WO2022155591A1

WO2022155591A1 - Combination of an antidepressant and dextromethorphan for neuropsychiatric conditions

Info

Publication number: WO2022155591A1
Application number: PCT/US2022/012768
Authority: WO
Inventors: Herriot TABUTEAU
Original assignee: Antecip Bioventures II LLC
Current assignee: Antecip Bioventures II LLC
Priority date: 2021-01-18
Filing date: 2022-01-18
Publication date: 2022-07-21
Anticipated expiration: 2023-07-18
Also published as: JP2024503114A; EP4277612A1; EP4277612A4; KR20230131927A; CN116981450A; AU2022207514A1

Abstract

Dosage forms, drug delivery systems, and methods related to sustained release of dextromethorphan or improved therapeutic effects are disclosed. Typically, an antidepressant, is orally administered to a human being to be treated with, or being treated with, dextromethorphan.

Description

COMBINATION OF AN ANTIDEPRESSANT AND DEXTROMETHORPHAN FOR NEUROPSYCHIATRIC CONDITIONS

Inventor: Herriot Tabuteau

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 63/138,757, filed January 18, 2021, which is incorporated by reference herein in its entirety.

SUMMARY

Antidepressant compounds can be used to improve the therapeutic properties, such as in the treatment of neurological and/or psychiatric disorders, of dextromethorphan.

Some embodiments include a method of treating a neurological or psychiatric disorder comprising administering a combination of an antidepressant compound and dextromethorphan to a human being in need thereof, wherein the human being is an extensive metabolizer of dextromethorphan.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of the mean plasma concentrations of dextromethorphan over time after dosing on Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.

FIG. 2 depicts mean AUC012 of dextromethorphan on Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.

FIG. 3 depicts mean AUC0-24 of dextromethorphan on Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.

FIG. 4 depicts mean AUCo-inf of dextromethorphan on Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.

FIG. 5 depicts the fold changes in AUCs of dextromethorphan on Day 8 for subjects administered dextromethorphan alone as compared to dextromethorphan and bupropion.

FIG. 6 depicts mean AUC012 of dextromethorphan on Day 1 and Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion. FIG. 7 depicts mean dextromethorphan trough plasma concentrations for subjects administered dextromethorphan alone or dextromethorphan and bupropion.

FIG. 8 depicts mean dextromethorphan maximum plasma concentrations on Day 1 and Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.

FIG. 9 is a plot of the mean plasma concentrations of dextrorphan over time after dosing on Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.

FIG. 10 depicts mean dextrorphan maximum plasma concentrations on Day 1 and Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.

FIG. 11 depicts mean AUC012 of dextrorphan on Day 1 and Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.

FIG. 12 depicts the potency of various antidepressant compounds for inhibition of the metabolism of dextromethorphan in human liver microsomes.

FIG. 13 is a plot of the average MADRS total score change from baseline over time during the 6-week dosing period for subjects administered bupropion alone or the combination of dextromethorphan and bupropion.

FIG. 14 depicts the percent of subjects achieving remission (MADRS < 10) over time during the 6-week dosing period for subjects administered bupropion alone or the combination of dextromethorphan and bupropion.

FIG. 15 is a plot of the reduction in MADRS total score over time for the subjects described in Example 6.

FIG. 16 is a plot of the percentage of responders over time for the subjects described in Example 6.

FIG. 17 is a plot of the percentage of subjects in remission over time for the subjects described in Example 6.

DETAILED DESCRIPTION

Some embodiments include a method of treating neurological and/or psychiatric disorders comprising administering a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant. Some embodiments include a method of enhancing the therapeutic properties of dextromethorphan in treating neurological disorders, comprising co-administering dextromethorphan and an antidepressant.

Some embodiments include a method of increasing dextromethorphan plasma levels in a human being that is an extensive metabolizer of dextromethorphan, comprising co-administering an antidepressant compound and dextromethorphan to the human being.

Some embodiments include a method of inhibiting the metabolism of dextromethorphan, comprising administering an antidepressant compound to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as the antidepressant.

Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan, including increasing the elimination half-life (T1/2) of dextromethorphan. These embodiments may comprise administering an antidepressant compound to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as the antidepressant compound.

Some embodiments include a method of correcting extensive metabolism of dextromethorphan, comprising administering an antidepressant compound to a human being in need thereof, such as a human being in need of treatment for pain.

Some embodiments include a method of improving the therapeutic properties of dextromethorphan in treating neurological and/or psychiatric disorders comprising administering an antidepressant compound, in conjunction with administration of dextromethorphan to a human being in need of treatment for a neurological and/or psychiatric disorder.

Some embodiments include a method of treating neurological and/or psychiatric disorders comprising administering a combination of an antidepressant compound, and dextromethorphan to a human being in need thereof.

Co-administration of an antidepressant compound with dextromethorphan may occur one or more times for a single day, or for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, or more consecutive days. In some embodiments, co-administration is at least daily for at least two consecutive days. In some embodiments, co-administration of an antidepressant compound with dextromethorphan may occur once a day for 1, 2, 3, 4, 5, 6, or 7 days, prior to co-administration twice a day.

Dextromethorphan has the structure shown below.

Dextromethorphan is used as a cough suppressant. According to the FDA's dextromethorphan product labeling requirement under the OTC Monograph [21CFR341.74], dextromethorphan should be dosed 6 times a day (every 4 hours), 4 times a day (every 6 hours), or 3 times a day (every 8 hours). The OTC Monograph [21CFR341.74] also states that "the dosage is equivalent to dextromethorphan hydrobromide...[o]ral dosage is 10 to 20 milligrams every 4 hours or 30 milligrams every 6 to 8 hours, not to exceed 120 milligrams in 24 hours, or as directed by a doctor."

Dextromethorphan is rapidly metabolized in the human liver. This rapid hepatic metabolism may limit systemic drug exposure in individuals who are extensive metabolizers. Human beings can be: 1) extensive metabolizers of dextromethorphan — those who rapidly metabolize dextromethorphan; 2) poor metabolizers of dextromethorphan — those who only poorly metabolize dextromethorphan; or 3) intermediate metabolizers of dextromethorphan — those whose metabolism of dextromethorphan is somewhere between that of an extensive metabolizer and a poor metabolizer. Extensive metabolizers can also be ultra-rapid metabolizers. Extensive metabolizers of dextromethorphan are a significant portion of the human population. Dextromethorphan can, for example, be metabolized to dextrorphan.

When given the same oral dose of dextromethorphan, plasma levels of dextromethorphan are significantly higher in poor metabolizers or intermediate metabolizers as compared to extensive metabolizers of dextromethorphan. The low plasma concentrations of dextromethorphan can limit its clinical utility as a single agent for extensive metabolizers, and possibly intermediate metabolizers, of dextromethorphan. Some therapeutically active compounds, including antidepressants, inhibit the metabolism of dextromethorphan, and raise the plasma concentration of dextromethorphan, and can thus improve its therapeutic efficacy. Similarly, antidepressants may allow dextromethorphan to be given less often, such as once a day instead of twice a day, once a day instead of three times a day, once a day instead of four times a day, twice a day instead of three times a day, or twice a day instead of four times a day, or in lower amounts, without loss of therapeutic efficacy.

Co-administration of an antidepressant with dextromethorphan or dextrorphan may enhance the mechanisms of action, or pharmacological properties of dextromethorphan and dextrorphan. Mechanisms of action of dextromethorphan and dextrorphan can include sigma-1 agonist and NMDA antagonist properties, calcium channel blockade, muscarinic binding, serotonin transporter (5HTT) inhibition, and mu receptor potentiation.

Some embodiments include co-administration of an antidepressant with dextromethorphan or dextrorphan to agonize, antagonize, or modulate a sigma-1 receptor, or an NMDA receptor; to block a calcium channel; to bind to a muscarinic receptor; to inhibit a serotonin transporter (5HTT); or to potentiate a mu receptor.

Pharmacological properties of dextromethorphan and dextrorphan can include NMDA high-affinity site activity, NMDR-2A activity, and functional NMDR-2B receptor antagonism, sigma- 1 stimulation, putative mTOR activation (by sigma-1 stimulation, mu potentiation, beta adrenoreceptor stimulation, and 5HTT inhibition), putative AMPA receptor trafficking (by mTOR activation, PCP antagonism, sigma-1 stimulation, beta stimulation, mu potentiation, and 5HTT inhibition), and dendritogenesis, spinogenesis, synaptogenesis, and neuronal survival by NMDA antagonism and sigma-1 and mTOR signaling. Some embodiments include co-administration of an antidepressant with dextromethorphan or dextrorphan to bind to, agonize, antagonize, stimulate, activate, inhibit, influence the trafficking of, or modulate an NMDA high-affinity site, NMDR-2A, a functional NMDR-2B receptor, sigma-1 receptor, a putative mTOR receptor (such as by stimulating sigma-1, potentiating a mu receptor, stimulating a beta adrenoreceptor, or inhibiting a 5HTT), or a putative AMPA receptor (such as by activating mTOR, antagonizing PCP activity, stimulating a sigma-1 receptor, stimulating a beta adrenergic receptor, potentiating a mu receptor, or inhibiting 5HTT). Some embodiments include co-administration of an antidepressant with dextromethorphan or dextrorphan to cause, increase, decrease, or otherwise modulate dendritogenesis, spinogenesis, or synaptogenesis. Some embodiments include co-administration of an antidepressant with dextromethorphan or dextrorphan to cause, increase, decrease, or otherwise modulate neuronal survival by NMDA antagonism and/or sigma-1 and/or mTOR signaling.

Pharmacological properties of dextromethorphan and dextrorphan can include 5HTT and norepinephrine transporter inhibition, sigma-1 stimulation, NMDA and PCP antagonism, and possible serotonin 5HTlb/d receptor stimulation. Some embodiments include co-administration of an antidepressant with dextromethorphan or dextrorphan to bind to, agonize, antagonize, stimulate, activate, inhibit, influence the trafficking of, or modulate the 5HTT and/or norepinephrine transporter, the sigma-1 receptor, NMDA and/or PCP receptor, and/or to stimulate the serotonin 5HTlb/d receptor.

Additional properties for dextromethorphan and dextrorphan can include possible presynaptic alpha-2 adrenoreceptor antagonism or postsynaptic alpha-2 stimulation, beta stimulation and possible muscarinic and mu antagonism. Some embodiments include co- administration of an antidepressant with dextromethorphan or dextrorphan to bind to, agonize, antagonize, stimulate, activate, inhibit, influence the trafficking of, or modulate a presynaptic alpha-2 adrenoreceptor, postsynaptic alpha-2 receptor, beta adrenoreceptor, muscarinic receptor, or mu receptor. Dextromethorphan and dextrorphan may be glial cell modulators. Some embodiments include co-administration of an antidepressant with dextromethorphan or dextrorphan to modulate glial cells.

Pain or other neurological and/or psychiatric disorders may be treated by enhancing dextromethorphan plasma levels or increasing dextromethorphan bioavailability, for example by a method comprising administering a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant compound to a person in need thereof.

Examples of neurological disorders that may be treated, or that may be treated with increased efficacy, by enhanced dextromethorphan levels, such as those achievable by a combination of dextromethorphan and an antidepressant include, but are not limited to: affective disorders, psychiatric disorders, cerebral function disorders, movement disorders, dementias, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches. Affective disorders that may be treated by enhanced dextromethorphan levels or by a combination of dextromethorphan and an antidepressant include, but are not limited to, depression, major depression, treatment resistant depression and treatment resistant bipolar depression, bipolar disorders including cyclothymia, seasonal affective disorder, mood disorders, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit disorder with hyperactivity (ADDH), and attention deficit/hyperactivity disorder (AD/HD), bipolar and manic conditions, obsessive- compulsive disorder, bulimia, obesity or weight-gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psycho-sexual dysfunction, pseudobulbar affect, and emotional lability.

Depression may be manifested by depressive symptoms. These symptoms may include psychological changes such as changes in mood, feelings of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal thoughts, or attempts, and/or self- deprecation. Physical symptoms of depression may include insomnia, anorexia, appetite loss, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, aches, pains, headaches, cramps, digestive issues, and/or abnormal hormonal circadian rhythms.

Some patients, even after treatment with medications such as antidepressants, may have an inadequate or no response to the treatment. Treatment resistant depression (TRD), or treatment-refractory depression, is a condition generally associated with patients who have failed treatment with at least two antidepressants. Part of the diagnosis for TRD is for the patient to have had an inadequate response to treatment with the antidepressants after an adequate dose and adequate course, e.g., in the current depressive episode. TRD may be more difficult to treat due to the comorbidity of other medical or psychological illnesses, such as drug/alcohol abuse or eating disorders, or TRD being misdiagnosed. Some TRD patients have had an inadequate response to 1, 2, 3, or more adequate antidepressant treatment trials or have failed or had an inadequate response to 1, 2, 3, or more prior antidepressant treatments. In some embodiments, a patient being treated for treatment resistant depression has failed treatment with at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more antidepressant therapies. Measures of treatment effect that may be improved by treatment by a combination of dextromethorphan and an antidepressant include, but are not limited to: Montgomery-Asberg Depression Rating Scale (MADRS), Quality of Life Enjoyment and Satisfaction Questionnaire Short Form, Range of Impaired Functioning Tool, Sheehan Disability Scale, Patient Rated Inventory of Side Effects (PRISE), Columbia-Suicide Severity Rating Scale (C-SSRS), Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR), Clinical Global Impression (CGI) scale, Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), 17-item Hamilton Rating Scale for Depression (HAM-D17), Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ), 16-item Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR16), Sheehan Disability Scale (SDS), Clinical Global Impression of Severity of Illness (CGI-S), Clinical Global Impression of Change (CGI-C), EuroQOL 5 Dimension 5 Level (EQ-5D-5L), Patient Global Impression of Change (PGIC), 7-item Generalized Anxiety Disorder (GAD-7), Clinical Global Impressions- Improvement (CGI-I). Sheehan Disability Scale (SDS). 16-item Quick Inventory of Depressive Symptomatology - Self Report (QIDS- SR16), Hamilton Anxiety Scale (HAM-A), Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), CPFQ-Cognitive subscales (Items 4 to 7), Brief Psychiatric Rating Scale (BPRS), etc.; Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Task (RAVLT), Trail Making Test (TMT), Stroop Colour Naming Test (STROOP), Simple Reaction Time (SRT), Choice Reaction Time (CRT), etc. In some embodiments, treating a person with a combination of dextromethorphan and an antidepressant may improve (e.g. reduce) the person's score in one of the above assessments by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 5-15%, about 15-25%, about 25-35%, about 35-45%, about 45-55%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100% as compared to baseline or placebo. In some embodiments, the improvement is compared to baseline. In some embodiments, the improvement is compared to placebo.

Administering a combination of an antidepressant and dextromethorphan may result in a rapid treatment effect, e.g., within about 1 week, within about 2 weeks, within about 3 weeks, or within about 4 weeks of beginning the treatment.

In some embodiments, an enhanced bioavailability of dextromethorphan, or a combination of dextromethorphan and an antidepressant may have an onset of action within 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 6-8 hours, 8-12 hours, 12 hours, a day, 1-7 days, 1 week, two weeks, three weeks, four weeks, six weeks, or eight weeks.

Patients who may benefit from the treatments described herein include pediatric patients, such as patients under about 18 years of age, about 0-5 years of age, about 5-10 years of age, about 10-12 years of age, or about 12-18 years of age; adult patients, such as patients having an age of about 18-70 years, about 18-65 years, about 18-30 years, about 10-20 years, about 20-30 years, about 30-40 years, about 40-50 years, about 50-60 years, about 60-70 years, about 70-80 years, about 80-90 years, about 30-50 years, about 50-65 years; elderly patients, such as patients over 65 years of age, about 65-75 years of age, about 75-90 years of age, or over 90 years of age; and about 41 years of age or older.

