments, the assessment may be used to determine a reduction in symptoms associated with depression. In some embodiments, a reduction in symptoms associated with depression includes a reduction in the degree or severity of one or more symptoms associated with depression. In some embodiments, a reduction in symptoms associated with depression includes a reduction in the number of categories of symptoms associated with depression. In some embodiments, a reduction in symptoms associated with depression includes remission of one or more symptoms associated with depression.In some embodiments, the reduction in symptoms associated with depression is maintained over a period of time. In some embodiments, the reduction in symptoms associated with depression is maintained over a period of time, and the subject continues to improve in terms of the severity of one or more symptoms associated with depression. In some embodiments, the period during which the subject experiences a reduction in one or more symptoms associated with depression is any period from one week to one year. In some embodiments, the period during which the subject experiences remission of one or more symptoms associated with depression is any period from one week to one year. In some embodiments, the reduction in one or more symptoms associated with depression improves the subject's self-reported quality of life assessment. In some embodiments, the remission of one or more symptoms associated with depression improves the subject's self-reported quality of life assessment. In some embodiments, the reduction in one or more symptoms associated with depression enables the subject to recover the ability to successfully complete one or more activities of daily living (ADL). In some embodiments, the remission of one or more symptoms associated with depression enables the subject to recover the ability to successfully complete one or more activities of daily living (ADL). In some embodiments, the reduction of one or more symptoms associated with depression allows for a reduction in the dosage of pharmacological antidepressants taken by the subject. In some embodiments, the reduction of one or more symptoms associated with depression allows for a reduction in the frequency of administration of pharmacological antidepressants taken by the subject. In some embodiments, the reduction of one or more symptoms associated with depression prevents the need to switch the medication being administered to the subject to a different pharmacological antidepressant as part of an attempt to improve treatment outcomes. In some embodiments, remission of one or more symptoms associated with depression allows for a reduction in the dosage of pharmacological antidepressants taken by the subject. In some embodiments, remission of one or more symptoms associated with depression allows for a reduction in the frequency of administration of pharmacological antidepressants taken by the subject. In some embodiments, remission of one or more symptoms associated with depression prevents the need to switch the medication being administered to the subject to a different pharmacological antidepressant as part of an attempt to improve treatment outcomes.In some embodiments, remission of one or more symptoms associated with depression allows the subject to gradually reduce the dose or frequency of pharmacological antidepressant administration and maintain remission of one or more symptoms associated with depression. In some embodiments, remission of one or more symptoms associated with depression allows the subject to gradually reduce the dose or frequency of pharmacological antidepressant administration and eventually discontinue pharmacological antidepressant administration and maintain remission of one or more symptoms associated with depression. In some embodiments, reduction of one or more symptoms associated with depression allows the subject to change the frequency of tES delivery to the subject. In some embodiments, remission of one or more symptoms associated with depression allows the subject to change the frequency of tES delivery to the subject. In some embodiments, reduction of one or more symptoms associated with depression allows the subject to reduce the frequency of tES delivery to the subject. In some embodiments, reduction of one or more symptoms associated with depression allows the subject to reduce the frequency of tES delivery to the subject. In some embodiments, remission of one or more symptoms associated with depression allows for a reduction in the intensity of tES delivered to the subject. In some embodiments, a reduction in one or more symptoms associated with depression after the initial phase of tES delivery to the subject allows for a reduction in the dosage of pharmacological antidepressants, a reduction in the frequency of pharmacological antidepressant administration, and / or a reduction in the number of tES sessions required to maintain improvement in the depressive state in the subject. In some embodiments, remission of one or more symptoms associated with depression after the initial phase of tES delivery to the subject allows for a reduction in the dosage of pharmacological antidepressants, a reduction in the frequency of pharmacological antidepressant administration, and / or a reduction in the number of tES sessions required to maintain improvement in the depressive state in the subject.

[0068] Changes in depressive symptoms in a subject with a depressive state can be determined by several methods. In some embodiments, the assessment may be performed to determine changes in depressive symptoms. In some embodiments, the assessment may be a self-assessment performed by the subject. In some embodiments, the assessment may be an assessment performed by a physician or healthcare professional providing treatment to the subject. In some embodiments, the assessment may be performed by the subject completing a questionnaire. In some embodiments, the questionnaire is a diagnostic questionnaire. In some embodiments, the assessment may be performed by a physical examination of the subject. In some embodiments, the assessment may be performed to determine a baseline score. In some embodiments, additional assessments may be performed according to the baseline score to determine the effectiveness of ongoing treatment. In some embodiments, additional assessments may be performed at intervals of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days. In some embodiments, additional evaluations may be performed at intervals of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 weeks. In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 additional evaluations may be performed.

[0069] One method that can be used as a measure of the severity of depressive episodes in a subject is assessment by completion of the Montgomery-Asberg Depression Rating Scale (MADRS) questionnaire. In some embodiments, the assessment is performed by the individual completing the MADRS questionnaire, which assesses the subject's symptoms. In some embodiments, a physician or healthcare professional completes the MADRS questionnaire. In some embodiments, the physician is a psychiatrist. The MADRS score can be calculated and can provide an overall assessment of the number and degree of depressive episodes or depressive symptoms in the subject at the time of assessment. In some embodiments, the MADRS score measures the overall severity of depressive episodes or depressive symptoms in a subject with a mood disorder. In some embodiments, the MADRS score measures the overall severity of depressive episodes or depressive symptoms in a subject with MDD. In some embodiments, the MADRS score is calculated on a scale of 0 to 60 points. In some embodiments, the MADRS score indicates the presence and degree of symptoms associated with several aspects of depressive episodes. In some embodiments, certain aspects of depression include outwardly expressed sadness, reported sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, inability to feel, pessimistic thoughts, and suicidal thoughts. In some embodiments, each item assessed in the MADRS is scored on a scale of 0 to 6 points. In some embodiments, a score of 0 indicates the absence of one or more depressive symptoms associated with the item. In some embodiments, a score of 6 indicates the maximum degree of one or more depressive symptoms associated with the item. In some embodiments, scores ranging from 1 to 5 indicate an increasing severity of one or more depressive symptoms associated with the item. In some embodiments, the subject's total point score is calculated by summing the point values ​​of each item. In some embodiments, a subject is determined to have a measure of the severity of a depressive episode at the time the assessment is performed by classifying the subject according to normal / symptom-free, mild depression, moderate depression, and severe depression.In some embodiments, normal / symptom-free is a determination of the severity of a depressive episode in a subject, following a total MADRS score of 0–6. In some embodiments, mild depression is a determination of the severity of a depressive episode in a subject, following a total MADRS score of 7–19. In some embodiments, moderate depression is a determination of the severity of a depressive episode in a subject, following a total MADRS score of 20–34. In some embodiments, severe depression is a determination of the severity of a depressive episode in a subject, following a total MADRS score of 34 or higher. In some embodiments, a change of at least 6–9 points from the baseline MADRS score to the MADRS score at a later time point has been shown to correspond to a clinically meaningful change in the depressive state in a subject. In some embodiments, a change of at least 6 points from the baseline MADRS score to the MADRS score at a later time point has been shown to correspond to a clinically meaningful change in the depressive state in a subject. In some embodiments, the depressive state is more severe at baseline, and a clinically meaningful change in MADRS may be greater than 6 points. In some embodiments, depressive state has improved compared to baseline, and further clinically significant improvement may be represented by a further decrease of 6 points or a further decrease of less than 6 points. In some embodiments, an increase in the MADRS score indicates an increase in the severity and / or degree of depressive state in the subject. In some embodiments, a decrease in the MADRS score indicates a decrease in the severity and / or degree of depressive state in the subject. In some embodiments, a decrease in the MADRS score indicates an improvement in depressive state in the subject. In some embodiments, when comparing different treatment groups including multiple subjects, a difference of 2 points or more in MADRS between groups has been found to be clinically significant. In some embodiments, when comparing different treatment groups including multiple subjects, a difference of 2 points or more in MADRS between groups has been found to be statistically significant. In some embodiments, when comparing different treatment groups including multiple subjects, a difference of 2 points or more in MADRS between groups has been found to represent a significantly different remission rate of depressive symptoms in the corresponding subjects.In some embodiments, when comparing different treatment groups containing multiple subjects, a difference of 2 points or more in MADRS between groups that prefer a particular different treatment group may represent a clinically relevant and significant clinical effect (including a change of 6 points or more in MADRS from baseline assessment) between subgroups of depressive subjects within the different treatment groups who benefited from the treatment.

[0070] One method that can be used as a measure of the severity of depressive episodes in a subject is assessment by completion of the Montgomery-Asberg Depression Rating Scale Self-assessment (MADRS-s) questionnaire. In some embodiments, the assessment is performed by the subject completing the MADRS-s questionnaire in which they assess their own symptoms. The MADRS-s score can be calculated and can provide an overall assessment of the number and degree of depressive episodes or depressive symptoms in the subject at the time of assessment. In some embodiments, the MADRS-s score measures the overall severity of depressive episodes or depressive symptoms in a subject with a mood disorder. In some embodiments, the MADRS-s score measures the overall severity of depressive episodes or depressive symptoms in a subject with MDD. In some embodiments, the MADRS-s score is calculated on a scale of 0 to 54 points. In some embodiments, the scores on a scale of 0 to 6 for each item are summed up to obtain the total MADRS-s score. In some embodiments, the MADRS-s score indicates the presence and severity of symptoms associated with several aspects of depression. In some embodiments, the number of aspects of depression includes reported sadness or reported mood, intrinsic tension or anxiety, sleep, appetite, difficulty concentrating or ability to concentrate, fatigue or spontaneity, inability to feel or emotional involvement, pessimistic thoughts or pessimism, and suicidal thoughts or will to live. In some embodiments, each item assessed in the MADRS-s is scored on a scale of 0 to 6 points. In some embodiments, a score of 0 indicates the absence of one or more symptoms of depression associated with the item. In some embodiments, a score of 6 indicates the maximum severity of one or more symptoms of depression associated with the item. In some embodiments, scores ranging from 1 to 5 indicate an increasing severity of the degree of one or more symptoms of depression associated with the item. In some embodiments, the total points score for the subject is calculated by summing the point values ​​of each item.In some embodiments, subjects are determined to have a measure of the severity of depressive episodes at the time of assessment by classifying them according to normal / symptom-free, mild depression, moderate depression, and severe depression. In some embodiments, normal / symptom-free or very mild depression is a determination of the severity of a subject's depressive episodes according to a total MADRS-s score of 0–12. In some embodiments, mild depression is a determination of the severity of a subject's depressive episodes according to a total MADRS-s score of 13–19. In some embodiments, moderate depression is a determination of the severity of a subject's depressive episodes according to a total MADRS-s score of 20–34. In some embodiments, severe depression is a determination of the severity of a subject's depressive episodes according to a total MADRS-s score of 35 or higher. In some embodiments, a change of at least 6–9 points from the baseline MADRS-s score to the MADRS-s score at a later time point has been shown to correspond to a clinically meaningful change in the subject's depression. In some embodiments, a change of at least 6 points from the baseline MADRS-s score to the MADRS-s score at a later time point has been shown to correspond to a clinically meaningful change in the depressive state of the subject. In some embodiments, the depressive state is more severe at baseline, and a clinically meaningful change in MADRS-s may be greater than 6 points. In some embodiments, the depressive state has improved compared to baseline, and further clinically meaningful improvement may be represented by a further decrease of 6 points or a further decrease of less than 6 points. In some embodiments, an increase in the MADRS-s score indicates an increase in the severity and / or degree of the depressive state of the subject. In some embodiments, a decrease in the MADRS-s score indicates a decrease in the severity and / or degree of the depressive state of the subject. In some embodiments, a decrease in the MADRS-s score indicates an improvement in the depressive state of the subject. In some embodiments, when comparing different treatment groups including multiple subjects, a difference of 2 points or more in MADRS-s between groups has been found to be clinically meaningful.In some embodiments, when comparing different treatment groups containing multiple subjects, a difference of 2 points or more in MADRS-s between groups has been found to be statistically significant. In some embodiments, when comparing different treatment groups containing multiple subjects, a difference of 2 points or more in MADRS-s between groups has been found to represent significantly different remission rates for depressive symptoms in the corresponding subjects. In some embodiments, when comparing different treatment groups containing multiple subjects, a difference of 2 points or more in MADRS-s between groups that prefer a particular different treatment group may represent a clinically relevant and significant clinical effect (including a change of 6 points or more in MADRS-s from baseline assessment) between subgroups of depressive subjects within different treatment groups who benefited from treatment. In some embodiments, subjects exhibit a decrease of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, or 54 points in their MADRS-S score compared to their baseline score, either during or after treatment. In some embodiments, the MADRS-S measurement is used in part to assess the subject's response to the treatment regimen and one or more stimulation sessions in order to determine treatment efficacy. In some embodiments, MADRS-S measurements are used in part to evaluate the subject's response to a treatment regimen and one or more stimulation sessions in order to determine the therapeutic effectiveness of the activation phase of nerve stimulation. In some embodiments, MADRS-S measurements are used in part to evaluate the subject's response to a treatment regimen and one or more stimulation sessions in order to determine the therapeutic effectiveness of the intensification phase of nerve stimulation.

