Combinations of anesthetics as therapies for depression

Abstract

Provided herein are methods, compositions, kits, and systems for treating depression and / or producing an electroencephalogram (EEG) profile using a combination of anesthetics. The combination of anesthetics may include a NMDA-type glutamatergic receptor antagonist anesthetic, a GABAergic anesthetic, or a α2-adrenergic receptor agonist anesthetic.

Description

COMBINATIONS OF ANESTHETICS AS THERAPIES FOR DEPRESSION CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. provisional application, U.S.S.N.63 / 707,524, filed October 15, 2024, which is incorporated herein by reference. BACKGROUND

[0002] Depression is “a serious mental health disorder characterized by persistently depressed mood or loss of interest in activities that causes significant impairment in daily life.” Major depressive disorder (MDD) is one of the most serious forms of depression. MDD is depression that persists for more than two weeks and has at least five of the following characteristics: depressed mood, loss of interest or pleasure, weight loss or gain, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, feeling worthless or excessive guilt, decreased concentration, and thoughts of death or suicide.

[0003] MDD has tremendous economic and social costs. In the United States, 21.0 million adults suffered a major depressive event in 2020. According to a recent meta-analysis, 53.1% of patients with MDD have suicidal ideation and 31% will attempt suicide. For young adults ages 15–34, suicide is the second leading cause of death. MDD enhances morbidity and mortality by worsening disorders such as diabetes, heart disease, and stroke. From a surgical perspective, MDD also augments postoperative delirium, acute and chronic pain, infections, and mortality. In the United States, in 2010, the estimated economic burden of MDD due to decreased productivity, loss of income, absenteeism, and unemployment was estimated to be $210.5 billion. These numbers worsened with the COVID-19 pandemic.

[0004] Most patients with MDD are treated with pharmacologic agents. However, after failing two or more evidence-based therapies, the patient is diagnosed with treatment- resistant depression (TRD), and alternative therapeutic options include: electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), vagal nerve stimulation (VNS), and deep brain stimulation (DBS).

[0005] Of TRD therapies, the most widely used since the early 1930s is ECT. The practice of ECT has evolved substantially during the last 90 years that it has been in use. However, the basic idea remains the same. The patient is administered a brief electrical shock either bilaterally or unilaterally to the temporal region. These standard therapy entails a series of 10–20 treatments, administered over a period of 4–6 weeks. The shock has two phases: the #14500304v1convulsive phase with seizure and the postictal phase where the EEG shows electrical suppression. Although this was not the case initially, the current practice of administering ECT entails sedating the patient first with an anesthetic and, once the patient is unconscious, administering a muscle relaxant to help prevent fractures from the brisk muscular contractions induced by the seizures. In addition to the potential harm from the seizures, a major and highly undesirable side effect of ECT is delirium and short-term memory loss. ECT is effective in about 60% of the cases. Most patients require repeat treatments after a time. ECT was developed and refined empirically. As a consequence, the mechanism through which it works remains an open question.

[0006] There is a need to develop alternative treatments for depression with improved efficacy and reduced side effects. SUMMARY

[0007] In recent years, one of the most exciting uses of anesthetics has been their application as therapies for patients with depression (e.g., treatment-resistant depression (TRD)). Herein, the characterizations of depression and the research that has been done to develop anesthetic administration as a reliable therapeutic option are reviewed. The present disclosure provides methods, uses, compositions, kits, and systems for treating depression comprising administering a combination of anesthetics. Combinations of anesthetics can be used to treat depression by modulating the state of sedation or unconsciousness and affected reagions of the brain. Combinations of anesthetics can also be used to treat depression at reduced doses and with reduced side effects. The present disclosure also provides kits and systems comprising anesthetics for administration to a subject, including, for example, for use in the methods disclosed herein.

[0008] In one aspect, provided herein are methods for treating depression in a subject in need thereof, the method comprising administering to the subject at least two anesthetics from the group of anesthetics consisting of: NMDA-type glutamatergic receptor antagonist anesthetics; GABAergic anesthetics; and 2-adrenergic receptor agonist anesthetics.

[0009] In another aspect, provided herein are methods of producing an electroencephalogram (EEG) profile of a subject, the method comprising: administering to the subject at least two anesthetics selected from the group of anesthetics consisting of: ģ14500304v1NMDA-type glutamatergic receptor antagonist anesthetics; GABAergic anesthetics; and 2-adrenergic receptor agonist anesthetics; and adjusting the dose of the anesthetics to achieve an EEG profile comprising a target slow modulation index (SMI) of about 0.2 to about 0.6.

[0010] In another aspect, provided herein are methods of producing an electroencephalogram (EEG) profile of a subject, the method comprising: administering to the subject at least two anesthetics selected from the group of anesthetics consisting of: NMDA-type glutamatergic receptor antagonist anesthetics; GABAergic anesthetics; and 2-adrenergic receptor agonist anesthetics; and adjusting the dose of the anesthetics to achieve an EEG profile comprising a target alpha modulation index (AMI) of about 0.2 to about 0.6.

[0011] In some embodiments, the method further comprises treating depression. In some embodiments, the depression is major depressive disorder. In some embodiments, the depression is treatment-resistant depression. In some embodiments, the depression is subclinical depression (e.g., depression that does not meet all the clinical requirements for depression). In some embodiments, the depression is unspecified depressive disorder.

[0012] In some embodiments, at least one anesthetic of the at least two anesthetics is administered intravenously, orally, intranasally, or as an inhalant.

[0013] In some embodiments, the first anesthetic of the at least two anesthetics is administered as an inhalant. In some embodiments, the first anesthetic of the at least two anesthetics is administered intravenously.

[0014] In some embodiments, the second anesthetic of the at least two anesthetics is administered intravenously.

[0015] In some embodiments, NMDA-type glutamatergic receptor antagonist anesthetic is at least one of ketamine, esketamine, nitrous oxide, or xenon.

[0016] In some embodiments, the GABAergic anesthetic is at least one of a barbiturate, etomidate, propofol, propanidid, isoflurane, sevoflurane, desflurane, or benzodiazenitropine.

[0017] In some embodiments, the 2-adrenergic receptor agonist anesthetic is dexmedetomidine, clonidine, medetomidine, or xylazine. In some embodiments, the 2- adrenergic receptor agonist anesthetic is dexmedetomidine. ģ14500304v1

[0018] In some embodiments, the at least two anesthetics include the NMDA-type glutamatergic receptor antagonist anesthetic and the GABAergic anesthetic.

[0019] In some embodiments, the NMDA-type glutamatergic receptor antagonist anesthetic is ketamine, and the GABAergic anesthetic is propofol.

[0020] In some embodiments, the at least two anesthetics include an GABAergic anesthetic and an 2-adrenergic receptor agonist anesthetic.

[0021] In some embodiments, the GABAergic anesthetic is propofol, and the 2-adrenergic receptor agonist anesthetic is dexmedetomidine.

[0022]

[0021] In some embodiments, the GABAergic anesthetic is propanidid, and the 2- adrenergic receptor agonist anesthetic is dexmedetomidine.

[0023] In some embodiments, administering at least two anesthetics includes administering each of the NMDA-type glutamatergic receptor antagonist anesthetic, the GABAergic anesthetic, and the 2-adrenergic receptor agonist anesthetic.

[0024] In another aspect, provided herein are methods for treating depression in a subject in need thereof, the method comprising administering to the subject propanidid intravenously. In some embodiments, the depression is treatment-resistant depression. In some embodiments, the depression is major depressive disorder.

[0025] In another aspect, provided herein are systems comprising: at least two anesthetics selected from the group of anesthetics consisting of: NMDA-2-an infusion line connected to a subject to administer a dose of each of the at least two a manual or automatic controller to adjust the dose of each of the at least two an electroencephalogram (EEG) recording device to measure an EEG profile of a a display of the recorded EEG profile.

[0026] In another aspect, provided herein are kits comprising: one or more containers comprising at least two anesthetics selected from the group of anesthetics consisting of: NMDA-ģ14500304v12-instructions for using the one or more containers.

[0027] All combinations of the foregoing concepts and additional concepts discussed in greater detail below (provided such concepts are not mutually inconsistent) are part of the inventive subject matter disclosed herein. In particular, all combinations of claimed subject matter appearing at the end of this disclosure are part of the inventive subject matter disclosed herein. The terminology used herein that also may appear in any disclosure incorporated by reference should be accorded a meaning most consistent with the particular concepts disclosed herein. BRIEF DESCRIPTIONS OF THE DRAWINGS

[0028] The skilled artisan will understand that the drawings primarily are for illustrative purposes and are not intended to limit the scope of the inventive subject matter described herein. The drawings are not necessarily to scale; in some instances, various aspects of the inventive subject matter disclosed herein may be shown exaggerated or enlarged in the drawings to facilitate an understanding of different features. In the drawings, like reference characters generally refer to like features (e.g., functionally similar and / or structurally similar elements).

[0029] FIG.1 illustrates a closed-loop anesthetic delivery (CLAD) system.

[0030] FIGs.2A-2C show control over SMI computed from local field potentials (LFPs) recorded from intracranial electrodes.

[0031] FIG.3 shows control over AMI computed from LFPs recorded from intracranial electrodes.

[0032] FIGs.4A-4B show control over SMI (FIG.4A) or over AMI (FIG.4B) initially computed from LFPs then computed from the scalp EEG.

[0033] FIGs.5A-5C show control over SMI as a result of combined dosing of propofol with dexmedetomidine.

[0034] FIGs.6A-6D show control over SMI computed from scalp EEG as a result of dosing propofol as the only anesthetic. DEFINITIONS

[0035] The following definitions are general terms used throughout the present application.

[0036] The terms “composition” and “formulation” are used interchangeably. #14500304v1

[0037] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey) or commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog)). The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a subject (e.g., a human subject) in need of treatment of a disease.

[0038] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.

[0039] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0040] An “effective amount” of a compound provided herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactically effective amount. In certain embodiments, the desired dosage is delivered once a day, every other day, every third day, every week, every two weeks, every three weeks, every four weeks, six weeks, every month, every other month, or once per quarter. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0041] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided compounds or pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0042] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have #14500304v1developed or have been observed. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0001] A “therapeutically effective amount” of a compound provided herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient to achieve an EEG profile comprising a target SMI (e.g., an SMI of about 0.2 to about 0.6) or comprising a target AMI (e.g., an AMI of about 0.2 to about 0.6). In certain embodiments, a therapeutically effective amount is an amount sufficient for treating depression, treating or ameliorating one or more symptoms of depression, or treating an episode of depression. In certain embodiments, a therapeutically effective amount is an amount sufficient to achieve an EEG profile comprising a target SMI (e.g., an SMI of about 0.2 to about 0.6) or comprising a target AMI (e.g., an AMI of about 0.2 to about 0.6) and treat depression, treat or ameliorate one or more symptoms of depression, or treat an episode of depression.

[0002] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population. In some embodiments, the subject previously had depression or symptoms of depression.

[0003] A “prophylactically effective amount” of a compound provided herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a #14500304v1prophylactically effective amount is an amount sufficient to achieve an EEG profile comprising a target SMI (e.g., an SMI of about 0.2 to about 0.6) or comprising a target AMI (e.g., an AMI of about 0.2 to about 0.6). In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing depression, preventing one or more symptoms of depression, preventing worsening of one or more symptoms of depression, or preventing an episode of depression. In certain embodiments, a prophylactically effective amount is an amount sufficient to achieve an EEG profile comprising a target SMI (e.g., an SMI of about 0.2 to about 0.6) or comprising a target AMI (e.g., an AMI of about 0.2 to about 0.6) and prevent depression, prevent one or more symptoms of depression, prevent worsening of one or more symptoms of depression, or prevent an episode of depression.

[0043] Other than in the examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, or more typically, within 5%, 4%, 3%, 2%, or 1% of a given value or range of values.

[0044] Unless otherwise required by context, singular terms shall include pluralities, and plural terms shall include the singular. DETAILED DESCRIPTION

[0045] Following below are more detailed descriptions of various concepts related to, and implementations of, combinations of anesthetics as therapies for depression. Also provided herein is disclosure related to, and implementations of, combinations of anesthetics to achieve an EEG profile comprising a target SMI and / or a target AMI. Also provided herein are kits and systems comprising anesthetics for administration to a subject. It should be appreciated that various concepts introduced above and discussed in greater detail below may be implemented in multiple ways. Examples of specific implementations and applications are provided primarily for illustrative purposes so as to enable those skilled in the art to practice the implementations and alternatives apparent to those skilled in the art. Methods and Uses

[0046] Provided herein are methods for treating depression using combinations of anesthetics, including, for example, combinations of anesthetics having different principal molecular targets and / or different mechanisms of action. Also provided herein are methods of using combinations of anesthetics for producing an EEG profile comprising a target SMI #14500304v1and / or a target AMI. While the SMI and / or AMI value corresponds to the degree of sedation or unconsciousness experienced by the subject, the same SMI and / or AMI values can be achieved with various different combinations of anesthetics. Using different combinations of anesthetics can affect different regions of the brain, e.g., where the anesthetic exerts its effect, and can achieve different brain states. This approach provides flexibility to tailor treatment to a subject. The methods provided herein may also enable lower doses of one or more anesthetics and reduce side effects.

[0047] In one aspect, provided herein are methods for treating depression in a subject in need thereof, the method comprising administering to the subject at least two anesthetics from the group of anesthetics consisting of: NMDA-type glutamatergic receptor antagonist anesthetics; GABAergic anesthetics; and 2-adrenergic receptor agonist anesthetics.

[0048] In another aspect, provided herein are methods of producing an electroencephalogram (EEG) profile of a subject, the method comprising: administering to the subject at least two anesthetics selected from the group of anesthetics consisting of: NMDA-type glutamatergic receptor antagonist anesthetics; GABAergic anesthetics; and 2-adrenergic receptor agonist anesthetics; and adjusting the dose of the anesthetics to achieve an EEG profile comprising a target slow modulation index (SMI) of about 0.2 to about 0.6.

[0049] In another aspect, provided herein are methods of producing an electroencephalogram (EEG) profile of a subject, the method comprising: administering to the subject at least two anesthetics selected from the group of anesthetics consisting of: NMDA-type glutamatergic receptor antagonist anesthetics; GABAergic anesthetics; and 2-adrenergic receptor agonist anesthetics; and adjusting the dose of the anesthetics to achieve an EEG profile comprising a target alpha modulation index (AMI) of about 0.2 to about 0.6.

[0050] In another aspect, provided herein are methods for treating depression in a subject in need thereof, the method comprising administering to the subject propanidid intravenously. In some embodiments, propanidid is administered as the sole anesthetic. ģ14500304v1DEPRESSION

[0051] In some embodiments, a method provided herein further comprises treating depression.