In some embodiments, the human being that is treated with a combination of dextromethorphan and an antidepressant, e.g. for a type of depression, has, or is selected for having, a diagnosis with major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Clinical Trials Version SCID-5-CT prior to treatment (e.g. on the same day as treatment starts but before treatment starts, or at a time within 0-1 weeks, within 0-2 weeks, within 0-3 weeks, within 0-4 weeks, within 0-2 months, within 0-3 months, within 0-4 months, within 0-5 months, within 0-6 months, or longer, prior to treatment). In some embodiments, the human being currently meets the DSM-5 criteria for MDD without psychotic features, based on the SCID-5-CT

In some embodiments, the human being that is treated with a combination of dextromethorphan and an antidepressant, e.g. for a type of depression, is suffering from, or is selected for suffering from, a major depressive episode that has lasted between about 8 weeks and about 24 months, about 1-6 months, about 6-12 months, about 1-2 years, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 6 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 18 months, at least about 2 years, about 1-12 weeks, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 2-4 years, about 4-6 years, about 6-10 years, about 10-20 years or longer. In some embodiments, the human being that is treated with a combination of dextromethorphan and an antidepressant, e.g. for a type of depression, has, or is selected having, about 1-100, or more, lifetime depressive episodes, such as a major depressive episodes, including at least 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 10, at least about 15, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, about 1-5, about 5-10, about 10-20, about 20-30, about 30-40, about 40-50, about 50-60, about 60-70, about 70-80, about 80-90, about 90-100, or about 4-7 lifetime depressive episodes prior to treatment.

In some embodiments, the human being that is treated with a combination of dextromethorphan and an antidepressant, e.g., for a type of depression, has, or is selected for having, an inadequate response to one or more prior antidepressant therapies, e.g., 1, 2, 3, 4, 5 or more prior antidepressant therapies, including prior antidepressant therapies in the current depressive episode (e.g., the current major depressive episode).

In some embodiments, the human being that is treated with a combination of dextromethorphan and an antidepressant, e.g., for a type of depression, has had, or is selected for having had a background antidepressant therapy taken at an adequate dose for at least 8 weeks, and at a stable dose for at least 4 weeks prior to entering the double-blind treatment period. In some embodiments, the antidepressant therapy is continued in conjunction with treatment with the combination of the antidepressant and dextromethorphan.

In some embodiments, the human being that is treated with a combination of dextromethorphan and an antidepressant, e.g., for a type of depression, is, or is selected for being male. In some embodiments, the human being that is treated with a combination of dextromethorphan and an antidepressant, e.g., for a type of depression, is, or is selected for being female.

In some embodiments, the human being that is treated with a combination of dextromethorphan and an antidepressant, e.g. for a type of depression, has, or is selected for having, a body mass index of about 18-40 kg/m², about 18.5 kg/m², less than 18.5 kg/m², about 19 kg/m², about 19-25 kg/m², about 25 kg/m², about 25-29 kg/m², about 29 kg/m², more than 29 kg/m², about 18-22 kg/m², about 22-24 kg/m², about 24-26 kg/m², about 26-28 kg/m², about 28- 30 kg/m², about 30-32 kg/m², about 32-34 kg/m², about 34-36 kg/m², about 36-38 kg/m², about 38-40 kg/m², about 18-26 kg/m², about 26-34 kg/m², or about 34-40 kg/m² prior to treatment (e.g. on the same day as treatment starts but before treatment, or at a time within 0-1 weeks, within 0-2 weeks, within 0-3 weeks, within 0-4 weeks, within 0-2 months, within 0-3 months, within 0-4 months, within 0-5 months, within 0-6 months, or longer, prior to treatment).

Treatment effect may be assessed at any appropriate time, such as during week 1, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, at the end of week 1; at the beginning of, during, or at the end of week 2; at the beginning of, during, or at the end of week 3; at the beginning of, during, or at the end of week 4; at the beginning of, during, or at the end of week 5; at the beginning of, during, or at the end of week 6; at the beginning of, during, or at the end of week 7; at the beginning of, during, or at the end of week 8; at the beginning of, during, or at the end of week 9; at the beginning of, during, or at the end of week 10; at the beginning of, during, or at the end of week 11; at the beginning of, during, or at the end of week 12; at the beginning of, during, or at the end of week 13; at the beginning of, during, or at the end of week 14; at the beginning of, during, or at the end of week 15; at the beginning of, during, or at the end of week 16, or at any other time.

In some embodiments, the combination of dextromethorphan and an antidepressant is a novel and oral NMDA receptor antagonist with multimodal activity for the treatment of central nervous system (CNS) disorders. The dextromethorphan is a non-competitive N-methyl-D- aspartate (NMDA) receptor antagonist, also known as a glutamate receptor modulator, which is a novel mechanism of action that works differently than currently available therapies for depression.

The dextromethorphan is also a sigma-1 receptor agonist, nicotinic acetylcholine receptor antagonist, and inhibitor of the serotonin and norepinephrine transporters. The antidepressant can increase the bioavailability of dextromethorphan.

In some embodiments, the combination of dextromethorphan and an antidepressant may be used to treat nicotine addiction. In some embodiments, the combination of dextromethorphan and an antidepressant may be administered once daily or twice daily to a human being. In some embodiments, the combination of dextromethorphan and an antidepressant may be administered twice daily to a human being. In some embodiments, the combination of dextromethorphan and an antidepressant may be administered once daily or twice daily to a human being for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6-months, about 6-12 months, about 1 year, about 2 years or longer. In some embodiments, the combination of dextromethorphan and an antidepressant may be administered twice daily to a human being for at least 1 week, at least 2 weeks, at least 3 weeks, or longer.

In some embodiments, the smoker may be, or may be selected for being, an ad-lib smoker. In some embodiments, the smoker may, or may be selected for, smoking 10 or more cigarettes daily on average, such as about 10, about 10-15, about 10-17, about 10-20, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 20-25, about 25-30, about 30-40, about 40-50 cigarettes, or more, before administration of the combination of dextromethorphan and an antidepressant.

In some embodiments, the combination of dextromethorphan and an antidepressant may be used to treat nicotine addiction, and the combination contains about 30-100 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 35 mg, about 45 mg, about 55 mg, about 65 mg, about 75 mg, about 85 mg, about 90 mg, or about 95 mg of dextromethorphan in a free base form or a salt form. In some embodiments, the dextromethorphan is in an HBr salt form.

In some embodiments, administration of the combination of dextromethorphan and an antidepressant to human beings results in the reduction of smoking intensity as measured using the number of cigarettes smoked per day, assessed via daily smoking diaries.

Administering the combination of dextromethorphan and an antidepressant to human beings may, in some instances, result in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, about 5-10%, about 10-15%, about 15-20%, about 20-25%, about 25-30%, 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-80%, about 80-100%, about 20%, about 25% greater, about 30%, or about 50% reduction in the average number of cigarettes smoked per day as compared to the antidepressant alone over a period of time, such as 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 3 months, 4 months, 6 months, or longer.

Administering the combination of dextromethorphan and an antidepressant to human beings who smoke cigarettes may, for some smokers, result in average reduction of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, at least 20, about 8-9, about 8-10, about 10-15, about 15-20, about 25, or more cigarettes per day.

Administering the combination of dextromethorphan and an antidepressant to human beings who smoke cigarettes may result in a greater proportion of smokers, such as at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, about 35%, about 50%, about 60%, about 60-80%, about 80-90%, about 90-100%, who experience a more than 50% reduction in expired carbon monoxide levels, a biochemical marker of smoking intensity, as compared to those treated with the antidepressant alone. In some embodiments, a given smoker may experience more than a 50% reduction in expired carbon monoxide levels, a biochemical marker of smoking intensity, as compared to what would result from administering the antidepressant alone, or as compared to baseline or immediately prior to receiving the first dose of the combination.

Missing a dose of the combination of dextromethorphan and an antidepressant may result in an increase in smoking activity. For example, smokers who miss one or more doses of the combination of dextromethorphan and the antidepressant may smoke at least 1, or about 1-2 more cigarettes on the day of the missed dose and at least 1, at least 2, about 1-2, or about 2-3 more cigarettes on the following day after the missed dose, as compared to smokers who do not miss any doses of the combination.

In some embodiments, an enhanced bioavailability of dextromethorphan, or a combination of dextromethorphan and an antidepressant may be used as an adjunctive therapy for treatment of any condition recited herein, including TRD. For example, the adjunctive therapy could be used in combination with another antidepressant, such as clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxy indanamine, benactyzine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, brasofensine, moclobemide, rasagiline, nialamide, iproniazid, iproclozide, toloxatone, butriptyline, dosulepin, dibenzepin, iprindole, lofepramine, opipramol, norfluoxetine, dapoxetine, ketamine, etc., or a metabolite or prodrug of any of these compounds, or a pharmaceutically acceptable salt of any of these compounds. A combination of dextromethorphan and an antidepressant may be used to treat a person suffering from TRD, and for some individuals, may result in a reduction of depressive symptoms of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100%, or any other reduction in a range bounded by any of these values.

A combination of dextromethorphan and an antidepressant may be used to treat people suffering from a psychiatric disorders, including, but not limited to, anxiety disorders, including but not limited to, phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD); mania, manic depressive illness, hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizotypy, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, and behavioral and psychological symptoms including agitation. AD is the most common form of dementia and afflicts an estimated 6 million individuals in the United States, a number that is anticipated to increase to approximately 14 million by 2050. Agitation in Alzheimer's disease occurs as the disease progresses. Agitation is reported in up to 70% of patients with AD and is characterized by emotional distress, aggressive behaviors, disruptive irritability, and disinhibition. Agitation may present itself as inappropriate verbal, emotional, and/or physical behaviors. Inappropriate behaviors may include, but are not limited to, incoherent babbling, inappropriate emotional response, demands for attention, threats, irritability, frustration, screaming, repetitive questions, mood swings, cursing, abusive language, physical outbursts, emotional distress, restlessness, shredding, sleeping disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body motions, hoarding, shadowing, hitting, scratching, biting, combativeness, hyperactivity, and/or kicking. Managing agitation is a priority in AD. Agitation in patients with AD has been associated with increased caregiver burden, decreased functioning, accelerated cognitive decline, earlier nursing home placement, and increased mortality. There are currently no therapies approved by the FDA for the treatment of agitation in patients with AD. A combination of dextromethorphan and an antidepressant may be used to treat people suffering from agitation in Alzheimer's disease, which in some embodiments may result in a reduction of agitation-related symptoms of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100%, or any other reduction in a range bounded by any of these values.

A combination of dextromethorphan and an antidepressant may be used to treat a person suffering from substance addiction and/or abuse, including, but not limited to, drug dependence, addiction to cocaine, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, anxiolytic and hypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes nicotine addiction of all known forms, such as smoking cigarettes, cigars and/or pipes, vaping, and addiction to chewing tobacco.

A combination of dextromethorphan and an antidepressant may be used to treat a person suffering from cerebral function disorders, including, but not limited to, disorders involving intellectual deficits such as senile dementia, Alzheimer's type dementia, memory loss, amnesia/amnestic syndrome, epilepsy, disturbances of consciousness, coma, lowering of attention, speech disorders, voice spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperkinetic syndrome, and schizophrenia. Cerebral function disorders also include disorders caused by cerebrovascular diseases including, but not limited to, stroke, cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis, head injuries, and the like where symptoms include disturbance of consciousness, senile dementia, coma, lowering of attention, and speech disorders.

Movement disorders that may be treated by a combination of dextromethorphan and an antidepressant include, but are not limited to, akathisia, akinesia, associated movements, athetosis, ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea, Huntington's disease, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, and Tourette's syndrome, and Wilson's disease.

Dementias that may be treated by a combination of dextromethorphan and an antidepressant include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, fronto-temporal dementia, Creutzfeldt- Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff Syndrome, and Pick's disease.

Motor neuron diseases that may be treated by a combination of dextromethorphan and an antidepressant include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophies, Tay-Sach's disease, Sandoff disease, and hereditary spastic paraplegia.

Neurodegenerative diseases that may be treated by a combination of dextromethorphan and an antidepressant include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophies, Charcot-Marie-Tooth disease (CMT), familial spastic paraparesis, neurofibromatosis, olivopontine cerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barre syndrome, and spastic paraplesia.

Seizure disorders that may be treated by a combination of dextromethorphan and an antidepressant, include, but are not limited to, epileptic seizures, nonepileptic seizures, epilepsy, febrile seizures; partial seizures including, but not limited to, simple partial seizures, Jacksonian seizures, complex partial seizures, and epilepsia partialis continua; generalized seizures including, but not limited to, generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

Types of headaches that may be treated by a combination of dextromethorphan and an antidepressant include, but are not limited to, migraine, tension, and cluster headaches.

Other neurological disorders that may be treated by a combination of dextromethorphan and an antidepressant include, Rett Syndrome, autism, tinnitus, disturbances of consciousness disorders, sexual dysfunction, intractable coughing, narcolepsy, cataplexy; voice disorders due to uncontrolled laryngeal muscle spasms, including, but not limited to, abductor spasmodic dysphonia, adductor spasmodic dysphonia, muscular tension dysphonia, and vocal tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity, such as methotrexate neurotoxicity; incontinence including, but not limited, stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.

In some embodiments, a combination of dextromethorphan and an antidepressant may be used to treat pain, joint pain, pain associated with sickle cell disease, pseudobulbar affect, depression (including treatment resistant depression), disorders related to memory and cognition, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rhett's syndrome, seizures, cough (including chronic cough), etc.

In some embodiments, a combination of dextromethorphan and an antidepressant may be used to treat treatment refractory depression.

In some embodiments, a combination of dextromethorphan and an antidepressant may be used to treat allodynia.

In some embodiments, a combination of dextromethorphan and an antidepressant may be used to treat treatment refractory hyperalgesia.

In some embodiments, a combination of dextromethorphan and an antidepressant may be used to treat dermatitis.

Pain relieving properties of dextromethorphan may be enhanced by a method comprising co-administering dextromethorphan and an antidepressant to a human being.

Pain relieving properties of an antidepressant may be enhanced by a method comprising co-administering dextromethorphan with the antidepressant.

In some embodiments, ketamine or another NMDA receptor antagonist may be administered with an antidepressant.

These methods may be used to treat, or provide relief to, any type of pain including, but not limited to, musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive pain, inflammatory pain, arthritis pain, complex regional pain syndrome, etc.

In some embodiments, co-administering dextromethorphan with an antidepressant may be used to treat or reduce inflammation or inflammatory conditions, such as Crohn's disease, including pain associated with inflammation. In some embodiments, co-administering dextromethorphan with an antidepressant may be used to treat psoriasis, cancer, viral infection, or as an adjuvant treatment for multiple myeloma.

Examples of musculoskeletal pain include low back pain (i.e., lumbosacral pain), primary dysmenorrhea, and arthritic pain, such as pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, axial spondyloarthritis including ankylosing spondylitis, pain associated with vertebral crush fractures, fibrous dysplasia, osteogenesis imperfecta, Paget's disease of bone, transient osteoporosis, and transient osteoporosis of the hip, etc.

In some embodiments, a combination of dextromethorphan and an antidepressant may be administered orally to relieve musculoskeletal pain including low back pain, and pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, peri-articular disorders, axial spondyloarthritis including ankylosing spondylitis, Paget's disease, fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip, vertebral crush fractures, osteoporosis, etc.

In some embodiments, a combination of dextromethorphan and an antidepressant may be administered to relieve inflammatory pain including musculoskeletal pain, arthritis pain, and complex regional pain syndrome.

Arthritis refers to inflammatory joint diseases that can be associated with pain. Examples of arthritis pain include pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, sero-negative (non-rheumatoid) arthropathies, non- articular rheumatism, peri-articular disorders, neuropathic arthropathies including Charcot's foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome.

In some embodiments, a combination of dextromethorphan and an antidepressant is used to treat chronic musculoskeletal pain.