[0071] In addition to the MADRS or MADRS-s, additional or alternative methods may be used as measures of the severity of depressive episodes in subjects. In some embodiments, subjects may be assessed using the Hamilton Depression Rating Scale (HAM-D). The HAM-D is a widely used clinician-administered depression rating scale. In some embodiments, the HAM-D includes 17 items related to depressive symptoms experienced over the past week. The HAM-D questionnaire is designed for use by clinicians to assess the severity of depressive symptoms in adults by examining mood, guilt, suicidal ideation, insomnia, agitation or delay, anxiety, weight loss, and physical symptoms. In some embodiments, subjects may be assessed for anxiety using the Hamilton Rating Scale for Anxiety (HAM-A). The HAM-A is a scale for measuring the severity of anxiety symptoms and, in some embodiments, consists of 14 items, each defined by a set of symptoms, measuring both mental anxiety, such as mental agitation and psychological distress, and physical anxiety, including somatic complaints related to anxiety. In some embodiments, subjects may be assessed by the Mini International Neuropsychiatric Interview (MINI), a short, structured diagnostic interview for DSM-IV and ICD-10 mental disorders. In some embodiments, subjects may be assessed by the Young Mania Rating Scale (YMRS), a scale for assessing the symptoms of mania. The YMRS scale consists of 11 items and is based on subjective reports of the patient's clinical state over the past 48 hours. In some embodiments, subjects may be assessed by the Rey Auditory Verbal Learning Test (RAVLT), a neuropsychological assessment designed to assess verbal memory in patients aged 16 years or older.The RAVLT can be used to assess the nature and severity of memory impairment and to track changes in memory function over time. In some embodiments, subjects may be assessed with respect to Clinical Global Impressions (CGI). In some embodiments, subscale scores of the CGI may be determined. In some embodiments, the subscale scores of the CGI may be a subscale of disease severity (CGI-S). In some embodiments, the subscale scores of the CGI may be a subscale of disease improvement (CGI-I). In some embodiments, the CGI-S score is referenced in an efficacy index subscale. In some embodiments, subjects may be assessed by the Symptoms of Depression Questionnaire (SDQ). In some embodiments, subjects may be assessed by determination using the Pittsburgh Sleep Quality Index (PSQI). In some embodiments, clinician-reported outcomes include HAM-D, MADRS, MINI, HAM-A, YMRS, RAVLT, CGI-S, CGI-I, SDQ, PSQI, or any combination thereof. In some embodiments, subjects may be tested using MADRS, MADRS-s, HAM-D, HAM-A, CGI-S, CGI-I, SDQ, or PSQI, or any combination thereof, to generate baseline scores. In some embodiments, subjects may be tested using MADRS, MADRS-s, HAM-D, HAM-A, CGI-S, CGI-I, SDQ, or PSQI, or any combination thereof, to compare scores during treatment to baseline scores. In some embodiments, the effectiveness of a medication regimen may be determined by evaluation using MADRS as the primary efficacy endpoint. In some embodiments, the effectiveness of a medication regimen may be determined by evaluation using MADRS-s as the primary efficacy endpoint.In some embodiments, the effectiveness of a medication regimen may be determined by evaluation using MADRS as the primary effectiveness endpoint, in relation to secondary effectiveness endpoints such as MADRS-s, HAM-D, HAM-A, CGI-S, CGI-I, SDQ, PSQI, or any combination thereof. In some embodiments, the frequency and dose of pharmacological antidepressants are selected to provide treatment for severe depression in subjects with a MADRS-s score of 34 or higher. In some embodiments, the frequency and dose of pharmacological antidepressants are selected to provide treatment for moderate depression in subjects with a MADRS-s score of 20 to 33. In some embodiments, the frequency and dosage of pharmacological antidepressants are selected to provide treatment for mild depression in subjects with a MADRS-s score of 13–19. In some embodiments, subjects complete a patient-reported outcome questionnaire. In some embodiments, the patient-reported outcome questionnaire is the MADRS-s. In some embodiments, the patient-reported outcome questionnaire is the EuroQol-5 Dimensionas-3 Level (EQ-5D-3L) score, the Symbol-Digit Modalities Test (SDMT), the Treatment Acceptability Questionnaire (TAQ), the Adverse Events Questionnaire (AEQ), the Columbia Suicide Severity Rating Scale (C-SSRS), or a combination thereof. The C-SSRS is an assessment scale for evaluating suicide risk. The C-SSRS scale identifies specific behaviors that may indicate suicidal intent in a subject.SDMT assessment detects cognitive impairment. SDMT allows clinicians to screen for organic brain dysfunction in both children (8 years and older) and adults. SDMT is quick, easy to administer, and has shown sensitivity in detecting the presence of brain damage and in detecting cognitive function over time in response to treatment. TAQ is a questionnaire used to survey how tolerable participants in tDCS clinical trials perceive the treatment. At baseline, TAQ measures participants' expectations regarding the trial (e.g., expected treatment outcomes, effort required, ethics, etc.) and then tracks these expectations during and / or at the end of the trial. AEQ is a specialized questionnaire developed to capture adverse events encountered by subjects during trials, including tDCS. The EQ-5D-3L assessment is a standardized measure of health-related quality of life.

[0072] In some embodiments, the frequency and dosage of the pharmacological antidepressant are selected to improve aspects of the depressive or depressive state in the subject. In some embodiments, aspects of the depressive or depressive state are reported sadness or reported mood. In some embodiments, aspects of the depressive or depressive state are internal tension or anxiety. In some embodiments, aspects of the depressive or depressive state are sleep. In some embodiments, aspects of the depressive or depressive state are appetite. In some embodiments, aspects of the depressive or depressive state are difficulty concentrating or ability to concentrate. In some embodiments, aspects of the depressive or depressive state are fatigue or spontaneity. In some embodiments, aspects of the depressive or depressive state are inability to feel or emotional involvement. In some embodiments, aspects of the depressive or depressive state are pessimistic thoughts or pessimism. In some embodiments, aspects of the depressive or depressive state are suicidal thoughts or will to live. In some embodiments, depressed mood is significantly improved in the subject. In some embodiments, a sense of well-being is significantly restored in the subject. In some embodiments, the sleep-related aspect of a depressive or depressive state in the subject is insomnia. In some embodiments, the degree of insomnia may be measured as latency to persistent sleep (LPS) compared to the LPS score during previous treatment. In some embodiments, the degree of insomnia may be measured as a decrease in wake time after sleep onset (WASO) compared to the wake time after sleep onset (WASO) score during previous treatment. In some embodiments, the degree of insomnia may be measured as the average total sleep time per sleep episode compared to a previous measurement of the average total sleep time per sleep episode. In some embodiments, the degree of insomnia may be measured as a function of sleep efficiency compared to a previous measurement of the subject's sleep efficiency before treatment. In some embodiments, total sleep time is the amount of actual sleep time in a sleep episode.In some embodiments, sleep efficiency is the percentage of total time spent in bed actually in a sleep state. In some embodiments, sustained sleep latency is the length of time it takes for a subject to achieve a transition from a fully awake state to a sleep state. In some embodiments, improvement in sleep-related state in a subject is defined as an increase of at least 25%, 37.5%, 50%, 62.5%, 75%, 87.5%, or 100% of WASO compared to the subject's previous WASO measurement. In some embodiments, improvement in sleep-related state in a subject is defined as a decrease of at least 25%, 37.5%, 50%, 62.5%, 75%, 87.5%, or 100% of LPS compared to the subject's previous LPS measurement. In some embodiments, improvement in sleep-related state in a subject is defined as an increase of at least 25%, 37.5%, 50%, 62.5%, 75%, 87.5%, or 100% of sleep efficiency compared to the subject's previous sleep efficiency measurement. In some embodiments, improvement in sleep-related conditions in a subject is defined as an increase of at least 25%, 37.5%, 50%, 62.5%, 75%, 87.5%, or 100% in total sleep time compared to the subject's previous total sleep time measurement. In some embodiments, improvement in sleep-related conditions in a subject is measured by assessment using the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), the Insomnia Severity Scale (ISI), the Athens Insomnia Scale (AIS), the Sleep Quality Index (SQI), or any combination thereof.

[0073] Improvement of the cognitive aspects of a subject can be achieved by the methods described herein. In some embodiments, neuronal stimulation via delivery of tES to the subject produces cognitive improvement. In some embodiments, administration of pharmacological antidepressants to the subject and neuronal stimulation via delivery of tES produce significant cognitive improvement. In some embodiments, a depressive state or a depressive state-related condition in the subject results in cognitive impairment in the subject. In some embodiments, a comorbid condition in the subject is associated with cognitive impairment in the subject. In some embodiments, the co-existing medical conditions of subjects with cognitive impairment include Alzheimer's disease, cancer, coronary heart disease, acute coronary syndrome, diabetes mellitus, epilepsy, HIV / AIDS, hypothyroidism, multiple sclerosis, Parkinson's disease, stroke, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, dementia, substance abuse disorder, psychiatric disorders, anorexia nervosa, bulimia nervosa, muscular dysplasia, bulimia nervosa, compulsive eating disorder, polycystic ovary syndrome, Prader-Willi syndrome, diabetic bulimia, autoimmune disorders, inflammatory disorders, or combinations thereof. In some embodiments, cognitive function improves in subjects during treatment. In some embodiments, cognitive function improves in subjects after a period of treatment. In some embodiments, cognitive function significantly improves in subjects during treatment. In some embodiments, cognitive function significantly improves in subjects after a period of treatment. In some embodiments, one or more executive functions of the brain improve in subjects. Executive functions refer to higher-level cognitive skills used to coordinate and control various other cognitive behaviors and abilities. Executive functions may also include organizational skills for gathering information and structuring that information for evaluation. Furthermore, executive functions may include regulatory skills, which include evaluating available information and regulating responses to a given environment. Organizational skills that fall under executive functions include attention, planning, sequencing, problem-solving, working memory, cognitive flexibility, abstract thinking, rule-following, and the selection of relevant sensory information.Regulatory skills corresponding to executive functions include behavior initiation, self-control, emotion regulation, monitoring of internal stimuli, monitoring of external stimuli, initiation and inhibition of situation-specific behaviors, moral and ethical reasoning, and decision-making. In some embodiments, attention is improved in the subject. In some embodiments, cognitive inhibition is improved in the subject. In some embodiments, inhibitory control is improved in the subject. In some embodiments, cognitive planning is improved in the subject. In some embodiments, working memory is improved in the subject. In some embodiments, emotion regulation is improved in the subject. In some embodiments, planning is improved in the subject. In some embodiments, ordering is improved in the subject. In some embodiments, problem solving is improved in the subject. In some embodiments, cognitive flexibility is improved in the subject. In some embodiments, abstract thinking is improved in the subject. In some embodiments, rule acquisition is improved in the subject. In some embodiments, behavior initiation is improved in the subject. In some embodiments, self-control is improved in the subject. In some embodiments, initiation and inhibition of situation-specific behaviors are improved in the subject. In some embodiments, moral and ethical reasoning is improved in the subject. In some embodiments, decision-making is improved in the subject.

[0074] Comorbidities Patients using the treatment methods described herein may have been diagnosed with a condition that puts them at risk of depression as a comorbidity. In some embodiments, the condition that puts them at risk of depression as a comorbidity may be an acute condition. In some embodiments, the condition that puts them at risk of depression as a comorbidity may be a chronic condition. In some embodiments, the condition that puts them at risk of depression as a comorbidity may be a neurological condition. In some embodiments, the condition that puts them at risk of depression as a comorbidity may be a personality disorder. In some embodiments, the condition that puts them at risk of depression as a comorbidity may be a metabolic condition. In some embodiments, the condition that puts them at risk of depression as a comorbidity may be an immune condition. In some embodiments, the condition that puts them at risk of depression as a comorbidity may be an inflammatory condition. In some embodiments, the condition that puts them at risk of depression as a comorbidity may be a genetic condition. In some embodiments, the condition that puts them at risk of depression as a comorbidity may be an environmentally induced condition. In some embodiments, conditions that carry a risk of depression as comorbidities include one or more of the following: Alzheimer's disease, cancer, coronary heart disease, acute coronary syndrome, diabetes mellitus, epilepsy, HIV / AIDS, hypothyroidism, multiple sclerosis, Parkinson's disease, stroke, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, chronic pain, neuropathic pain, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, dementia, substance abuse disorder, psychiatric disorders, anorexia nervosa, bulimia nervosa, muscular dysplasia, bulimia nervosa, compulsive eating disorder, polycystic ovary syndrome, Prader-Willi syndrome, diabetic bulimia, autoimmune disorders, or inflammatory disorders. In some embodiments, the methods described herein enable the therapeutic benefits of depression or depression-related conditions without exacerbation induced by treatment of the comorbid condition. In some embodiments, the methods described herein enable the therapeutic benefits of depression or depression-related conditions without interference with treatment of the comorbid condition.In some embodiments, the methods described herein enable therapeutic benefits for a depressive or depressive-related condition using lower doses of pharmacological antidepressants that may worsen the symptoms of a comorbid condition. In some embodiments, the methods described herein enable therapeutic benefits for a depressive or depressive-related condition using lower doses of pharmacological antidepressants that may interfere with the treatment of a comorbid condition.