[0052] Any form of depression may be treated or prevented using the methods, compositions, and systems disclosed herein. Depression may include major depressive disorders (e.g., unipolar depression), dysthymic disorders (e.g., chronic, mild depression), bipolar disorders (e.g., manic-depression), seasonal affective disorder, and / or depression associated with drug or alcohol dependence or addiction (e.g., withdrawal), among other forms of depression. The depression can be clinical or subclinical depression. Depression may include major depressive disorder, dysthymia or persistent depressive disorder, melancholia, seasonal affective disorder, premenstrual dysphoric disorder, prenatal depression, perinatal or postpartum depression, bipolar disorder, cyclothymic disorder, disruptive mood dysregulation disorder, psychotic depression, atypical depression, situational depression, treatment-resistant depression, subclinical depression, or unspecified depressive disorder. In some embodiments, the depression being treated is major depressive disorder, dysthymia or persistent depressive disorder, melancholia, seasonal affective disorder, premenstrual dysphoric disorder, prenatal depression, perinatal or postpartum depression, bipolar disorder, cyclothymic disorder, disruptive mood dysregulation disorder, psychotic depression, atypical depression, situational depression, treatment-resistant depression. In some embodiments, the depression being treated is major depressive disorder. In some embodiments, the depression being treated is dysthymia or persistent depressive disorder. In some embodiments, the depression being treated is melancholia. In some embodiments, the depression being treated is seasonal affective disorder. In some embodiments, the depression being treated is premenstrual dysphoric disorder. In some embodiments, the depression being treated is prenatal depression. In some embodiments, the depression being treated is perinatal or postpartum depression. In some embodiments, the depression being treated is bipolar disorder. In some embodiments, the depression being treated is cyclothymic disorder. In some embodiments, the depression being treated is disruptive mood dysregulation disorder. In some embodiments, the depression being treated is psychotic depression. In some embodiments, the depression being treated is atypical depression. In some embodiments, the depression being treated is situational depression. In some embodiments, the depression being treated is treatment-resistant depression. In some embodiments, the depression being treated is subclinical depression (e.g., depression that does not meet all the clinical requirements for ģ14500304v1depression). In some embodiments, the depression being treated is unspecified depressive disorder.

[0053] In some embodiments, the depression comprises one or more symptoms of depressed mood, fatigue, lethargy, apathy, loss of interest or pleasure, irritability, decreased concentration, withdrawal from activities, withdrawal from social interaction, neglecting responsibilities, changes in appetite, weight loss or gain, insomnia or hypersomnia, alcohol use, drug use, feeling worthless, feeling hopeless, headaches, digestive problems, forgetfulness, slowed cognition, thoughts of death or suicide, suicide attempts, anxiety, psychomotor agitation or retardation, restlessness, slowed patterns of speech, slowed movement, difficulty making decisions, or unexplained physical problems. In some embodiments, the depression comprises one or more symptoms of depressed mood, loss of interest or pleasure, weight loss or gain, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, feeling worthless or excessive guilt, decreased concentration, and thoughts of death or suicide. In some embodiments, the depression comprises one or more symptoms of depressed mood, lethargy, or apathy.

[0054] In some embodiments, the depression comprises one or more of these symptoms. In some embodiments, the depression comprises two or more of these symptoms. In some embodiments, the depression comprises three or more of these symptoms. In some embodiments, the depression comprises four or more of these symptoms. In some embodiments, the depression comprises five or more of these symptoms.

[0055] In some embodiments, treating depression comprises reducing the severity of one or more symptoms. In some embodiments, treating depression comprises reducing the frequency of one or more symptoms. In some embodiments, treating depression comprises alleviating one or more symptoms. In some embodiments, treating depression comprises elevating mood. In some embodiments, treating depression comprises increasing emotional stability. In some embodiments, treating depression comprises an improvement in the ability to engage in daily life. In some embodiments, treating depression comprises an improvement on one or more metrics, for example, but not limited to, on patient health questionnaires, rating scales for depression, or inventories of depressive symptoms. In some embodiments, treating depression comprises preventing the return of symptoms, relapse, and / or onset of new symptoms or depressive episodes. In some embodiments, treating depression comprises reduced reliance on one or more therapies for depression. In some embodiments, treating depression comprises reduced reliance on drugs and / or alcohol. ģ14500304v1

[0056] In some embodiments, the method reduces side effects relative to administration of another treatment for depression. In some embodiments, administration of the at least two anesthetics does not cause memory loss. NMDA-TYPE GLUTAMATERGIC RECEPTOR ANTAGONIST ANESTHETICS

[0057] NMDA-type glutamatergic receptor antagonist anesthetics inhibit the action of N- methyl-D-aspartate receptor and may induce, for example, dissociative anesthesia. In some embodiments, one of the at least two anesthetics is an NMDA-type glutamatergic receptor antagonist anesthetic. In some embodiments, the NMDA-type glutamatergic receptor antagonist anesthetic is ketamine, esketamine, nitrous oxide, or xenon. In some embodiments, the NMDA-type glutamatergic receptor antagonist anesthetic is ketamine, nitrous oxide, or xenon. In some embodiments, the NMDA-type glutamatergic receptor antagonist anesthetic is ketamine. In some embodiments, the NMDA-type glutamatergic receptor antagonist anesthetic is nitrous oxide. In some embodiments, the NMDA-type glutamatergic receptor antagonist anesthetic is xenon. Ketamine

[0058] At present, ketamine is the most widely used anesthetic agent as a treatment for TRD. Ketamine is an NMDA antagonist and phencyclidine that creates a dissociative state. In addition, it is a potent analgesic. Ketamine was initially studied for its psychotomimetic effects. Subsequent preclinical and preliminary studies revealed a possible antidepressant effect. In 2000, the first double-blinded, placebo-controlled crossover trial of ketamine as a treatment for TRD was published. The patients in the treatment group received 0.5 mg / kg of ketamine administered intravenously over 40 minutes. Treatment and control administrations were separated a week apart. A decrease in HDRS-254 hours post-treatment that lasted for 3 days was reported in four patients. Additionally, four out of the 8 patients showed treatment response (>50% declined in depression score).

[0059] Six years later, a randomized, placebo-controlled, double-blind crossover study on 18 subjects with TRD was conducted. After a 2-week drug-free period, patients also received 0.5 mg / kg of intravenous ketamine or saline infusion as the control. Treatment and control administrations were separated a week apart. Within 110 minutes after injection, the ketamine subjects showed significant improvement in HDRS-21 relative to placebo. The improvement remained significant throughout the following week. Twelve of the 17 treatment subjects met criteria for response, whereas 5 of the 17 subjects met criteria for remission the day following ketamine treatment. Six of the 17 subjects maintained their responses for a week or more. It ģ14500304v1was concluded that a single intravenous administration of ketamine could produce an antidepressant effect that began within 2 hours post-administration and lasted for more than a week. Subsequently, the rapid antidepressant effects of single-dose intravenous ketamine to decrease suicidal ideation are substantiated by multiple studies, culminating in a meta- analysis conducted in 2018 that concluded that within one day, ketamine reduced suicidal thoughts in patients with suicidal ideations and that the effect lasted for as long as one week.

[0060] Ketamine is now a widely used therapy for TRD that often gives a rapid response. Its success has popularized ketamine clinics, where patients can receive infusions. However, there is no standardized treatment regimen. It can be administered intravenously, subcutaneously, intramuscularly, intranasally, sublingually, transmucosally, and more recently as an oral preparation. A single intravenous infusion session of 0.5 kg / mg over 40 minutes is the most common regimen and can achieve rapid antidepressant effects, but the effects are only partially sustained after a week. An infusion dose-response from patients from as low as 0.1 mg / kg to as high as 0.75 mg / kg has been reported. Multiple treatment sessions have seen increased success for patients unresponsive to a single treatment. In addition, prolonged ketamine infusions of 4 to 14 days have provided a more robust and sustained response and relief of symptoms. The undesired psychotomimetic side effects can be mediated by co-administration of clonidine. Nevertheless, numerous case reports indicate that chronic ketamine abuse can cause damage to the urinary tract.

[0061] While recommendations for establishing standard intravenous ketamine clinics have been outlined, official clinical guidelines are warranted to determine the optimal intravenous treatment regimen. Specifically, the guidelines must include the dosing, frequency of treatment, and method of administration for rapid or durable antidepressant effects and minimize the risk of adverse events. In 2019, the FDA approved intranasal esketamine for TRD as a Class III Scheduled drug. This formulation of ketamine also produces rapid antidepressant effects. It is often used as an adjunct to monoamine antidepressants to achieve both rapid and slow antidepressant effects. To ensure proper usage, FDA established a Risk Evaluation and Management (REMS) strategy for intranasal esketamine. They have determined that intranasal esketamine cannot be sold directly to patients and can only be administered by medical personnel within ketamine clinics because of the risks of adverse events and misuse. Patients also require a two-hour observation period after esketamine administration.

[0062] Ketamine’s biomolecular mechanism of action is postulated to be due to a neurotrophic cascade. It blocks NMDA receptors of GABAergic inhibitory interneurons, #14500304v1which leads to disinhibition of glutamatergic pyramidal neurons and increased glutamate release. In preclinical studies, this is observed as a delayed firing rate increase of pyramidal neurons relative to GABA interneurons. Subsequently, the stimulation of postsynaptic AMPA receptors lead to increased release of brain-derived neurotrophic factor (BDNF), which is key to signaling pathways for synaptogenesis, including extracellular signal-regulated protein kinase (ERK), eukaryotic elongation factor 2 (eEF2), glycogen synthase kinase-3 (GSK-3), and mechanistic target of rapamycin (mTOR). The antidepressant effects of ketamine due to increased BDNF signaling are well established in many preclinical studies. BDNF signaling also underlies the mechanism of action of many currently prescribed antidepressants and psychedelics-based treatments of depression. In animal models, the long-term antidepressant effects are linked to spine formation and synaptogenesis in the PFC.

[0063] The neurocircuitry mechanism in which ketamine provides antidepressant effects may be due to its pro-cognitive effects, deemphasizing the link between negative emotional content and cognitive processing. Specifically, the rapid anti-suicidal effects of ketamine may relate to better executive function, executive control, and decreased impulsivity. In an fMRI study of functional connectivity, the effects of prolonged ketamine infusion (96 hours) on patients with TRD were explored. A response-dependent decrease in hyperconnectivity from the subgenual anterior cingulate cortex (sgACC) to other default mode network (DMN) regions and a treatment-dependent decrease in limbic system hyperconnectivity were observed. This is supported by other studies which have found correlations between the functional connectivity between the dorsolateral PFC, sgACC, other DMN regions, and the limbic system with depression severity and antidepressant response. The prolonged ketamine infusion regimen may provide a sustained effect on brain connectivity at these loci of interest, hence a persistent antidepressant effect. Other mechanisms of action, including the activation of opioid receptors in the lateral habenula and increased levels of dopamine, may also play a role in the antidepressant mechanisms of ketamine. However, clinical studies have yet to provide consistent findings with preclinical studies. Nitrous Oxide

[0064] Nitrous oxide is an NMDA antagonist that provides moderate sedation. It is often administered as an adjunct agent with other inhalation or intravenous anesthetics. Nagele postulated that nitrous oxide may have antidepressant effects because it, like ketamine, targets NMDA receptors. Therefore, a double-blind, placebo-controlled crossover study on 20 subjects with TRD was conducted in 2015. Patients received 1-hour inhalation of 50% ģ14500304v1nitrous oxide / 50% oxygen as the treatment or 50% nitrogen / 50% oxygen as the control. Subjects were evaluated with the HDRS-21 scale at baseline, 2 hours, and 24 hours after treatment. During treatment, subjects had a median inspiratory concentration of 44%. In the treatment phase, patients showed significant improvement in their HDRS-21 scores at 2 hours and 24 hours relative to the placebo phase. Four of the 20 patients treated with nitrous oxide met criteria for response the day following treatment, whereas 3 of the 20 met criteria for remission. In the placebo phase, 1 of the 20 patients had a response, whereas none had remission. Only temporary adverse effects are reported, with no serious adverse events. These included typical dissociative effects, nausea, and vomiting. It was concluded that nitrous oxide has rapid (within 2 hours) antidepressant effect in TRD patients.

[0065] In a follow-up commentary, the efficacy of 50% nitrous oxide as a therapy for TRD was accepted. Nagele et al. (2015). However, several important issues were also raised in the commentary. The near absence of side effects that had been previously reported was questioned and it was postulated that the nitrous oxide antidepressant effect was likely broader than NMDA inhibition. Additionally, whether the patients were adequately blinded to treatment was questioned. It was concluded that there is a need to define proper clinical adaptation of nitrous oxide for the treatment of TRD.

[0066] As a follow-on, it was investigated whether the persistent antidepressant effects of nitrous oxide could be achieved with fewer adverse effects by administering 25% instead of 50%. A phase 2 randomized crossover clinical trial on 24 patients with severe TRD was conducted. The treatments were 1-hour inhalation of: 50% nitrous oxide; 25% nitrous oxide; and placebo. Subjects were evaluated with the HDRS-21 scale at 2 hours, 24 hours, 1 week, and 2 weeks post-treatment. Both treatment groups had significant improvements in depressive symptoms relative to placebo. There was no significant difference in the HDRS- 21 between the two treatment groups (25% and 50% nitrous oxide). Adverse events were significantly fewer in the 25% treatment phase relative to the 50% treatment phase. These results have helped establish the potential efficacy of nitrous oxide as a TRD treatment and suggest that a lower dose may achieve desirable therapeutic goals with fewer adverse side effects.

[0067] Nitrous oxide, like ketamine, is an NMDA antagonist and likely has a mechanism of action similar to ketamine’s disinhibition hypothesis. In vivo preclinical studies show similar histological changes and neuroprotective and neurotoxic action as other NMDA antagonists. Likewise, an animal study has also shown that exposure to nitrous oxide promotes synaptogenesis through BDNF signaling, which has been hypothesized for ketamine’s #14500304v1antidepressant mechanism of action. Yet, there are a few distinctions between nitrous oxide and ketamine’s mechanism of action. Nitrous oxide is not an open-channel inhibitor. Therefore, it has different binding affinity, voltage-dependency, and kinetic effects on the NMDA receptor than ketamine. Also, its EEG dynamics show profound slow oscillations followed by beta and gamma oscillations, dissimilar to ketamine. How these specific differences between nitrous oxide and ketamine relate to the brain circuits relevant to its antidepressant effects has yet to be described. While ketamine and nitrous oxide both have antidepressant effects, not all NMDA receptor antagonists have this effect. For example, memantine, an NMDA receptor antagonist that slows the progression of Alzheimer’s disease, does not have antidepressant effects. The lack of antidepressant efficacy may result from different pharmacokinetics and effects on NMDA channels or subtypes. Therefore, it would be key to profile the pharmacokinetic properties of these anesthetic agents and their effects on neural circuitry associated with antidepressant efficacy. Xenon

[0068] Xenon, like ketamine and nitrous oxide, is an NMDA antagonist which has been postulated to have antidepressant effects. Preclinical studies have shown xenon leads to increased expression of BDNF, which has been implicated in ketamine and nitrous oxide’s mechanism of action. This suggests that xenon may achieve its antidepressant effects through a mechanism of action related to synaptogenesis. However, unlike ketamine and nitrous oxide, xenon has neuroprotective properties without the co-existing neurotoxicity, which may make it more favorable as a treatment for depression. As of 2023, xenon is currently being studied in a clinical trial as a potential therapeutic agent for TRD and bipolar depression. GABAERGIC ANESTHETICS

[0069] GABAergic anesthetics modulate the function of GABAAreceptors. In some embodiments, one of the at least two anesthetics is a GABAergic anesthetic. In some embodiments, the GABAergic anesthetic is a barbiturate, etomidate, propofol, propanidid, isoflurane, sevoflurane, desflurane, or benzodiazenitropine. In some embodiments, the GABAergic anesthetic is at least one of propofol, propanidid, isoflurane, or sevoflurane. In some embodiments, the GABAergic anesthetic is a barbiturate. In some embodiments, the barbiturate is amobarbital, aprobarbital, barbital, butalbital, cyclobarbital, ethobarbital, mephobarbital, methohexital, phenobarbital, pentobarbital, phenytoin, probarbital, propallylonal, secobarbital, thiamylal, or thiopental. In some embodiments, the barbiturate is methohexital, thiopental, pentobarbital, or secobarbital. In some embodiments, the barbiturate #14500304v1is methohexital or thiopental. In some embodiments, the GABAergic anesthetic is methohexital. In some embodiments, the GABAergic anesthetic is thiopental. In some embodiments, the GABAergic anesthetic is etomidate. In some embodiments, the GABAergic anesthetic is propofol. In some embodiments, the GABAergic anesthetic is propanidid. In some embodiments, the GABAergic anesthetic is isoflurane. In some embodiments, the GABAergic anesthetic is sevoflurane. In some embodiments, the GABAergic anesthetic is desflurane. In some embodiments, the GABAergic anesthetic is benzodiazenitropine. Isoflurane and Sevoflurane

[0070] Perhaps the first anesthetic proposed as a treatment for TRD was isoflurane. Isoflurane is a halogenated methyl ethyl ether. It produces burst suppression on the EEG at a dose of about 1.5 minimal alveolar concentration (MAC) and an isoelectric state at about 2 MAC. Because the isoelectric periods of burst suppression resembled the postictal periods following ECT, it has been postulated that isoflurane could be an alternative to ECT. It has also been suggested that seizures are not necessary for antidepressant effect, and that isoflurane-mediated burst suppression should be sufficient. This was termed isoflurane narcotherapy.