In some embodiments, a combination of dextromethorphan and an antidepressant may be administered to relieve complex regional pain syndrome, such as complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or another type of CRPS. CRPS is a type of inflammatory pain. CRPS can also have a neuropathic component. Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain in a limb that can be accompanied by edema, and autonomic, motor, and sensory changes. In some embodiments, a combination of dextromethorphan and an antidepressant may be administered orally to relieve neuropathic pain.

Examples of neuropathic pain include diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, central pain, etc. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-associated neuropathy, and radio- or chemotherapy associated neuropathy, etc.

In some embodiments, a combination of dextromethorphan and an antidepressant may be administered to relieve fibromyalgia.

The term "treating", or "treatment" includes the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals, or any activity that otherwise affects the structure or any function of the body of man or other animals.

Any antidepressant may be used in combination with dextromethorphan to improve the therapeutic properties of dextromethorphan. Dextromethorphan and the antidepressant compound may be administered in separate compositions or dosage forms. In some embodiments, dextromethorphan and the antidepressant compound may be administered in a single dosage form.

Antidepressant compounds that can be co-administered with dextromethorphan include, but are not limited to, clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2- chloroimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxy indanamine, benactyzine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, brasofensine, moclobemide, rasagiline, nialamide, iproniazid, iproclozide, toloxatone, butriptyline, dosulepin, dibenzepin, iprindole, lofepramine, opipramol, norfluoxetine, dapoxetine, ketamine, etc., or a metabolite or prodrug of any of these compounds, or a pharmaceutically acceptable salt of any of these compounds.

In some embodiments, the antidepressant may be a selective serotonin reuptake inhibitor, such as Citalopram (Celexa, Cipramil), Escitalopram (Lexapro, Cipralex), Fluoxetine (Prozac, Sarafem), Fluvoxamine (Luvox, Faverin), Paroxetine (Paxil, Seroxat), Sertraline (Zoloft, Lustral), etc.; a Serotonin-norepinephrine reuptake inhibitor (SNRI) such as Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixel, Savella), Venlafaxine (Effexor), etc.; a Serotonin modulator and stimulator (SMS) such as Vilazodone (Viibryd), Vortioxetine (Trintellix), etc.; a Serotonin antagonist and reuptake inhibitor (SARI) such as Nefazodone (Dutonin, Nefadar, Serzone), Trazodone (Desyrel), a Norepinephrine reuptake inhibitor (NRI), such as Atomoxetine (Strattera), Reboxetine (Edronax), Teniloxazine (Lucelan, Metatone), Viloxazine (Vivalan), etc.; a Tricyclic antidepressant (TCA) such as Amitriptyline (Elavil, Endep), Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin), Clomipramine (Anafranil), Desipramine (Norpramin, Pertofrane), Dibenzepin (Noveril, Victoril), Dimetacrine (Istonil), Dosulepin (Prothiaden), Doxepin (Adapin, Sinequan), Imipramine (Tofranil), Lofepramine (Lomont, Gamanil), Melitracen (Dixeran, Melixeran, Trausabun), Nitroxazepine (Sintamil), Nortriptyline (Pamelor, Aventyl), Noxiptiline (Agedal, Elronon, Nogedal), Opipramol (Insidon), Pipofezine (Azafen/Azaphen), Protriptyline (Vivactil), Trimipramine (Surmontil), etc.; a Tetracyclic antidepressant (TeCA)such as Amoxapine (Asendin), Maprotiline (Ludiomil), Mianserin (Tolvon), Mirtazapine (Remeron), Setiptiline (Tecipul), etc.; a Monoamine oxidase inhibitor (MAOI) such as Isocarboxazid (Marplan), Phenelzine (Nardil), Tranylcypromine (Parnate), Selegiline (Eldepryl, Zelapar, Emsam), Caroxazone (Surodil, Timostenil), Metralindole (Inkazan), Moclobemide (Aurorix, Manerix), Pirlindole (Pirazidol), Toloxatone (Humoryl), Eprobemide (Befol), minaprine (Brantur, Cantor), Bifemelane (Alnert, Celeport); Agomelatine (Valdoxan), Esketamine (Spravato), Ketamine (Ketalar), Tandospirone (Sediel), Tianeptine (Stabion, Coaxil), a-Methyltryptamine [aMT] (Indopan), Etryptamine [a-Ethyltryptamine (aET)] (Monase), Indeloxazine (Elen, Noin), Medifoxamine (Cledial, Gerdaxyl), Oxaflozane (Conflictan), Pivagabine (Tonerg), Ademetionine [S- Adenosyl-L-methionine (SAMe)] (Heptral, Transmetil, Samyl), Hypericum perforatum [St. John's Wort (SJW)] (Jarsin, Kira, Movina), Oxitriptan [5-Hydroxytryptophan (5-HTP)] (Cincofarm, Levothym, Triptum), Rubidium chloride [RbCI] (Rubinorm), Tryptophan (Tryptan, Optimax, Aminomine), Magnesium, Acetylcarnitine, Saffron, Amisulpride (Solian), Aripiprazole (Ability), Brexpiprazole (Rexulti), Lurasidone (Latuda), Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone (Risperdal), Buspirone (Buspar), Lithium (Eskalith, Lithobid), Modafinil, Thyroxine (T4), Triiodothyronine (T3), Minocycline, Amitriptyline/chlordiazepoxide, Amitriptyline/perphenazine (Etafron), Flupentixol/melitracen (Deanxit), Olanzapine/fluoxetine (Symbyax), Tranylcypromine/trifluoperazine (Parstelin, Parmodalin, Jatrosom N, Stelapar), a glutamatergic, including an NMDA receptor modulator, such as 4-Chlorokynurenine, AGN-241751, Apimostinel (NRX-1074), Arketamine (PCN-101, HR-071603). Dextromethadone (REL-1017), EVT- 101 (ENS-101), Ketamine (Ketalar), Rislenemdaz (CERC-301, MK-0657), etc., another type of glutamatergic, such as Basimglurant (RG-7090); a Monoaminergic, such as a Monoamine reuptake inhibitor including AN-788 (NSD-788), Toludesvenlafaxine (ansofaxine; LY03005, LPM570065), PDC-1421 (BLI-1005), etc., a Monoamine reuptake inhibitors and receptor modulator such as MIN- 117 (WF-516), TGBA01AD (FKB01MD), etc.; a Monoamine receptor modulator, including Gepirone (TGFK07AD; Travivo), Pimavanserin (Nuplazid; ACP-103; BVF-048), Psilocybin, etc.; an Atypical antipsychotic, including Brilaroxazine (RP-5063, RP-5000), Lumateperone (ITI-007), etc.; Ademetionine (SAMe; MSI-190, MSI-195, Strada); a Neurosteroid, such as a GABAA receptor positive modulator, including Ganaxolone (CCD-1042), Zuranolone (SAGE-217), etc., another neurosteroid such as 3(3-Methoxypregnenolone (MAP-4343), PH-10 - vomeropherine, etc.; an Opioidergic, such as a K-Opioid receptor antagonist, including Aticaprant (JNJ-67953964, CERC- 501, LY-2456302), BTRX-335140 (BTRX-140), Buprenorphine/samidorphan (ALKS-5461), another opoidergics such as BTRX-246040 (LY-2940094); Hydroxynorketamine ((2R,6R)-HNK), JNJ- 39393406, JNJ-54175446, JNJ-61393215 (JNJ-3215, JNJ-61393215; Orexin-1), NNI-351, NSI-189, NV-5138, OnabotulinumtoxinA (botulinum toxin A, Botox), Pramipexole (CTC-501, CTC-413), Seltorexant (MIN-202, JNJ-42847922, JNJ-922), Sirukumab (CNTO-136), SUVN-911, TS-121 etc.; Tramadol (ETS6103; Viotra); Cycloserine/lurasidone; 7,8-Dihydroxyflavone (7,8-DHF), Minocycline, Nitrous oxide, Pramipexole, R13, etc.

In some embodiments, about 40-120 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Levomilnacipran (Fetzima) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.5-1.4 mg/kg (for children), about 40-100 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140- 160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300- 350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Atomoxetine (Strattera) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Teniloxazine (Lucelan, Metatone) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 5-20 mg, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450- 500 mg of Viloxazine (Vivalan) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin), and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Dimetacrine (Istonil) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Melitracen (Dixeran, Melixeran, Trausabun) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Nitroxazepine (Sintamil and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Noxiptiline (Agedal, Elronon, Nogedal) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Pipofezine (Azafen/Azaphen) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Setiptiline (Tecipul) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Caroxazone (Surodil, Timostenil) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Metralindole (Inkazan) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Pirlindole (Pirazidol) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Eprobemide (Befol) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of minaprine (Brantur, Cantor) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Bifemelane (Alnert, Celeport) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Agomelatine (Valdoxan) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Esketamine (Spravato) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Tandospirone (Sediel) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Tianeptine (Stabion, Coaxil) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of a- Methyltryptamine [aMT] (Indopan) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Etryptamine [a-Ethyltryptamine (aET)] (Monase) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Indeloxazine (Elen, Noin), Medifoxamine (Cledial, Gerdaxyl) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Oxaflozane (Conflictan) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Pivagabine (Tonerg) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Ademetionine [S-Adenosyl-L-methionine (SAMe)] (Heptral, Transmetil, Samyl) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Hypericum perforatum [St. John's Wort (SJW)] (Jarsin, Kira, Movina) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Oxitriptan [5-Hydroxytryptophan (5-HTP)] (Cincofarm, Levothym, Triptum) Rubidium chloride [RbCI] (Rubinorm) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Tryptophan (Tryptan, Optimax, Aminomine) and about 30-60 mg, about 40-50 mg, or about 60- 120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Magnesium, Acetylcarnitine, Saffron, Amisulpride (Solian) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Aripiprazole (Ability) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Brexpiprazole (Rexulti) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Lurasidone (Latuda) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Olanzapine (Zyprexa) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Quetiapine (Seroquel) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Risperidone (Risperdal) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Buspirone (Buspar) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Lithium (Eskalith, Lithobid) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Modafinil and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Thyroxine (T4) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease. In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Triiodothyronine (T3) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Minocycline and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Amitriptyline/chlordiazepoxide and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease. In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Amitriptyline/perphenazine (Etafron) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Flupentixol/melitracen (Deanxit) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Olanzapine/fluoxetine (Symbyax) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease. In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Tranylcypromine/trifluoperazine (Parstelin, Parmodalin, Jatrosom N, Stelapar) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of 4- Chlorokynurenine and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of AGN- 241751 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease. In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Apimostinel (NRX-1074) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Arketamine (PCN-101, HR-071603) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Dextromethadone (REL-1017) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease. In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of EVT- 101 (ENS-101) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Rislenemdaz (CERC-301, MK-0657) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Basimglurant (RG-7090) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease. In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of AN- 788 (NSD-788) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Toludesvenlafaxine (ansofaxine; LY03005, LPM570065) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of PDC- 1421 (BLI-1005) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease. In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of MIN- 117 (WF-516) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of TGBA01AD (FKB01MD) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Gepirone (TGFK07AD; Travivo) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease. In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Pimavanserin (Nuplazid; ACP-103; BVF-048) and about 30-60 mg, about 40-50 mg, or about 60- 120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Psilocybin and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Brilaroxazine (RP-5063, RP-5000) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Lumateperone (ITI-007) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Ademetionine (SAMe; MSI-190, MSI-195, Strada) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Ganaxolone (CCD-1042) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Zuranolone (SAGE-217) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of 3(3- Methoxypregnenolone (MAP-4343) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of PH-10 - vomeropherine and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Aticaprant (JNJ-67953964, CERC-501, LY-2456302) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of BTRX- 335140 (BTRX-140) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Buprenorphine/samidorphan (ALKS-5461) BTRX-246040 (LY-2940094) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Hydroxynorketamine ((2R,6R)-HNK) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of JNJ- 39393406 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of JNJ- 54175446 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of JNJ- 61393215 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of (JNJ-3215, JNJ-61393215; Orexin-1) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of NNI-351 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of NSI-189 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of NV-5138 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of OnabotulinumtoxinA (botulinum toxin A, Botox) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Pramipexole (CTC-501, CTC-413) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease. In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Seltorexant (MIN-202, JNJ-42847922, JNJ-922) and about 30-60 mg, about 40-50 mg, or about 60- 120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Sirukumab (CNTO-136) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of SUVN-911 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of TS-121 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Tramadol (ETS6103; Viotra) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Cycloserine/lurasidone and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of 7,8- Dihydroxyflavone (7,8-DHF) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Nitrous oxide and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of Pramipexole and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of R13 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in another amount described herein) are administered (e.g. orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, a combination of about 10-60 mg or about 20-30 mg of agomelatine and about 30-60 mg or about 40-50 mg of dextromethorphan (or in another amount described herein) are administered (e.g., orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease. The two compounds may be administered separately, or in a single dosage form.

In some embodiments, a combination of about 2-10 mg or about 3-5 mg of reboxetine and about 30-60 mg or about 40-50 mg of dextromethorphan (or in another amount described herein) are administered (e.g., orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, a combination of about 2-10 mg or about 3-5 mg of esreboxetine and about 30-60 mg or about 40-50 mg of dextromethorphan (or in another amount described herein) are administered (e.g., orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, a combination of about 2-40 mg, about 4-6 mg, about 8-12 mg, or about 16-24 mg of vortioxetine and about 30-60 mg or about 40-50 mg of dextromethorphan (or in another amount described herein) are administered (e.g., orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, a combination of about 10-240 mg or about 20-120 mg of levomilnacepran and about 30-60 mg or about 40-50 mg of dextromethorphan (or in another amount described herein) are administered (e.g., orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, a combination of about 5-80 mg, about 10-30 mg, or about 20-40 mg of vilazodone, and about 30-60 mg or about 40-50 mg of dextromethorphan (or in another amount described herein) are administered (e.g., orally) once or twice daily to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

In some embodiments, about 15-120 pg/kg/hr of brexanolone is administered (e.g., by intravenous injection) over a period of 60 hours, and about 60-120 mg or about 80-100 mg of dextromethorphan (or in another amount described herein) is administered (e.g., orally) once or twice daily, to a human being to treat a neuropsychiatric condition, such as depression or agitation with Alzheimer's disease.

Combining an antidepressant with dextromethorphan may provide greater efficacy, such as greater pain relief, than would otherwise be achieved by administering either component alone. In extensive metabolizers, dextromethorphan can be rapidly and extensively metabolized, yielding low systemic exposure even at high doses. Antidepressants are inhibitors of dextromethorphan metabolism.

As explained above, this inhibition may augment dextromethorphan plasma levels, resulting in additive or synergistic efficacy such as relief of neurological disorders including pain, depression, smoking cessation, etc. Thus, while inhibition of dextromethorphan metabolism is only one of many potential benefits of the combination, co-administration of dextromethorphan with an antidepressant may thereby enhance the efficacy of the antidepressant for many individuals. Co-administration of dextromethorphan with an antidepressant may enhance the analgesic properties of the antidepressant for many individuals. Co-administration of dextromethorphan with an antidepressant may also enhance the antidepressant properties of the antidepressant for many individuals, including faster onset of action.

Another potential benefit of co-administration of dextromethorphan and an antidepressant is that it may be useful to reduce the potential for an adverse event, such as somnolence, associated with treatment by dextromethorphan. This may be useful, for example, in human patients at risk of experiencing the adverse event as a result of being treated with dextromethorphan.

Another potential benefit of co-administration of dextromethorphan and an antidepressant is that it may be useful to reduce the potential for an adverse event, such as seizure, associated with treatment with an antidepressant. This may be useful, for example, in human patients at risk of experiencing the adverse event as a result of being treated with an antidepressant.