[0075] Subjects using the treatment methods described herein may have one or more comorbid conditions that are modulated by the treatment methods. In some embodiments, one or more comorbid conditions of a subject may be aggravated by the treatment methods described herein. In some embodiments, one or more comorbid conditions of a subject may be improved by the treatment methods described herein. In some embodiments, one or more comorbid conditions of a subject may not be affected by the treatment methods described herein. In some embodiments, improvement of one or more comorbid conditions by using the treatment methods may include improvement of one or more symptoms of the comorbid conditions. In some embodiments, one or more comorbid conditions of a subject that can be improved by the treatment methods are selected from anxiety disorders, post-traumatic stress disorder, schizophrenia, chronic pain, neuropathic pain, eating disorders, conduct / antisocial behavior disorders, sleep disorders, neurodevelopmental disorders, personality disorders, traumatic brain injury, stroke, or autoimmune disorders.

[0076] In some embodiments, the comorbid sleep disorders that are improved by the treatment methods described herein are bruxism, central sleep apnea, chronic fatigue syndrome, circadian rhythm sleep disorders, excessive sleepiness, hypersomnia, insomnia, narcolepsy, night terrors, non-24-hour sleep-wake disorder, obstructive sleep apnea, parasomnias, periodic limb movement disorders, REM sleep behavior disorder, delayed sleep phase disorder, nocturia, rapid eye movement sleep behavior disorder, somniphobia, restless legs syndrome, shift work disorder, sleepwalking, sleep apnea, sleep-related breathing disorders, sleep-related movement disorders, sleep paralysis, or any combination thereof.

[0077] In some embodiments, the comorbid personality disorders that are improved by the treatment methods described herein are paranoid personality disorder, schizotypal personality disorder, schizotypal personality disorder, antisocial personality disorder, borderline personality disorder, histrionic personality disorder, narcissistic personality disorder, or avoidant personality disorder.

[0078] In some embodiments, the comorbid eating disorders that are improved by the treatment methods described herein are anorexia nervosa, bulimia nervosa, muscular dysplasia, bulimia nervosa, compulsive eating disorder, diabetic eating disorder, neurotic orthorexia, selective eating disorder, drunken orexia, or pregolexia.

[0079] In some embodiments, the neurodevelopmental disorders of comorbidities that are improved by the treatment methods described herein are attention deficit hyperactivity disorder (ADHD), learning disabilities (e.g., dyslexia, motor coordination disorder, dyscalculia, or dysgraphia), autism spectrum disorder, communication disorders, cerebral palsy, neurodevelopmental motor disorders, developmental language disorders, traumatic brain injury during neurodevelopment, or fetal alcohol spectrum disorder.

[0080] In some embodiments, the comorbid autoimmune disorders that are improved by the treatment methods described herein are Addison's disease, celiac disease, dermatomyositis, Graves' disease, multiple sclerosis, myasthenia gravis, pernicious anemia, reactive arthritis, rheumatoid arthritis, Sjögren's syndrome, or systemic lupus erythematosus.

[0081] Transcranial electrical stimulation Several methods of stimulating the brain, including delivering electrical or chemical stimuli, have been studied. One such technique is called transcranial magnetic stimulation (TMS), a non-invasive technique involving the placement of a specialized electromagnetic coil on the subject's scalp to induce an electric current in the brain using repetitive magnetic pulses. This treatment requires specialized equipment and medical supervision and is therefore not suitable for home use. Electroconvulsive therapy (ECT) is a technique that uses a strong electric current (generally around 800 mA) to induce a seizure or convulsion in the subject's brain. To minimize discomfort, ECT is administered under general anesthesia. Immediately after treatment, many subjects who receive ECT experience headache, muscle pain, and transient amnesia about the period immediately preceding ECT. Confusion may also occur after ECT treatment, mainly in elderly subjects, and can last for up to three days. Long-term memory impairment has also been reported in subjects receiving ECT. Due to its procedure and the need for medical management, ECT is an expensive and labor-intensive treatment, requiring the care of medical professionals and the use of a medical facility by the patient. Deep brain stimulation (DBS) is another technique used to stimulate the brain of a patient. DBS involves a neurosurgical procedure for the placement of a device called a neurostimulator, which delivers electrical impulses to specific targets deep within the brain through implanted electrodes. DBS has been used to target specific brain nuclei to provide a means of treating disorders such as dystonia, Parkinson's disease, essential tremor, and epilepsy. Because it involves a surgical procedure, DBS carries the risk of major surgery and surgical complications such as bleeding and infection. Other potential risks of DBS treatment include neuropsychiatric side effects, such as apathy, hallucinations, erotomania, cognitive impairment, depression, and euphoria. In contrast to TMS, ECT, and DBS, transcranial electrical stimulation (tES) offers a non-invasive, cost-effective alternative form of neurostimulation that can be performed at home and has a minimal risk profile of potential side effects.

[0082] tES is a non-invasive brain stimulation technique that uses electrical currents to alter brain function. tES works by inducing neuromodulation, which alters neural activity through targeted delivery of electrical stimuli. The current is typically applied to the scalp of the subject via two or more electrodes. While the large current applied is conducted between electrodes through the outer layers of soft tissue and the skull, some of the current has been shown to penetrate the scalp and skull and be conducted through brain tissue. Through this means of conducting small currents through the brain, the excitability of the subject's neurons can be altered. The arrangement of two or more electrodes used in tES allows for influence on nearby brain tissue through neuromodulatory interventions that alter neural activity through targeted delivery of stimuli. In contrast to some other brain stimulation techniques, the current delivered in tES is not strong enough to induce action potentials and is maintained at a subthreshold level to produce only neuronal excitability. tES can alter neural oscillations in neural networks and modulate functional connectivity between brain regions. Examples of tES include transcranial direct current stimulation (tDCS) devices, transcranial alternating current stimulation (tACS) devices, or transcranial random noise stimulation (tRNS) devices.

[0083] tDCS utilizes direct current delivered at low intensity through one or more active electrodes (anodes). In some embodiments, the electrical intensity used in tDCS is 0.5 to 4 mA. In some embodiments, the electrical intensity used in tDCS is 0.5 to 2 mA. In some embodiments, the electrical intensity used in tDCS is 0.8 to 2 mA. In some embodiments, the electrical intensity used in tDCS is 1.0 to 2.0 mA. In some embodiments, the electrical intensity output used in tDCS is approximately 0.5 mA. In some embodiments, the electrical intensity output used in tDCS is approximately 0.6 mA. In some embodiments, the electrical intensity output used in tDCS is approximately 0.7 mA. In some embodiments, the electrical intensity output used in tDCS is approximately 0.8 mA. In some embodiments, the electrical intensity output used in tDCS is approximately 0.9 mA. In some embodiments, the electrical intensity output used in tDCS is approximately 1.0 mA. In some embodiments, the electrical intensity output used in tDCS is approximately 1.1 mA. In some embodiments, the electrical intensity output used in the tDCS is approximately 1.2 mA. In some embodiments, the electrical intensity output used in the tDCS is approximately 1.3 mA. In some embodiments, the electrical intensity output used in the tDCS is approximately 1.4 mA. In some embodiments, the electrical intensity output used in the tDCS is approximately 1.5 mA. In some embodiments, the electrical intensity output used in the tDCS is approximately 1.6 mA. In some embodiments, the electrical intensity output used in the tDCS is approximately 1.7 mA. In some embodiments, the electrical intensity output used in the tDCS is approximately 1.8 mA. In some embodiments, the electrical intensity output used in the tDCS is approximately 1.9 mA. In some embodiments, the electrical intensity output used in the tDCS is approximately 2.0 mA. In some embodiments, the electrical intensity output used in the tDCS is approximately 2.1 mA. In some embodiments, the electrical intensity output used in the tDCS is approximately 2.2 mA. In some embodiments, the electrical intensity output used in the tDCS is approximately 2.3 mA.In some embodiments, the electrical intensity output used in tDCS is approximately 2.4 mA. In some embodiments, the electrical intensity output used in tDCS is approximately 2.5 mA. When current is applied to tDCS, the direction of current flow is from positive voltage (anode) to negative voltage (cathode). This net unidirectional flow of electrical stimulation in tDCS modulates neuronal excitability by typically increasing excitability in nerves closer to the anode electrode and typically decreasing excitability in nerves closer to the cathode electrode. Because the electric field used in tDCS is subthreshold, it can modify the nerve membrane potential difference and modulate neuronal excitability, thereby bringing specific nerves closer to or away from their firing potentials without initiating action potentials. In some embodiments, tDCS is used during one or more non-invasive brain stimulation sessions to achieve approximately + / -0.5mA, + / -0.6mA, + / -0.7mA, + / -0.8mA, + / -0.9mA, + / -1.0mA, + / -1.1mA, + / -1.2mA, + / -1.3mA, + / -1.4mA, + / -1.5mA, + / -1.6mA, + / -1.7mA, + / -1.8mA, + / -1.9mA, + / -2.0mA, + / -2.1mA, + / -2 The system delivers currents of 0.2mA, + / -2.3mA, + / -2.4mA, + / -2.5mA, + / -2.6mA, + / -2.7mA, + / -2.8mA, + / -2.9mA, + / -3.0mA, + / -3.1mA, + / -3.2mA, + / -3.3mA, + / -3.4mA, + / -3.5mA, + / -3.6mA, + / -3.7mA, + / -3.8mA, + / -3.9mA, + / -4.0mA, + / -4.5mA, or + / -5.0mA. In some embodiments, the level of current delivered in the enhancement phase is lower than the level of current delivered in the activation phase. In some embodiments, the level of current delivered in the enhancement phase is about 0.1 mA, 0.2 mA, 0.3 mA, 0.4 mA, 0.5 mA, 0.6 mA, 0.7 mA, 0.8 mA, 0.9 mA, 1 mA, 1.1 mA, 1.2 mA, 1.3 mA, 1.4 mA, 1.5 mA, 1.6 mA, 1.7 mA, 1.8 mA, 1.9 mA, 2 mA, 2.1 mA, 2.2 mA, 2.3 mA, 2.4 mA, or 2.5 mA lower than the level of current delivered in the activation phase.

[0084] tDCS electrodes can be placed anywhere on the scalp of the subject. At most scalp locations, the nearest brain tissue is the cerebral cortex. In some embodiments, a tES device may be used in which the first and second electrodes are in close proximity to or in contact with the frontal lobe of the subject. tDCS has been proposed as a technique for targeted neural modulation of the cerebral cortex. Changes in the tDCS electrode placement, also called montage, alter the distribution of the induced electric field in the brain. Different montages may be used depending on the symptoms to be targeted in the subject. In some embodiments, the frontal lobe of the subject's brain is stimulated to induce neural modulation. In some embodiments, the parietal lobe of the subject's brain is stimulated to induce neural modulation. In some embodiments, the temporal lobe of the subject's brain is stimulated to induce neural modulation. In some embodiments, a montage targeting the prefrontal cortex can be used in a method of treating depression. In some embodiments, the montage targets the prefrontal cortex of the subject, stimulating the prefrontal cortex to induce neural modulation. In some embodiments, montages targeting the dorsolateral prefrontal cortex (DLPFC) may be used in methods to treat depression. In some embodiments, the montage targets the DLPFC of the subject and stimulates the DLPFC to induce neuromodulation. In some embodiments, neural activity in the DLPFC increases at time after one or more non-invasive brain stimulation sessions. In some embodiments, functional connectivity increases between the DLPFC and one or more primary association areas of the orbitofrontal cortex, thalamus, dorsal caudate nucleus, hippocampus, neocortex, or one or more secondary association areas of the neocortex, or any combination thereof. In some embodiments, neural plasticity in the subject's brain increases. In some embodiments, administering a pharmacological antidepressant to the subject and delivering tDCS to the subject results in improvement of one or more symptoms of depression or depression-related conditions in the subject.