[0071] In an open-label study of isoflurane-mediated burst suppression for TRD, patients received from 1 to 6 treatments of isoflurane. Each treatment started from 4% and decreased to around 2 MAC to achieve 80% suppression for 15 minutes. Rapid antidepressant effects were observed in 9 of 11 patients. In a number of cases, the effects lasted for several weeks and, most importantly, there were no adverse side effects. Subsequent open-label studies and a small randomized controlled clinical trial (RCT) comparing isoflurane and ECT, using the treatment schedule of isoflurane described above, corroborated these findings. In the RCT, the antidepressant effects were comparable for the isoflurane and ECT groups. However, unlike the ECT patients, none of the isoflurane-treated patients had significant cognitive side effects. The isoflurane patients had further improvements in their psychometric variables during follow-up, whereas the ECT patients deteriorated.

[0072] Conversely, in an open-label follow-up study, little improvement in depressive symptoms in 6 isoflurane-treated elderly patients was reported. Five patients were aged 74– 82 and two had significant hypotension. A possible explanation for the lack of improvement is in the patient selection criteria. Five of 6 patients had had ECT before and relapsed. Based on the GABA hypothesis of ECT, these patients could have developed high tolerance to #14500304v1GABAergic agents, decreasing the efficacy of the isoflurane treatment. Alternatively, these patients may have been unsuitable for the treatment.

[0073] Inspired by the isoflurane studies, in 2001, a small RCT comparing sevoflurane- induced burst suppression to propofol sham in patients with TRD was designed. Sevoflurane over isoflurane was chosen, citing sevoflurane’s better safety profile. The results failed to show significant improvements in depression scores. In response to these results, it was noted that the sevoflurane dose in the treatment group had a lower MAC equivalence of isoflurane than that in previous isoflurane studies. Patients also received only four treatments compared to the six treatments in the studies discussed above. Since propofol and isoflurane are both GABAergic agents with potential antidepressant effects, the propofol group could have received partially effective treatments. Similar concerns about true control in studies comparing ECT and sham ECT groups have been raised previously. It has also been suggested that these inconclusive findings led to a cessation of investigating inhaled anesthetics as a treatment for TRD.

[0074] Despite this, appreciable preclinical data supporting the use of inhaled anesthetics for treating TRD have recently accrued. In 2013, it was reinvestigated whether isoflurane has antidepressant effects comparable to ECT, but with fewer adverse effects on cognitive function. In this study, depressive state measured by the 24-item Hamilton Depression Rating Scale (HDRS-24) and a battery of neurocognitive tests between 10 treatment sessions of bifrontal ECT (n = 20) and 10 treatment sessions of isoflurane (n = 8) was compared over a 3-week period. The isoflurane treatment regimen replicated the original isoflurane study design discussed above. Both the ECT and isoflurane treatments showed important decreases in depressive scores immediately post-treatment and at 4-week follow-up. The ECT patients, however, showed declines in processing speed, memory, and fluency immediately post- treatment, with declines in autobiographical memory scores persisting for 4 weeks. ECT had noticeably better antidepressant effects at 4-week follow-up in patients who had comparable MDD severity. This study helped reestablish the utility of isoflurane as a treatment for TRD that is comparable to ECT but with fewer adverse cognitive effects.

[0075] When isoflurane was first proposed as a treatment for TRD, the rationale was to mimic the postictal suppression generated by ECT using the burst suppression induced by high MAC dosage of isoflurane. However, it is now known that their mechanisms of action are not completely equivalent. Based on the GABA hypothesis, postictal suppression of ECT may be due to the endogenous release of GABA, while isoflurane has both broad inhibitory effects on brain networks and metabolic effects on the mitochondria. This is exhibited on #14500304v1frontal EEG as alpha and slow-delta oscillations—and at levels above MAC as theta oscillations—which may indicate network disruptions throughout the brainstem, thalamus, and / or cortex. Under the hyperconnectivity hypothesis of depression, the antidepressant effects of isoflurane may work by stimulating neurogenesis through a GABAergic mechanism. Propofol

[0076] Propofol is a GABAergic anesthetic that is used primarily for induction and maintenance of unconsciousness as part of general anesthesia. It is known to also target NMDA receptors. At sufficiently high doses, propofol, like other GABAergic anesthetics, will cause burst suppression. In 2018, an open-label trial was conducted to investigate “the feasibility, tolerability, and efficacy of deep propofol” for the treatment of TRD. It was hypothesized that propofol, like isoflurane, could act as an antidepressant by maintaining prolonged isoelectric periods during burst suppression. The control group consisted of 20 patients receiving ECT. The treatment group consisted of 10 patients (ages 18–45) with moderate to severe TRD. Each patient received 10 treatment sessions of propofol infusions designed to maintain 80% burst suppression for 15 minutes. This resulted in a dosing regimen of a bolus ranging from 200 to 600 mg, a continuous infusion of 300 to 650 μg / kg / min, and repeated small boluses ranging from 50 to 100 mg. Of note, these propofol doses are substantially higher than that typically used for sedation. The primary outcomes were the Montreal Cognitive Assessment (MOCA) scores in the immediate postoperative period as well as the 24-item HDRS-24 and self-evaluated depression scores assessed at baseline, mid- treatment, and post-treatment. Propofol was well tolerated by all patients with no serious adverse events. Patients in the propofol treatment group showed stable MOCA scores and significant decreases in HDRS-24. Six of 10 propofol patients met criteria for therapeutic response (>50% improvement), five of which remained well for at least 3 months. It was found that propofol and ECT treatment groups had similar self-evaluated depression scores. According to Mickey and colleagues, propofol may be an effective alternative to ECT for TRD “without ECT’s commonly observed cognitive side effects.” It was also noted that sufficient but not excessive EEG burst suppression was associated with less hypotension, quicker recovery, and more improvement in depression scores (HDRS-24). This suggests the need for future investigations through controlled studies to define more clearly the appropriate level of EEG burst suppression needed to optimally treat TRD. #14500304v1

[0077] The mechanism of GABAergic agents, such as propofol and isoflurane, to treat depression is not well-understood. The EEG signature of propofol is characterized by alpha and delta oscillations, which indicates a disruption of the thalamocortical network. At higher doses, these oscillations devolve into burst suppression through a metabolic and modulatory mechanism. Although propofol, like isoflurane, also produces burst suppression at high doses, postictal suppression periods during ECT and burst suppression induced by GABAergic agents show different spatiotemporal dynamics. This may suggest a different mechanism of action between GABAergic agents and ECT. For example, propofol, unlike endogenous GABA, has mitochondrial toxicity in the brain. Thus, the connection between propofol treatment, the GABA deficit hypothesis, and the GABA hypothesis of ECT is unclear.

[0078] Other mechanisms that lead to the antidepressant properties of GABAergic agents have also been studied. The short-term effects of propofol have been described as euphoria, as reported by patients after gastrointestinal endoscopy. This anti-anhedonia effect has been implicated in preclinical studies showing that propofol inhibits dopamine transporter (DAT) and increases dopamine concentration in the nucleus accumbens. However, this pathway is also related to drugs of potential abuse, such as cocaine and methamphetamine. Therefore, caution should be applied when using propofol as a treatment for TRD to minimize the possible risk of abuse. Lastly, preclinical studies of propofol also show inhibition of NMDA receptors, suggesting a possible overlap in the mechanism of action with ketamine and nitrous oxide. Propanidid

[0079] Propanidid is a novel, intravenous short-acting sedative-hypnotic agent of the eugenol group. It has been previously used for induction and maintenance of anesthesia. Similar to propofol, it acts in the central nervous system as a positive allosteric modulator of the gamma-aminobutyric acid type A (GABAA) receptor. Even though propanidid is not approved by the FDA for human-use in the United States, it has been safely used in clinical practice in Mexico for over 20 years.

[0080] Even though standard anesthetics like propofol have relatively fast degradation and clearance, prolonged postoperative cognitive dysfunction may occur, especially after long surgical procedures and with elderly patients. Propanidid is thought to be metabolized faster than propofol, due to its metabolism in both blood serum and liver and rapid clearance, ģ14500304v1thereby possibly allowing for tighter control over the patient’s anesthetic state and faster cognitive recovery from general anesthesia.

[0081] Despite its long-term use in Mexico, the neurophysiological and pharmacological signatures have not been characterized as extensively. An initial investigation shows that the neurophysiological signatures for propofol and propanidid during general anesthesia may be very similar. Due to its similarities with propofol and rapid clearance properties, it is conjectured that the anti-depressant effects of propanidid may offer a great alternative to propofol-based treatment. Propanidid treatment could be administered using propanidid only or by using propanidid as the replacement for propofol in the treatment combinations mentioned above. For single-drug treatment using propanidid, the drug could be administered intravenously (bolus in the beginning, if needed) during the daytime. The treatments could be repeated every other day for 3–4 weeks. When using propanidid to replace propofol, the same procedure as propofol could be used while adjusting the dose of propanidid using the recommended dose ranges. 2-ADRENERGIC RECEPTOR AGONIST ANESTHETICS

[0082] 2-Adrenergic receptor agonist anesthetics stimulate alpha receptors, such as presynaptic alpha-2 receptors in the central nervous system. In some embodiments, one of the at least two anesthetics is an 2-adrenergic receptor agonist anesthetic. In some embodiments, the 2-adrenergic receptor agonist anesthetic is dexmedetomidine, clonidine, medetomidine, or xylazine. In some embodiments, the 2-adrenergic receptor agonist anesthetic is dexmedetomidine or clonidine. In some embodiments, the 2-adrenergic receptor agonist anesthetic is dexmedetomidine. In some embodiments, the 2-adrenergic receptor agonist anesthetic is clonidine. Dexmedetomidine

[0083] Dexmedetomidine is an 2-adrenergic receptor agonist that acts on both the brain and spinal cord (Brown et al.2018). It is known to mimic certain EEG features of nonrapid eye movement (NREM) sleep, specifically sleep spindles (12–16 Hz) and slow-delta oscillations (Akeju et al.2018). While dexmedetomidine is predominantly used for intravenous sedation in intensive care units and as an anesthetic adjunct in operating rooms, its sublingual form is used to manage agitation in adults with schizophrenia or bipolar disorder under the supervision of healthcare professionals (FDA 2022). In addition to its role in reducing delirium, dexmedetomidine has well-documented antinociceptive and anxiolytic effects #14500304v1across various administration routes (oral, intranasal, inhalational, intrathecal, and intramuscular) (Naaz & Ozair 2014).

[0084] In a pilot study conducted by Liu et al. (2024), 76 patients with TRD were randomized to receive either 10 sessions of intravenous dexmedetomidine or ECT administered under propofol. The study found that both dexmedetomidine and ECT significantly reduced depression scores (HDRS-24). However, the dexmedetomidine group showed a greater reduction during the initial sessions. It did not affect cognitive scores, while ECT temporarily decreased cognition. The ECT group experienced adverse effects such as tachycardia, memory gaps, and insomnia during and after treatment. The dexmedetomidine group reported only a few cases of temporary injection site discomfort and mild nausea. However, due to propofol’s own antidepressant effects, its use during ECT introduced a confounding factor that likely reduced the treatment difference between the two groups. In addition, other studies have shown the benefits of dexmedetomidine for preventing postpartum depression (Yu et al.2019, Zhou et al.2024).

[0085] The exact mechanisms by which dexmedetomidine produces antidepressant are effects are not fully understood. However, they may involve several factors, including promoting slow-wave-like sleep, (Goldstein et al.2022), reducing inflammation (Kopschina Feltes et al.2017), and alleviating pain (Bair et al.2003). These factors are related to depression. Dexmedetomidine acts on the locus coeruleus adrenergic projections in the brainstem, enhancing EEG slow-wave and spindle activity, a dynamic that closely resembles NREM sleep (Akeju et al.2018). Additionally, it reduces inflammatory factors (Li et al. 2015) and promotes neuronal survival by increasing BDNF concentrations (Dehbozorgi et al. 2024). These actions may also contribute to dexmedetomidine’s analgesic effects (Xu et al. 2022). During dexmedetomidine-mediated sedation, reduced connectivity has been observed within the brain’s default mode network, the fronto-parietal network and the limbic system. (Akeju et al.2014a, Guldenmund et al.2017). This altered connectivity, associated with EEG slow-delta and spindle oscillations, may contribute to the antidepressant effects of dexmedetomidine (Akeju et al.2016).

[0086] Dexmedetomidine has also been investigated as a therapy for postpartum depression in women following Cesarean section. In this 2019 study, 600 women scheduled for elective Cesarean sections were randomly assigned to receive sufentanil infusion with normal saline or sufentanil infusions with dexmedetomidine as a prophylactic intervention for postpartum depression. Postpartum depression was measured by the Edinburgh Postnatal Depression Scale (EPDS) at day 7 and day 42 following delivery. EPDS scores and self-harm ideation #14500304v1were significantly lower for the dexmedetomidine group relative to the control group at both time points. In addition, pain scores and sleep quality were significantly better in the dexmedetomidine group. These findings suggest that dexmedetomidine may have therapeutic benefits in reducing the incidence of postpartum depression. Though the mechanism causing postpartum depression differs from TRD, these results still justify an investigation into dexmedetomidine as a treatment for TRD. One possible mechanism by which dexmedetomidine treats postpartum depression could be through improved sleep, most likely through slow-wave sleep, which has been characterized as EEG signatures for dexmedetomidine. Therefore, it is hypothesized that dexmedetomidine may have therapeutic use for depressed patients with sleep deprivation as a comorbidity. MULTIMODAL ANESTHETIC THERAPY FOR TREATING DEPRESSION

[0087] Just as anesthetics can create distinct conscious states, they may provide antidepressant effects through different mechanisms of action. Some common themes include replicating postictal suppression from ECT using burst suppression from GABAergic agents, facilitating synaptogenesis through the NMDA-induced neurotrophic cascade and reducing connectivity within principal brain networks. These observations are also in line with other commonly accepted treatment modalities for depression, such as monoaminergic antidepressants and ECT. Even so, research suggests that their exact antidepressant mechanism varies. Ketamine has already become a common treatment for TRD, particularly for its rapid antidepressant effects. Its success has paved the way for other anesthetics to follow. It is proposed herein that the success of anesthetics for treatment of depression, and including but not limited to TRD, depends on understanding how molecular mechanisms create prolonged changes in neural circuitry, optimizing a treatment regimen, and characterizing adverse effects for each anesthetic agent. Additionally, it is proposed that combining anesthetics together or with other treatment could lead to far more personalized treatment plans tailored to each patients’ needs.