With respect to antidepressants, co-administration with dextromethorphan may reduce a central nervous system adverse event, a gastrointestinal event, or another type of adverse event associated with the antidepressant. Central nervous system (CNS) adverse events include, but are not limited to, nervousness, dizziness, sleeplessness, light-headedness, tremor, hallucinations, convulsions, CNS depression, fear, anxiety, headache, increased irritability or excitement, tinnitus, drowsiness, dizziness, sedation, somnolence, confusion, disorientation, lassitude, incoordination, fatigue, euphoria, nervousness, insomnia, sleeping disturbances, convulsive seizures, excitation, catatonic-like states, hysteria, hallucinations, delusions, paranoia, headaches and/or migraine, and extrapyramidal symptoms such as oculogyric crisis, torticollis, hyperexcitability, increased muscle tone, ataxia, and/or tongue protrusion.

Gastrointestinal adverse events include, but are not limited to, nausea, vomiting, abdominal pain, dysphagia, dyspepsia, diarrhea, abdominal distension, flatulence, peptic ulcers with bleeding, loose stools, constipation, stomach pain, heartburn, gas, loss of appetite, feeling of fullness in stomach, indigestion, bloating, hyperacidity, dry mouth, gastrointestinal disturbances, and gastric pain.

Co-administering dextromethorphan and an antidepressant does not necessarily require that the two compounds be administered in the same dosage form. For example, the two compounds may be administered in a single dosage form, or they may be administered in two separate dosage forms. Additionally, the two compounds may be administered at the same time, but this is not required. The compounds can be given at different times as long as both are in a human body at the same time for at least a portion of the time that treatment by co- administration is being carried out. Side effects of an antidepressant may be reduced by administering the antidepressant with dextromethorphan. Examples of side effects that may be reduced include abnormal sensation of rotation and movement, agitation, arm weakness, bloating, blurred vision, burning sensation in the eyes, buzzing sound(s) in the ear(s), changes in vital signs (including, but not limited to, heart rate, respiratory rate, body temperature, and blood pressure), cold sensation, constipation, difficulty concentrating, difficulty sleeping, difficulty in falling asleep, difficulty urinating, difficulty with bowel movement, discomfort in the ear, discomfort in the eye, discomfort in the stomach, dizziness, dry lips, dry mouth, dry throat, dysmenorrhea, fatigue, feeling feverish, feeling heavy headed, feeling more agitated than usual, feeling more tired than usual, feeling tired, hand tremors, hand weakness, headache, heartburn, hot flashes, increased blood pressure, increased skin sensitivity, increased skin sensitivity at head and face, involuntary muscle contraction, involuntary muscle contractions all over the body, knee pain, leg weakness, lightheadedness, loose stool, loss of appetite, low back pain, menstrual disorder, metallic taste, more saliva than usual, mucosal dryness, nasal congestion, nausea, runny nose, sensation of light pressure sensation in the eyes, shivers when stretching or yawning, skin sensitivity, skin sensitivity in arm, face, and/or head, sleep difficulties, soft stools, stomach ache, stomach discomfort, sweaty hands and/or feet, throat irritation, throat pain, tinnitus, tremors, and/or weakness. Any of these side effects may also be referred to, or grouped, according to a corresponding, equivalent, or otherwise relevant term found in the Medical Dictionary for Regulatory Activities (MedRA).

In some embodiments, co-administration of a combination of an antidepressant and dextromethorphan results in both the antidepressant and dextromethorphan contributing to the pain relieving properties of the combination. For example, the combination may have improved pain-relieving properties as compared the antidepressant alone or compared to dextromethorphan alone, including potentially faster onset of action.

In some embodiments, the combination may have improved pain relieving properties of at least about 0.5%, at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least 100%, up to about 500% or up to 1000%, about 0.5% to about 1000%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100% to about 110%, about 110% to about 120%, about 120% to about 130%, about 130% to about 140%, about 140% to about 150%, about 150% to about 160%, about 160% to about 170%, about 170% to about 180%, about 180% to about 190%, about 190% to about 200%, or any amount of pain relief in a range bounded by, or between, any of these values, as compared to the antidepressant alone.

In some embodiments, the combination may have improved pain relieving properties of at least about 0.5%, at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least 100%, up to about 500% or up to 1000%, about 0.5% to about 1000%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100% to about 110%, about 110% to about 120%, about 120% to about 130%, about 130% to about 140%, about 140% to about 150%, about 150% to about 160%, about 160% to about 170%, about 170% to about 180%, about 180% to about 190%, about 190% to about 200%, or any amount of pain relief in a range bounded by, or between, any of these values, as compared to as compared to dextromethorphan alone.

Unless otherwise indicated, any reference to a compound herein, such as dextromethorphan or an antidepressant, by structure, name, or any other means, includes pharmaceutically acceptable salts; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; deuterium-modified compounds, such as deuterium modified dextromethorphan; or any chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.

In some embodiments, an excess of one stereoisomer of an antidepressant may be administered. In other embodiments, an excess of the S-enantiomer (such as at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or enantiomerically pure S-enantiomer) or an excess of the R-enantiomer (such as at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or enantiomerically pure R-enantiomer) of the antidepressant may be administered.

In some embodiments, both dextromethorphan and the antidepressant are formulated to be immediate release. In some embodiments, both the dextromethorphan and the antidepressant is formulated to be sustained release. In some embodiments, the dextromethorphan is formulated to be immediate release and the antidepressant is formulated to be sustained release. In some embodiments, the dextromethorphan is formulated to be sustained release and the antidepressant is formulated to be immediate release. Examples of deuterium modified dextromethorphan include, but are not limited to, those shown below.

d6-dextromethorphan A dosage form or a composition may be a blend or mixture of dextromethorphan and an antidepressant, either alone or within a vehicle. For example, dextromethorphan and the antidepressant may be dispersed within each other or dispersed together within a vehicle. A dispersion may include a mixture of solid materials wherein small individual particles are substantially one compound, but the small particles are dispersed within one another, such as might occur if two powders of two different drugs are blended with a solid vehicle material, and the blending is done in the solid form. In some embodiments, dextromethorphan and the antidepressant may be substantially uniformly dispersed within a composition or dosage form. Alternatively, dextromethorphan and the antidepressant may be in separate domains or phases within a composition or dosage form. For example, one drug may be in a coating and another drug may be in a core within the coating. For example, one drug may be formulated for sustained release and another drug may be formulated for immediate release.

Some embodiments include administration of a tablet that contains the antidepressant in a form that provides sustained release and dextromethorphan in a form that provides immediate release. While there are many ways that sustained release of the antidepressant may be achieved, in some embodiments, the antidepressant is combined with hydroxypropyl methylcellulose. For example, particles of the antidepressant could be blended with microcrystalline cellulose and hydroxypropyl methylcellulose (e.g., METHOCEL®) to form an admixture of blended powders. This could then be combined with immediate release dextromethorphan in a single tablet.

Dextromethorphan and/or an antidepressant (all of which are referred to collectively herein as "therapeutic compounds" for convenience) may be combined with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice as described, for example, in Remington's Pharmaceutical Sciences, 2005. The relative proportions of active ingredient and carrier may be determined, for example, by the solubility and chemical nature of the compounds, chosen route of administration and standard pharmaceutical practice.

Therapeutic compounds may be administered by any means that may result in the contact of the active agent(s) with the desired site or site(s) of action in the body of a patient. The compounds may be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. For example, they may be administered as the sole active agents in a pharmaceutical composition, or they can be used in combination with other therapeutically active ingredients.

Therapeutic compounds may be administered to a human patient in a variety of forms adapted to the chosen route of administration, e.g., orally, or parenterally. Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial including transdermal, ophthalmic, sublingual, and buccal; topically including ophthalmic, dermal, ocular, rectal and nasal inhalation via insufflation, aerosol and rectal systemic.

The amount of dextromethorphan in a therapeutic composition may vary. For example, some liquid compositions may comprise about 0.0001% (w/v) to about 50% (w/v), about 0.01% (w/v) to about 20% (w/v), about 0.01% to about 10% (w/v), about 0.001% (w/v) to about 1% (w/v), about 0.1% (w/v) to about 0.5% (w/v), about 1% (w/v) to about 3% (w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) to about 7% (w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) to about 40% (w/v), or about 40% (w/v) to about 50% (w/v) of dextromethorphan.

Some liquid dosage forms may contain about 10 mg to about 500 mg, about 30 mg to about 350 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 55 mg, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 80 mg to about 100 mg, about 110 mg to about 130 mg, about 170 mg to about 190 mg, about 45 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of dextromethorphan, or any amount of dextromethorphan in a range bounded by, or between, any of these values.

Some solid compositions may comprise at least about 5% (w/w), at least about 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), at least about 70% (w/w), at least about 80%, about 10% (w/w) to about 30% (w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40% (w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80% (w/w), about 50% (w/w) to about 60% (w/w), about 70% (w/w) to about 80% (w/w), or about 80% (w/w) to about 90% (w/w) of dextromethorphan. Some solid dosage forms may contain about 10 mg to about 500 mg, about 30 mg to about 350 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 80 mg to about 100 mg, about 110 mg to about 130 mg, about 170 mg to about 190 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of dextromethorphan, or any amount of dextromethorphan in a range bounded by, or between, any of these values.

In some embodiments, the amount of dextromethorphan may range from about 0.1 mg/kg to about 20 mg/kg, about 0.75 mg/kg to about 7.5 mg/kg, about 0.1 mg/kg to about 5 mg/kg, about 0.1 mg/kg to about 3 mg/kg, about 0.3 mg/kg to about 0.9 mg/kg, about 0.3 mg/kg to about 1 mg/kg, about 0.6 mg/kg to about 0.8 mg/kg, about 0.7 mg/kg to about 0.8 mg/kg, about 0.75 mg/kg, about 0.4 mg/kg to about 1.5 mg/kg, about 1 mg/kg to about 2 mg/kg, about 10 mg/kg to about 20 mg/kg, about 12 mg/kg to about 17 mg/kg, about 15 mg/kg to about 20 mg/kg, about 1 mg/kg, about 1 mg/kg to about 10 mg/kg, or any value bounded by or in between these ranges based on the body weight of the patient.

The amount of an antidepressant in a therapeutic composition may vary. If increasing the plasma level of dextromethorphan is desired, the antidepressant should be administered in an amount that increases the plasma level of dextromethorphan. For example, the antidepressant may be administered in an amount that results in a plasma concentration of dextromethorphan in the human being, on day 8, day 9, or day 10, that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, at least about 40 times, at least about 50 times, at least about 60 times, at least about 70 times, or at least about 80 times, the plasma concentration of the same amount of dextromethorphan administered without the antidepressant.

In some embodiments, an antidepressant may be administered to a human being in an amount that results in a 12 hour area under the curve from the time of dosing (AUC012), or average plasma concentration in the human being for the 12 hours following dosing (C_aVg) of dextromethorphan, on day 8, day 9, or day 10, that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, at least about 40 times, at least about 50 times, at least about 60 times, at least about 70 times, or at least about 80 times the plasma concentration of the same amount of dextromethorphan administered without the antidepressant.

In some embodiments, an antidepressant may be administered to a human being in an amount that results in a maximum plasma concentration (C_max) of dextromethorphan in the human being, on day 8, day 9, or day 10, that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, or at least about 40 times the plasma concentration of the same amount of the antidepressant.

For co-administration of an antidepressant with a dextromethorphan, the dextromethorphan plasma level can occur on the first day that the antidepressant is administered, as compared to the same amount of dextromethorphan administered without the antidepressant. For example, the dextromethorphan plasma level on the first day that the antidepressant is administered may be at least about 1.5 times, at least about at least 2 times, at least about 2.5 times, at least about 3 times, at least about 4 times, at least about 5 times, at least about 6 times at least about 7 times, at least about 8 times, at least about 9 times, or at least about 10 times the level that would be achieved by administering the same amount of dextromethorphan without the antidepressant.

In some embodiments, the dextromethorphan AUC on the first day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant is administered may be at least twice the AUC that would be achieved by administering the same amount of dextromethorphan without the antidepressant.

In some embodiments, the dextromethorphan AUC012 on the first day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 15 ng«hr/mL, at least about 17 ng«hr/mL, at least about 19 ng«hr/mL, at least about 20 ng«hr/mL, at least about 22 ng«hr/mL, at least about 23 ng«hr/mL, at least about 24 ng«hr/mL, at least about 25 ng«hr/mL, at least about 26 ng«hr/mL, at least about 27 ng«hr/mL, at least about 28 ng«hr/mL, at least about 29 ng«hr/mL, at least about 30 ng«hr/mL, at least about 31 ng«hr/mL, at least about 32 ng«hr/mL, at least about 33 ng«hr/mL, at least about 34 ng«hr/mL, at least about 35 ng«hr/mL, at least about 36 ng«hr/mL, at least about 37 ng«hr/mL, at least about 38 ng«hr/mL, at least about 39 ng«hr/mL, at least about 40 ng«hr/mL, at least about 41 ng«hr/mL, at least about 42 ng«hr/mL, at least about 43 ng«hr/mL, at least about 44 ng«hr/mL, at least about 45 ng«hr/mL, at least about 46 ng«hr/mL, at least about 47 ng«hr/mL, at least about 48 ng«hr/mL, at least about 49 ng«hr/mL, at least about 50 ng«hr/mL, at least about 51 ng«hr/mL, at least about 52 ng«hr/mL, at least about 53 ng«hr/mL, at least about 54 ng«hr/mL, at least about 55 ng«hr/mL, at least about 56 ng«hr/mL, at least about or 56.7 ng«hr/mL, and may be up to 10,000 ng«hr/mL.

In some embodiments, the dextromethorphan AUC012 on the eighth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 40 ng«hr/mL, at least about 50 ng«hr/mL, at least about 60 ng«hr/mL, at least about 70 ng«hr/mL, at least about 80 ng«hr/mL, at least about 90 ng«hr/mL, at least about 100 ng«hr/mL, at least about 150 ng«hr/mL, at least about 200 ng«hr/mL, at least about 250 ng«hr/mL, at least about 300 ng«hr/mL, at least about 350 ng«hr/mL, at least about 400 ng«hr/mL, at least about 450 ng«hr/mL, at least about 500 ng«hr/mL, at least about 550 ng«hr/mL, about 500 ng«hr/mL to about 600 ng«hr/mL, about 500 ng«hr/mL to about 550 ng«hr/mL, about 500 ng«hr/mL to about 525 ng«hr/mL, about 525 ng«hr/mL to about 600 ng«hr/mL, at least about 600 ng«hr/mL, at least about 650 ng«hr/mL, at least about 700 ng«hr/mL, at least about 750 ng«hr/mL, at least about 800 ng«hr/mL, about 800 ng«hr/mL to about 900 ng«hr/mL, about 850 ng«hr/mL to about 900 ng«hr/mL, about 850 ng«hr/mL to about 875 ng«hr/mL, about 875 ng«hr/mL to about 900 ng«hr/mL, about 900 ng«hr/mL to about 1,000 ng«hr/mL, about 1,000 ng«hr/mL to about 1,100 ng«hr/mL, about 1,100 ng«hr/mL to about 1,200 ng«hr/mL, about 1,200 ng«hr/mL to about 1,300 ng«hr/mL, about 1,300 ng«hr/mL to about 1,400 ng«hr/mL, about 1,400 ng«hr/mL to about 1,500 ng«hr/mL, about 1,500 ng«hr/mL to about 1,600 ng«hr/mL, about 1,600 ng«hr/mL to about 1,700 ng«hr/mL, about 1,700 ng«hr/mL to about 1,800 ng«hr/mL, about 1,800 ng«hr/mL to about 2,000 ng«hr/mL, at least about 850 ng«hr/mL, at least about 900 ng«hr/mL, at least about 950 ng«hr/mL, at least about

1000 ng«hr/mL, at least about 1050 ng«hr/mL, at least about 1100 ng«hr/mL, at least about 1150 ng«hr/mL, at least about 1200 ng«hr/mL, at least about 1250 ng«hr/mL, at least about 1300 ng«hr/mL, at least about 1350 ng«hr/mL, at least about 1400 ng«hr/mL, at least about 1450 ng«hr/mL, at least about 1500 ng«hr/mL, at least about 1550 ng«hr/mL, at least about 1600 ng«hr/mL, at least about 1625 ng«hr/mL, at least about 1650 ng«hr/mL, at least about 1675 ng«hr/mL, or at least about 1686.3 ng«hr/mL, and, in some embodiments, may be up to about 50,000 ng«hr/mL. In some embodiments, the dextromethorphan AUC0-24 on the eighth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 50 ng«hr/mL, at least about 75 ng«hr/mL, at least about 100 ng«hr/mL, at least about 200 ng«hr/mL, at least about 300 ng«hr/mL, at least about 400 ng«hr/mL, at least about 500 ng«hr/mL, at least about 600 ng«hr/mL, at least about 700 ng«hr/mL, at least about 800 ng«hr/mL, at least about 900 ng«hr/mL, at least about 1000 ng«hr/mL, at least about 1100 ng«hr/mL, at least about 1200 ng«hr/mL, at least about 1300 ng«hr/mL, at least about 1400 ng«hr/mL, at least about 1500 ng«hr/mL, at least about 1600 ng«hr/mL, at least about 1700 ng«hr/mL, at least about 1800 ng«hr/mL, at least about 1900 ng«hr/mL, at least about 2000 ng«hr/mL, at least about 2100 ng«hr/mL, at least about 2200 ng«hr/mL, at least about 2300 ng«hr/mL, at least about 2400 ng«hr/mL, at least about 2500 ng«hr/mL, at least about 2600 ng«hr/mL, at least about 2700 ng«hr/mL, at least about 2800 ng«hr/mL, at least about 1850 ng«hr/mL, at least about 2900 ng«hr/mL, at least about 2950 ng«hr/mL, or at least about 2975.3 ng«hr/mL, and, in some embodiments, may be up to about 100,000 ng«hr/mL.