[0085] When an electric current is applied in tDCS, negatively charged ions move from the cathode to the anode. In some embodiments described herein, the nerve cell bodies and axons beneath the anode electrode used in tDCS tend to depolarize. In some embodiments described herein, the nerve cell bodies and axons beneath the cathode electrode used in tDCS tend to hyperpolarize. These results in depolarization and hyperpolarization depend in part on the orientation of the nerve. Many pyramidal nerves near the surface to which the tDCS anode is applied may be oriented parallel to the direction of the current, and therefore these pyramidal nerves may depolarize after the tDCS session. Many pyramidal nerves near the surface to which the tDCS cathode is applied may be oriented parallel to the direction of the current, and therefore these pyramidal nerves may hyperpolarize after the tDCS session. Thus, nerves near the anode or cathode in a tDCS session will be exposed to current flows in different directions. It should be noted that, due to the gyri and sulci of the cerebral cortex, the orientation of cylindrical pyramidal neurons in different cortical regions changes depending on their specific location within the gyri or sulcus, resulting in a change in their respective orientation toward any direction of current flow in the tDCS. In some embodiments, anode tDCS depolarizes the cell bodies and hyperpolarizes the apical dendrites of nearby neurons, which generally increases excitability. In some embodiments, cathode tDCS hyperpolarizes the cell bodies and depolarizes the apical dendrites of nearby neurons, which generally decreases excitability. In some embodiments, anode tDCS depolarizes nearby interneurons. In some embodiments, cathode tDCS hyperpolarizes nearby interneurons. In some embodiments, pyramidal cells in the cerebral cortex exhibit depolarized cell bodies and axons. In some embodiments, pyramidal cells in the cerebral cortex exhibit hyperpolarized cell bodies and axons. In some embodiments, pyramidal cells in the cerebral cortex exhibit depolarized apical dendrites. In some embodiments, pyramidal cells in the cerebral cortex exhibit hyperpolarized apical dendrites. In some embodiments, conventional tDCS uses larger conductive pads to generate diffusive flow through the brain, thereby avoiding stimulation of specific gyri in the cerebral cortex.In some embodiments, at the level of a single gyrus in the cerebral cortex, the tDCS current flows in and out of various orientations of cells within the gyrus, creating a pattern of neural stimulation. In some embodiments, high-definition tDCS (hd tDCS) may be used to concentrate neural stimulation on specific cortical regions. In some embodiments, multi-electrode arrays may be used to concentrate neural stimulation on multiple cortical regions. In some embodiments, in conventional tDCS, the goal of neural modulation is called circuit therapy. In circuit therapy, multiple nodes in the brain are stimulated as a whole, and the result observed in the subject is the effect of stimulating different brain regions. When the same tDCS is applied across a population, the collective response reflects individual variability (e.g., anatomical differences such as brain and skull size and shape). In some embodiments, tDCS may make the subject's brain more responsive to TMS. In some embodiments, the effect of tDCS is specific to particular neural network pathways. In some embodiments, the effect of tDCS depends on the specific size of the electrodes used, the precise placement of the electrodes on the scalp surface, the electrical intensity of the tDCS session, the duration of the tDCS session, the frequency of tDCS sessions delivered to the subject, the state of connectivity within the subject's various neural networks at the time of tDCS, and the overall state of depolarization and hyperpolarization of cortical cells in the subject.

[0086] tACS works by applying a low-intensity sinusoidal current to the target brain via electrodes on the scalp. In some embodiments, tACS acts as a neuromodulatory technique in a similar manner to tDCS, but instead of applying a direct current, tACS vibrates a sinusoidal current at a selected frequency. In some embodiments, tACS interacts with the innate cortical oscillations in the target brain. In some embodiments, large electrodes are placed across a target region in the target brain, with the large electrodes applying the stimulation while a reference electrode is placed at the neural location in the target. In some embodiments, when a single low-frequency tACS stimulus is applied, this extrinsic oscillation can synchronize with the endogenous frequency of the target brain. In some embodiments, when several vibrations of tACS pulsate, desynchronization of cortical oscillations can occur. In some embodiments, the tACS effect depends on the frequency, amplitude, and phase of the applied electrical stimulation. In some embodiments, tACS can be applied in the EEG frequency range of 0.1–80 Hz to synchronize and enhance neural oscillations. In some embodiments, higher frequency oscillations of tACS in the 1–5 kHz range may induce cortical excitability, although they are less likely to induce oscillatory interactions. In some embodiments, administering a pharmacological antidepressant to a subject and delivering tACS to a subject results in improvement of one or more symptoms of a depressive state or a depressive state-related condition in the subject.

[0087] tRNS is a non-invasive electrical stimulation of the brain, in which a weak alternating current oscillating at random frequencies is delivered through the scalp of the subject using two or more electrodes. In some embodiments, the frequency range used in tRNS encompasses the range of 0.1 to 640 Hz. In some embodiments, tRNS may be delivered to the subject in a low frequency range of about 0.1 to 100 Hz. In some embodiments, tRNS may be delivered to the subject in a high frequency range of about 101 to 640 Hz. In some embodiments, delivery of tRNS to the subject improves motor tasks. In some embodiments, delivery of tRNS to the subject improves sensory tasks. In some embodiments, delivery of tRNS to the subject improves cognitive tasks. In some embodiments, improvement in sensory tasks includes improvement in sensation or perceptual processing. In some embodiments, delivery of tRNS to the subject improves pain associated with a comorbid condition. In some embodiments, the comorbid condition is multiple sclerosis. In some embodiments, delivery of tRNS to the subject improves depressive symptoms in schizophrenia. In some embodiments, delivery of tRNS to a subject improves perceptual and motor learning. In some embodiments, administering a pharmacological antidepressant to a subject and delivering tRNS to the subject results in improvement of one or more symptoms of a depressive state or a depressive state-related condition in the subject.

[0088] tES in a single session may be delivered to the subject for a sufficient duration to induce neuromodulation. The length of time sufficient to induce neuromodulation may depend on several factors, including the type of tES used, the electrical intensity, size, positioning, and conductivity of the electrodes used, the subject's neurological state, psychological state, pathological state, distinct characteristics of the subject's neural network being stimulated, the time of the session, the latency from the previous tES session, the total number of tES sessions recently delivered to the subject, the total duration of the most recent tES sessions, and the synergistic effect with any pharmacological antidepressants administered to the subject. In some embodiments, each non-invasive brain stimulation session delivers tES to the subject for a duration of approximately 1 to 50 minutes. In some embodiments, each of one or more non-invasive brain stimulation sessions delivers tES to the subject for a duration of at least approximately 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 28 minutes, 29 minutes, 30 minutes, 31 minutes, 32 minutes, 33 minutes, 34 minutes, 35 minutes, 40 minutes, 45 minutes, or 50 minutes. In some embodiments, each of one or more non-invasive brain stimulation sessions delivers tES to the subject for a duration of approximately 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 28 minutes, 29 minutes, 30 minutes, 31 minutes, 32 minutes, 33 minutes, 34 minutes, 35 minutes, 40 minutes, 45 minutes, or less than 50 minutes. In some embodiments, the duration of the tES session delivered to the subject during the reinforcement phase is shorter than the duration of the tES session delivered to the subject during the activation phase. In some embodiments, the duration of the tES session delivered to the target during the enhancement phase is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 minutes shorter than the duration of the tES session delivered to the target during the activation phase.In some embodiments, the current is delivered continuously for the duration of one or more non-invasive brain stimulation sessions.

[0089] tES sessions may be delivered to a subject at a frequency sufficient to induce neuromodulation. The frequency of tES sufficient to induce neuromodulation may depend on several factors, including the type of tES used, the electrical intensity, size, positioning, and conductivity of the electrodes used, the subject's neurological state, psychological state, pathological state, distinct characteristics of the subject's neural network being stimulated, the time of the session, the latency from the previous tES session, the total number of tES sessions recently delivered to the subject, the total duration of the tES sessions recently delivered to the subject, and the synergistic effect with pharmacological antidepressants administered to the subject. In some embodiments, the method includes an activation phase. In some embodiments, the activation phase lasts for a period of 1 to 3 weeks. In some embodiments, the activation phase lasts for a period of 1 to 6 weeks. In some embodiments, the method includes an intensification phase. In some embodiments, the intensification phase begins in the second week of treatment. In some embodiments, the intensification phase begins in the third week of treatment. In some embodiments, the intensification phase begins in the fourth week of treatment. In some embodiments, the reinforcement phase begins in week 5 of treatment. In some embodiments, the reinforcement phase begins in week 6 of treatment. In some embodiments, the reinforcement phase begins in week 7 of treatment. In some embodiments, the reinforcement phase continues from approximately week 2–7 of treatment until the subject achieves the desired treatment outcome. In some embodiments, the reinforcement phase continues from approximately week 2–7 of treatment until one or more symptoms of depression show improvement. In some embodiments, the reinforcement phase continues from approximately week 2–7 of treatment until one or more symptoms of depression show remission. In some embodiments, the subject receives one or more non-invasive brain stimulation sessions at frequencies of twice daily, once every 18 hours, once daily, once every 36 hours, once every other day, six times a week, five times a week, four times a week, three times a week, twice a week, once a week, or once every two weeks. In some embodiments, the activation phase includes the delivery of at least three tES sessions per week to the subject. In some embodiments, the activation phase includes the delivery of at least four tES sessions per week to the subject. In some embodiments, the activation phase includes the delivery of at least five tES sessions per week to the subject.In some embodiments, the activation phase includes the delivery of at least six tES sessions per week to the subject. In some embodiments, the activation phase includes the delivery of at least seven tES sessions per week to the subject. In some embodiments, the activation phase includes the delivery of at least eight tES sessions per week to the subject. In some embodiments, the activation phase includes the delivery of at least nine tES sessions per week to the subject. In some embodiments, the activation phase includes the delivery of at least ten tES sessions per week to the subject. In some embodiments, the reinforcement phase includes the delivery of at least one tES session every two weeks to the subject. In some embodiments, the reinforcement phase includes the delivery of at least one tES session per week to the subject. In some embodiments, the reinforcement phase includes the delivery of at least three tES sessions every two weeks to the subject. In some embodiments, the reinforcement phase includes the delivery of at least two tES sessions per week to the subject. In some embodiments, the reinforcement phase includes the delivery of at least three tES sessions per week to the subject. In some embodiments, the reinforcement phase includes the delivery of at least four tES sessions per week to the subject. In some embodiments, the enhancement phase includes the delivery of at least five tES sessions per week to the subject. In some embodiments, the enhancement phase includes the delivery of at least six tES sessions per week to the subject. In some embodiments, the enhancement phase includes the delivery of at least seven tES sessions per week to the subject. In some embodiments, the activation phase includes the delivery of at least 1 to 10 tES sessions to the subject over a three-week treatment period. In some embodiments, the activation phase includes the delivery of at least 11 to 14 tES sessions to the subject over a three-week treatment period. In some embodiments, the activation phase includes the delivery of at least 15 to 16 tES sessions to the subject over a three-week treatment period. In some embodiments, the activation phase includes the delivery of more than 16 tES sessions to the subject over a three-week treatment period. In some embodiments, the method includes the delivery of at least 1 to 10 tES sessions to the subject over a six-week treatment period.In some embodiments, the method includes the delivery of at least 11 to 15 tES sessions to a subject over a 6-week treatment period. In some embodiments, the method includes the delivery of at least 16 to 20 tES sessions to a subject over a 6-week treatment period. In some embodiments, the method includes the delivery of 21 or more tES sessions to a subject over a 6-week treatment period. In some embodiments, the method includes the delivery of 20 or fewer tES sessions to a subject over a 10-week treatment period. In some embodiments, the method includes the delivery of 21 to 24 tES sessions to a subject over a 10-week treatment period. In some embodiments, the method includes the delivery of 25 to 28 tES sessions to a subject over a 10-week treatment period. In some embodiments, the method includes the delivery of 29 or more tES sessions to a subject over a 10-week treatment period. In some embodiments, the method includes the delivery of 30 or fewer tES sessions to a subject over a 25-week treatment period. In some embodiments, the method includes the delivery of 31 to 58 tES sessions to a subject over a 25-week treatment period. In some embodiments, the method includes the delivery of 59 or more tES sessions to a subject over a 25-week treatment period. In some embodiments, the method includes the delivery of 1 to 6 tES sessions to a subject over an 8-week treatment period. In some embodiments, the method includes the delivery of 7 to 8 tES sessions to a subject over an 8-week treatment period. In some embodiments, the method includes the delivery of 9 to 10 tES sessions to a subject over an 8-week treatment period. In some embodiments, the method includes the delivery of 11 to 12 tES sessions to a subject over an 8-week treatment period. In some embodiments, the method includes the delivery of 13 to 14 tES sessions to a subject over an 8-week treatment period. In some embodiments, the method includes the delivery of 15 to 16 tES sessions to a subject over an 8-week treatment period.