[0088] Every day, over 60,000 people are put under general anesthesia for a surgical procedure in the United States alone. This reversible, drug-induced state of unconsciousness is induced and maintained by an anesthesia care giver (e.g., an anesthesiologist). To reach the proper level of unconsciousness, anesthesia care givers typically administer a combination of intravenous and / or inhaled anesthetics. Under their guidance, general anesthesia is one of the safest and most commonly used practices of modern medicine. #14500304v1

[0089] As disclosed herein, anesthetics can be combined to produce an immediate and long- lasting antidepressant effect similar to how anesthesiologists maintain unconsciousness in surgical settings. These combination therapies may provide patients with a better experience by achieving instant relief that is sustained longer than current sole-dosed anesthetic therapies. Combining anesthetics together or with other treatments may yield personalized treatment plans tailored to each patient’s needs. In addition, these therapies can be delivered in either an in-patient or out-patient setting.

[0090] Table 1 presents three groups of drugs, categorized based on their mechanism of action or principal molecular targets. Group 1 contains NMDA-type glutamatergic receptor antagonists, such as ketamine, esketamine, nitrous oxide, and xenon. Group 2 includes GABAergic drugs such as propofol, propanidid, isoflurane, sevoflurane, etomidate, thiopental, methohexital, desflurane, and benzodiazenitropine. Group 3 contains 2- adrenergic receptor agonists, such as dexmedetomidine, clonidine, medetomidine, and xylazine.

[0091] Table 1: Grouping of anesthetics based on mechanism of action.

[0092] The combinations disclosed herein include one anesthetic from two or more of these groups. In some embodiments, two of the anesthetics are selected from different classes. In some embodiments, the at least two anesthetics are each selected from different classes. In #14500304v1some embodiments, the at least two anesthetics are administered in any combination provided herein. In some embodiments, administering at least two anesthetics comprises administering each of the NMDA-type glutamatergic receptor antagonist anesthetic, the GABAergic anesthetic, and the 2-adrenergic receptor agonist anesthetic.

[0093] In some embodiments, the at least two anesthetics comprise an NMDA-type glutamatergic receptor antagonist anesthetic and an 2-adrenergic receptor agonist anesthetic. In some embodiments, the NMDA-type glutamatergic receptor antagonist anesthetic is ketamine, and the 2-adrenergic receptor agonist anesthetic is dexmedetomidine.

[0094] In some embodiments, the at least two anesthetics comprise an NMDA-type glutamatergic receptor antagonist anesthetic and a GABAergic anesthetic. In some embodiments, the NMDA-type glutamatergic receptor antagonist anesthetic is ketamine, and the GABAergic anesthetic is propofol. In some embodiments, the NMDA-type glutamatergic receptor antagonist anesthetic is ketamine, and the GABAergic anesthetic is propanidid.

[0095] In some embodiments, the at least two anesthetics comprise a GABAergic anesthetic and an 2-adrenergic receptor agonist anesthetic. In some embodiments, the GABAergic anesthetic is propanidid, and the 2-adrenergic receptor agonist anesthetic is dexmedetomidine. In some embodiments, the GABAergic anesthetic is propofol, and the 2- adrenergic receptor agonist anesthetic is dexmedetomidine.

[0096] The administration routes, approximate doses, and regimen may follow the guidelines presented in Table 2, below. Combinations of anesthetics, rationales for these combinations, and the potential therapeutic effects are outlined below. Anesthetic Combination 1: Ketamine (1) + Propofol (2)

[0097] The combination of ketamine and propofol may be an effective treatment for depressed patients (e.g., patients with TRD or MDD). Ketamine, administered intravenously, orally, or as a nasal spray, is already used as an antidepressant therapy. Its antidepressant effect is rapid–within minutes of administration–but the duration of these effects varies from days to weeks. Propofol, administered intravenously, can be used in conjunction with ketamine to reduce the time until a treatment effect appears and to enhance the longevity of the treatment. Propofol induces a euphoric effect on emergence, whereas ketamine induces a state of dissociation during emergence. Their different timing and behavioral effects are due to their differing mechanisms in the brain that are linked to depression, making them compatible with a combination therapy. Targeting both mechanisms simultaneously may amplify the antidepressant effect by treating a wider array of brain circuits as opposed to only #14500304v1a portion of the depression circuitry, and thereby may promote longer effects. The combination of ketamine and propofol can be administered simultaneously as a day-time treatment, given every other day for 3–4 weeks similar to the current ketamine treatment protocol. Anesthetic Combination 2: Ketamine (1) + Propofol (2) + Dexmedetomidine (3)

[0098] The combination of ketamine, propofol, and dexmedetomidine may be an effective treatment for depressed patients (e.g., patients with TRD or MDD) with insomnia as a comorbidity. There is a link between depression and sleep and insomnia issues. For positive treatment outcomes, getting good quality sleep for the duration of the main daytime treatment is highly beneficial. Dexmedetomidine is an anesthetic whose mechanism of action and EEG signatures closely mimic those of natural sleep. Dexmedetomidine has been used to improve sleep quality and can be administered orally (e.g., sublingually) or intravenously. Therefore, the inclusion of dexmedetomidine in the multi-drug treatment plan may offer great benefits to patients with insomnia as a component of their depression. The dexmedetomidine is administered by a qualified health care professional (e.g., an anesthesia care giver).

[0099] In one embodiment, the 3-drug treatment regimen may use ketamine and propofol as the daytime treatment agents and dexmedetomidine at night. The same protocol summarized in the ketamine + propofol section immediately above may be used for the daytime treatment. In addition, adding dexmedetomidine (intravenously or orally) every night for the duration of treatment may support the antidepressant effects of the daytime therapy and treat patients with a comorbidity of insomnia related to their depression.

[0100] In another embodiment, the 3-drug treatment regimen may administer ketamine, propofol, and dexmedetomidine as a daytime treatment. One or more of the ketamine, propofol, and dexmedetomidine may be administered simultaneously. The same protocol summarized in the ketamine + propofol section above may be used for the daytime treatment. A combined ketamine, propofol, and dexmedetomidine protocol may allow for a lower dose of ketamine, propofol, and / or dexmedetomidine. Anesthetic Combination 3: Ketamine (1) + Dexmedetomidine (3)

[0101] The combination of ketamine and dexmedetomidine may provide a treatment for depressed patients (e.g., patients with TRD or MDD) with insomnia as a comorbidity. For clinicians interested in exclusively outpatient treatment, a combination of intranasal ketamine by day and dexmedetomidine by night would be available. As described above, the dexmedetomidine may be administered orally (e.g., sublingually) or intravenously. Since #14500304v1ketamine clinics are already widely available, dexmedetomidine can be prescribed as an adjunct to manage the patient’s sleep.

[0102] In one embodiment, a possible treatment regimen may follow the typical protocol administered at ketamine clinics by day (e.g., every other day for 3–4 weeks) with oral dexmedetomidine every night for the duration of the treatment. Intravenous (IV) dexmedetomidine could also be added to the prolonged ketamine treatment regimen (96 hours). This could provide a more sustained antidepressant response and support for sleep cycles that could be disrupted during prolonged ketamine infusion. The dexmedetomidine is administered by a qualified health care professional (e.g., an anesthesia care giver).

[0103] In another embodiment, a possible treatment regimen may include administering both ketamine and dexmedetomidine during the day. Preferably, the ketamine and dexmedetomidine are delivered intravenously. The ketamine and dexmedetomidine may also be administered simultaneously. The same protocol summarized in the ketamine + propofol section above may be used for the combined ketamine and dexmedetomidine protocol. A combined ketamine and dexmedetomidine protocol may allow for a lower dose of ketamine and / or dexmedetomidine. Anesthetic Combination 4: Propofol (2) + Dexmedetomidine (3)

[0104] The combination of propofol and dexmedetomidine may effectively treat depressed patients (e.g., patients with TRD or MDD) with insomnia as a comorbidity. Propofol is known for its rapid euphoric effect, and it can be administered intravenously. Dexmedetomidine can be used to improve the quality of sleep and can be administered orally. Alterations to REM sleep are the most evident sleep characteristics in patients with MDD. By mimicking natural sleep onset, dexmedetomidine may increase total NREM sleep and subsequently decrease REM sleep. As sleep disturbance may be responsible for increased inflammatory gene expression in patients with MDD, improved sleep induced by dexmedetomidine may complement the euphoric effects of propofol.

[0105] Propofol should be administered intravenously only by anesthesiologists or qualified health professionals. In one embodiment, a possible treatment regimen would follow the typical propofol protocol administered during the day, and dexmedetomidine (oral or IV) at night to support sleep cycles and sustain the dopaminergic effect of propofol. The treatment could be repeated every other day for 3-4 weeks with dexmedetomidine treatment repeated every night during the course of the treatment. Dexmedetomidine (including oral dexmedetomidine) should be administered by a qualified health professional. #14500304v1

[0106] In another embodiment, a possible treatment regimen may include administering both propofol and dexmedetomidine during the day. Preferably, the propofol and dexmedetomidine are delivered intravenously. The propofol and dexmedetomidine may also be administered simultaneously. The same protocol summarized above in the ketamine + propofol may be used for the combined propofol and dexmedetomidine protocol. A combined propofol and dexmedetomidine protocol may allow for a lower dose of propofol and / or dexmedetomidine.

[0107] The addition of dexmedetomidine to propofol as a treatment for depression (e.g., TRD or MDD) may decrease the propofol doses required to achieve the same level of sedation or unconsciousness. By administering a low level of dexmedetomidine, equivalent antidepressant effects may be achieved through a propofol-based therapy.

[0108] Propofol and dexmedetomidine may be used in combination to achieve a target SMI and / or target AMI value. Dosage of propofol and dexmedetomidine may be adjusted, for example, to achieve a propofol-dominated state or a dexmedetomidine-dominated state. When the target SMI and / or target AMI value is achieved by using mostly dexmedetomidine relative to propofol, then the primary effects are observed the brainstem relative to the cortex and thalamus, approximating a slow-wave sleep like state. Alternatively, when the target SMI and / or target AMI value is achieved by using mostly propofol relative to dexmedetomidine, the resulting state is more similar to propofol-mediated unconsciousness. In that case, effects in the brainstem, thalamus and cortex are observed, and the slow oscillations have a different mechanism with more direct action on cortical connectivity. For example, in that case, propofol may act directly on the thalamus, and may create an alpha oscillation between the cortex and thalamus, coherent slow-waves across the cortex, and anteriorization of alpha oscillations. Administration, Dosing, SMI and / or AMI Targets

[0109] Table 2 discloses administration routes, approximate doses, and regimens for the use of anesthetics from Table 1. In Table 2, BS corresponds to burst suppression, and MAC corresponds to minimal alveolar concentration. ģ14500304v1.noisserpedrofseiparehtcitehtseenX3M(0a2lado) ssuoeuo%nm1rit5it(i 7 2lu1- rt diixon / m e P N %dO05i6mx–rUo0O2 3ofRseGe: : ni rsso n 5dmh se / dr ;arh / d i od7.;0gknieg / ggkk / wem otgnk / rlat elg –1 / .gm h0ol / egcot gmdegp om6Knmi0m4 9SrPm 5a1.t00a3rt6xit.0E:t2n 1elV aIlv4b a 0h30an0I5T41#)3(3-P UOR G)2(2-P U OR GdidinaporP lofoporP noneX)1s(u1 oe- rt dPi ixNoUOR Gengme) gni 0 ki20 / g4m 2gmmmart8e r atoe ,A7– o003–K6 k5sD EF 5(2. 502l1avsla4a r03N O00541#

[0110] In some embodiments, at least one anesthetic of the at least two anesthetics is administered intravenously, orally, intranasally, or as an inhalant. In some embodiments, a first anesthetic of the at least two anesthetics is administered intravenously, orally, intranasally, or as an inhalant. In some embodiments, a first anesthetic of the at least two anesthetics is administered intravenously. In some embodiments, a first anesthetic of the at least two anesthetics is administered orally. In some embodiments, a first anesthetic of the at least two anesthetics is administered intranasally. In some embodiments, a first anesthetic of the at least two anesthetics is administered as an inhalant. In some embodiments, a second anesthetic of the at least two anesthetics is administered intravenously, orally, intranasally, or as an inhalant. In some embodiments, a second anesthetic of the at least two anesthetics is administered intravenously. In some embodiments, a second anesthetic of the at least two anesthetics is administered orally. In some embodiments, a second anesthetic of the at least two anesthetics is administered intranasally. In some embodiments, a second anesthetic of the at least two anesthetics is administered as an inhalant. In some embodiments, a first anesthetic of the at least two anesthetics is administered as an inhalant, and a second anesthetic of the at least two anesthetics is administered intravenously. In some embodiments, a first anesthetic of the at least two anesthetics is administered intravenously, and a second anesthetic of the at least two anesthetics is administered intravenously.

[0111] In some embodiments, the at least two anesthetics are administered manually. In some embodiments, at least one of the at least two anesthetics is administered manually. In some embodiments, the at least two anesthetics are administered by constant rate infusion. In some embodiments, at least one of the at least two anesthetics is administered constant rate infusion. In some embodiments, the at least two anesthetics are administered via a closed-loop anesthesia delivery (CLAD) system. In some embodiments, at least one of the at least two anesthetics is administered via a closed-loop anesthesia delivery (CLAD) system.

[0112] In some embodiments, propofol is administered intravenously.

[0113] In some embodiments, propofol is administered at a rate of about 50 mcg / kg / min to about 650 mcg / kg / min. In some embodiments, propofol is administered at a rate of about 50 mcg / kg / min to about 150 mcg / kg / min. In some embodiments, propofol is administered at a rate of about 150 mcg / kg / min to about 250 mcg / kg / min. In some embodiments, propofol is administered at a rate of about 250 mcg / kg / min to about 350 mcg / kg / min. In some embodiments,31 / 69 #14500304v1propofol is administered at a rate of about 350 mcg / kg / min to about 450 mcg / kg / min. In some embodiments, propofol is administered at a rate of about 450 mcg / kg / min to about 550 mcg / kg / min. In some embodiments, propofol is administered at a rate of about 550 mcg / kg / min to about 650 mcg / kg / min. In some embodiments, propofol is administered for about 10 minutes to about 15 minutes.

[0114] In some embodiments, propofol is initially administered at a rate of about 50 mcg / kg / min to about 150 mcg / kg / min. In some embodiments, propofol is initially administered at a rate of about 50 mcg / kg / min to about 70 mcg / kg / min. In some embodiments, propofol is initially administered at a rate of about 70 mcg / kg / min to about 90 mcg / kg / min. In some embodiments, propofol is initially administered at a rate of about 90 mcg / kg / min to about 110 mcg / kg / min. In some embodiments, propofol is initially administered at a rate of about 90 mcg / kg / min to about 100 mcg / kg / min. In some embodiments, propofol is initially administered at a rate of about 100 mcg / kg / min to about 110 mcg / kg / min. In some embodiments, propofol is initially administered at a rate of about 100 mcg / kg / min. In some embodiments, propofol is initially administered at a rate of about 110 mcg / kg / min to about 130 mcg / kg / min. In some embodiments, propofol is initially administered at a rate of about 130 mcg / kg / min to about 150 mcg / kg / min.

[0115] In some embodiments, propofol is administered as a bolus in an amount of about 50 mg to about 100 mg. In some embodiments, propofol is administered as a bolus in an amount of about 50 mg to about 60 mg. In some embodiments, propofol is administered as a bolus in an amount of about 60 mg to about 70 mg. In some embodiments, propofol is administered as a bolus in an amount of about 70 mg to about 80 mg. In some embodiments, propofol is administered as a bolus in an amount of about 80 mg to about 90 mg. In some embodiments, propofol is administered as a bolus in an amount of about 90 mg to about 100 mg.

[0116] In some embodiments, the dose of propofol is reduced by about 20% to about 40% when administered in combination with a second anesthetic. In some embodiments, the dose of propofol is reduced by about 20% to about 40% upon administration of the second anesthetic. In some embodiments, the dose of propofol is reduced by about 25% to about 35% when administered in combination with a second anesthetic. In some embodiments, the dose of propofol is reduced by about 25% to about 35% upon administration of the second anesthetic.