In some embodiments, the dextromethorphan AUCo-inf on the eighth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 75 ng«hr/mL, at least about

100 ng«hr/mL, at least about 200 ng«hr/mL, at least about 300 ng«hr/mL, at least about 400 ng«hr/mL, at least about 500 ng«hr/mL, at least about 600 ng«hr/mL, at least about 700 ng«hr/mL, at least about 800 ng«hr/mL, at least about 900 ng«hr/mL, at least about 1000 ng«hr/mL, at least about 1100 ng«hr/mL, at least about 1200 ng«hr/mL, at least about 1300 ng«hr/mL, at least about 1400 ng«hr/mL, at least about 1500 ng«hr/mL, at least about 1600 ng«hr/mL, at least about 1700 ng«hr/mL, at least about 1800 ng«hr/mL, at least about 1900 ng«hr/mL, at least about 2000 ng«hr/mL, at least about 2100 ng«hr/mL, at least about 2200 ng«hr/mL, at least about 2300 ng«hr/mL, at least about 2400 ng«hr/mL, at least about 2500 ng«hr/mL, at least about 2600 ng«hr/mL, at least about 2700 ng«hr/mL, at least about 2800 ng«hr/mL, at least about 2900 ng«hr/mL, at least about 3000 ng«hr/mL, at least about 3100 ng«hr/mL, at least about 3200 ng«hr/mL, at least about 3300 ng«hr/mL, at least about 3400 ng«hr/mL, at least about 3500 ng«hr/mL, at least about 3600 ng«hr/mL, at least about 3700 ng«hr/mL, at least about 3800 ng«hr/mL, at least about 3900 ng«hr/mL, at least about 4000 ng«hr/mL, at least about 4100 ng«hr/mL, at least about 4200 ng«hr/mL, at least about 4300 ng«hr/mL, at least about 4400 ng«hr/mL, at least about 4500 ng«hr/mL, at least about 4600 ng«hr/mL, at least about 4700 ng«hr/mL, at least about 4800 ng«hr/mL, at least about 4900 ng«hr/mL, at least about 5000 ng«hr/mL, at least about 5100 ng«hr/mL, at least about 5200 ng«hr/mL, at least about 5300 ng«hr/mL, at least about 5400 ng«hr/mL, at least about 5500 ng«hr/mL, at least about 5600 ng«hr/mL, at least about 5700 ng«hr/mL, at least about 5800 ng«hr/mL, at least about 5900 ng«hr/mL, at least about 6000 ng«hr/mL, at least about 6100 ng«hr/mL, at least about 6200 ng«hr/mL, at least about 6300 ng«hr/mL, at least about 6400 ng«hr/mL, at least about 6500 ng«hr/mL, at least about 6600 ng«hr/mL, at least about 6700 ng«hr/mL, at least about 6800 ng«hr/mL, at least about 6900 ng«hr/mL, at least about 7000 ng«hr/mL, at least about 7100 ng«hr/mL, at least about 7150 ng«hr/mL, at least about 7200 ng«hr/mL, or at least about 7237.3 ng«hr/mL, and, in some embodiments, may be up to about

100,000 ng«hr/mL.

In some embodiments, the dextromethorphan AUC012 on the ninth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 40 ng«hr/mL, at least about 50 ng«hr/mL, at least about 60 ng«hr/mL, at least about 70 ng«hr/mL, at least about 80 ng«hr/mL, at least about 90 ng«hr/mL, at least about 100 ng«hr/mL, at least about 150 ng«hr/mL, at least about 200 ng«hr/mL, at least about 250 ng«hr/mL, at least about 300 ng«hr/mL, at least about 350 ng«hr/mL, at least about 400 ng«hr/mL, at least about 450 ng«hr/mL, at least about 500 ng«hr/mL, at least about 550 ng«hr/mL, about 500 ng«hr/mL to about 600 ng«hr/mL, about 500 ng«hr/mL to about 550 ng«hr/mL, about 500 ng«hr/mL to about 525 ng«hr/mL, about 525 ng«hr/mL to about 600 ng«hr/mL, at least about 600 ng«hr/mL, at least about 650 ng«hr/mL, at least about 700 ng«hr/mL, at least about 750 ng«hr/mL, at least about 800 ng«hr/mL, about 800 ng«hr/mL to about 900 ng«hr/mL, about 850 ng«hr/mL to about 900 ng«hr/mL, about 850 ng«hr/mL to about 875 ng«hr/mL, about 875 ng«hr/mL to about 900 ng«hr/mL, about 900 ng«hr/mL to about 1,000 ng«hr/mL, about 1,000 ng«hr/mL to about 1,100 ng«hr/mL, about 1,100 ng«hr/mL to about 1,200 ng«hr/mL, about 1,200 ng«hr/mL to about 1,300 ng«hr/mL, about 1,300 ng«hr/mL to about 1,400 ng«hr/mL, about 1,400 ng«hr/mL to about 1,500 ng«hr/mL, about 1,500 ng«hr/mL to about 1,600 ng«hr/mL, about 1,600 ng«hr/mL to about 1,700 ng«hr/mL, about 1,700 ng«hr/mL to about 1,800 ng«hr/mL, about 1,800 ng«hr/mL to about 2,000 ng«hr/mL, at least about 850 ng«hr/mL, at least about 900 ng«hr/mL, at least about 950 ng«hr/mL, at least about 1000 ng«hr/mL, at least about 1050 ng«hr/mL, at least about 1100 ng«hr/mL, at least about 1150 ng«hr/mL, at least about 1200 ng«hr/mL, at least about 1250 ng«hr/mL, at least about 1300 ng«hr/mL, at least about 1350 ng«hr/mL, at least about 1400 ng«hr/mL, at least about 1450 ng«hr/mL, at least about 1500 ng«hr/mL, at least about 1550 ng«hr/mL, at least about 1600 ng«hr/mL, at least about 1625 ng«hr/mL, at least about 1650 ng«hr/mL, at least about 1675 ng«hr/mL, or at least about 1686.3 ng«hr/mL, and, in some embodiments, may be up to about 50,000 ng«hr/mL.

In some embodiments, the dextromethorphan AUC0-24 on the ninth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 50 ng«hr/mL, at least about 75 ng«hr/mL, at least about 100 ng«hr/mL, at least about 200 ng«hr/mL, at least about 300 ng«hr/mL, at least about 400 ng«hr/mL, at least about 500 ng«hr/mL, at least about 600 ng«hr/mL, at least about 700 ng«hr/mL, at least about 800 ng«hr/mL, at least about 900 ng«hr/mL, at least about 1000 ng«hr/mL, at least about 1100 ng«hr/mL, at least about 1200 ng«hr/mL, at least about 1300 ng«hr/mL, at least about 1400 ng«hr/mL, at least about 1500 ng«hr/mL, at least about 1600 ng«hr/mL, at least about 1700 ng«hr/mL, at least about 1800 ng«hr/mL, at least about 1900 ng«hr/mL, at least about 2000 ng«hr/mL, at least about 2100 ng«hr/mL, at least about 2200 ng«hr/mL, at least about 2300 ng«hr/mL, at least about 2400 ng«hr/mL, at least about 2500 ng«hr/mL, at least about 2600 ng«hr/mL, at least about 2700 ng«hr/mL, at least about 2800 ng«hr/mL, at least about 1850 ng«hr/mL, at least about 2900 ng«hr/mL, at least about 2950 ng«hr/mL, or at least about 2975.3 ng«hr/mL, and, in some embodiments, may be up to about 100,000 ng«hr/mL.

In some embodiments, the dextromethorphan AUCo-inf on the ninth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 75 ng«hr/mL, at least about 100 ng«hr/mL, at least about 200 ng«hr/mL, at least about 300 ng«hr/mL, at least about 400 ng«hr/mL, at least about 500 ng«hr/mL, at least about 600 ng«hr/mL, at least about 700 ng«hr/mL, at least about 800 ng«hr/mL, at least about 900 ng«hr/mL, at least about 1000 ng«hr/mL, at least about 1100 ng«hr/mL, at least about 1200 ng«hr/mL, at least about 1300 ng«hr/mL, at least about 1400 ng«hr/mL, at least about 1500 ng«hr/mL, at least about 1600 ng«hr/mL, at least about 1700 ng«hr/mL, at least about 1800 ng«hr/mL, at least about 1900 ng«hr/mL, at least about 2000 ng«hr/mL, at least about 2100 ng«hr/mL, at least about 2200 ng«hr/mL, at least about 2300 ng«hr/mL, at least about 2400 ng«hr/mL, at least about 2500 ng«hr/mL, at least about 2600 ng«hr/mL, at least about 2700 ng«hr/mL, at least about 2800 ng«hr/mL, at least about 2900 ng«hr/mL, at least about 3000 ng«hr/mL, at least about 3100 ng«hr/mL, at least about 3200 ng«hr/mL, at least about 3300 ng«hr/mL, at least about 3400 ng«hr/mL, at least about 3500 ng«hr/mL, at least about 3600 ng«hr/mL, at least about 3700 ng«hr/mL, at least about 3800 ng«hr/mL, at least about 3900 ng«hr/mL, at least about 4000 ng«hr/mL, at least about 4100 ng«hr/mL, at least about 4200 ng«hr/mL, at least about 4300 ng«hr/mL, at least about 4400 ng«hr/mL, at least about 4500 ng«hr/mL, at least about 4600 ng«hr/mL, at least about 4700 ng«hr/mL, at least about 4800 ng«hr/mL, at least about 4900 ng«hr/mL, at least about 5000 ng«hr/mL, at least about 5100 ng«hr/mL, at least about 5200 ng«hr/mL, at least about 5300 ng«hr/mL, at least about 5400 ng«hr/mL, at least about 5500 ng«hr/mL, at least about 5600 ng«hr/mL, at least about 5700 ng«hr/mL, at least about 5800 ng«hr/mL, at least about 5900 ng«hr/mL, at least about 6000 ng«hr/mL, at least about 6100 ng«hr/mL, at least about 6200 ng«hr/mL, at least about 6300 ng«hr/mL, at least about 6400 ng«hr/mL, at least about 6500 ng«hr/mL, at least about 6600 ng«hr/mL, at least about 6700 ng«hr/mL, at least about 6800 ng«hr/mL, at least about 6900 ng«hr/mL, at least about 7000 ng«hr/mL, at least about 7100 ng«hr/mL, at least about 7150 ng«hr/mL, at least about 7200 ng«hr/mL, or at least about 7237.3 ng«hr/mL, and, in some embodiments, may be up to about 100,000 ng«hr/mL.

In some embodiments, the dextromethorphan AUC012 on the tenth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 40 ng«hr/mL, at least about 50 ng«hr/mL, at least about 60 ng«hr/mL, at least about 70 ng«hr/mL, at least about 80 ng«hr/mL, at least about 90 ng«hr/mL, at least about 100 ng«hr/mL, at least about 150 ng«hr/mL, at least about 200 ng«hr/mL, at least about 250 ng«hr/mL, at least about 300 ng«hr/mL, at least about 350 ng«hr/mL, at least about 400 ng«hr/mL, at least about 450 ng«hr/mL, at least about 500 ng«hr/mL, at least about 550 ng«hr/mL, about 500 ng«hr/mL to about 600 ng«hr/mL, about 500 ng«hr/mL to about 550 ng«hr/mL, about 500 ng«hr/mL to about 525 ng«hr/mL, about 525 ng«hr/mL to about 600 ng«hr/mL, at least about 600 ng«hr/mL, at least about 650 ng«hr/mL, at least about 700 ng«hr/mL, at least about 750 ng«hr/mL, at least about 800 ng«hr/mL, about 800 ng«hr/mL to about 900 ng«hr/mL, about 850 ng«hr/mL to about 900 ng«hr/mL, about 850 ng«hr/mL to about 875 ng«hr/mL, about 875 ng«hr/mL to about 900 ng«hr/mL, about 900 ng«hr/mL to about 1,000 ng«hr/mL, about 1,000 ng«hr/mL to about 1,100 ng«hr/mL, about 1,100 ng«hr/mL to about 1,200 ng«hr/mL, about 1,200 ng«hr/mL to about 1,300 ng«hr/mL, about 1,300 ng«hr/mL to about 1,400 ng«hr/mL, about 1,400 ng«hr/mL to about 1,500 ng«hr/mL, about 1,500 ng«hr/mL to about 1,600 ng«hr/mL, about 1,600 ng«hr/mL to about 1,700 ng«hr/mL, about 1,700 ng«hr/mL to about 1,800 ng«hr/mL, about 1,800 ng«hr/mL to about 2,000 ng«hr/mL, at least about 850 ng«hr/mL, at least about 900 ng«hr/mL, at least about 950 ng«hr/mL, at least about

1000 ng«hr/mL, at least about 1050 ng«hr/mL, at least about 1100 ng«hr/mL, at least about 1150 ng«hr/mL, at least about 1200 ng«hr/mL, at least about 1250 ng«hr/mL, at least about 1300 ng«hr/mL, at least about 1350 ng«hr/mL, at least about 1400 ng«hr/mL, at least about 1450 ng«hr/mL, at least about 1500 ng«hr/mL, at least about 1550 ng«hr/mL, at least about 1600 ng«hr/mL, at least about 1625 ng«hr/mL, at least about 1650 ng«hr/mL, at least about 1675 ng«hr/mL, or at least about 1686.3 ng«hr/mL, and, in some embodiments, may be up to about 50,000 ng«hr/mL.

In some embodiments, the dextromethorphan AUC0-24 on the tenth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 50 ng«hr/mL, at least about 75 ng«hr/mL, at least about 100 ng«hr/mL, at least about 200 ng«hr/mL, at least about 300 ng«hr/mL, at least about 400 ng«hr/mL, at least about 500 ng«hr/mL, at least about 600 ng«hr/mL, at least about 700 ng«hr/mL, at least about 800 ng«hr/mL, at least about 900 ng«hr/mL, at least about 1000 ng«hr/mL, at least about 1100 ng«hr/mL, at least about 1200 ng«hr/mL, at least about 1300 ng«hr/mL, at least about 1400 ng«hr/mL, at least about 1500 ng«hr/mL, at least about 1600 ng«hr/mL, at least about 1700 ng«hr/mL, at least about 1800 ng«hr/mL, at least about 1900 ng«hr/mL, at least about 2000 ng«hr/mL, at least about 2100 ng«hr/mL, at least about 2200 ng«hr/mL, at least about 2300 ng«hr/mL, at least about 2400 ng«hr/mL, at least about 2500 ng«hr/mL, at least about 2600 ng«hr/mL, at least about 2700 ng«hr/mL, at least about 2800 ng«hr/mL, at least about 1850 ng«hr/mL, at least about 2900 ng«hr/mL, at least about 2950 ng«hr/mL, or at least about 2975.3 ng«hr/mL, and, in some embodiments, may be up to about 100,000 ng«hr/mL.