[0090] In some embodiments, the method includes delivery of tES to a subject about five times per week. In some embodiments, the method includes delivery of tES to a subject about five times per week for at least three weeks. In some embodiments, the method includes delivery of tES to a subject about five times per week for at least three weeks, and thereafter tES is delivered to the subject about three times per week for at least seven weeks. In some embodiments, the method includes delivery of tES to a subject about five times per week for at least three weeks, and thereafter tES is delivered to the subject about three times per week for at least seven weeks, and tES is not delivered to the subject more than 36 times in a 10-week period and / or tES is not delivered to the subject more than five times per week. In some embodiments, the method includes delivery of tES to a subject about five times per week for at least three weeks, and thereafter tES is delivered to the subject about three times per week for at least seven weeks, and tES is not delivered to the subject more than 36 times in a 10-week period and tES is not delivered to the subject more than five times per week. In some embodiments, the method includes delivery of tES to a subject approximately five times per week for at least three weeks, thereafter tES is delivered to the subject approximately three times per week for at least seven weeks, and tES is not delivered to the subject more than 36 times over a 10-week period, or tES is not delivered to the subject more than five times per week. In some embodiments, the method includes delivery of tES to a subject approximately five times per week for at least three weeks, thereafter tES is delivered to the subject approximately three times per week for at least seven weeks, and tES is not delivered to the subject more than 36 times over a 10-week period. In some embodiments, the method includes delivery of tES to a subject approximately five times per week for at least three weeks, thereafter tES is delivered to the subject approximately three times per week for at least seven weeks, and tES is not delivered to the subject more than five times per week.

[0091] In some embodiments, the method includes delivery of tES to a subject at least once a day. In some embodiments, the method includes delivery of tES to a subject at least five times a week. In some embodiments, the method includes delivery of tES to a subject at least five times a week, and tES is delivered at least once a day. In some embodiments, the method includes delivery of tES to a subject 36 times or less over a 10-week period. In some embodiments, the method includes delivery of tES to a subject 36 times or less over a 10-week period and at least five times a week. In some embodiments, the method includes delivery of tES to a subject 36 times or less over a 10-week period, or at least five times a week. In some embodiments, the method includes delivery of tES to a subject 36 times or less over a 10-week period, and tES is not delivered to the subject more than five times a week, and tES is not delivered to the subject more than once a day. In some embodiments, the method includes delivery of tES to a subject approximately five times per week for at least three weeks, thereafter tES is delivered to the subject approximately three times per week for at least seven weeks, with tES not being delivered to the subject more than five times per week, and tES not being delivered to the subject more than once per day. In some embodiments, the method includes delivery of tES to a subject approximately five times per week for at least three weeks, thereafter tES is delivered to the subject approximately three times per week for at least seven weeks, with tES not being delivered to the subject more than 36 times over a 10-week period, tES not being delivered to the subject more than five times per week, and tES not being delivered to the subject more than once per day.

[0092] In some embodiments, adherence to the delivery of several tES sessions to the subject during the activation phase results in greater improvement in one or more symptoms of depression. In some embodiments, the number of tES sessions in the activation phase required for greater improvement in one or more symptoms of depression is at least 3, 4, 5, 6, 7, 8, 9, or 10 sessions per week. In some embodiments, adherence to the delivery of several tES sessions to the subject during the reinforcement phase results in greater improvement in one or more symptoms of depression. In some embodiments, the number of tES sessions in the reinforcement phase required for greater improvement in one or more symptoms of depression is at least 0, 1, 2, 3, 4, 5, 6, or 7 sessions per week. In some embodiments, the subject receives one or more non-invasive brain stimulation sessions according to the initial activation phase schedule, at frequencies of twice daily, once every 18 hours, once daily, once every 36 hours, once every other day, six times a week, five times a week, four times a week, three times a week, twice a week, once a week, or once every two weeks. In some embodiments, subjects receive one or more non-invasive brain stimulation sessions at frequencies of twice daily, once every 18 hours, once daily, once every 36 hours, once every other day, six times a week, five times a week, four times a week, three times a week, twice a week, once a week, or once every two weeks, according to the schedule of the secondary reinforcement phase. In some embodiments, the initial activation phase lasts for a period of approximately 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeks. In some embodiments, the secondary strengthening phase begins after the completion of the initial activation phase, during a period of approximately 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or 25 weeks.In some embodiments, the subject completes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 non-invasive brain stimulation sessions. In some embodiments, subjects with moderate depression show a significant reduction in MADRS-s after at least 6 weeks of tDCS treatment including at least 21 non-invasive brain stimulation sessions. In some embodiments, subjects with moderate depression show a significant reduction in MADRS-S after at least 10 weeks of tDCS treatment including at least 21 non-invasive brain stimulation sessions. In some embodiments, subjects with severe depression show a significant reduction in MADRS-S after at least 6 weeks of tDCS treatment including at least 21 non-invasive brain stimulation sessions. In some embodiments, subjects with severe depression show a significant reduction in MADRS-s after at least 10 weeks of tDCS treatment including at least 21 non-invasive brain stimulation sessions. In some embodiments, subjects with depression who are administered sertraline as part of a treatment regimen and who undergo at least 6 weeks of tDCS treatment including at least 21 non-invasive brain stimulation sessions show a significant reduction in MADRS-S. In some embodiments, the significant reduction in MADRS-s in subjects administered sertraline is greater than the reduction in MADRS-s in a second subject after 6 weeks of tES treatment, which includes fluoxetine as part of a treatment regimen and at least 21 non-invasive brain stimulation sessions. In some embodiments, administering a pharmacological antidepressant to a subject, and delivering multiple tDCS sessions to the subject during the activation phase, and continuing to deliver multiple tDCS sessions to the subject during the reinforcement phase, provides sufficient improvement of one or more symptoms of depression to achieve the desired treatment outcome for the subject.In some embodiments, administering a pharmacological antidepressant to a subject, and delivering multiple tDCS sessions to the subject during the activation phase, and continuing to deliver multiple tDCS sessions to the subject during the reinforcement phase, provides remission of one or more symptoms of depression and achieves the desired therapeutic outcome for the subject. In some embodiments, administering a pharmacological antidepressant to a subject, and delivering multiple tDCS sessions to the subject during the activation phase, and continuing to deliver multiple tDCS sessions to the subject during the reinforcement phase, allows for evaluation of the subject's response to the treatment regimen and enables the ability to adjust the parameters of administering the pharmacological antidepressant and delivering multiple tDCS sessions to the subject to achieve the desired therapeutic outcome.

[0093] tES can be delivered to a target by various neurostimulation devices. In some embodiments, the tES device includes a transcranial direct current stimulation (tDCS) device. In some embodiments, the tES device includes a transcranial alternating current stimulation (tACS) device. In some embodiments, the tES device includes a transcranial random noise stimulation (tRNS) device. In some embodiments, the tES device is configured as a headset comprising a circuit including a first electrode, a second electrode, and a power supply configured to supply power to the circuit. In some embodiments, the tES device further comprises a wireless transceiver configured to wirelessly communicate with an electronic device having processing power so that transcranial brain stimulation is performed according to a schedule for performing transcranial brain stimulation, and a controller configured to control the power supply to the circuit according to a control signal of the headset. In some embodiments, the headset further comprises a memory configured to store a schedule for performing transcranial brain stimulation. In some embodiments, the processing-capable electronic device includes a non-temporary computer-readable recording medium on which a program executable on the electronic device is recorded, the program including a portion of program code configured, when executed on the electronic device, to store in computer memory a schedule for performing transcranial brain stimulation, generate and maintain control signals according to the schedule for performing transcranial brain stimulation, and display information on the display of the electronic device according to a schedule for displaying information, the schedule for displaying information relating to the schedule for performing transcranial brain stimulation. In some embodiments, the headset further includes a frontal frame, defined by an elongated arch; a first electrode positioned at a first end of the elongated arched frontal frame; a second electrode positioned at a second end of the elongated arched frontal frame; and an elongated arched frontal frame, configured to support a bracket, fixed to the central portion of the elongated arched frontal frame.In some embodiments, when using a headset to simultaneously deliver one or more non-invasive brain stimulation sessions to a subject, the elongated arched frontal frame is configured such that a first electrode is positioned on the left side of the subject's frontal region and a second electrode is positioned on the right side of the subject's frontal region, and a bracket is configured to extend from the elongated arched frontal frame across the subject's skull toward the subject's neck. In some embodiments, the program further includes a portion of program code configured, when run on an electronic device, to prompt the subject to input information about the subject's condition, the information about the subject's condition includes information about the subject's current health status. In some embodiments, the program further includes a portion of program code configured, when run on an electronic device, to store information about performed transcranial brain stimulation in computer memory. In some embodiments, the program further includes a portion of program code configured, when run on an electronic device, to remind the subject to use the headset according to a schedule for performing transcranial brain stimulation. In some embodiments, the program further includes a portion of program code configured, when run on an electronic device, to update the schedule for performing transcranial brain stimulation. In some embodiments, the headset further comprises a first electrode and a second electrode that are pivotable so as to be able to conform to the shape of the forehead of the subject. In some embodiments, the headset further comprises a first electrode and a second electrode having an adhesive layer configured such that the adhesive layer adheres to the forehead of the subject. In some embodiments, the bracket has a longitudinal extension that extends from the forehead of the subject toward the back of the subject when the headset is used, and the bracket has a variable extension from the forehead frame. In some embodiments, the bracket further comprises a support cushion positioned at the end of the bracket opposite to where the bracket is fixed to the forehead frame, and the forehead frame is a single member molded as an elongated arch.In some embodiments, prompting the subject to input information about their current health status includes displaying the subject a self-assessment MADRS-S questionnaire, allowing the subject to complete the questionnaire, and storing the results from the completed questionnaire in the computer memory of an electronic device. In some embodiments, the electronic device is a handheld device.

[0094] Figure 9 is a schematic block diagram showing an example of a transcranial stimulation device 100 for delivering tES, such as tDCS, according to one of the methods described herein. The device 100 can be configured to implement a protocol for delivering tES, as described in the following study. As shown, the device 100 may comprise a pair of electrodes 120a, 120b coupled to a frame 110 configured to fit across the user's forehead. In some embodiments, the first electrode 120a from the pair of electrodes may be coupled to the inner surface of the frame 110 on the first end of the frame 110, such that electrode 120a is positioned on the first side of the forehead. The second electrode 120b from the pair of electrodes may be coupled to the inner surface of the frame 110 on the second end of the frame 110, such that the second electrode 120b is positioned on the second side of the forehead.

[0095] In some embodiments, the device 100 includes a support member (e.g., a bracket) 130 that is coupled to the frame 110 and configured to secure the frame 110 across the user's forehead. In some embodiments, the bracket 130 may extend longitudinally from the frame 110 over the user's crown and toward the user's occipital region to support the frame when fitted across the forehead, ensuring that the first electrode 120a and the second electrode 120b are positioned on the first and second sides of the forehead. In some embodiments, the bracket 130 may prevent the user from incorrectly fitting the device 100. For example, the bracket 130 may prevent the user from fitting the device 100 in the wrong orientation (e.g., upside down). In other words, the bracket 130 may be configured to extend over the head of the subject to ensure that the frame is fitted by the subject in a predetermined orientation. The bracket 130 may prevent the user from fitting the device 100 with the electrodes 120a, 120b positioned over the wrong cortical target. In some embodiments, the bracket 130 can ensure that the user can position electrodes 120a, 120b across the desired nerve stimulation target (DLPFC) in a home setting. In some embodiments, a portion of the support member 130 may include a cushion configured to rest at the back of the user's head. In some embodiments, the support member 130 may be adjustable so that the device 100 can be fitted by users with different head sizes.

[0096] In some embodiments, the support member 130 may alternatively be a band extending around the user's head to secure the frame 110 across the user's forehead. In some embodiments, the band may be made of a stretchable material so that the electrodes 120a, 120b are secured to the surface of the forehead when the device 100 is worn by the user and the band is positioned around the back of the user's head. In some embodiments, the device 100 may comprise an electronic subsystem 140 and a power supply 150 configured to power the electronic subsystem 140.

[0097] In some embodiments, the device 100 is configured such that, when fitted by the user, the pair of electrodes 120a, 120b are fixed to the user's forehead so as to target the user's prefrontal cortex. In some embodiments, the pair of electrodes 120a, 120b are fixed to the user's forehead to target the DLPFC. In some embodiments, the pair of electrodes 120a, 120b are fixed to the user's forehead to target the left DLPFC. In some embodiments, the pair of electrodes 120a, 120b are fixed to the user's forehead according to an F3 / F4 electrode montage to target the DLPFC. For example, the first electrode 120a may be positioned on the F3 electrode region, and the second electrode 120b may be positioned on the F4 electrode region. In some embodiments, the first electrode 120a may be configured as an anode and positioned on the F3 region (e.g., the left side of the forehead), and the second electrode 120b may be configured as a cathode and positioned on the F4 region (e.g., the right side of the forehead). In some embodiments, each electrode 120a, 120b may be provided with an adhesive material configured to improve contact between the electrodes 120a, 120b and the surface of the user's forehead.