[0117] In some embodiments, propanidid is administered intravenously.32 / 69 #14500304v1

[0118] In some embodiments, propanidid is administered at a rate of about 100 mcg / kg / min to about 1500 mcg / kg / min. In some embodiments, propanidid is administered at a rate of about 100 mcg / kg / min to about 250 mcg / kg / min. In some embodiments, propanidid is administered at a rate of about 250 mcg / kg / min to about 500 mcg / kg / min. In some embodiments, propanidid is administered at a rate of about 500 mcg / kg / min to about 750 mcg / kg / min. In some embodiments, propanidid is administered at a rate of about 750 mcg / kg / min to about 1000 mcg / kg / min. In some embodiments, propanidid is administered at a rate of about 1000 mcg / kg / min to about 1250 mcg / kg / min. In some embodiments, propanidid is administered at a rate of about 1250 mcg / kg / min to about 1500 mcg / kg / min. In some embodiments, propanidid is administered for about 10 minutes to about 15 minutes.

[0119] In some embodiments, propanidid is administered as a bolus in an amount of about 20 mg to about 100 mg. In some embodiments, propanidid is administered as a bolus in an amount of about 20 mg to about 40 mg. In some embodiments, propanidid is administered as a bolus in an amount of about 40 mg to about 60 mg. In some embodiments, propanidid is administered as a bolus in an amount of about 60 mg to about 80 mg. In some embodiments, propanidid is administered as a bolus in an amount of about 80 mg to about 100 mg.

[0120] In some embodiments, the dose of propanidid is reduced by about 20% to about 40% when administered in combination with a second anesthetic. In some embodiments, the dose of propanidid is reduced by about 20% to about 40% upon administration of the second anesthetic. In some embodiments, the dose of propanidid is reduced by about 25% to about 35% when administered in combination with a second anesthetic. In some embodiments, the dose of propanidid is reduced by about 25% to about 35% upon administration of the second anesthetic.

[0121] In some embodiments, dexmedetomidine is administered intravenously.

[0122] In some embodiments, dexmedetomidine is administered at a rate of about 0.2 mcg / kg / hr to about 2.5 mcg / kg / hr. In some embodiments, dexmedetomidine is administered at a rate of about 0.2 mcg / kg / hr to about 1 mcg / kg / hr. In some embodiments, dexmedetomidine is administered at a rate of about 0.2 mcg / kg / hr to about 0.4 mcg / kg / hr. In some embodiments, dexmedetomidine is administered at a rate of about 0.4 mcg / kg / hr to about 0.6 mcg / kg / hr. In some embodiments, dexmedetomidine is administered at a rate of about 0.6 mcg / kg / hr to about 0.8 mcg / kg / hr. In some embodiments, dexmedetomidine is administered at a rate of about 0.8 mcg / kg / hr to about 1 mcg / kg / hr. In some embodiments, dexmedetomidine is administered at a33 / 69 #14500304v1rate of about 1 mcg / kg / hr to about 1.5 mcg / kg / hr. In some embodiments, dexmedetomidine is administered at a rate of about 1.5 mcg / kg / hr to about 2.5 mcg / kg / hr. In some embodiments, dexmedetomidine is administered for about 30 minutes to about 60 minutes. In some embodiments, dexmedetomidine is administered for about 30 minutes to about 40 minutes. In some embodiments, dexmedetomidine is administered for about 40 minutes to about 50 minutes. In some embodiments, dexmedetomidine is administered for about 50 minutes to about 60 minutes.

[0123] In some embodiments, dexmedetomidine is initially administered at a rate of about 1.5 mcg / kg / hr to about 2.5 mcg / kg / hr. In some embodiments, dexmedetomidine is initially administered at a rate of about 1.5 mcg / kg / hr to about 1.7 mcg / kg / hr. In some embodiments, dexmedetomidine is initially administered at a rate of about 1.7 mcg / kg / hr to about 1.9 mcg / kg / hr. In some embodiments, dexmedetomidine is initially administered at a rate of about 1.9 mcg / kg / hr to about 2.1 mcg / kg / hr. In some embodiments, dexmedetomidine is initially administered at a rate of about 2 mcg / kg / hr. In some embodiments, dexmedetomidine is initially administered at a rate of about 2.1 mcg / kg / hr to about 2.3 mcg / kg / hr. In some embodiments, dexmedetomidine is initially administered at a rate of about 2.2 mcg / kg / hr to about 2.3 mcg / kg / hr.

[0124] In some embodiments, dexmedetomidine is administered orally. In some embodiments, dexmedetomidine is administered in an amount of about 35 mcg to about 700 mcg. In some embodiments, dexmedetomidine is administered in an amount of about 35 mcg to about 200 mcg. In some embodiments, dexmedetomidine is administered in an amount of about 35 mcg to about 50 mcg. In some embodiments, dexmedetomidine is administered in an amount of about 50 mcg to about 75 mcg. In some embodiments, dexmedetomidine is administered in an amount of about 75 mcg to about 100 mcg. In some embodiments, dexmedetomidine is administered in an amount of about 100 mcg to about 300 mcg. In some embodiments, dexmedetomidine is administered in an amount of about 300 mcg to about 500 mcg. In some embodiments, dexmedetomidine is administered in an amount of about 500 mcg to about 700 mcg.

[0125] In some embodiments, the dose of dexmedetomidine is reduced by about 20% to about 40% when administered in combination with a second anesthetic. In some embodiments, the dose of dexmedetomidine is reduced by about 20% to about 40% upon administration of the second anesthetic. In some embodiments, the dose of dexmedetomidine is reduced by about 25%34 / 69 #14500304v1to about 35% when administered in combination with a second anesthetic. In some embodiments, the dose of dexmedetomidine is reduced by about 25% to about 35% upon administration of the second anesthetic.

[0126] In some embodiments, ketamine is administered intravenously.

[0127] In some embodiments, ketamine is administered at a rate of about 30 mcg / kg / min to about 0.6 mcg / kg / hr. In some embodiments, ketamine is administered at a rate of about 30 mcg / kg / min to about 0.15 mcg / kg / hr. In some embodiments, ketamine is administered at a rate of about 0.15 mcg / kg / hr to about 0.6 mcg / kg / hr.

[0128] In some embodiments, ketamine is administered in a single dose of about 0.1 mg / kg to about 0.75 mg / kg. In some embodiments, ketamine is administered in a single dose of about 0.1 mg / kg to about 0.25 mg / kg. In some embodiments, ketamine is administered in a single dose of about 0.25 mg / kg to about 0.5 mg / kg. In some embodiments, ketamine is administered in a single dose of about 0.5 mg / kg to about 0.75 mg / kg. In some embodiments, ketamine is administered for up to about 40 min. In some embodiments, ketamine is administered for about 35 minutes to about 45 minutes. In some embodiments, ketamine is administered for about 40 minutes.

[0129] In some embodiments, ketamine is administered nasally. In some embodiments, ketamine is administered in an amount of about 50 mg to about 90 mg. In some embodiments, ketamine is administered in an amount of about 50 mg to about 60 mg. In some embodiments, ketamine is administered in an amount of about 60 mg to about 70 mg. In some embodiments, ketamine is administered in an amount of about 70 mg to about 80 mg. In some embodiments, ketamine is administered in an amount of about 80 mg to about 90 mg. In some embodiments, ketamine is administered in an amount of 56 mg. In some embodiments, ketamine is administered in an amount of 84 mg.

[0130] In some embodiments, ketamine is administered orally. In some embodiments, ketamine is administered in an amount of about 0.25 mg / kg to about 7 mg / kg. In some embodiments, ketamine is administered in an amount of about 0.25 mg / kg to about 1 mg / kg. In some embodiments, ketamine is administered in an amount of about 1 mg / kg to about 2 mg / kg. In some embodiments, ketamine is administered in an amount of about 2 mg / kg to about 4 mg / kg. In some embodiments, ketamine is administered in an amount of about 4 mg / kg to about 7 mg / kg. In some embodiments, ketamine is administered in an amount of about 25 mg to about35 / 69 #14500304v1300 mg. In some embodiments, ketamine is administered in an amount of about 25 mg to about 50 mg. In some embodiments, ketamine is administered in an amount of about 50 mg to about 100 mg. In some embodiments, ketamine is administered in an amount of about 100 mg to about 200 mg. In some embodiments, ketamine is administered in an amount of about 200 mg to about 300 mg.

[0131] In some embodiments, the dose of ketamine is reduced by about 10% to about 20% when administered in combination with a second anesthetic. In some embodiments, the dose of ketamine is reduced by about 10% to about 20% upon administration of the second anesthetic.

[0132] In some embodiments, nitrous oxide is administered as an inhalant. In some embodiments, nitrous oxide is administered as a mixture with oxygen in a 25:75 ratio for about 30 minutes to about 60 minutes. In some embodiments, nitrous oxide is administered as a mixture with oxygen in a 25:75 ratio for about 30 minutes to about 40 minutes. In some embodiments, nitrous oxide is administered as a mixture with oxygen in a 25:75 ratio for about 40 minutes to about 50 minutes. In some embodiments, nitrous oxide is administered as a mixture with oxygen in a 25:75 ratio for about 50 minutes to about 60 minutes.

[0133] In some embodiments, xenon is administered as an inhalant. In some embodiments, xenon is administered as 35%.

[0134] In some embodiments, isofluorane is administered as an inhalant.

[0135] In some embodiments, sevofluorane is administered as an inhalant.

[0136] Generally, as provided herein, the at least two anesthetics are administered during the same session of treatment and / or period of sedation. In some embodiments, the administration occurs over a period of about 10 minutes to about 180 minutes. In some embodiments, the administration occurs over a period of about 10 minutes to about 60 minutes. In some embodiments, the administration occurs over a period of about 60 minutes to about 180 minutes. In some embodiments, the administration occurs over a period of about 60 minutes to about 120 minutes. In some embodiments, the administration occurs over a period of about 100 minutes to about 140 minutes. Optionally, in some embodiments, the at least two anesthetics are administered at different frequences or on different dosage regimens.

[0137] In some embodiments, the at least two anesthetics are administered simultaneously during the session of treatment and / or period of sedation. In some embodiments, the at least two anesthetics are administered sequentially during the session of treatment and / or period of36 / 69 #14500304v1sedation. In some embodiments, the at least two anesthetics are administered sequentially, wherein administration of the first anesthetic is continued upon administration of the second anesthetic. In some embodiments, the at least two anesthetics are administered sequentially, wherein administration of the first anesthetic is continued upon administration of the second anesthetic and the dose of the first anesthetic is adjusted.

[0138] Administration of a second anesthetic in combination with a first anesthetic can require adjustments to the dose of the first and / or second anesthetic, for example, to treat depression and / or to maintain or adjust a desired level of unconsciousness, a target SMI, and / or a target AMI. Accordingly, in some embodiments, the dose or rate of administration of the first anesthetic is adjusted upon administration of the second anesthetic. In some embodiments, the dose or rate of administration of the first anesthetic is adjusted upon administration of the second anesthetic to achieve a higher target SMI or AMI in the EEG profile. In some embodiments, the dose or rate of administration of the first anesthetic is adjusted upon administration of the second anesthetic to achieve a lower target SMI or AMI in the EEG profile. In some embodiments, the dose or rate of administration of the first anesthetic is adjusted upon administration of the second anesthetic to maintain approximately the same target SMI or AMI in the EEG profile.

[0139] In some embodiments, the dose or rate of administration of the first anesthetic is reduced upon administration of the second anesthetic. In some embodiments, the dose or rate of administration of the first anesthetic is reduced upon administration of the second anesthetic, wherein the first anesthetic is propofol. In some embodiments, the dose or rate of administration of the first anesthetic is reduced upon administration of the second anesthetic, wherein the second anesthetic is dexmedetomidine. In some embodiments, the dose or rate of administration of the first anesthetic is reduced upon administration of the second anesthetic, wherein the first anesthetic is propofol, and the second anesthetic is dexmedetomidine.

[0140] In some embodiments, the dose of the first anesthetic is reduced by about 10% to about 50% upon administration of the second anesthetic. In some embodiments, the dose of the first anesthetic is reduced by about 10% to about 20% upon administration of the second anesthetic. In some embodiments, the dose of the first anesthetic is reduced by about 10% to about 30% upon administration of the second anesthetic. In some embodiments, the dose of the first anesthetic is reduced by about 20% to about 40% upon administration of the second anesthetic. In some embodiments, the dose of the first anesthetic is reduced by about 20% to about 30%37 / 69 #14500304v1upon administration of the second anesthetic. In some embodiments, the dose of the first anesthetic is reduced by about 25% to about 35% upon administration of the second anesthetic. In some embodiments, the dose of the first anesthetic is reduced by about 30% to about 40% upon administration of the second anesthetic. In some embodiments, the dose of the first anesthetic is reduced by about 40% to about 50% upon administration of the second anesthetic.

[0141] The target SMI and / or AMI value is selected based on the desired level of unconsciousness of the subject. Smaller SMI and / or AMI values correlate with increased sedation and / or deeper unconsciousness. In some embodiments, the EEG profile is held at a target SMI or AMI over the course of the administration. In some embodiments, the EEG profile is held at a target SMI or AMI for a first period. In some embodiments, the EEG profile is held at a first target SMI or AMI level for a first period and later adjusted to a second target SMI or AMI level for a second period. In some embodiments, the second target SMI or AMI level is increased relative to the first target SMI or AMI level. In some embodiments, the second target SMI or AMI level is decreased relative to the first target SMI or AMI level. In some embodiments, the first period is about 15 minutes to 45 minutes in duration. In some embodiments, the second period is about 15 minutes to 45 minutes in duration.

[0142] In some embodiments, the target SMI is about 0.2 to about 0.6. In some embodiments, the target SMI is about 0.2 to about 0.5. In some embodiments, the target SMI is about 0.3 to about 0.6. In some embodiments, the target SMI is about 0.2 to about 0.4. In some embodiments, the target SMI is about 0.4 to about 0.6. In some embodiments, the target SMI is about 0.2 to about 0.3. In some embodiments, the target SMI is about 0.3 to about 0.4. In some embodiments, the target SMI is about 0.4 to about 0.5. In some embodiments, the target SMI is about 0.5 to about 0.6.

[0143] In some embodiments, the target AMI is about 0.2 to about 0.6. In some embodiments, the target AMI is about 0.2 to about 0.5. In some embodiments, the target AMI is about 0.3 to about 0.6. In some embodiments, the target AMI is about 0.2 to about 0.4. In some embodiments, the target AMI is about 0.4 to about 0.6. In some embodiments, the target AMI is about 0.2 to about 0.3. In some embodiments, the target AMI is about 0.3 to about 0.4. In some embodiments, the target AMI is about 0.4 to about 0.5. In some embodiments, the target AMI is about 0.5 to about 0.6.38 / 69 #14500304v1

[0144] In some embodiments, the target SMI or AMI is adjusted (e.g., within an administration or from one administration to another) based on the desired degree of sedation of the subject. In some embodiments, the target SMI or AMI is adjusted (e.g., within an administration or from one administration to another) to increase the sedation of the subject. In some embodiments, the target SMI or AMI is adjusted (e.g., within an administration or from one administration to another) to decrease sedation of the subject. In some embodiments, the target SMI or AMI is adjusted (e.g., within an administration or from one administration to another) based on the subject’s response to a prior treatment. In some embodiments, the prior treatment comprises a prior administration of at least two anesthetics according to a method provided herein. In some embodiments, the prior treatment comprises an additional therapy for depression.