In some embodiments, the dextromethorphan AUCo-inf on the tenth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 75 ng«hr/mL, at least about 100 ng«hr/mL, at least about 200 ng«hr/mL, at least about 300 ng«hr/mL, at least about 400 ng«hr/mL, at least about 500 ng«hr/mL, at least about 600 ng«hr/mL, at least about 700 ng«hr/mL, at least about 800 ng«hr/mL, at least about 900 ng«hr/mL, at least about 1000 ng«hr/mL, at least about 1100 ng«hr/mL, at least about 1200 ng«hr/mL, at least about 1300 ng«hr/mL, at least about 1400 ng«hr/mL, at least about 1500 ng«hr/mL, at least about 1600 ng«hr/mL, at least about 1700 ng«hr/mL, at least about 1800 ng«hr/mL, at least about 1900 ng«hr/mL, at least about 2000 ng«hr/mL, at least about 2100 ng«hr/mL, at least about 2200 ng«hr/mL, at least about 2300 ng«hr/mL, at least about 2400 ng«hr/mL, at least about 2500 ng«hr/mL, at least about 2600 ng«hr/mL, at least about 2700 ng«hr/mL, at least about 2800 ng«hr/mL, at least about 2900 ng«hr/mL, at least about 3000 ng«hr/mL, at least about 3100 ng«hr/mL, at least about 3200 ng«hr/mL, at least about 3300 ng«hr/mL, at least about 3400 ng«hr/mL, at least about 3500 ng«hr/mL, at least about 3600 ng«hr/mL, at least about 3700 ng«hr/mL, at least about 3800 ng«hr/mL, at least about 3900 ng«hr/mL, at least about 4000 ng«hr/mL, at least about 4100 ng«hr/mL, at least about 4200 ng«hr/mL, at least about 4300 ng«hr/mL, at least about 4400 ng«hr/mL, at least about 4500 ng«hr/mL, at least about 4600 ng«hr/mL, at least about 4700 ng«hr/mL, at least about 4800 ng«hr/mL, at least about 4900 ng«hr/mL, at least about 5000 ng«hr/mL, at least about 5100 ng«hr/mL, at least about 5200 ng«hr/mL, at least about 5300 ng«hr/mL, at least about 5400 ng«hr/mL, at least about 5500 ng«hr/mL, at least about 5600 ng«hr/mL, at least about 5700 ng«hr/mL, at least about 5800 ng«hr/mL, at least about 5900 ng«hr/mL, at least about 6000 ng«hr/mL, at least about 6100 ng«hr/mL, at least about 6200 ng«hr/mL, at least about 6300 ng«hr/mL, at least about 6400 ng«hr/mL, at least about 6500 ng«hr/mL, at least about 6600 ng«hr/mL, at least about 6700 ng«hr/mL, at least about 6800 ng«hr/mL, at least about 6900 ng«hr/mL, at least about 7000 ng«hr/mL, at least about 7100 ng«hr/mL, at least about 7150 ng«hr/mL, at least about 7200 ng«hr/mL, or at least about 7237.3 ng«hr/mL, and, in some embodiments, may be up to about 100,000 ng«hr/mL.

In some embodiments, the dextromethorphan C_max on the first day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least twice the C_max that would be achieved by administering the same amount of dextromethorphan without the antidepressant.

In some embodiments, the dextromethorphan C_max on the first day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 1.0 ng/mL, at least about 1.5 ng/mL, at least about 2.0 ng/mL, at least about 2.5 ng/mL, at least about 3.0 ng/mL, at least about 3.1 ng/mL, at least about 3.2 ng/mL, at least about 3.3 ng/mL, at least about 3.4 ng/mL, at least about 3.5 ng/mL, at least about 3.6 ng/mL, at least about 3.7 ng/mL, at least about 3.8 ng/mL, at least about 3.9 ng/mL, at least about 4.0 ng/mL, at least about 4.1 ng/mL, at least about 4.2 ng/mL, at least about 4.3 ng/mL, at least about 4.4 ng/mL, at least about 4.5 ng/mL, at least about

4.6 ng/mL, at least about 4.7 ng/mL, at least about 4.8 ng/mL, at least about 4.9 ng/mL, at least about 5.0 ng/mL, at least about 5.1 ng/mL, at least about 5.2 ng/mL, at least about 5.3 ng/mL, at least about 5.4 ng/mL, at least about 5.5 ng/mL, at least about 5.6 ng/mL, at least about 5.7 ng/mL, at least about 5.8 ng/mL, at least about 5.9 ng/mL, at least about 6.0 ng/mL, at least about

6.1 ng/mL, at least about 6.2 ng/mL, at least about 6.3 ng/mL, at least about 6.4 ng/mL, at least about 6.5 ng/mL, at least about 6.6 ng/mL, at least about 6.7 ng/mL, at least about 6.8 ng/mL, at least about 6.9 ng/mL, at least about 7.0 ng/mL, at least about 7.1 ng/mL, at least about 7.2 ng/mL, at least about 7.3 ng/mL, at least about 7.4 ng/mL, at least about 7.5 ng/mL, at least about

7.6 ng/mL, at least about 7.7 ng/mL, at least about 7.8 ng/mL, at least about 7.9 ng/mL, at least about 8.0 ng/mL, at least about 8.1 ng/mL, at least about 8.2 ng/mL, at least about 8.3 ng/mL, at least about 8.4 ng/mL, at least about 8.5 ng/mL, at least about 8.6 ng/mL, or at least about 8.7 ng/mL, and, in some embodiments, may be up to about 1000 ng«hr/mL.

In some embodiments, the dextromethorphan C_max on the eighth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be about 50 ng/mL to about 60 ng/mL, about 50 ng/mL to about 55 ng/mL, about 55 ng/mL to about 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng/mL, about 95 ng/mL to about 100 ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110 ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL, about 150 ng/mL to about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170 ng/mL, about 170 ng/mL to about 200 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, at least about 135 ng/mL, at least about 140 ng/mL, at least about 145 ng/mL, at least about 150 ng/mL, at least about 155 ng/mL, or at least about 158.1 ng/mL, and, in some embodiments, may be up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan C_max on the ninth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be about 50 ng/mL to about 60 ng/mL, about 50 ng/mL to about 55 ng/mL, about 55 ng/mL to about 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng/mL, about 95 ng/mL to about 100 ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110 ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL, about 150 ng/mL to about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170 ng/mL, about 170 ng/mL to about 200 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, at least about 135 ng/mL, at least about 140 ng/mL, at least about 145 ng/mL, at least about 150 ng/mL, at least about 155 ng/mL, or at least about 158.1 ng/mL, and, in some embodiments, may be up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan Cmax on the tenth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be about 50 ng/mL to about 60 ng/mL, about 50 ng/mL to about 55 ng/mL, about 55 ng/mL to about 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng/mL, about 95 ng/mL to about 100 ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110 ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL, about 150 ng/mL to about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170 ng/mL, about 170 ng/mL to about 200 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, at least about 135 ng/mL, at least about 140 ng/mL, at least about 145 ng/mL, at least about 150 ng/mL, at least about 155 ng/mL, or at least about 158.1 ng/mL, and, in some embodiments, may be up to about 10,000 ng/mL.

In some embodiments, the antidepressant, which is in combination with dextromethorphan, is administered in an amount that results in a C_aV of dextromethorphan, over the period between two separate and consecutive administrations of dextromethorphan, that is at least about 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, at least about 135 ng/mL, at least about 140 ng/mL, or at least about 140.5 ng/mL, about 20 ng/mL to about 30 ng/mL, about 30 ng/mL to about 40 ng/mL, about 40 ng/mL to about 50 ng/mL, about 50 ng/mL to about 55 ng/mL, about 55 ng/mL to about 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng/mL, about 95 ng/mL to about 100 ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110 ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL, about 150 ng/mL to about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170 ng/mL, about 170 ng/mL to about 200 ng/mL, and, in some embodiments, may be up to about 10,000 ng/mL. For example, if dextromethorphan is administered at 8 am and at 8 pm on day 1, and no dextromethorphan is administered after 8 am and before 8 pm on day 1, the period between two separate and consecutive administrations of dextromethorphan is from immediately after 8 am to immediately before 8 pm on day 1.

In some embodiments, the dextromethorphan C_avg on the eighth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, at least about 135 ng/mL, at least about 140 ng/mL, or at least about 140.5 ng/mL, about 20 ng/mL to about 30 ng/mL, about 30 ng/mL to about 40 ng/mL, about 40 ng/mL to about 50 ng/mL, about 50 ng/mL to about 55 ng/mL, about 55 ng/mL to about 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng/mL, about 95 ng/mL to about 100 ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110 ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL, about 150 ng/mL to about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170 ng/mL, about 170 ng/mL to about 200 ng/mL, and, in some embodiments, may be up to about 10,000 ng/mL. The C_avg values given above can be for the period between two separate and consecutive administrations of dextromethorphan, or if dextromethorphan is administered only once on Day 8, the C_avg can be for 12 hours after the first dose of dextromethorphan.

In some embodiments, the dextromethorphan C_avg on the ninth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, at least about 135 ng/mL, at least about 140 ng/mL, or at least about 140.5 ng/mL, about 20 ng/mL to about 30 ng/mL, about 30 ng/mL to about 40 ng/mL, about 40 ng/mL to about 50 ng/mL, about 50 ng/mL to about 55 ng/mL, about 55 ng/mL to about 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng/mL, about 95 ng/mL to about 100 ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110 ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL, about 150 ng/mL to about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170 ng/mL, about 170 ng/mL to about 200 ng/mL, and, in some embodiments, may be up to about 10,000 ng/mL. The C_avg values given above can be for the period between two separate and consecutive administrations of dextromethorphan, or if dextromethorphan is administered only once on Day 9, the C_avg can be for 12 hours after the first dose of dextromethorphan.

In some embodiments, the dextromethorphan C_avg on the tenth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, at least about 135 ng/mL, at least about 140 ng/mL, or at least about 140.5 ng/mL, about 20 ng/mL to about 30 ng/mL, about 30 ng/mL to about 40 ng/mL, about 40 ng/mL to about 50 ng/mL, about 50 ng/mL to about 55 ng/mL, about 55 ng/mL to about 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng/mL, about 95 ng/mL to about 100 ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110 ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL, about 150 ng/mL to about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170 ng/mL, about 170 ng/mL to about 200 ng/mL, and, in some embodiments, may be up to about 10,000 ng/mL. The C_avg values given above can be for the period between two separate and consecutive administrations of dextromethorphan, or if dextromethorphan is administered only once on Day 10, the C_avg can be for 12 hours after the first dose of dextromethorphan.

The dextromethorphan fluctuation index values Fl(%) can be determined by equation: 100

In some embodiments, the dextromethorphan Fl(%) on the eighth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, is reduced by at least 1.5-fold or at least 2-fold as compared to dextromethorphan that is administered for eight days without plasma level enhancement, such as by co-administration of dextromethorphan with the antidepressant.

In some embodiments, the dextromethorphan Fl(%) on the ninth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, is reduced by at least 1.5-fold or at least 2-fold as compared to dextromethorphan that is administered for nine days without plasma level enhancement, such as by co-administration of dextromethorphan with the antidepressant.

In some embodiments, the dextromethorphan Fl(%) on the tenth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, is reduced by at least 1.5-fold or at least 2-fold as compared to dextromethorphan that is administered for ten days without plasma level enhancement, such as by co-administration of dextromethorphan with the antidepressant.

In some embodiments, the dextromethorphan Fl(%) on the eighth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, is less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any Fl(%) value in a range bounded by any of these values.

In some embodiments, the dextromethorphan Fl(%) on the ninth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, is less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any Fl(%) value in a range bounded by any of these values.

In some embodiments, the dextrorphan Fl(%) on the eighth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, is reduced by at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 6-fold as compared to dextromethorphan that is administered for eight days without plasma level enhancement, such as by co-administration of dextromethorphan with the antidepressant.

In some embodiments, the dextrorphan Fl(%) on the ninth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, is reduced by at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 6-fold as compared to dextromethorphan that is administered for nine days without plasma level enhancement, such as by co-administration of dextromethorphan with the antidepressant.

In some embodiments, the dextrorphan Fl(%) on the tenth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, is reduced by at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 6-fold as compared to dextromethorphan that is administered for ten days without plasma level enhancement, such as by co-administration of dextromethorphan with the antidepressant.

In some embodiments, the dextrorphan Fl(%) on the eighth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, is less than 100%, less than 70%, less than 60%, less than 50%, less than 40%, about 30-70%, about 30-60%, about 30-50%, or any Fl(%) value in a range bounded by any of these values.

In some embodiments, the dextrorphan Fl(%) on the ninth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, is less than 100%, less than 70%, less than 60%, less than 50%, less than 40%, about 30-70%, about 30-60%, about 30-50%, or any Fl(%) value in a range bounded by any of these values.

In some embodiments, the dextrorphan Fl(%) on the ninth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, is less than 100%, less than 70%, less than 60%, less than 50%, about 30-70%, about 30-60%, about 30-50%, or any Fl(%) value in a range bounded by any of these values.

In some embodiments, the dextromethorphan trough level (e.g., plasma level 12 hours after administration; also referred herein as "C_min") on the first day that the antidepressant and dextromethorphan are administered, may be at least twice the trough level that would be achieved by administering the same amount of dextromethorphan without the antidepressant.

In some embodiments, the dextromethorphan C_min on the first day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 0.8 ng/mL, at least about 0.9 ng/mL, at least about 1.0 ng/mL, at least about 1.1 ng/mL, at least about 1.2 ng/mL, at least about 1.3 ng/mL, at least about 1.4 ng/mL, at least about 1.5 ng/mL, at least about 1.6 ng/mL, at least about 1.7 ng/mL, at least about 1.8 ng/mL, at least about 1.9 ng/mL, at least about 2.0 ng/mL, at least about 2.1 ng/mL, at least about 2.2 ng/mL, at least about 2.3 ng/mL, at least about 2.4 ng/mL, at least about 2.5 ng/mL, or at least about 2.5 ng/mL, and may be up to about 100 ng/mL.

In some embodiments, the dextromethorphan C_min on the fifth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 1.5 ng/mL, at least about 2.0 ng/mL, at least about 3.0 ng/mL, at least about 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, or at least about 80.9 ng/mL, and may be up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan C_min on the sixth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 1.5 ng/mL, at least about 2.0 ng/mL, at least about 3.0 ng/mL, at least about 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, or at least about 102.2 ng/mL, and may be up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan C_min on the seventh day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 1.5 ng/mL, at least about 2.0 ng/mL, at least about 3.0 ng/mL, at least about 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, or at least about 110.6 ng/mL, and may be up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan C_min on the eighth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 1.5 ng/mL, at least about 2.0 ng/mL, at least about 3.0 ng/mL, at least about 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 119.3 ng/mL, about 20 ng/mL to about 30 ng/mL, about 30 ng/mL to about 40 ng/mL, about 40 ng/mL to about 50 ng/mL, about 50 ng/mL to about 55 ng/mL, about 55 ng/mL to about 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng/mL, about 95 ng/mL to about 100 ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110 ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL, about 150 ng/mL to about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170 ng/mL, or about 170 ng/mL to about 200 ng/mL, and may be up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan C_min on the ninth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 1.5 ng/mL, at least about 2.0 ng/mL, at least about 3.0 ng/mL, at least about 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 119.3 ng/mL, about 20 ng/mL to about 30 ng/mL, about 30 ng/mL to about 40 ng/mL, about 40 ng/mL to about 50 ng/mL, about 50 ng/mL to about 55 ng/mL, about 55 ng/mL to about 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng/mL, about 95 ng/mL to about 100 ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110 ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL, about 150 ng/mL to about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170 ng/mL, or about 170 ng/mL to about 200 ng/mL, and may be up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan C_min on the tenth day that the dextromethorphan plasma level is enhanced, for example by co-administration of dextromethorphan with the antidepressant, may be at least about 1.5 ng/mL, at least about 2.0 ng/mL, at least about 3.0 ng/mL, at least about 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 119.3 ng/mL, about 20 ng/mL to about 30 ng/mL, about 30 ng/mL to about 40 ng/mL, about 40 ng/mL to about 50 ng/mL, about 50 ng/mL to about 55 ng/mL, about 55 ng/mL to about 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng/mL, about 95 ng/mL to about 100 ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110 ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL, about 150 ng/mL to about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170 ng/mL, or about 170 ng/mL to about 200 ng/mL, and may be up to about 10,000 ng/mL.