[0098] In some embodiments, each electrode of the pair of electrodes 120a, 120b includes conductive surfaces 122a, 122b configured to contact the user's forehead. In some embodiments, each electrode 120a, 120b may be pivotable so that when the device 100 is fitted by the user, the conductive surfaces 122a, 122b are positioned parallel to the surface of the forehead to improve contact between the conductive surfaces 122a, 122b and the user's forehead. In some embodiments, the conductive surfaces 122a, 122b of each electrode 120a, 120b may have a length of about 3.0 cm to about 5.0 cm and a width of about 5.0 cm to about 7.0 cm, including all and partial ranges between these. In some embodiments, the conductive surfaces 122a, 122b may have a length of about 15 cm 2 ~Approx. 35cm 2The surface area may be such that it includes all and partial ranges between them. In some embodiments, the surface area of ​​the conductive surfaces 122a and 122b is about 20 cm². 2 ~Approx. 25cm 2 This is possible. In some embodiments, the surface area of ​​the conductive surfaces 122a and 122b is at least 15 cm². 2 Also 25cm 2 It may be less than 20 cm². In some embodiments, the surface area of ​​the conductive surfaces 122a and 122b is at least 20 cm². 2 Also 25cm 2 It may be less than 23 cm². In some embodiments, the surface area of ​​the conductive surfaces 122a and 122b is about 23 cm². 2 It is possible.

[0099] The pair of electrodes 120a, 120b may be configured to provide nerve stimulation (e.g., tDCS) to the user. In some embodiments, approximately 23 cm 2 Conductive surfaces 122a and 122b having a surface area of ​​approximately 23 cm² may help concentrate nerve stimulation on a target cortical region (e.g., DLPFC). In some embodiments, this is approximately 23 cm². 2 Conductive surfaces 122a and 122b having a surface area may contribute to an improvement in at least one of remission rates and response rates by delivering more concentrated nerve stimulation to target cortical regions. The surface area of ​​conductive surfaces 122a and 122b is inversely proportional to the current density (or charge density, or field density) of the stimulation delivered by electrodes 120a and 120b. As the surface area of ​​conductive surfaces 122a and 122b decreases, the current density increases, and therefore the delivered stimulation can be more concentrated. If the current density (or charge density, or field density) delivered by electrodes 120a and 120b exceeds a threshold, a thermal effect may begin to occur on the conductive surfaces 122a and 122b (for example, the temperature of conductive surfaces 122a and 122b may rise), which may pose a risk to the user of experiencing pain and / or burns on the skin in contact with and / or around the conductive surfaces 122a and 122b. Therefore, the surface conductive surfaces 122a and 122b must be large enough so that the current density does not exceed a threshold, in order to ensure user safety.

[0100] In some embodiments, the conductive surfaces 122a, 122b may include a hydrophilic material (e.g., an electrolyte) configured to conduct electrical output (e.g., electric current) to the user's brain. In some embodiments, the conductive surfaces 122a, 122b include a hydrophilic pad. In some embodiments, the hydrophilic pad may be disposable so that a new hydrophilic pad is placed on each electrode 120a, 120b before each use of the device 100. In some embodiments, the hydrophilic layer may be bonded to a conductive substrate (e.g., a conductive polymer), and the conductive substrate may electrically connect the hydrophilic material to the electronic subsystem 140.

[0101] In some embodiments, the electronic subsystem 140 and the power supply 150 are integrated into the device 100. The electronic subsystem 140 may be configured to stimulate a user with a pair of electrodes 120a, 120b according to the methods described herein. For example, the electronic subsystem 140 may be configured to deliver a current of 2 mA to the user's DLPFC with the pair of electrodes 120a, 120b for a predetermined amount of time (e.g., 30 minutes). In some embodiments, the electronic subsystem 140 may include a processor 142 and a memory 144. In some embodiments, the processor 142 may be configured to periodically power a circuit including electrodes 120a, 120b in order to deliver tES according to a predetermined schedule. In some embodiments, the memory 144 may store instructions and / or code that, when executed by the processor 144, cause the device 144 to deliver tES according to a predetermined schedule. In some embodiments, the processor 142 may be configured to receive instructions and / or code related to a predetermined schedule from a remote server. In some embodiments, memory 144 may be configured to store code and / or instructions for delivering tES sessions in accordance with any of the methods described herein. For example, memory 144 and / or processor 142 may be configured to cause device 100 to deliver 36 tES sessions over a 10-week period. In some embodiments, memory 144 and / or processor 142 may be configured to cause device 100 to deliver tES sessions five times per week for three weeks, and then three times per week for seven weeks. In some embodiments, memory 144 and / or processor 142 may be configured to prevent device 100 from delivering more than one tES per day. In some embodiments, memory 144 and / or processor 142 may be configured to prevent device 100 from delivering more than five tES per week. In some embodiments, memory 144 and / or processor 142 may be configured to prevent the user from delivering excessive tES sessions in order to ensure user safety.In some embodiments, the memory 144 and / or processor 142 are fully integrated into the hardware of device 100 so that the user can receive tES at home without expert supervision.

[0102] In some embodiments, memory 144 and / or processor 142 may be configured to deliver tES (or tDCS) sessions according to the following instructions: (1) The user initiates six preparatory stimulation sessions at the start of the treatment plan. (2) Processor 142 does not allow device 100 to deliver more than five tES sessions per week and more than one per day. (3) If device 100 delivers more than three sessions in a week, one of the preparatory stimulation sessions is used for each of the three sessions in that week. The user may be instructed (e.g., through the user device and / or a third party such as a physician or researcher) to stimulate for five sessions per week over the first three weeks, meaning that if the user complies and the device delivers five sessions per week over the first three weeks, two preparatory stimulation sessions per week are used over the first three weeks. Therefore, if the user complies with the instructions, all six preliminary stimulation sessions are used by the end of the first three weeks so that the processor 142 allows the device 100 to deliver only three sessions per week for the remainder of the treatment period (e.g., 10 weeks). (4) If the user has remaining preliminary stimulation sessions, the processor 142 allows the device to deliver sessions (as long as the number of weekly sessions is less than five per week). In some embodiments, the memory 144 and / or the processor 142 may implement all of instructions 1-4. In some embodiments, the memory 144 and / or the processor 142 may implement a subset of instructions 1-4.

[0103] In some embodiments, device 100 may include a communication interface for communicating with one or more external devices, for example, via wired and / or wireless connections. For example, device 100 may include a wireless transceiver and be configured to wirelessly communicate with an electronic device. In some embodiments, device 100 may be configured to communicate with a user device, for example, a mobile device, telephone, tablet, personal computer, or laptop. In some embodiments, device 100 may be configured to communicate with one or more remote devices, for example, a server, via the user device. In some embodiments, the external device may have a processor configured to send signals and / or instructions to device 100, including a schedule for performing transcranial brain stimulation. The schedule may include or be based on any one of the protocols and / or methods described herein. In some embodiments, the schedule may be stored in the onboard memory 144 of device 100, and the processor 142 may be configured to implement the schedule, for example, by delivering transcranial brain stimulation (e.g., tDCS) according to the schedule.

[0104] Further examples of systems and devices for delivering tDCS include U.S. Patent Application No. 14 / 470,683 (now U.S. Patent No. 9,889,290), filed on 27 August 2014; U.S. Patent Application No. 14 / 878,647 (now U.S. Patent No. 9,486,618), filed on 8 October 2015; and U.S. Patent Application No. 15 / 916,170 (now U.S. Patent No. 10), filed on 8 March 2018. These disclosures are described in U.S. Patent Application No. 16 / 480,679 (now U.S. Patent No. 11,351,362), filed on 25 July 2019, U.S. Patent Publication No. 2021 / 0275801, filed on 25 July 2019, and U.S. Patent Publication No. 2021 / 0299434, filed on 29 January 2021, and the disclosures of each of these are incorporated herein by reference.

[0105] psychosocial intervention Further intervention methods may be combined with methods of administering pharmacological antidepressants to the subject and methods of delivering tES as described herein for the treatment of depressive states or depressive-related conditions. In some embodiments, regular psychotherapy sessions are completed between the subject and a licensed professional psychotherapist. In some embodiments, the regular psychotherapy sessions are psychoanalytic or psychodynamic therapy sessions. In some embodiments, the subject receives psychotherapy sessions three times a week, twice a week, once a week, once every 10 days, or every other week. In some embodiments, the subject receives cognitive behavioral therapy sessions. In some embodiments, the subject receives behavioral therapy sessions. In some embodiments, the subject receives humanistic therapy. In some embodiments, the subject completes 0-2, 3-4, or more than 4 sessions of psychoanalytic or psychodynamic therapy, cognitive behavioral therapy, behavioral therapy, and / or humanistic therapy in treatment within the past month. In some embodiments, the subject adds regular meditation sessions to the treatment regimen. In some embodiments, the subject receives meditation sessions at least 8, 7, 6, 5, 4, 3, 2, or 1 per day, or once every 2, 3, 4, 5, 6, or 7 days. In some embodiments, the meditation sessions are performed concurrently with the tES sessions. In some embodiments, the subject adds regular relaxation sessions to the treatment regimen. In some embodiments, the subject receives relaxation sessions at least 8, 7, 6, 5, 4, 3, 2, or 1 per day, or once every 2, 3, 4, 5, 6, or 7 days. In some embodiments, the relaxation sessions are performed concurrently with the tES sessions.

[0106] II. Definition Unless otherwise defined, all technical terms, expressions, and other technical and scientific or specialized terms used herein are intended to have the same meaning as those generally understood by those skilled in the art to which the claimed subject matter relates. In some cases, terms having a generally understood meaning are defined herein for clarity and / or for easy reference, and the inclusion of such definitions herein should not necessarily be interpreted as representing a substantial difference from the generally understood meaning in the art.

[0107] Throughout this application, various embodiments may be presented in scope form. It should be understood that the scope form is merely for convenience and brevity and should not be interpreted as an inflexible limitation to the scope of this disclosure. Therefore, a scope description should be considered to have all possible sub-scopes specifically disclosed and the individual numbers within those scopes. For example, a scope description such as 1 to 6 should be considered to have specifically disclosed sub-scopes such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, and the individual numbers within those scopes, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the scope.

[0108] When used in the specification and claims, the singular forms "a," "an," and "the" also include their plural forms unless the context clearly indicates otherwise. For example, the term "sample" includes multiple samples and mixtures thereof.

[0109] The terms “determine,” “measure,” “evaluate,” “assess,” “assay,” and “analyze” are often used interchangeably herein to refer to forms of measurement. The terms include determining whether an element is present or absent (e.g., detection). These terms may include quantitative, qualitative, or both quantitative and qualitative determinations. Assessments may be relative or absolute. “Detecting the presence of ~” may, depending on the context, include determining the amount of something present, in addition to determining whether something is present or absent.

[0110] The terms “subject,” “individual,” and “patient” are often used interchangeably herein. A “subject” may be a biological entity containing expressed genetic material. A biological entity may be a plant, animal, or microorganism (including, for example, bacteria, viruses, fungi, and protozoa). A subject may be a tissue, cell, or offspring of a biological entity obtained in vivo or cultured in vitro. A subject may be a mammal. A mammal may be a human. A subject may be diagnosed with or suspected to be at high risk for a disease. In some cases, a subject may not necessarily be diagnosed with or suspected to be at high risk for the disease.

[0111] As used herein, the term “approximately” refers to that number plus or minus 10%. The term “approximately” refers to the range minus 10% of its lowest value and plus 10% of its highest value.

[0112] As used herein, the terms “treatment” or “to treat” are used in reference to pharmaceutical or other intervention regimens for obtaining beneficial or desired outcomes in a recipient. Beneficial or desired outcomes include, but are not limited to, therapeutic benefits and / or preventive benefits. A therapeutic benefit may refer to the eradication or improvement of the symptom or underlying disease being treated. A therapeutic benefit may also be achieved by the eradication or improvement of one or more symptoms of physiological symptoms associated with an underlying disease, such that improvement is observed in the subject, even though the subject may still have the underlying disease. A preventive effect includes delaying, preventing, or eliminating the onset of a disease or condition; delaying or eliminating the onset of symptoms of a disease or condition; delaying, halting, or reversing the progression of a disease or condition; or any combination thereof. For a preventive benefit, a subject at risk of developing a particular disease, or a subject reporting one or more physiological symptoms of a disease, may receive treatment even if a diagnosis of the disease has not been made.

[0113] As used herein, the term “therapeutic dose” (and its grammatical variations) means an amount sufficient to provide some improvement or benefit to a subject. For example, a “therapeutic dose” could be an amount that provides some reduction, alleviation, decrease, or stabilization of at least one symptom (e.g., clinical symptom) or condition associated with a disorder in a subject. Those skilled in the art will understand that the therapeutic effect does not need to be complete or curative, as long as some benefit is provided to the subject.

[0114] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described herein.

[0115] Examples The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.

[0116] Example 1: Completion of the MADRS-s questionnaire In this embodiment, subjects completed the MADRS-s questionnaire at baseline (defined as the time preceding the initiation of neuronal stimulation) to determine the starting measure to be used in evaluating treatment efficacy. Ideally, the baseline measurement was taken close to the time when the first neuronal stimulation session was initiated. Subjects completed the same MADRS-s questionnaire weekly throughout the course of ongoing treatment, which included administration of prescribed pharmacological antidepressants and delivery of multiple tDCS sessions to subjects. The number and date of completion of each tDCS session were recorded to analyze subjects according to how frequently they successfully completed tDCS sessions as part of their treatment regimen. Subjects were divided into four groups: 1) no symptoms of depression, 2) mild depression, 3) moderate depression, or 4) severe depression, to further allow for analysis of changes in MADRS-s scores according to the severity of depression and adherence to the recommended tDCS session schedule. The groups were analyzed by analysis of variance to determine any statistically significant differences between them. The following are copies of the questionnaires that participants completed weekly at baseline and during treatment.