[0145] In some embodiments, the target SMI or AMI is adjusted based on whether the subject’s symptoms improved, went unchanged, or worsened in response to a prior treatment. In some embodiments, the dose of at least anesthetic is adjusted based on whether the subject’s symptoms improved, went unchanged, or worsened in response to a prior treatment. In some embodiments, the dose of at least one anesthetic is increased if the subject’s symptoms went unchanged or worsened in response to a prior treatment. In some embodiments, the dose of at least one anesthetic is decreased if the subject’s symptoms improved in response to a prior treatment.

[0146] In some embodiments, the target SMI or AMI is adjusted based on side effects of a prior treatment. In some embodiments, the dose of at least one anesthetic is adjusted based on side effects of a prior treatment. In some embodiments, the dose of at least one anesthetic is reduced if the subject experienced extreme drowsiness after a prior treatment.

[0147] In some embodiments, the target SMI or AMI is increased by about 0.1 to about 0.4. In some embodiments, the target SMI or AMI is increased by about 0.1 to about 0.3. In some embodiments, the target SMI or AMI is increased by about 0.2 to about 0.4. In some embodiments, the target SMI or AMI is increased by about 0.1 to about 0.2. In some embodiments, the target SMI or AMI is increased by about 0.2 to about 0.3. In some embodiments, the target SMI or AMI is increased by about 0.3 to about 0.4.

[0148] In some embodiments, the target SMI or AMI is decreased by about 0.1 to about 0.4. In some embodiments, the target SMI or AMI is decreased by about 0.1 to about 0.3. In some embodiments, the target SMI or AMI is decreased by about 0.2 to about 0.4. In some embodiments, the target SMI or AMI is decreased by about 0.1 to about 0.2. In some39 / 69 #14500304v1embodiments, the target SMI or AMI is decreased by about 0.2 to about 0.3. In some embodiments, the target SMI or AMI is decreased by about 0.3 to about 0.4.

[0149] In certain embodiments, administration of the at least two anesthetics is performed once a day, every other day, every third day, every week, every two weeks, every three weeks, every four weeks, six weeks, every month, every other month, or once per quarter. In some embodiments, the at least two anesthetics are administered according to the same regimen or frequency. In some embodiments, each of the at least two anesthetics is administered according to a distinct regimen or frequency. In some embodiments, the frequency of administration is adjusted based on results of subjecting the subject to a clinical evaluation.

[0150] In some embodiments, the method further comprises subjecting the subject to a clinical evaluation following administration. In some embodiments, the method further comprises subjecting the subject to a clinical evaluation immediately following administration. In some embodiments, the method further comprises subjecting the subject to a clinical evaluation one to seven days after administration. In some embodiments, the method further comprises subjecting the subject to a clinical evaluation one week to two weeks after administration. In some embodiments, the method further comprises subjecting the subject to a clinical evaluation two weeks to one month after administration.

[0151] In some embodiments, the method further comprises monitoring one or more of the electrocardiogram, blood pressure, oxygen saturation, expired CO2, and / or temperature of the subject. In some embodiments, the method further comprises monitoring one or more of the unprocessed EEG, the spectrogram, spatial coherence (e.g., when used with an EEG cap over the subject’s entire head), filtered alpha signal, filtered slow-delta signal, spectral edge frequency, median frequency, connectivity, entropy, and / or spectral power in the slow-delta, alpha, or beta bands. In some embodiments, the method further comprises use of whole-head EEG. Whole- head EEG measurements may provide, for example, information about underlying networks, including for example default mode network or frontal parietal network, and changes to such networks.

[0152] In some embodiments, the method further comprises administering a drug that reverses the effect of an anesthetic. In some embodiments, the method further comprises administering atipamezole.40 / 69 #14500304v1SUBJECTS

[0153] In some embodiments, the subject is a mammal. In some embodiments, the subject is a primate. In some embodiments, the subject is a non-human primate. In some embodiments, the subject is a monkey. In some embodiments, the subject is a human. In some embodiments, the subject is an adult. In some embodiments, the subject is a young adult. In some embodiments, the subject is an adolescent. In some embodiments, the subject is a child. In some embodiments, the subject is an elderly adult. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject has a family history of depression. In some embodiments, the subject has experienced or is experiencing a stressful or traumatic life event. In some embodiments, the subject has one or more additional medication conditions. In some embodiments, the subject is using or has previously used drugs or alcohol.

[0154] In some embodiments, the subject has been diagnosed with clinical depression. In some embodiments, the subject has not been diagnosed with clinical depression. In some embodiments, the subject has not been diagnosed with clinical depression but exhibits at least one symptom of depression.

[0155] In some embodiments, the subject has been diagnosed with or experiences major depressive disorder. In some embodiments, the subject has been diagnosed with or experiences dysthymia or persistent depressive disorder. In some embodiments, the subject has been diagnosed with or experiences melancholia. In some embodiments, the subject has been diagnosed with or experiences seasonal affective disorder. In some embodiments, the subject has been diagnosed with or experiences premenstrual dysphoric disorder. In some embodiments, the subject has been diagnosed with or experiences prenatal depression. In some embodiments, the subject has been diagnosed with or experiences perinatal or postpartum depression. In some embodiments, the subject has been diagnosed with or experiences bipolar disorder. In some embodiments, the subject has been diagnosed with or experiences cyclothymic disorder. In some embodiments, the subject has been diagnosed with or experiences disruptive mood dysregulation disorder. In some embodiments, the subject has been diagnosed with or experiences psychotic depression. In some embodiments, the subject has been diagnosed with or experiences atypical depression. In some embodiments, the subject has been diagnosed with or experiences situational depression. In some embodiments, the subject has been diagnosed with or experiences treatment- resistant depression. In some embodiments, the subject experiences subclinical depression. In41 / 69 #14500304v1some embodiments, the subject has been diagnosed with or experiences unspecified depressive disorder.

[0156] In some embodiments, the subject is concurrently receiving or has previously received an additional therapy for depression. In some embodiments, the subject is concurrently receiving an additional therapy for depression. In some embodiments, the subject has previously received an additional therapy for depression. In some embodiments, the additional therapy comprises one or more of antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, light therapy, or psychotherapy (e.g., cognitive behavioral therapy, analytical psychotherapy, depth psychotherapy, systemic therapy). In some embodiments, the subject has experienced one or more side effects associated with an additional therapy for depression. In some embodiments, the additional therapy for depression has resulted in no improvement or minimal improvement in one or more of the subject’s symptoms of depression. Systems and Kits

[0157] Also provided herein are systems for controlling administration of anesthetics to a subject, including, for example, modulating the dose of one or more anesthetics upon administration of at least one other anesthetic. The systems provided herein are also useful, for example, for controlling administration of anesthetics to a subject to achieve a target SMI and / or target AMI value. Also provided herein are kits comprising anesthetics. The systems and kits may be used, for example, in a method provided herein.

[0158] In another aspect, provided herein are systems comprising: at least two anesthetics selected from the group of anesthetics consisting of: NMDA-2-an infusion line connected to a subject to administer a dose of each of the at least two and a display of the recorded EEG profile.42 / 69 #14500304v1

[0159] Administration of one or more of the anesthetics provided herein (e.g., anesthetics from Table 1) may be controlled using a closed-loop anesthesia delivery (CLAD) system. The CLAD system may allow for automatic and / or manual control of delivery of one or more anesthetics to a patient during treatment for depression (e.g., TRD or MDD). In one embodiment, the CLAD system may be used to monitor the delivery of a first anesthetic. In some embodiments, at least one anesthetic is administered intravenously, facilitating titration and dosage control. Preferably the first anesthetic is delivered intravenously. In combination with the first anesthetic, a second anesthetic may also be delivered manually without the use of the CLAD system. In some embodiments, the second anesthetic is delivered orally, nasally, or as an inhalant. In another embodiment, the CLAD system may be used to monitor the delivery of both a first anesthetic and a second anesthetic. Preferably, the first and second anesthetic are delivered intravenously. In yet another embodiment, the CLAD system may be used to monitor the delivery of a first anesthetic and a second anesthetic. Preferably, the first and second anesthetic are delivered intravenously. In combination with the first and second anesthetic, a third anesthetic may also be delivered manually without the use of the CLAD system. In some embodiments, the third anesthetic is delivered orally, nasally, or as an inhalant.

[0160] The system is configured to allow the user to determine the state of unconsciousness of the subject and adjust the dose of the at least two anesthetics. In some embodiments, the EEG recording device is operably connected to a monitor to filter oscillatory signals out of the EEG from desired frequency bands. The monitor may also be connected to the controller to determine the state of unconsciousness of the subject and / or adjust the dose of the at least two anesthetics based on, for example, the state of anesthetic-mediated unconsciousness and the desired level of unconsciousness of the subject. The monitor and / or EEG recording device and / or controller may further be operably connected to a graphical user interface (GUI) to allow the user to assess and adjust the level of unconsciousness of the subject. The controller, monitor, and / or GUI may also be operably connected to an infusion pump to deliver the dose of the at least two anesthetics via the infusion line(s). In some embodiments, the system comprises one or more infusion lines. In some embodiments, the system comprises at least two infusion lines.

[0161] FIG.1 shows a closed-loop anesthetic delivery (CLAD) system 100 that determines and uses MIs for automatic and / or manual control of anesthetic delivery to a patient 101 during unconsciousness. The system 100 may include an EEG recording system 110, a monitor 120, a43 / 69 #14500304v1controller 130, an infusion pump 140, and a user interface, shown in FIG.1 as a graphical user interface (GUI) 150. The EEG recording system 110, monitor 120, controller 130, infusion pump 140, and GUI 150 may be implemented in separate (purpose-built) devices, different combinations of devices, or a single device, such as an appropriately programmed computer. If implemented as separate devices or combinations of devices, the EEG recording system 110, monitor 120, controller 130, infusion pump 140, and / or GUI 150 may be connected through one or more wires and / or wireless connections (e.g., through the use of Wi-Fi connections, Bluetooth connections, cellular connections, satellite links, and / or a local area network). The monitor 120, controller 130, and GUI 150 may be combined into a single physical device (e.g., a computing device such as a computer). Alternatively, the monitor 120, controller 130, and GUI 150 may be contained in one or more separate devices (e.g., multiple computing devices, such as multiple computers).

[0162] The CLAD system may monitor multiple electroencephalogram (EEG) signatures through the use of EEG electrodes 111 (e.g., an amplitude modulation index (AMI) and / or a slow-wave frequency modulation index (SMI)) that may provide an indication of the patient’s level of unconsciousness. The EEG electrodes 111 may be conductive electrodes in the form of single electrodes (e.g., a reference electrode, a ground electrode, and a measurement electrode), strips (e.g., six electrodes), and / or a cap (e.g., a whole head cap including at least 32 electrodes with a plurality of channels).

[0163] The CLAD system may additionally monitor one or more of the unprocessed EEG, the spectrogram, spatial coherence (e.g., when used with an EEG cap over the subject’s entire head), filtered alpha signal, filtered slow-delta signal, spectral edge frequency, median frequency, connectivity, entropy, and / or spectral power in the slow-delta, alpha, and / or beta bands.

[0164] The monitor 120 and controller 130 may be operably connected to the pump 140 through a wired or wireless connection. The pump 140 may include the infusion data receiver that receives the infusion rate from the controller 130. The pump 140 may also include an infusion pump and an infusion line 143. The infusion pump pumps the anesthetic into the infusion line 143. The infusion line 143 is tubing through which the anesthetic is pumped through a catheter 145 into a vein of the patient 101. The vein may be in the patient’s arm 102 or in the back of the patient’s hand, for example. Alternatively, the vein may be in the patient’s foot or neck (e.g., the jugular vein).44 / 69 #14500304v1

[0165] The CLAD system allows for the automatic and / or manual control of delivery of an intravenously delivered anesthetic(s). The pump 140 may deliver one or more anesthetics through the infusion line 143. Alternatively, the pump 140 may be operably connected to a plurality of infusion lines 143 to deliver more than one anesthetic to the patient 101, wherein each infusion line delivers a separate anesthetic to the patient 101. For example, the pump 140 may be operably connected to one infusion line 143 (as shown in FIG.1), two infusion lines, three infusion lines, and / or four infusion lines.

[0166] The CLAD system may automatically adjust the rate of administration of the one or more anesthetics from Table 1 to maintain a desired therapeutic level in the patient. The desired therapeutic level for each anesthetic from Table 1 may vary based on the neurophysiological properties of the anesthetic(s). The CLAD system may be used to administer one or more of the anesthetics from Table 1 at the approximate doses disclosed in Table 2 for each anesthetic. The CLAD system may automatically control the dose of the anesthetic(s) being administered. The CLAD system may also allow for manual control (e.g., by an anesthesiologist or qualified health professional) of the dose of the anesthetic(s) being administered.

[0167] In some embodiments, the system is useful in a method provided herein.

[0168] Further details regarding a CLAD system and examples of use of a CLAD system for tracking a level of anesthesia-mediated unconsciousness are disclosed in International Patent Application No. PCT / US2024 / 034967, which is hereby incorporated by reference in its entirety.

[0169] In another aspect, provided herein are kits comprising: one or more containers comprising at least two anesthetics selected from the group of anesthetics consisting of: NMDA-2-instructions for using the one or more containers.

[0170] In some embodiments, the kits comprise one or more containers for use in a method or system provided herein. In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the45 / 69 #14500304v1pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.

[0171] In some embodiments, the kits are useful for treating depression in a subject in need thereof. In some embodiments, the kits are useful for preventing depression in a subject in need thereof. In some embodiments, the kits are useful for producing an electroencephalogram (EEG) profile of a subject comprising a target AMI or SMI. In some embodiments, the kits are useful in a system provided herein. In some embodiments, the kits are useful in a method provided herein.

[0172] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is information for administration. In certain embodiments, the kits and instructions provide for treating depression in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing depression in a subject in need thereof. EXAMPLES

[0173] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting in their scope. Example 1

[0174] Research in human volunteers and surgical patients has shown that unconsciousness under general anesthesia can be reliably tracked using real-time electroencephalogram processing. A closed-loop anesthesia delivery (CLAD) system that maintains precisely specified levels of unconsciousness can be used to treat depression.

[0175] The US Federal Drug Administration has approved no CLAD system for human use due partly to a lack of testing in appropriate animal models. A nonhuman primate (NHP) CLAD system was implemented that controlled the level of unconsciousness using the anesthetic propofol. The system components include a local field potential (LFP) recording system; propofol pharmacokinetics and pharmacodynamic models; the control variable (LFP power between 20 and 30 Hz), a programmable infusion system, and a linear quadratic integral controller. The CLAD system accurately controlled the level of unconsciousness along two different 125-minute dynamic target trajectories for 18 hours and 45 minutes in nine experiments46 / 69 #14500304v1in two NHPs. System performance measures were comparable or superior to those in previous CLAD reports. The results demonstrated that an NHP CLAD system can reliably and accurately control in real-time unconsciousness maintained by anesthesia. Administration of anesthesia and modulation of unconsciousness via the CLAD system may be further used to treat depression. (Chakravarty et al. PNAS Nexus, 2023) CLAD using AMI and SMI

[0176] Unconsciousness maintained by GABAergic anesthetics, such as propofol and sevoflurane, can be characterized by frequency modulation of the slow-delta oscillations (0.3 to 4 Hz) and amplitude modulation of the alpha oscillations (8 to 14 Hz). The alpha amplitude modulation is readily visible in the unprocessed electroencephalogram (EEG). At higher doses, these slow-delta–alpha (SDA) oscillations transitioned into burst suppression. Burst suppression is an EEG and LFP signature of profound brain inactivation. The only state of more profound brain inactivation is flat or isoelectric EEG. During burst suppression, isoelectric (flatline) periods alternate with periods of the SDA patterns present at lower doses. While the SDA and burst suppression patterns have been analyzed separately, the transition from one to the other has not. Using state–space methods, the dynamic evolution of brain activity was characterized from SDA to burst suppression and back during unconsciousness maintained with propofol in 10 volunteer subjects; propofol in 10 surgical patients; propofol in 10 surgical patients who had either diminished or no alpha oscillations; and sevoflurane in 10 surgical patients. Two dynamical processes were uncovered that continuously modulated the SDA oscillations: alpha- wave amplitude and slow-wave frequency modulation. An alpha modulation index (AMI) and a slow modulation index (SMI) were derived which characterize how these processes tracked the transition from SDA oscillations to burst suppression and back to SDA oscillations as a function of increasing and decreasing anesthetic doses, respectively (Adam et al. PNAS, 2023).