In some embodiments, the antidepressant, is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that the antidepressant, and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without the antidepressant. For example, the dextrorphan plasma level on the first day may be reduced by at least 5% as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without the antidepressant.

In some embodiments, the antidepressant, are co-administered with dextromethorphan for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the fifth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan without the antidepressant, for five consecutive days. For example, the dextromethorphan plasma level on the fifth day (for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) may be at least 5 times, at least 10 times, at least 20 times, at least 40 times, at least 50 times, at least 60 times, at least 65 times, or up to about 500 times, the level that would be achieved by administering the same amount of dextromethorphan without the antidepressant, for five consecutive days.

In some embodiments, the antidepressant and dextromethorphan, are co-administered for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the sixth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without the antidepressant, for six consecutive days. For example, the dextromethorphan plasma level on the sixth day (for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) may be at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 75 times, or up to about 500 times, the level that would be achieved by administering the same amount of dextromethorphan without the antidepressant, for six consecutive days.

In some embodiments, the antidepressant and dextromethorphan, are co-administered for at least seven consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the seventh day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without the antidepressant, for seven consecutive days. For example, the dextromethorphan plasma level on the seventh day (for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) may be at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 70 times, at least 80 times, at least 90 times, or up to about 500 times, the level that would be achieved by administering the same amount of dextromethorphan without the antidepressant, for seven consecutive days.

In some embodiments, the antidepressant and dextromethorphan, are co-administered for at least eight consecutive days, wherein, on the eighth day, dextromethorphan has a plasma level, for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours, after co-administering the antidepressant with dextromethorphan that is at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or up to about 1,000 times, the plasma level that would be achieved by administering the same amount of dextromethorphan without the antidepressant, for eight consecutive days.

In some embodiments, the antidepressant and dextromethorphan are co-administered for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without the antidepressant, for eight consecutive days. For example, the dextrorphan plasma level on the eighth day (for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%, as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without the antidepressant, for eight consecutive days. In some embodiments, the antidepressant and dextromethorphan, are co-administered for at least nine consecutive days, wherein, on the ninth day, dextromethorphan has a plasma level, for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours, after co-administering the antidepressant with dextromethorphan that is at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or up to about 1,000 times, the plasma level that would be achieved by administering the same amount of dextromethorphan without the antidepressant, for nine consecutive days.

In some embodiments, the antidepressant and dextromethorphan are co-administered for at least nine consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the ninth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without the antidepressant, for nine consecutive days. For example, the dextrorphan plasma level on the ninth day (for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%, as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without the antidepressant, for nine consecutive days.

In some embodiments, the antidepressant and dextromethorphan, are co-administered for at least ten consecutive days, wherein, on the tenth day, dextromethorphan has a plasma level, for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours, after co-administering the antidepressant with dextromethorphan that is at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or up to about 1,000 times, the plasma level that would be achieved by administering the same amount of dextromethorphan without the antidepressant, for ten consecutive days.

In some embodiments, the antidepressant and dextromethorphan are co-administered for at least ten consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the tenth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without the antidepressant, for ten consecutive days. For example, the dextrorphan plasma level on the tenth day (for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%, as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without the antidepressant, for ten consecutive days.

For compositions comprising both dextromethorphan and an antidepressant, some liquids may comprise about 0.0001% (w/v) to about 50% (w/v), about 0.01% (w/v) to about 20% (w/v), about 0.01% to about 10% (w/v), about 1% (w/v) to about 3% (w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) to about 7% (w/v), about 5% (w/v) to about 15% (w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) to about 40% (w/v), about 40% (w/v) to about 50% (w/v) of dextromethorphan and antidepressant combined, or any amount in a range bounded by, or between, any of these values.

Some solid compositions may comprise at least about 5% (w/w), at least about 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), at least about 70% (w/w), at least about 80%, about 10% (w/w) to about 30% (w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40% (w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80% (w/w), about 50% (w/w) to about 60% (w/w), about 70% (w/w) to about 80% (w/w), about 80% (w/w) to about 90% (w/w) of dextromethorphan and antidepressant combined, or any amount in a range bounded by, or between, any of these values.

A therapeutically effective amount of a therapeutic compound may vary depending upon the circumstances. For example, a daily dose of dextromethorphan may in some instances range from about 0.1 mg to about 1000 mg, about 40 mg to about 1000 mg, about 20 mg to about 600 mg, about 60 mg to about 700 mg, about 100 mg to about 400 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 20 mg to about 60 mg, about 60 mg to about 100 mg, about 100 mg to about 200 mg, about 100 mg to about 140 mg, about 160 mg to about

200 mg, about 200 mg to about 300 mg, about 220 mg to about 260 mg, about 300 mg to about

400 mg, about 340 mg to about 380 mg, about 400 mg to about 500 mg, about 500 mg to about

600 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 180 mg, about 240 mg, about 360 mg, or any daily dose in a range bounded by, or between, any of these values. Dextromethorphan may be administered once daily; or twice daily or every 12 hours, three times daily, four times daily, or six times daily in an amount that is about half, one third, one quarter, or one sixth, respectively, of the daily dose.

In some embodiments: about 15 mg/day to about 60 mg/day, about 15 mg/day to about 30 mg/day, about 30 mg/day to about 45 mg/day, about 45 mg/day to about 60 mg/day, about 60 mg/day to about 100 mg/day, about 80 mg/day to about 110 mg/day, about 100 mg/day to about 150 mg/day, or about 100 mg/day to about 300 mg/day of dextromethorphan, are administered to a human being in need thereof.

An antidepressant compound may be administered for as long as needed to treat a neurological condition, such as pain, depression, or cough. In some embodiments, an antidepressant compound and dextromethorphan are administered at least once a day, such as once daily or twice daily, for at least 1 day, at least 3 days, at least 5 days, at least 7 days, at least 8 days, at least 9 days, or at least 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 35 days, at least 42 days, at least 60 days, at least 90 days, at least 6 months, at least 9 months, at least 180 days, at least 365 days, at least 18 months, at least 2 years, or longer, up to 1 year, up to 18 months, up to 2 years, up to 3 years, up to 5 years, or longer.

In some embodiments, co-administration of dextromethorphan with an antidepressant may occur once a day for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more days prior to co-administering dextromethorphan with the antidepressant for twice a day.

Therapeutic compounds may be formulated for oral administration, for example, with an inert diluent or with an edible carrier, or it may be enclosed in hard- or soft-shell gelatin capsules, compressed into tablets, or incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

Tablets, troches, pills, capsules, and the like may also contain one or more of the following: a binder such as gum tragacanth, acacia, corn starch, or gelatin; an excipient, such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose, or saccharin; or a flavoring agent such as peppermint, oil of Wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as a coating, for example, tablets, pills, or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. It may be desirable for material in a dosage form or pharmaceutical composition to be pharmaceutically pure and substantially nontoxic in the amounts employed.

Some compositions or dosage forms may be a liquid or may comprise a solid phase dispersed in a liquid.

Therapeutic compounds may be formulated for parental or intraperitoneal administration. Solutions of the active compounds as free bases or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. A dispersion can also have an oil dispersed within, or dispersed in, glycerol, liquid polyethylene glycols, and mixtures thereof. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

In some embodiments, the human being or the patient is, or is selected for being, Black or African American.

In some embodiments, the human being or the patient is, or is selected for being, white.

In some embodiments, the human being or the patient is, or is selected for being, Asian.

In some embodiments, the human being or the patient is, or is selected for being, Native Hawaiian or other Pacific Islander.

In some embodiments, the human being or the patient is, or is selected for being, Hispanic or Latino.

In some embodiments, the human being or the patient is, or is selected for being, Native American or Alaska Native.

In some embodiments, the human being or the patient is not, or is selected for not being, Hispanic or Latino.

Specifically, Contemplated Embodiments

The following are examples of embodiments that are specifically contemplated by the inventor: Embodiment 1. A method of treating pain or a neurological and/or psychiatric disorder comprising administering a therapeutically effective amount of a combination of dextromethorphan and an antidepressant compound, to a person in need thereof.

Embodiment 2. A method of treating pain comprising administering a combination of an antidepressant compound and dextromethorphan to a human being in need thereof.

Embodiment 3. A method of enhancing the pain-relieving properties of dextromethorphan, comprising co-administering dextromethorphan and an antidepressant compound.

Embodiment 4. A method of increasing dextromethorphan plasma levels in a human being that is an extensive metabolizer of dextromethorphan, comprising co-administering an antidepressant compound to the human being receiving a treatment that includes administration of dextromethorphan.

Embodiment s. A method of inhibiting the metabolism of dextromethorphan, comprising administering an antidepressant compound to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as the antidepressant compound.

Embodiment 6. A method of increasing the metabolic lifetime of dextromethorphan, comprising administering an antidepressant compound to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as the antidepressant compound.

Embodiment 7. A method of correcting extensive metabolism of dextromethorphan, comprising administering an antidepressant compound to a human being in need thereof.

Embodiment s. A method of improving pain relieving properties of dextromethorphan comprising administering an antidepressant compound in conjunction with administration of dextromethorphan to a human being in need of treatment for pain.

Embodiment s. A method of improving antitussive properties of dextromethorphan comprising administering an antidepressant compound in conjunction with administration of dextromethorphan to a human being in need of treatment for cough.

Embodiment 10. A method of treating cough comprising administering a combination of an antidepressant compound and dextromethorphan to a human being in need thereof. Embodiment 11. A method of improving a therapeutic property of dextromethorphan comprising administering an antidepressant compound in conjunction with administration of dextromethorphan to a human being in need of treatment for a neurological and/or psychiatric disorder.

Embodiment 12. A method of treating a neurological and/or psychiatric disorder comprising administering a combination of an antidepressant compound and dextromethorphan to a human being in need thereof.

Embodiment 13. The method of Embodiment 12, wherein the human being is an extensive metabolizer of dextromethorphan.

Embodiment 14. The method of any preceding embodiment, such as embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the dextromethorphan and the antidepressant compound are administered in separate dosage forms.

Embodiment 15. A pharmaceutical composition comprising a therapeutically effective amount of dextromethorphan, a therapeutically effective amount of an antidepressant compound, and a pharmaceutically acceptable excipient.

Embodiment 16. An oral dosage form comprising at least 20 mg of dextromethorphan and an effective amount of an antidepressant compound to inhibit the metabolism of dextromethorphan in a human being that is an extensive metabolizer of dextromethorphan.

Embodiment 17. The oral dosage form of embodiment 16, wherein about 30 mg to about 350 mg of dextromethorphan is present in the dosage form.

Embodiment 18. The method of any preceding embodiment, wherein dextromethorphan is administered to the human being for the treatment of cough.

Embodiment 19. The method of any preceding embodiment, wherein dextromethorphan is administered to the human being at least daily for at least 8 days, at least 9 days, or at least 10 days.

Embodiment 20. The method of any preceding embodiment, wherein the antidepressant is administered in an amount that results in a plasma concentration of dextromethorphan in the human being, on day 8, that is at least 10 times the plasma concentration of the same amount of dextromethorphan administered without the antidepressant. Embodiment 21. The method of any preceding embodiment, wherein the human being is an extensive metabolizer of dextromethorphan.

Embodiment 22. The method of any preceding embodiment, wherein dextromethorphan is administered to the human being for the treatment of pain.

Embodiment 23. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises postoperative pain, cancer pain, arthritic pain, lumbosacral pain, musculoskeletal pain, central multiple sclerosis pain, nociceptive pain, or neuropathic pain.

Embodiment 24. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, or nociceptive pain.

Embodiment 25. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises postoperative pain.

Embodiment 26. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises cancer pain.

Embodiment 27. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises arthritic pain.

Embodiment 28. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises lumbosacral pain.

Embodiment 29. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises musculoskeletal pain.

Embodiment 30. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises neuropathic pain.

Embodiment 31. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises nociceptive pain.

Embodiment 32. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises chronic musculoskeletal pain.

Embodiment 33. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with rheumatoid arthritis. Embodiment 34. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with juvenile rheumatoid arthritis.

Embodiment 35. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with osteoarthritis.

Embodiment 36. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with an axial spondyloarthritis.

Embodiment 37. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with ankylosing spondylitis.

Embodiment 38. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with diabetic peripheral neuropathy.

Embodiment 39. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with post-herpetic neuralgia.

Embodiment 40. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with trigeminal neuralgia.

Embodiment 41. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with monoradiculopathies.

Embodiment 42. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with phantom limb pain.

Embodiment 43. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with central pain.

Embodiment 44. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises cancer-related pain.

Embodiment 45. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with lumbar nerve root compression.

Embodiment 46. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with spinal cord injury.

Embodiment 47. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with post-stroke pain. Embodiment 48. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with central multiple sclerosis pain.

Embodiment 49. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with HIV-associated neuropathy.

Embodiment 50. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with radiotherapy associated neuropathy.

Embodiment 51. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with chemotherapy associated neuropathy.

Embodiment 52. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises dental pain.

Embodiment 53. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with primary dysmenorrhea.

Embodiment 54. The method of any preceding embodiment, wherein 90 mg/day of dextromethorphan is administered to the human being.

Embodiment 55. The method of any preceding embodiment, such as embodiment 54, wherein 45 mg of dextromethorphan is administered twice a day to the human being.

Embodiment 56. The method of any preceding embodiment, wherein the antidepressant is administered in an amount that results in an AUC012 of dextromethorphan that is at least about 40 ng«hr/mL.

Embodiment 57. The method of any preceding embodiment, wherein the AUC012 of dextromethorphan is at least about 50 ng«hr/mL.

Embodiment 58. The method of any preceding embodiment, wherein the human being is in need of treatment with dextromethorphan.

Embodiment 59. The method of any preceding embodiment, wherein the AUC012 of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 100 ng«hr/mL.

Embodiment 60. The method of any preceding embodiment, wherein the AUC0-12 of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 400 ng«hr/mL.

Embodiment 61. The method of any preceding embodiment, wherein the AUC012 of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 800 ng«hr/mL. Embodiment 62. The method of any preceding embodiment, wherein the AUC012 of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 1500 ng«hr/mL.

Embodiment 63. The method of any preceding embodiment, wherein the AUC0-24 of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 100 ng«hr/mL.

Embodiment 64. The method of any preceding embodiment, wherein the AUC0-24 of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 1500 ng«hr/mL.

Embodiment 65. The method of any preceding embodiment, wherein the AUC0-24 of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 2900 ng«hr/mL.

Embodiment 66. The method of any preceding embodiment, wherein the AUCo-inf of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 100 ng«hr/mL.

Embodiment 67. The method of any preceding embodiment, wherein the AUCo-inf of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 1500 ng«hr/mL.

Embodiment 68. The method of any preceding embodiment, wherein the AUCo-inf of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 3500 ng«hr/mL.

Embodiment 69. The method of any preceding embodiment, wherein the AUCo-inf of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 5000 ng«hr/mL.