[0117] The MADRS-s consists of nine questions. Each question has seven answer choices ranging from score 0 to 6. Note that only the even-numbered choices are described. Instructions for the target: Based on how you've felt over the past three days, try to answer the following nine questions as accurately as possible.

[0118] feeling Here, you should try to indicate your mood, whether you felt sad or depressed. Try to recall how you felt over the past three days, whether your mood is changeable or always pretty much the same. In particular, try to recall whether you felt brighter when something good happened. 0. Depending on the situation, it can be either cheerful or sad. 2. Sometimes it gets a little easier, but most of the time I feel a bit down. 4. Feeling completely down and depressed. Even things that would normally cheer you up don't give you energy. 6. I feel completely depressed, miserable, and can't imagine anything worse.

[0119] Anxiety Here, you should indicate the extent to which you have experienced internal tension, uneasiness, anxiety, or vague fear over the past three days. Pay particular attention to how intense these feelings were, whether they came and went, or whether they were almost constant. 0. I feel calm in most aspects. 2. Sometimes, I experience unpleasant feelings of anxiety. 4. I am constantly troubled by anxiety that can become very strong, and I must make an effort to overcome it. 6. There is a terrifying, persistent, or unbearable feeling of anxiety.

[0120] sleep Note: This section is not the same as MADRS.

[0121] Here, you should indicate how well you sleep, how long you sleep, and how well your sleep has been over the past three nights. Your rating should reflect how well you actually slept, regardless of whether you used sleeping pills. If you slept more than usual, you should mark the scale as zero (0). 0. I have no sleep problems and get as much sleep as I need. I have no difficulty falling asleep. 2. I have some sleep problems. Sometimes I have difficulty falling asleep, or I sleep more lightly or restlessly than usual. 4. You sleep at least two hours less per night than usual. You often wake up during the night, even without any disturbance. 6. I have very poor sleep, not getting more than 2-3 hours of sleep per night.

[0122] appetite Here, you should try to describe how your appetite was affected and recall whether it was any different from normal. If your appetite was better than normal, you should mark the scale as zero (0). 0. Appetite was almost the same as usual. 2. Their appetite was weaker than usual. 4. I had almost no appetite. Food seemed tasteless, and I had to feed myself. 6. I had absolutely no desire to eat. If I were to eat, I would need to be persuaded to understand why.

[0123] ability to concentrate Here, you should try to demonstrate your ability to gather your thoughts in order to focus on what you are doing. For example, try to recall how well you have been able to handle tasks that require different levels of concentration, such as comparing your ability to read a more complex text to your ability to read a simple excerpt from a newspaper, or paying attention to television. 0. I have no difficulty concentrating. 2. Occasionally, I find it difficult to concentrate on things that I would normally be interested in. (For example, reading or watching television). 4. I find it particularly difficult to concentrate on things that don't normally require much effort (for example, reading or talking with other people). 6. I can't concentrate on anything at all.

[0124] Spontaneity Here, you should try to assess your ability to get things done. This item relates to how difficult or easy it is for you to start something you think you should do, and to the extent that you feel you have to overcome internal resistance (inertia) to start something. 0. I have no difficulty starting new tasks. 2. When I have to do something, I find it more difficult than usual. 4. It takes considerable effort for me to start simple tasks that I normally perform with more or less no thought. 6. I can't start with the simplest daily tasks.

[0125] Emotional involvement Note: This section is not the same as MADRS. Here, you should appreciate your surroundings, other people, and your interest in activities that normally bring you pleasure. 0. They become interested in their surroundings, engage with them, and derive joy from this. 2. I don't usually feel very strongly about things that pique my interest. If there is a reason, it is more difficult than usual to become cheerful or angry. 4. Even friends and acquaintances show no interest in those around them. 6. There are no longer any emotions. I feel deeply indifferent even to those closest to me.

[0126] pessimism Here, you should consider how you see your future and how you feel about yourself. Think about how self-critical you feel, whether you are plagued by guilt, and whether you are more worried than usual (for example, about your finances or your health). 0. I look to the future with confidence. Overall, I am quite satisfied with my life. 2. Sometimes I am self-critical and think I am less valuable than others. 4. I tend to dwell on my failures and feel inferior or worthless, even if others disagree. 6. Everything seems black, and there is no glimmer of hope. You feel completely useless and have no chance of forgiveness for the terrible things you have done.

[0127] The desire to live This section concerns your will to live and whether you have felt apathy and exhaustion in your life. Have you ever considered suicide, and if so, to what extent do you consider it a realistic escape? 0. My will to live is normal. 2. I don't want to die, but I don't think life has any particular meaning. 4. I often think that death would be better, and although I never actually attempt suicide, it seems like a possible solution. 6. I am quite convinced that my only solution is death, and I often think about the best way to end my own life.

[0128] Example 2: Severity of depressive state in outcomes of combination of nerve stimulation and pharmacological treatment In this embodiment, subjects diagnosed with major depressive disorder (MDD) after clinical evaluation by a psychiatrist were identified. Subjects currently experiencing depressive episodes were enrolled, and ...

Claims

1. A treatment method for depression in the subject, (a) Administering pharmacological antidepressants to the subject, (b) A method comprising delivering transcranial electrical stimulation (tES) to the subject.

2. A treatment method for depression in the subject, A method comprising administering a pharmacological antidepressant to the subject, wherein the subject is further subjected to transcranial electrical stimulation (tES).

3. A treatment method for depression in the subject, A method comprising delivering transcranial electrical stimulation (tES) to the subject.

4. The method according to claim 3, wherein the subject is further administered a pharmacological antidepressant.

5. The method according to any one of claims 1, 2, and 4, wherein the pharmacological antidepressant is administered as part of a treatment regimen.

6. The method according to claim 5, further comprising evaluating the subject's response to the treatment regimen.

7. The method according to any one of claims 1, 2, and 4 to 6, wherein the pharmacological antidepressant is administered in a therapeutically effective dose.

8. The method according to claim 1, wherein the delivery of the tES to the subject includes delivery of the tES before administration, delivery of the tES as part of a treatment regimen and concurrently with administration, delivery of the tES after administration, delivery of the tES concurrently with or after a change in the dosage of the pharmacological antidepressant to be administered, or delivery of the tES after completion of the administration schedule.

9. The method according to any one of claims 1 and 3 to 8, wherein the delivery comprises one or more non-invasive brain stimulation sessions.

10. The method according to claim 9, further comprising evaluating the subject's response to one or more non-invasive brain stimulation sessions.

11. The method according to claim 9 or 10, wherein evaluating the response of the subject is to determine the effectiveness of the treatment.

12. The method according to any one of claims 1 and 3 to 11, wherein the delivery includes delivering a tES via a tES device.

13. The method according to claim 12, wherein delivering tES via the tES device induces neuromodulation in the subject.

14. The method according to any one of claims 1 to 13, further comprising adjusting parameters in the administration or delivery to achieve a desired therapeutic outcome.

15. A treatment method for depression in the subject, As part of a treatment regimen, one or more non-invasive brain stimulation sessions via a transcranial electrical stimulation (tES) device to induce neuromodulation are delivered to the subject, which also receives a pharmacological antidepressant as part of the treatment regimen. To evaluate the subject's response to the aforementioned treatment regimen and determine the effectiveness of the treatment, A method comprising adjusting parameters in the delivery to achieve a desired therapeutic outcome.

16. The aforementioned pharmacological antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic antidepressants (NaSSAs), serotonin modulators and stimulants (SMSs), serotonin antagonists and reuptake inhibitors (SARIs), serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs), norepinephrine reuptake inhibitors (NRIs), and norepinephrine reuptake inhibitors (NRIs). The method according to any one of claims 1, 2, and 4 to 13, comprising a nephrine-dopamine reuptake inhibitor (NDRI), a norepinephrine-dopamine-releasing agent (NDRA), a serotonin-norepinephrine-dopamine-releasing agent (SNDRA), a tricyclic antidepressant (TCA), a tetracyclic antidepressant (TeCA), a monoamine oxidase inhibitor (MAOI), an NMDA receptor modulator, an atypical antipsychotic, an atypical antidepressant, a benzodiazepine, or any combination thereof.

17. The method according to claim 16, wherein the SSRI comprises fluoxetine, citalopram, escitalopram, paroxetine, sertraline, dapoxetine, fluvoxamine, or vortioxetine.

18. The method according to any one of claims 1, 2, and 4 to 17, wherein the pharmacological antidepressant is administered in the form of a formulation including a tablet, a capsule, a delayed-release capsule, or a liquid.

19. The method according to any one of claims 1, 2, and 4 to 18, wherein the pharmacological antidepressant is administered orally, sublingually, orally, nasally, rectally, vaginally, intravenously, intramuscularly, subcutaneously, or by inhalation.

20. The aforementioned therapeutically effective dose is at least about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.30 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.50 mg, 0.55 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9mg, 1mg, 1.25mg, 1.5mg, 1.75mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5 mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19m g, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 32mg, 34mg, 35mg, 36mg, 37. 5mg, 38mg, 40mg, 42mg, 44mg, 46mg, 48mg, 50mg, 52mg, 54mg, 56mg, 58mg, 60mg, 65mg, 70mg, 75mg, 8 The method according to any one of claims 7 to 19, comprising a dose of the pharmacological antidepressant of 0 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg, 300 mg, or 400 mg.

21. The aforementioned effective therapeutic doses are approximately 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.30 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.50 mg, 0.55 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg. mg, 1mg, 1.25mg, 1.5mg, 1.75mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg , 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg , 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 32mg, 34mg, 35mg, 36mg, 37.5mg, 38 mg, 40mg, 42mg, 44mg, 46mg, 48mg, 50mg, 52mg, 54mg, 56mg, 58mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85m The method according to any one of claims 7 to 20, comprising a dose of the pharmacological antidepressant of g, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg, 300 mg, 400 mg, or less than 600 mg.

22. The method according to any one of claims 9 to 21, further comprising the subject receiving concentrated meditation exercises or concentrated relaxation exercises during one or more non-invasive brain stimulation sessions.

23. The method according to any one of claims 5 to 22, wherein the treatment regimen comprises a drug administration regime in which the dose of the pharmacological antidepressant is administered up to approximately every hour, every two hours, every three hours, every four hours, every five hours, every six hours, every seven hours, every eight hours, every nine hours, every ten hours, every eleven hours, every twelve hours, every thirteen hours, every fourteen hours, every fifteen hours, every sixteen hours, every seventeen hours, every eighteen hours, every nineteen hours, every twenty hours, every twenty-one hours, every twenty-one hours, every twenty-two hours, every twenty-three hours, every twenty-four hours, every twenty-eight hours, every thirty-two hours, every thirty-four hours, every twenty-one hours, every twenty-eight hours, every twenty-two

24. The method according to any one of claims 5 to 23, wherein the treatment regimen includes a drug administration regime in which the dose of the pharmacological antidepressant is administered approximately once a month, once every three weeks, once every two weeks, once every 10 days, once a week, once every six days, once every five days, once every four days, once every three days, once every two days, once daily, twice daily, three times daily, four times daily, five times daily, six times daily, seven times daily, eight times daily, nine times daily, ten times daily, eleven times daily, or twelve times daily.

25. The method according to any one of claims 23 to 24, wherein the drug administration regime continues for a period of at least one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, thirteen weeks, fourteen weeks, fifteen weeks, sixteen weeks, seventeen weeks, eighteen weeks, nineteen weeks, twenty weeks, twenty weeks, twenty-one weeks, twenty-two weeks, twenty-three weeks, twenty-four weeks, twenty-five weeks, twenty-six weeks, seven months, eight months, nine months, ten months, eleven months, twelve months, thirteen months, fourteen months, fifteen months, sixteen months, seventeen months, eighteen months, or two years.

26. The method according to any one of claims 5 to 25, wherein the treatment regimen comprises a multi-dose drug administration regimen.

27. The method according to any one of claims 12 to 26, wherein the tES device includes a transcranial direct current stimulation (tDCS) device, a transcranial alternating current stimulation (tACS) device, or a transcranial random noise stimulation (tRNS) device.

28. The method according to any one of claims 12 to 26, wherein the tES device includes a transcranial direct current stimulation (tDCS) device.

29. The method according to any one of claims 12 to 28, wherein the tES device is configured as a headset comprising a circuit comprising a first electrode, a second electrode, and a power supply configured to supply power to the circuit.

30. The method according to claim 29, wherein the tES device further comprises a wireless transceiver configured to wirelessly communicate with an electronic device having processing power so that the transcranial brain stimulation is performed according to a schedule for performing the transcranial brain stimulation, and a controller configured to control the power supply to the circuit according to a control signal of the headset.