[0177] This biophysical model revealed that these dynamics tracked the combined evolution of the neurophysiological and metabolic effects of a GABAergic anesthetic on brain circuits. The characterization of the modulatory dynamics mediated by GABAergic anesthetics offered insights into the mechanisms of these agents and strategies for monitoring and precisely controlling the level of unconsciousness in patients under general anesthesia (Adam et al. PNAS, 2023).47 / 69 #14500304v1

[0178] It was illustrated that either AMI or SMI could serve as a marker of unconsciousness in a closed loop anesthesia delivery system using propofol as the primary anesthetic agent. Using the non-human primate model, it was demonstrated that unconsciousness could be maintained using either SMI (FIGs.2A-2C) or AMI (FIG.3) computed from local field potentials (LFPs) recorded from intracranial electrodes. It was shown that control of anesthetic-mediated unconsciousness could be well-maintained using either SMI (FIG.4A) or AMI (FIG.4B) computed from the intracortical local field potentials (LFP). Furthermore, as part of those same experiments tight control remained when SMI computation (FIG.4A) or AMI computation (FIG. 4B) were switched from being computed from the intracortical LFP to being computed from the scalp electroencephalogram (EEG). Tight control using the SMI and AMI computed from the EEG is notable because in human use of the CLAD system, the AMI and SMI control markers are computed from the scalp EEG of the patient. It was also demonstrated that the SMI controller continued to maintain tight control when a constant rate infusion of dexmedetomidine infusion was started, as well as when the effects of the dexmedetomidine were abruptly reversed with an intraperitoneal injection of atipamezole (FIGs.5A-5C). These observations demonstrated that tight control of the anesthtetic state was maintained with propofol alone as well as with propofol and dexmedetomidine. These results also show that when the effects of the dexmedetomidine were blocked using atipamezole, the CLAD system maintained control with just propofol alone. It was further demonstrated that using propofol as the only anesthetic and SMI as the control marker computed from the scalp EEG, tight control of the anesthetic state was maintained through multiple full experiments (FIGs.6A-6D).

[0179] SMI and AMI Control of Anesthetic State Using LFP

[0180] To illustrate that the SMI and AMI markers and control algorithms work as well as the previous ones, a set of control experiments were conducted in which the SMI and AMI were controlled from intracranial local field potentials. For each case of SMI control, the initial target SMI was set at 0.5 and the initial propofol infusion rate at 100 mcg / kg / hr for all three examples. At approximately 10 minutes after the start of the propofol infusion, the animal closed its eyes and the SMI marker achieved the initial target level within 10 minutes. For the balance of the control experiment the controller updated its infusion rate every 4 seconds. The target level was changed approximately every 40 minutes for a total control period of 125 minutes. Three different target trajectories were used: down-down-middle (FIG.2A); down-up-up (FIG.2B);48 / 69 #14500304v1and down-up-below (FIG.2C), where middle was between the two previous control targets and below was below the initial control target. The 20-second segment of slow-wave oscillations displayed below each panel is the filtered EEG signal extracted between 1 to 4Hz. These time- domain traces clearly show that the longer (shorter) EEG down-states corresponded to lower (higher) SMI values. Within 5 to 10 minutes of stopping the propofol infusion the animal opened its eyes.

[0181] Experiments were conducted to test the quality of the AMI control using the same strategy as applied above for the SMI using a down-middle control trajectory (FIG.3). All other aspects of the experiment were executed as in the SMI control experiment. Here, as well, the control targets were well maintained. AMI control was more challenging in the animals because the alpha oscillations (8 to 14 Hz) were less prominent in the NHP during unconsciousness compared with humans.

[0182] Anesthesia State Control with LFP Markers Switched to EEG Markers

[0183] Two experiments were performed using SMI and AMI computed from the EEG to test the anesthesia state control. In the first, SMI was initiated and controlled at 0.5 computed from the LFP (FIG.4A, L1, LFP). Twenty minutes into that experiment, control was switched to SMI computed from the EEG, still at 0.5 (FIG.4A, L1 EEG). The switch between the different sources for computing the control signal transpired smoothly. After 30 minutes under EEG control at 0.5, the target level of the EEG control was lowered to 0.4 (FIG.4A, L2 EEG) and maintained the latter level of control for an additional 30 minutes. After this period, the propofol infusion was turned off, and the animal opened its eyes approximately 10 minutes later. During the experiment, the filtered slow-wave oscillations from the LFP and the EEG closely resembled each other. Towards the end of this experiment, appreciable noise interference in the EEG was observed (gray hashed lines). Its source could not be clearly defined.

[0184] In the second experiment, AMI was initiated and controlled beginning at a target level of 0.5 computed from the LFP for 20 minutes (FIG.4B, L1, LFP). At minute twenty of the experiment, control was switched to AMI computed from the EEG, still at a target level of 0.5 (FIG.4B, L1 EEG). After 30 minutes under EEG control at 0.5, the target level of the EEG control was deepened to 0.4 (FIG.4B, L2 EEG), and this level of control was maintained for an additional 30 minutes. As was the case with the slow wave oscillations, the filtered alpha oscillations from the LFP and the EEG closely resembled each other.49 / 69 #14500304v1

[0185] Closed Loop Control of Anesthetic State with Combined Administration of Propofol and Dexmedetomidine

[0186] Propofol is the most widely used anesthetic agent for sedation and for maintaining unconsciousness for patients undergoing general anesthesia and for those requiring critical care in the intensive care unit. Dexmedetomidine is an alpha-2 agonist that is now widely used for sedation in the intensive care unit and as an anesthetic adjunct along with propofol to maintain unconsciousness during general anesthesia. When administered together, dexmedetomidine reduces the dose of propofol that is required to maintain unconsciousness. The effective use of these two anesthetics in combination when titrated manually is reported (Brown et al.2018). The non-human primate data provided herein demonstrate that it is possible to use the two anesthetics in combination with closed loop control.

[0187] As demonstrated above, precise control of unconsciousness was maintained with propofol as a single agent as part of a closed loop control system in which the slow-wave modulation index (SMI) was used as the control signal. SMI quantifies the fraction of the slow- wave cycle that is below the median value of the oscillations (Adam et al.2023). The SMI was computed from local field potentials (LFPs) filtered between 0.1 and 4Hz. At the bottom of each panel (FIGs.5A-5C), the LFP, the slow-delta oscillations filtered from the LFP, and the alpha oscillations obtained by filtering the LFP between 8 to 14Hz are denoted. The LFPs were recorded from intracranial electrodes in the animal’s prefrontal cortex.

[0188] In FIGs.5A-5C, the SMI target value was selected to be 0.5. The value of the SMI that was achieved by the control system is denoted by the curve. For the first 30 minutes in each of the three examples (FIGs.5A-5C, column 1) propofol was administered as the sole anesthetic agent for control. The closed loop control system maintained highly precise control of the SMI marker. As illustrated in FIGs.2A-2C, the actual SMI (curve) tracks very closely the target SMI value (flat line).

[0189] In column 2, for the next 30 minutes in each experiment, dexmedetomidine was infused at a rate of 2mcg / kg / hour. Dexmedetomidine produced spindles, waxing and waning oscillations in the alpha band, as well as slow delta oscillations in the 0.1 to 4 Hz range. The spectrogram of propofol and the spectrogram of propofol administered with dexmedetomidine were indistinguishable (Purdon et al., Anesthesiology, 2015). The closed loop system maintained precise control by reducing the propofol infusion rate. The dynamic range of the propofol50 / 69 #14500304v1infusion was less during the second 30 minutes of this experiment compared with the first 30 minutes. During dexmedetomidine administration, the total amount of propofol administered decreased by 26% in FIG.5A, by 35% in FIG.5B and by 30.6% in FIG.5C. Hence, the controller took account of the effect of the dexmedetomidine on the slow-wave oscillations and reduced the propofol infusion rate to maintain precise control.

[0190] During the final 30 minutes of each of these three experiments (FIGs.5A-5C, column 3), the dexmedetomidine infusion was continued at 2mcg / kg / hour. However, an intramuscular dose of 0.85 mg of atipamezole was administered at the start of the start of this 30-minute segment. Atipamezole is a direct agonist of dexmedetomidine and is used in veterinary medicine to hasten recovery from sedation maintained with alpha-2 agonists such as dexmedetomidine, medetomidine or xylazine (Hahn et al. LabMan, 2005). Despite receiving the direct reversal agent along with the dexmedetomidine infusion, the closed loop control system maintained precise control of the SMI marker at 0.5 in FIGs.5A-5C by changing the propofol infusion rate.

[0191] These experiments illustrated how the propofol mediated control could be precisely maintained when administered simultaneously with dexmedetomidine, an anesthetic agent that also augments slow oscillations. Because a component of the slow oscillations was created by dexmedetomidine along with propofol, the resultant anesthetic state was different from the one created by propofol alone. By changing the dose of dexmedetomidine and the SMI target value, such as 0.4 or 0.6, it was possible to produce a range of anesthetic mediated states of unconsciousness for either managing general anesthesia for surgery or designing pharmacological regimens to be used as therapies for treatment resistant depression.

[0192] SMI Control of Anesthetic State Using SMI Computed from the Scalp EEG

[0193] The goal was to use SMI as a control marker computed from EEG to control unconsciousness in humans. Therefore, the closed loop control system was tested in the NHP model using SMI computed from scalp EEG (FIG.6). For nearly 120 minutes, good control of the SMI marker was maintained across 3 different levels. These findings were noisier than the previous EEG control experiments, which started with either the SMI or the AMI computed from the LFP and switched to the markers computed from the EEG (FIGs.4A-4B).

[0194] The present example demonstrated that by using AMI or SMI as a marker of unconsciousness computed either from intracortical LFPs or scalp EEG of macques NHPs, a successful closed loop control of anesthetic state could be carried out. A previous disclosure51 / 69 #14500304v1reported that these modulatory dynamics were conspicuous in the EEG of humans in whom a GABAergic agent, such as propofol or sevoflurane, was administered to maintain unconsciousness (Adam et al., PNAS, 2023). Moreover, both the frequency modulation in the slow-delta band and the amplitude modulation in the alpha band changed systematically with changes in level of unconsciousness. For this reason, it was conjectured that markers based on these dynamics could be used as reliable control signals.

[0195] It was first established that, as in the human EEG, the alpha amplitude modulation and slow-delta frequency modulation were present in the LFP of the NHP and that they tracked the level of unconsciousness as in the human EEG. Successful control of unconsciousness was demonstrated using the SMI (AMI) markers computed from the LFP as the control signals (FIGs. 2A-2C and FIG.3). In the second set of experiments, control was initiated with SMI (AMI) computed from the LFP and then control was switched to SMI (AMI) computed from the animal’s scalp EEG (FIGs.4A-4B). This switchover established that the same characteristics present in the LFP were also present in the EEG, and the control transitioned smoothly with the change (FIGs.4A-4B).

[0196] In the next experiment, control was maintained with SMI recorded from the LFP (FIGs. 5A-5C, column 1). Then, an infusion of dexmedetomidine, an anesthetic that binds to alpha-2 adrenergic receptors presynaptically and produces slow oscillations through a different mechanism from propofol, was administered (FIGs.5A-5C, column 2). In all three experiments the controller rapidly adjusted the propofol infusion rate to maintain the same target level of control after the dexmedetomidine infusion was initiated (FIGs.5A-5C, column 2). As noted previously, the CLAD system maintained the target level of control in these experiments using 26 to 35% less propofol. The same level of control was also maintained when an infusion of a second drug, atipamezole, dexmedetomidine antagonist, was introduced (FIGs.5A-5C, column 3).

[0197] Next, a set of experiments was conducted with control maintained by SMI computed from the animal’s EEG (FIG.6). As in the other experiments, unconsciousness was controlled at three levels (FIGs.2A-2C and FIG.3). These findings suggested that it is possible to achieve anesthesia state control in humans using SMI, and most probably AMI, as markers of unconsciousness.52 / 69 #14500304v1

[0198] Recording the EEG from the NHP scalp was more challenging than recording it from the human scalp because the animals have hair across their entire forehead and because they have very bulky frontalis muscles. These two factors together made it a challenge to record a noise free EEG from the NHP as was done with humans. However, an alpha band signal in the NHP was recorded, and two LFP AMI control experiments and two LFP switch to EEG AMI experiments were conducted, the power in this range was far less remarkable in the NHP compared with humans. The SMI signal is a useful marker since the slow-delta band was present for all patients in whom unconsciousness was maintained using a GABAergic anesthetic.

[0199] The control model comprised at least 3 components: the marker of unconsciousness, the PK and PD models, the time-varying PK and PD model parameter estimation algorithms and the control algorithm. The SMI and the AMI were selected as markers of unconsciousness. Previous work established that the slow oscillation frequency modulation and the alpha amplitude modulation reliably tracked the state of unconsciousness. SMI and AMI were logistic transformations of the degree of frequency modulation and of alpha amplitude modulation in the EEG or LFP when a GABAergic anesthetic was the principal anesthetic agent for maintaining unconscious. An appeal of the AMI was that the degree of alpha amplitude modulation was readily visible in the unprocessed EEG for patients who had alpha power. The SMI had broader use since all patients anesthetized with a GABAergic anesthetic to maintain unconsciousness had slow frequency modulation. By contrast, elderly patients (> 60 years), patients with overwhelming sepsis and children less than 3 months of age will often not show alpha modulation.

[0200] The control algorithm used adaptive control. For the system PK and PD models the parameters were re-estimated every 12 seconds to track how the anesthetic’s PK and PD properties changed through the course of the experiment. The marker of unconsciousness, i.e. either SMI or AMI, was updated every 4 seconds.

[0201] Supplemental Information

[0202] The control algorithm transitioned to a precise modulation target by predicting the future deviation in modulation from the target then deciding on the present infusion rate to correct it.

[0203] The control algorithm relied on three principles: (i) By increasing infusion rates, the drug effect-site concentration was increased and the modulation was lightened; (ii) By allowing53 / 69 #14500304v1the drug to clear, the drug effect-site concentration decreased and the modulation deepened; (iii) The drug infused in the present took effect after a delay and this effect persisted for some time.

[0204] The algorithm captured these principles in an equation:

[0205] Change in modulation = clearance – effectiveness * amount-of-drug

[0206] For chosen variables “clearance” and “effectiveness”, the change in modulation was computed as a function of the amount of drug infused. This consideration incorporated principles (i) and (ii). The amount of drug that can affect the marker was defined as the amount infused for a full minute ending at 40 seconds in the past. This consideration incorporated principle (iii).

[0207] The amount of drug infused was selected such that the projected change in the modulation caused by the past infusion drug and by the to-be-infused drug moved the present modulation to the target modulation. This amount of drug was then translated into an infusion rate. This falls within a broader approach termed model predictive control (Schwenzer et al. 2021).

[0208] This approach allowed precise control around any level of unconsciousness.

[0209] The design had three benefits:

[0210] As the decision only relies on one minute of past infusion data, our system can be stopped and started at any time to transition to or maintain levels of unconsciousness.

[0211] As the system corrects the modulation towards a target, it can be operated either (A) to transition to a pre-set target (GO-TO then MAINTAIN function) or (B) to maintain the current level of unconsciousness when dynamically set as the target (MAINTAIN function).

[0212] The algorithm relies on a transparent calculation that the operator can assess throughout the system’s operation.

[0213] The control algorithm reliably maintained a modulation target by adaptively learning and updating drug pharmacokinetics and pharmacodynamics.

[0214] The control algorithm relied on two scalar variables: ‘clearance’ and ‘effectiveness’. These variables were continually learned (using the method of least-squares) to reflect the current pharmacokinetics and pharmacodynamics of the anesthetics despite changing conditions.

[0215] These variables were learned at two timescales: long and short. In the long timescale, the variables were learned from changes in the past 600 seconds (10 minutes). In the short timescale, the variables were learned from changes in the past 100 seconds (1 minute and 40 seconds). Combining these variables allowed the system to quickly react to sudden deviations in54 / 69 #14500304v1the level of unconsciousness (through the short timescale) while providing stable estimation for a more proactive infusion (through the long timescale).

[0216] This allowed reliable control over a prolonged period (2 hours).

[0217] The design had additional benefits:

[0218] The system was designed to work without any prior information about a patient.

[0219] The system was designed to work with interventions and other administered drugs and changes in the cardiovascular system that alter the effectiveness of the drug and its clearance.

[0220] The system reliably maintained target levels of unconsciousness despite sudden alterations in the pharmacokinetic and pharmacodynamic properties. References

[0221] Adam E, Kwon O, Montejo KA, Brown EN. Modulatory dynamics mark the transition between anesthetic states of unconsciousness. Proc. Natl. Acad. Sci. USA.2023 Jul 25;120(30):e2300058120. doi: 10.1073 / pnas.2300058120. Epub 2023 Jul 19. PMID: 37467269; PMCID: PMC10372635.

[0222] Breault MS, Orguc S, Kwon O, Kang GH, Tseng B, Schreier DR, Brown EN. Anesthetics as Treatments for Depression: Clinical Insights and Underlying Mechanisms. Annu Rev Neurosci.2025 Jul;48(1):103-124. doi: 10.1146 / annurev-neuro-112723-062031. Epub 2025 Feb 19. PMID: 39971384.

[0223] Brown EN, Pavone KJ, Naranjo M. Multimodal General Anesthesia: Theory and Practice. Anesth Analg.2018 Nov;127(5):1246-1258. doi: 10.1213 / ANE.0000000000003668. PMID: 30252709; PMCID: PMC6203428.

[0224] Chakravarty S, Donoghue J, Waite AS, Mahnke M, Garwood IC, Gallo S, Miller EK, Brown EN. Closed-loop control of anesthetic state in nonhuman primates. PNAS Nexus.2023 Oct 31;2(10):pgad293. doi: 10.1093 / pnasnexus / pgad293. PMID: 37920551; PMCID: PMC10619513.

[0225] Hahn N, Eisen RJ, Eisen L, Lane RS. Ketamine-medetomidine anesthesia with atipamezole reversal: practical anesthesia for rodents under field conditions. Lab Anim (NY). 2005 Feb;34(2):48-51. doi: 10.1038 / laban0205-48. PMID: 15685192.

[0226] Purdon PL, Sampson A, Pavone KJ, Brown EN. Clinical Electroencephalography for Anesthesiologists: Part I: Background and Basic Signatures. Anesthesiology.201555 / 69 #14500304v1Oct;123(4):937-60. doi: 10.1097 / ALN.0000000000000841. PMID: 26275092; PMCID: PMC4573341.

[0227] Schwenzer, M., Ay, M., Bergs, T. et al. Review on model predictive control: an engineering perspective. Int J Adv Manuf Technol 117, 1327–1349 (2021). doi.org / 10.1007 / s00170-021-07682-3.

[0228] Shanechi MM, Chemali JJ, Liberman M, Solt K, Brown EN. A brain-machine interface for control of medically-induced coma. PLoS Comput Biol.2013 Oct;9(10):e1003284. doi: 10.1371 / journal.pcbi.1003284. Epub 2013 Oct 31. PMID: 24204231; PMCID: PMC3814408. EQUIVALENTS AND SCOPE

[0229] While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the function and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the inventive teachings is / are used. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.

[0230] Also, various inventive concepts may be embodied as one or more methods, of which an example has been provided. The acts performed as part of the method may be ordered in any suitable way. Accordingly, embodiments may be constructed in which acts are performed in an56 / 69 #14500304v1order different than illustrated, which may include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments.

[0231] All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0232] The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”

[0233] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0234] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0235] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily57 / 69 #14500304v1including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0236] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0237] The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0238] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the present disclosure, or aspects of the present disclosure, is / are referred to as comprising particular elements and / or features, certain embodiments of the present disclosure or aspects of the present58 / 69 #14500304v1disclosure consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein.

[0239] Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0240] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0241] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.59 / 69 #14500304v1

Claims

CLAIMS What is claimed is:

1. A method for treating depression in a subject in need thereof, the method comprising: administering to the subject at least two anesthetics from the group of anesthetics consisting of: NMDA-type glutamatergic receptor antagonist anesthetics; GABAergic anesthetics; and 2-adrenergic receptor agonist anesthetics.

2. A method of producing an electroencephalogram (EEG) profile of a subject, the method comprising: administering to the subject at least two anesthetics selected from the group of anesthetics consisting of: NMDA-2-adjusting the dose of the anesthetics to achieve an EEG profile comprising a target slow modulation index (SMI) of about 0.2 to about 0.

6.

3. A method of producing an electroencephalogram (EEG) profile of a subject, the method comprising: administering to the subject at least two anesthetics selected from the group of anesthetics consisting of: NMDA-2-adjusting the dose of the anesthetics to achieve an EEG profile comprising a target alpha modulation index (AMI) of about 0.2 to about 0.6.60 / 69 14500304v14. The method of any one of the preceding claims, wherein two of the anesthetics are selected from different classes.

5. The method of claim 2 or 3, further comprising treating depression.

6. The method of claim 1 or 5, wherein the depression comprises one or more symptoms of depressed mood, fatigue, lethargy, apathy, loss of interest or pleasure, irritability, decreased concentration, withdrawal from activities, withdrawal from social interaction, neglecting responsibilities, changes in appetite, weight loss or gain, insomnia or hypersomnia, alcohol use, drug use, feeling worthless or excessive guilt, feeling hopeless, headaches, digestive problems, forgetfulness, slowed cognition, thoughts of death or suicide, suicide attempts, anxiety, psychomotor agitation or retardation, restlessness, slowed patterns of speech, slowed movement, difficulty making decisions, or unexplained physical problems.

7. The method of claim 1 or 5, wherein the depression comprises one or more symptoms of depressed mood, lethargy, or apathy.

8. The method of claim 1 or 5, wherein the depression is major depressive disorder, dysthymia or persistent depressive disorder, melancholia, seasonal affective disorder, premenstrual dysphoric disorder, prenatal depression, perinatal or postpartum depression, bipolar disorder, cyclothymic disorder, disruptive mood dysregulation disorder, psychotic depression, atypical depression, situational depression, treatment-resistant depression, subclinical depression, or unspecified depressive disorder.

9. The method of claim 1 or 5, wherein the depression is major depressive disorder.

10. The method of claim 1 or 5, wherein the depression is treatment-resistant depression.

11. The method of any one of claims 1-10, wherein at least one anesthetic of the at least two anesthetics is administered intravenously, orally, intranasally, or as an inhalant.61 / 69 14500304v112. The method of any one of claims 1-11, wherein a first anesthetic of the at least two anesthetics is administered as an inhalant.

13. The method of any one of claims 1-11, wherein a first anesthetic of the at least two anesthetics is administered intravenously.

14. The method of any one of the preceding claims, wherein a second anesthetic of the at least two anesthetics is administered intravenously.

15. The method of any one of the preceding claims, wherein one of the at least two anesthetics is an NMDA-type glutamatergic receptor antagonist anesthetic.

16. The method of any one of the preceding claims, wherein the NMDA-type glutamatergic receptor antagonist anesthetic is ketamine, nitrous oxide, or xenon.

17. The method of any one of the preceding claims, wherein one of the at least two anesthetics is a GABAergic anesthetic.

18. The method of any one of the preceding claims, wherein the GABAergic anesthetic is a barbiturate, etomidate, propofol, propanidid, isoflurane, or sevoflurane.

19. The method of any one of the preceding claims, wherein the GABAergic anesthetic is at least one of propofol, propanidid, isoflurane, or sevoflurane.

20. The method of any one of the preceding claims, wherein the GABAergic anesthetic is propofol.

21. The method of any one of the preceding claims, wherein the GABAeric anesthetic is propanidid.62 / 69 14500304v122. The method of any one of the preceding claims, wherein one of the at least two anesthetics is an 2-adrenergic receptor agonist anesthetic.

23. The method of any one of the preceding claims, wherein the 2-adrenergic receptor agonist anesthetic is dexmedetomidine or clonidine.

24. The method of any one of the preceding claims, wherein the 2-adrenergic receptor agonist anesthetic is dexmedetomidine.

25. The method of any one of the preceding claims, wherein the at least two anesthetics comprise an NMDA-type glutamatergic receptor antagonist anesthetic and an 2-adrenergic receptor agonist anesthetic.

26. The method of claim 25, wherein the NMDA-type glutamatergic receptor antagonist anesthetic is ketamine, and the 2-adrenergic receptor agonist anesthetic is dexmedetomidine.

27. The method of any one of the preceding claims, wherein the at least two anesthetics comprise an NMDA-type glutamatergic receptor antagonist anesthetic and a GABAergic anesthetic.

28. The method of claim 27, wherein the NMDA-type glutamatergic receptor antagonist anesthetic is ketamine, and the GABAergic anesthetic is propofol.

29. The method of any one of the preceding claims, wherein the at least two anesthetics comprise a GABAergic anesthetic and an 2-adrenergic receptor agonist anesthetic.

30. The method of claim 29, wherein the GABAergic anesthetic is propanidid, and the 2- adrenergic receptor agonist anesthetic is dexmedetomidine.

31. The method of claim 29, wherein the GABAergic anesthetic is propofol, and the 2- adrenergic receptor agonist anesthetic is dexmedetomidine.63 / 69 14500304v132. The method of any one of claims 18-20, 28, or 31, wherein propofol is initially administered at a rate of about 90 mcg / kg / hr to about 110 mcg / kg / hr.

33. The method of any one of claims 18-20, 28, 31, or 32, wherein propofol is initially administered at a rate of about 100 mcg / kg / hr.

34. The method of any one of claims 23, 24, 26, 30, or 31, wherein dexmedetomidine is initially administered at a rate of about 1.5 mcg / kg / hr to about 2.5 mcg / kg / hr.

35. The method of any one of claims 23, 24, 26, 30, 31, or 34, wherein dexmedetomidine is initially administered at a rate of about 2 mcg / kg / hr.

36. The method of any one of the preceding claims, wherein administering at least two anesthetics comprises administering each of the NMDA-type glutamatergic receptor antagonist anesthetic, the GABAergic anesthetic, and the 2-adrenergic receptor agonist anesthetic.

37. The method of claim 36, wherein the 2-adrenergic receptor agonist anesthetic is dexmedetomidine.

38. The method of any one of the preceding claims, wherein the at least two anesthetics are administered simultaneously.

39. The method of any one of the preceding claims, wherein the at least two anesthetics are administered sequentially.

40. The method of any one of the preceding claims, wherein the dose or rate of administration of the first anesthetic is reduced upon administration of the second anesthetic.64 / 69 14500304v141. The method of any one of the preceding claims, wherein the dose of the first anesthetic is reduced by about 20% to about 40% upon administration of the second anesthetic.

42. The method of any one of the preceding claims, wherein the dose of the first anesthetic is reduced by about 25% to about 35% upon administration of the second anesthetic.

43. The method of any one of the preceding claims, wherein the first anesthetic is propofol.

44. The method of any one of the preceding claims, wherein the second anesthetic is dexmedetomidine.

45. The method of any one of claims 40-44, further comprising maintaining approximately the same target SMI or AMI.

46. The method of any one of the preceding claims, wherein the at least two anesthetics are administered via a closed-loop anesthesia delivery system.

47. The method of any one of the preceding claims, wherein the at least two anesthetics are administered manually.

48. The method of any one of claims 2-47, wherein the target SMI or AMI is adjusted based on the subject’s response to a prior treatment.

49. The method of claim 48, wherein the target SMI or AMI is adjusted based on whether the subject’s symptoms improved, went unchanged, or worsened in response to a prior treatment.

50. The method of any one of claims 2-49, wherein the EEG profile is held at a first target SMI or AMI level for a first period and later adjusted to a second target SMI or AMI level for a second period.65 / 69 14500304v151. The method of claim 50, wherein the second target SMI or AMI level is increased relative to the first target SMI or AMI level.

52. The method of claim 50, wherein the second target SMI or AMI level is decreased relative to the first target SMI or AMI level.

53. The method of any one of claims 50-52, wherein the first period is about 15 minutes to 45 minutes in duration.

54. The method of any one of claims 50-53, wherein the second period is about 15 minutes to 45 minutes in duration.

55. The method of any one of the preceding claims, wherein the total administration occurs over a period of about 10 minutes to about 180 minutes.

56. The method of any one of the preceding claims, wherein the total administration occurs over a period of about 60 minutes to about 180 minutes.

57. The method of any one of the preceding claims, wherein the total administration occurs over a period of about 100 minutes to about 140 minutes.

58. The method of any one of the preceding claims, wherein administration of the at least two anesthetics does not cause memory loss.

59. A method for treating depression in a subject in need thereof, the method comprising administering to the subject propanidid intravenously.

60. The method of claim 59, wherein the depression comprises one or more symptoms of depressed mood, fatigue, lethargy, apathy, loss of interest or pleasure, irritability, decreased concentration, withdrawal from activities, withdrawal from social interaction, neglecting responsibilities, changes in appetite, weight loss or gain, insomnia or hypersomnia, alcohol66 / 69 14500304v1use, drug use, feeling worthless or excessive guilt, feeling hopeless, headaches, digestive problems, forgetfulness, slowed cognition, thoughts of death or suicide, suicide attempts, anxiety, psychomotor agitation or retardation, restlessness, slowed patterns of speech, slowed movement, difficulty making decisions, or unexplained physical problems.

61. The method of claim 59 or 60, wherein the depression comprises one or more symptoms of depressed mood, lethargy, or apathy.

62. The method of any one of claims 59-61, wherein the depression is major depressive disorder, dysthymia or persistent depressive disorder, melancholia, seasonal affective disorder, premenstrual dysphoric disorder, prenatal depression, perinatal or postpartum depression, bipolar disorder, cyclothymic disorder, disruptive mood dysregulation disorder, psychotic depression, atypical depression, situational depression, treatment-resistant depression, subclinical depression, or unspecified depressive disorder.

63. The method of any one of claims 59-62, wherein the depression is major depressive disorder.

64. The method of any one of claims 59-62, wherein the depression is treatment-resistant depression.

65. The method of any one of the preceding claims, wherein the subject is a human.

66. The method of any one of the preceding claims, wherein the subject is concurrently receiving or has previously received an additional therapy for depression.

67. The method of claim 66, wherein the additional therapy comprises one or more of antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, light therapy, or psychotherapy.

68. A system comprising: at least two anesthetics selected from the group of anesthetics consisting of:67 / 69 14500304v1NMDA-2-an infusion line connected to a subject to administer a dose of each of the at least two and a display of the recorded EEG profile.

69. A kit comprising: one or more containers comprising at least two anesthetics selected from the group of anesthetics consisting of: NMDA-2-instructions for using the one or more containers.68 / 69 14500304v1

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