31. The method according to claim 29 or 30, wherein the headset further comprises a memory configured to store the schedule for performing the transcranial brain stimulation.

32. The method according to claim 30 or 31, wherein the electronic device having the processing capability comprises a non-temporary computer-readable recording medium on which a program executable on the electronic device is recorded, and the program includes a portion of program code configured to store in computer memory a schedule for performing transcranial brain stimulation when executed on the electronic device, generate and maintain the control signals according to the schedule for performing transcranial brain stimulation, and display information on the display of the electronic device according to a schedule for displaying information, the schedule for displaying information being related to the schedule for performing transcranial brain stimulation.

33. The method according to any one of claims 29 to 32, wherein the headset further comprises: a forehead frame defined by an elongated arch; a first electrode disposed at a first end of the elongated arched forehead frame; a second electrode disposed at a second end of the elongated arched forehead frame; and a bracket fixed to the central portion of the elongated arched forehead frame, configured to support the bracket.

34. The method according to claim 33, wherein, when using the headset to simultaneously deliver one or more non-invasive brain stimulation sessions to a subject, the elongated arched frontal frame is configured such that the first electrode is located on the left side of the subject's frontal region and the second electrode is located on the right side of the subject's frontal region, and the bracket is configured to extend from the elongated arched frontal frame across the subject's skull toward the subject's neck.

35. The method according to any one of claims 32 to 34, wherein the program further includes a portion of program code configured to prompt the object to input information regarding the state of the object when the program is executed on the electronic device, the information regarding the state of the object includes information regarding the current health status of the object.

36. The method according to any one of claims 32 to 35, further comprising a portion of program code configured to store information relating to transcranial brain stimulation performed in computer memory when the program is executed on the electronic device.

37. The method according to any one of claims 32 to 36, further comprising a portion of program code configured to update the schedule for performing the transcranial brain stimulation when the program is executed on the electronic device.

38. The method according to any one of claims 32 to 37, further comprising a first electrode and a second electrode that are pivotable so as to be able to conform to the shape of the forehead of the subject.

39. The method according to any one of claims 1 to 38, wherein the subject is diagnosed with one or more conditions or disorders selected from the group consisting of depressive state, mild depressive state, moderate depressive state, severe depressive state, major depressive disorder, major depressive disorder, depression with anxiety distress, melancholy, melancholic depression, agitation, persistent depressive disorder, type 1 bipolar disorder, type 2 bipolar disorder, bipolar disorder not otherwise specified, cyclothymic disorder, seasonal affective disorder, psychotic depression, psychotic major depressive disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, sudden onset depression, atypical depression, treatment-resistant depression, catatonic depression, dysthymia, double depression, unspecified depressive disorder, depressive personality disorder, recurrent short-term depressive state, mild depressive disorder, alcohol-induced depression, substance-induced depression, benzodiazepine-induced depression, and mixed anxiety-depressive disorder.

40. The method according to any one of claims 1 to 39, wherein the subject is at risk of developing a condition or disorder selected from the group consisting of depressive state, mild depressive state, moderate depressive state, severe depressive state, major depressive disorder, major depressive disorder, depression with anxiety distress, melancholy, melancholic depression, agitation, persistent depressive disorder, type 1 bipolar disorder, type 2 bipolar disorder, bipolar disorder not otherwise specified, cyclothymic disorder, seasonal affective disorder, psychotic depression, psychotic major depressive disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, sudden onset depression, atypical depression, treatment-resistant depression, catatonic depression, dysthymia, double depression, unspecified depressive disorder, depressive personality disorder, recurrent short-term depressive state, mild depressive disorder, alcohol-induced depression, substance-induced depression, benzodiazepine-induced depression, and mixed anxiety-depressive disorder.

41. The method according to any one of claims 1 to 40, wherein the subject achieves remission from symptoms associated with a condition or disorder selected from the group consisting of depressive state, mild depressive state, moderate depressive state, severe depressive state, major depressive disorder, major depressive disorder, depression with anxiety distress, melancholy, melancholic depression, agitation, persistent depressive disorder, type 1 bipolar disorder, type 2 bipolar disorder, bipolar disorder not otherwise specified, cyclothymia, seasonal affective disorder, psychotic depression, psychotic major depressive disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, sudden onset depression, atypical depression, treatment-resistant depression, catatonic depression, dysthymia, double depression, unspecified depressive disorder, depressive personality disorder, recurrent short-term depressive state, mild depressive disorder, alcohol-induced depression, substance-induced depression, benzodiazepine-induced depression, and mixed anxiety-depressive disorder.

42. The method according to any one of claims 1 to 41, wherein the subject shows improvement of one or more symptoms related to a condition or disorder selected from the group consisting of depressive state, mild depressive state, moderate depressive state, severe depressive state, major depressive disorder, major depressive disorder, depression with anxiety distress, melancholy, melancholic depression, agitation, persistent depressive disorder, type 1 bipolar disorder, type 2 bipolar disorder, bipolar disorder not otherwise specified, cyclothymic disorder, seasonal affective disorder, psychotic depression, psychotic major depressive disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, sudden onset depression, atypical depression, treatment-resistant depression, catatonic depression, dysthymia, double depression, unspecified depressive disorder, depressive personality disorder, recurrent short-term depressive state, mild depressive disorder, alcohol-induced depression, substance-induced depression, benzodiazepine-induced depression, and mixed anxiety-depressive disorder.

43. The method according to any one of claims 1 to 42, wherein the subject is diagnosed with one or more conditions or disorders selected from the group consisting of Alzheimer's disease, cancer, coronary heart disease, acute coronary syndrome, diabetes mellitus, epilepsy, HIV / AIDS, hypothyroidism, multiple sclerosis, Parkinson's disease, stroke, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, dementia, substance abuse disorder, mental disorders, anorexia nervosa, bulimia nervosa, muscular dysplasia, bulimia nervosa, compulsive eating disorder, polycystic ovary syndrome, Prader-Willi syndrome, diabetic bulimia, autoimmune disorders, and inflammatory disorders, and which have a risk of depression as a comorbidity.

44. The method according to any one of claims 12 to 43, wherein the one or more non-invasive brain stimulation sessions include using the tES device with the first electrode and the second electrode in close proximity to or in contact with the frontal lobe of the subject.

45. The method according to claim 44, wherein the frontal lobe of the brain of the subject is stimulated to induce neuromodulation.

46. The method according to any one of claims 44 to 45, wherein the prefrontal cortex of the subject is stimulated in a manner that induces neural modulation.

47. The method according to any one of claims 44 to 46, wherein the dorsolateral prefrontal cortex (DLPFC) of the subject is stimulated to induce neuromodulation.

48. The method according to claim 47, wherein neural activity in the DLPFC increases at the time after one or more non-invasive brain stimulation sessions.

49. The method according to any one of claims 47 to 48, wherein functional connectivity is increased between the DLPFC and one or more primary association areas of the orbitofrontal cortex, thalamus, dorsal caudate nucleus, hippocampus, neocortex, or one or more secondary association areas of the neocortex, or any combination thereof.

50. The method according to any one of claims 1 to 49, wherein one or more symptoms of a depressive state are significantly improved in the subject.

51. The method according to any one of claims 9 to 50, wherein each of the one or more non-invasive brain stimulation sessions delivers tES to the subject for a duration of at least about 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 28 minutes, 29 minutes, 30 minutes, 31 minutes, 32 minutes, 33 minutes, 34 minutes, 35 minutes, 40 minutes, 45 minutes, or 50 minutes.

52. The method according to any one of claims 9 to 51, wherein each of the one or more non-invasive brain stimulation sessions delivers tES to the subject for a duration of approximately 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 28 minutes, 29 minutes, 30 minutes, 31 minutes, 32 minutes, 33 minutes, 34 minutes, 35 minutes, 40 minutes, 45 minutes, or less than 50 minutes.

53. The method according to any one of claims 9 to 52, wherein the subject receives one or more non-invasive brain stimulation sessions at a frequency of approximately twice a day, once every 18 hours, once a day, once every 36 hours, once every other day, six times a week, five times a week, four times a week, three times a week, twice a week, once a week, or once every two weeks.

54. The method according to any one of claims 9 to 53, wherein the subject receives one or more non-invasive brain stimulation sessions at a frequency of approximately twice a day, once every 18 hours, once a day, once every 36 hours, once every other day, six times a week, five times a week, four times a week, three times a week, twice a week, once a week, or once every two weeks, according to the schedule of the initial activation stage.

55. The method according to any one of claims 9 to 54, wherein the subject receives one or more non-invasive brain stimulation sessions at a frequency of approximately twice a day, once every 18 hours, once a day, once every 36 hours, once every other day, six times a week, five times a week, four times a week, three times a week, twice a week, once a week, or once every two weeks, according to the schedule of the secondary reinforcement stage.

56. The method according to claim 54 or 55, wherein the initial activation stage continues for a period of approximately 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeks.

57. The method according to claim 55 or 56, wherein the secondary strengthening stage begins approximately 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or 25 weeks after the completion of the initial activation stage.

58. The method according to any one of claims 1 to 57, wherein tDCS delivers a current of approximately + / - 3.0 mA to the subject during the one or more non-invasive brain stimulation sessions.

59. The method according to claim 58, wherein the current is delivered continuously during the duration of one or more non-invasive brain stimulation sessions.

60. The method according to any one of claims 9 to 59, wherein the subject completes at least 110, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 of the aforementioned one or more non-invasive brain stimulation sessions.

61. The method according to any one of claims 1 to 60, wherein the subject exhibits a decrease of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, or 54 points in the MADRS-S during or after treatment, compared to the MADRS-S obtained before the start of treatment or at an earlier point in treatment.

62. The method according to any one of claims 14 to 61, wherein the desired treatment outcome is improvement of the symptoms of the subject.

63. The method according to claim 62, wherein the symptoms of the subject are symptoms of a depressive state.

64. The method according to claim 62 or 63, wherein the improvement includes a reduction in the target MADRS-S.

65. The method according to claim 64, wherein the reduction in the target MADRS-S is sustained for a period of at least one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, thirteen weeks, fourteen weeks, fifteen weeks, sixteen weeks, seventeen weeks, eighteen weeks, nineteen weeks, twenty weeks, twenty-one weeks, twenty-two weeks, twenty-three weeks, twenty-four weeks, or twenty-five weeks.

66. The method according to any one of claims 1 to 65, wherein a subject having moderate depression shows a significant reduction in MADRS-S after at least six weeks of tES treatment including at least 21 non-invasive brain stimulation sessions.

67. The method according to any one of claims 1 to 65, wherein a subject having moderate depression shows a significant reduction in MADRS-S after at least 10 weeks of tES treatment including at least 21 non-invasive brain stimulation sessions.

68. The method according to any one of claims 1 to 65, wherein a subject having a severe depressive state shows a significant reduction in MADRS-S after at least six weeks of tES treatment, which includes at least 21 non-invasive brain stimulation sessions.

69. The method according to any one of claims 1 to 65 and 68, wherein a subject having a severe depressive state shows a significant reduction in MADRS-S after at least 10 weeks of tES treatment including at least 21 non-invasive brain stimulation sessions.

70. The method according to any one of claims 1 to 69, wherein a subject having a depressive state is administered sertraline as part of a treatment regimen and shows a significant reduction in MADRS-S after at least six weeks of tES treatment including at least 21 non-invasive brain stimulation sessions.

71. The method according to any one of claims 14 to 70, comprising adjusting the parameters in the administration or delivery to reduce the ongoing dose of the pharmacological antidepressant administered to the subject, which is necessary to maintain improvement in one or more symptoms of the depressive state in order to achieve the desired therapeutic outcome.

72. The method according to any one of claims 14 to 71, comprising adjusting the parameters in the administration or delivery to reduce the frequency of ongoing administration of the pharmacological antidepressant to the subject, which is necessary to maintain improvement in one or more symptoms of a depressive state in order to achieve a desired therapeutic outcome.

73. The method according to any one of claims 14 to 72, comprising adjusting the parameters in the administration or delivery to reduce the frequency of tES sessions required for the subject to maintain improvement in one or more symptoms of depression in order to achieve a desired therapeutic outcome.

74. The method according to any one of claims 14 to 73, comprising adjusting the parameters in the administration or delivery to reduce the duration of the tES session required for the subject to maintain improvement in one or more symptoms of depression in order to achieve the desired therapeutic outcome.

75. The method according to any one of claims 14 to 74, comprising adjusting the parameters in the administration or delivery to reduce the current applied to the subject in an ongoing tES session, which is necessary to maintain improvement in one or more symptoms of depression in order to achieve a desired therapeutic outcome.

76. Use of a pharmaceutical composition comprising a pharmacological antidepressant for the manufacture of a medicament for administering treatment to a subject requiring treatment for a depressive state, wherein the pharmaceutical composition is administered to the subject and transcranial electrical stimulation (tES) is applied to the subject.

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