Embodiment 70. The method of any preceding embodiment, wherein the antidepressant is administered in an amount that results in a C_max of dextromethorphan that is at least about 6 ng/mL.

Embodiment 71. The method of any preceding embodiment, such as embodiment 70, wherein the C_max of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 10 ng/mL.

Embodiment 72. The method of any preceding embodiment, wherein the C_max of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 20 ng/mL.

Embodiment 73. The method of any preceding embodiment, wherein the C_max of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 60 ng/mL.

Embodiment 74. The method of any preceding embodiment, wherein the Cmax of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 120 ng/mL. Embodiment 75. The method of any preceding embodiment, wherein the antidepressant is administered in an amount that results in a C_avg of dextromethorphan over a 12 hour period, after one administration, that is at least about 5 ng/mL.

Embodiment 76. The method of any preceding embodiment, wherein the C_avg of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 20 ng/mL.

Embodiment 77. The method of any preceding embodiment, wherein the C_avg of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 70 ng/mL.

Embodiment 78. The method of any preceding embodiment, wherein the C_avg of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 120 ng/mL.

Embodiment 79. The method of any preceding embodiment, wherein the antidepressant is administered in an amount that results in an AUC012 of dextromethorphan that is at least about 40 ng«hr/mL.

Embodiment 80. The method of any preceding embodiment, wherein the AUC012 of dextromethorphan is at least about 50 ng«hr/mL.

Embodiment 81. The method of any preceding embodiment, wherein the antidepressant is co-administered with dextromethorphan at least daily for at least two consecutive days.

Embodiment 82. The method of any preceding embodiment, wherein the AUC012 of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 100 ng«hr/mL.

Embodiment 83. The method of any preceding embodiment, wherein the AUC012 of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 800 ng«hr/mL.

Embodiment 84. The method of any preceding embodiment, wherein the AUC012 of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 1500 ng«hr/mL.

Embodiment 85. The method of any preceding embodiment, wherein the AUC0-24 of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 100 ng«hr/mL.

Embodiment 86. The method of any preceding embodiment, wherein the AUC0-24 of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 1500 ng«hr/mL.

Embodiment 87. The method of any preceding embodiment, wherein the AUCo-inf of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 100 ng«hr/mL. Embodiment 88. The method of any preceding embodiment, wherein the AUCo-inf of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 3500 ng«hr/mL.

Embodiment 89. The method of any preceding embodiment, wherein the AUCo-inf of dextromethorphan on Day 8, Day 9, or Day 10 is at least about 5000 ng«hr/mL.

Embodiment 90. The method of any preceding embodiment, wherein about 0.6 mg/kg to about 0.8 mg/kg of the dextromethorphan is orally administered once or twice a day.

Embodiment 91. The method of any preceding embodiment, wherein the human being is suffering from treatment-resistant depression.

Embodiment 92. The method of any preceding embodiment, wherein the dextromethorphan is orally administered in a dosage form that provides immediate release of the dextromethorphan.

Embodiment 93. The method of any preceding embodiment, wherein the antidepressant is orally administered in a dosage form that provides sustained release of the antidepressant.

Embodiment 94. The method of any preceding embodiment, wherein the antidepressant and the dextromethorphan are orally administered together in a single dosage form that is orally administered once or twice a day.

Embodiment 95. The method of any preceding embodiment, wherein the dextromethorphan and the antidepressant are orally administered for at least 5 weeks.

Embodiment 96. The method of any preceding embodiment, wherein the human being is suffering from major depressive disorder.

Embodiment 97. The method of any preceding embodiment, wherein the antidepressant comprises an enantiomeric excess of an R-enantiomer.

Embodiment 98. The method of any preceding embodiment, wherein the antidepressant comprises an enantiomeric excess of an S-enantiomer.

Embodiment 99. The method of any preceding embodiment, wherein the dextromethorphan comprises a deuterium-modified dextromethorphan.

Embodiment 100. The method of any preceding embodiment, wherein the human being is currently suffering from depression and has previously been unsuccessfully treated with at least two antidepressants. Embodiment 101. A method of rapidly relieving the symptoms of depression, comprising administering a combination of antidepressant and dextromethorphan once daily or twice daily to a human being in need thereof, wherein the human being experiences a therapeutic effect within 2 weeks of the first day that the combination of antidepressant and dextromethorphan is administered.

Embodiment 102. Use of a combination of an antidepressant and dextromethorphan in the manufacture of a medicament for rapidly relieving the symptoms of depression, wherein the medicament is administered once daily or twice daily to achieve a therapeutic effect within 2 weeks of the first day that the medicament is administered.

Embodiment 103. The method or the use of any preceding embodiment, wherein the human being has previously had an inadequate response to at least one antidepressant therapy.

Embodiment 104. The method or the use of any preceding embodiment, wherein the depression is major depressive disorder.

Embodiment 105. The method or the use of any preceding embodiment, wherein the depression is treatment resistant depression.

Embodiment 106. The method or the use of any preceding embodiment, wherein the combination of the antidepressant and dextromethorphan is administered once daily or twice daily for at least 30 days.

Embodiment 107. The method or the use of any preceding embodiment, wherein the combination of the antidepressant and dextromethorphan is administered once daily or twice daily for at least 42 days.

Embodiment 108. A method of treating nicotine addiction associated with smoking tobacco comprising administering a combination of an antidepressant and a dextromethorphan daily for at least 21 consecutive days to a person suffering from nicotine addiction, wherein the person is an ad-lib tobacco smoker, wherein a total amount of 80 mg to 140 mg of dextromethorphan are administered to the person daily, and wherein the method is more effective than administering the same amount of the antidepressant alone.

Embodiment 109. The method of embodiment 108, wherein the person taking a medication of the combination of the antidepressant and the dextromethorphan twice a day in 2 equal amount of divided doses resulted in greater reduction in an intensity of the nicotine self-administration on the day or following day of the administration than the person taking only one of the 2 divided doses or not taking the medication of the combination.

Embodiment 110. The method of embodiment 108 or 109, wherein the combination of the antidepressant and the dextromethorphan is administered to the person daily for at least 42 consecutive days.

Embodiment 111. The method of embodiment 108, 109, or 110, wherein about 90 mg of the dextromethorphan is administered to the person daily.

Embodiment 112. The method of any one of embodiments 109-111, wherein about 40 mg to about 50 mg of the dextromethorphan in each dose is administered to the person twice daily.

Embodiment 113. The method of any one of embodiments 109-112, wherein, to the person addicted to nicotine, the method is more effective than administering the dextromethorphan alone.

Embodiment 114. The method of any one of embodiments 109-113, wherein the antidepressant is deuterium enriched.

Embodiment 115. The method of embodiment 108, wherein the dextromethorphan is deuterium enriched.

EXAMPLES

The effect of the combination of bupropion, an antidepressant, and dextromethorphan in human beings is demonstrated in several of the examples below. Example 2 shows that the results for bupropion are also likely to be observable with other antidepressants.

Example 1

Fifteen human subjects were randomized into one of two treatment groups receiving either dextromethorphan (DM) alone, or DM in combination with bupropion, as shown in Table 1 below.

Table 1. Study Design

All subjects were extensive, including ultra-rapid, metabolizers of dextromethorphan as determined by CYP2D6 genetic testing. Dextromethorphan was dosed at 12-hour intervals on Days 1-8, with a final morning dose on Day 8. Bupropion was dosed once daily on Days 1-3, and at 12-hour intervals thereafter, with a final morning dose on Day 8.

Plasma samples were collected for concentration analysis of dextromethorphan, total dextrorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion on days 1 and 8. Plasma samples for determination of trough concentrations of dextromethorphan were obtained approximately 12 hours after dosing on days 1, 5, 6, and 8.

Concentrations of dextromethorphan, total dextrorphan (unconjugated and glucuronide forms), bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion, were determined using LC-MS/MS. Pharmacokinetic parameters were calculated.

Phenotypic determination of dextromethorphan metabolizer status was performed by calculating the dextromethorphan/dextrorphan metabolic ratio as described in Jurica et al. Journal of Clinical Pharmacy and Therapeutics, 2012, 37, 486-490. Plasma concentrations of dextromethorphan and dextrorphan 3 hours after dosing were used, with a dextromethorphan/dextrorphan ratio of 0.3 or greater indicating a poor metabolizer phenotype.

Results

Plasma concentrations of dextromethorphan were significantly increased with bupropion administration, as illustrated in Fig. 1 and Table 2.

Table 2. Mean Day 8 Dextromethorphan Plasma Concentrations (ng/mL)

The AUC of dextromethorphan was significantly increased with administration of bupropion as show in Figs. 2-4. As shown in Fig. 5 and Table 2A, administration of bupropion with dextromethorphan resulted in an approximately 60-fold, 80-fold, and 175-fold increase in mean dextromethorphan AUC012, AUC0-24, and AUCo-inf, respectively on Day 8 as compared to administration of dextromethorphan alone. As shown in Fig. 6 and Table 2B, the increase in dextromethorphan AUC occurred as early as Day 1 (an approximate 3-fold increase in AUCo i2).

Table 2A. Day 8 Values

Table 2B. Day 1 Values

Trough plasma concentrations (also referred to as "minimum mean plasma concentrations" or "C_min") of dextromethorphan were significantly increased with administration of bupropion as illustrated in Fig. 7 and Tables 2A and 3. Administration of bupropion with dextromethorphan resulted in an approximately 105-fold increase in mean trough plasma concentration of dextromethorphan on Day 8 as compared to administration of dextromethorphan alone.

Mean average plasma concentrations (C_aVg) of dextromethorphan on Day 8 increased approximately 60-fold with bupropion administration as compared to administration of dextromethorphan alone, as illustrated in Table 2A. Maximum mean plasma concentrations (C_max) were also significantly increased as illustrated in Fig. 8 and Table 2A.

Table 3. Mean Trough Dextromethorphan Plasma Concentrations (ng/mL)

The Tmax and elimination half-life (T1/2 _ei) of dextromethorphan were significantly increased with administration of bupropion on Day 8. The increase of T1/2 ei shows that the metabolic lifetime of dextromethorphan was increased. Administration of bupropion with dextromethorphan resulted in a mean T_max of 3.6 hours, compared to 2.3 hours for dextromethorphan alone. Administration of bupropion with dextromethorphan resulted in a mean Ti/2ei of 27.7 hours, compared to 6.6 hours for dextromethorphan alone. Plasma concentrations of dextrorphan were significantly decreased with bupropion administration, as illustrated in Fig. 9 and Table 4.

Table 4. Mean Day 8 Dextrorphan Plasma Concentrations (ng/mL)

As shown in Figs. 10-11, there was an approximate 78% reduction in mean dextrorphan Cmax, and an approximate 55% reduction in mean dextrorphan AUC012 on Day 8 with administration of bupropion.

Phenotypic determination of dextromethorphan metabolizer status showed that no subjects in either treatment arm were poor metabolizers on Day 1. On Day 8 however, 100% of subjects treated with bupropion had converted to poor metabolizer status as compared to 0% of subjects treated with dextromethorphan alone. The mean plasma dextromethorphan/dextrorphan metabolic ratio increased from 0.01 on Day 1 to 0.71 on Day 8 with bupropion administration. The mean ratio in the group administered DM alone was 0.00 on Day 1 and remained unchanged on Day 8.

On Day 8, average plasma concentrations of bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion were at least 10 ng/mL, 200 ng/mL, 20 ng/mL, and 100 ng/mL, respectively after bupropion administration.

As used in this section, the term "fold change" or "fold increase" refers to the ratio of a value for bupropion with dextromethorphan to the same value for dextromethorphan alone (i.e., the value for bupropion with dextromethorphan divided by the same value for dextromethorphan alone).

Example 2

The ability of various antidepressant compounds to inhibit the metabolism of dextromethorphan was examined using human liver microsomes. Each antidepressant compound was incubated at seven increasing concentrations (0.1-100 pM) in duplicate with human liver microsomes (0.5 mg/mL) in the presence of dextromethorphan (5 pM) at 37 °C. The assay was performed in the presence of 2 mM NADPH in 100 mM potassium phosphate (pH 7.4) containing 5 mM magnesium chloride, in a 200 pL assay final volume.

After optimal incubation at 37 °C, the reactions were terminated by addition of methanol containing internal standard for analytical quantification. The quenched samples were incubated at 4 °C for 10 minutes and centrifuged at 4 °C for 10 minutes. The supernatant was removed, and the metabolite of dextromethorphan (dextrorphan) was analyzed by LC-MS/MS. A decrease in the formation of the metabolite compared to vehicle control was used to calculate an IC50 value (the test concentration which produces 50% inhibition of dextromethorphan metabolism) for each antidepressant compound, with a lower IC50 indicating greater potency.

The results are summarized in Table 5 below, and the corresponding potencies are depicted in FIG. 12.

Table 5. Potency of Various Antidepressant Compounds for Inhibition of the Metabolism of Dextromethorphan in Human Liver Microsomes

Example 3

Phase 2 clinical trial design:

The Phase 2 clinical trial with the administration of a combination of dextromethorphan and bupropion (DM/BU) was a randomized, double-blind, active-controlled, multi-center, U.S. trial with 80 adult patients with confirmed diagnosis of moderate to severe major depressive disorder (MDD), who received a twice daily dose for a 6-week treatment period. Dose groups (1:1 randomization) included DM/BU (45 mg dextromethorphan/105 mg bupropion) with 43 patients, or active comparator bupropion (105 mg) with 37 patients. Among these patients, 23% of them had received prior first line treatment for depression. The clinical trial had extensive quality control measures.

The Primary Endpoint:

The changes from baseline in the Montgomery-AsbergDepression Rating Scale (MADRS) total score over the 6-week treatment period were calculated at each time point and averaged.

Figure 13 and Table A shows the changes in MADRS total score over the time during the 6- week dosing period for the subjects administered bupropion (BU) or the combination of dextromethorphan and bupropion (DM/BU).

Table A

The Secondary Endpoints:

Table B listed the secondary endpoints with P-values.

Table B

*P-values are for DM/BU versus active comparator bupropion ( BU ). Multiple secondary endpoints favored DM/BU.

Figure 14 shows the percent of subjects achieving remission (as determined by MADRS < 10) over the time during the 6-week dosing period for the subjects administered bupropion (BU) or the combination of dextromethorphan and bupropion (DM/BU).

Safety:

The clinical study showed that the administration of the DM/BU was safe and well tolerated with similar rates of adverse events in the DM/BU and bupropion arms. No serious adverse events were observed. There was no meaningful difference between the two treatment arms in discontinuations due to adverse events. The most commonly reported adverse events in the DM/BU arm were nausea, dizziness, dry mouth, decreased appetite, and anxiety. The DM/BU was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction.

Summary:

Statistically significant improvements on MADRS and secondary efficacy endpoints for DM/BU in patients with MDD were achieved. Early and sustained separation from active comparator bupropion were observed. The administration of DM/BU was safe and well-tolerated with no psychotomimetic effects, weight gain, or increased sexual dysfunction

Thus, DM/BU demonstrated significant and rapid antidepressant activity with a favorable safety profile in the clinical trial in MDD.

Results:

Figures 13 and 14 are prepared based on the results of the US clinical trials with 80 adult patients having depression with 43 patients treated with the combination of 45 mg of DM and 105 mg of BU, and 37 patients treated with 105 mg of BU alone who received a twice daily dose for the 6-week treatment period. Among these patients, 23% of them had received prior first line treatment for depression.

As shown in Figure 13 and Table A, the MADRS total score (depression rating scale) was significantly reduced with the combination of DM and BU than that of BU alone even at the first week of the treatment. At week 6, administration of the combination DM/BU reduced the MADRS total score by about 42% as compared to bupropion alone.

As shown in Figure 14, even in as early as the second week of the treatment, the remission rate for the combination of DM/BU is significantly higher than that for the comparator BU alone (about 8 times) with about 20% higher remission rate. At week 6 of the treatment, the administration of combination DM/BU resulted in about 30% higher remission rate than that of the comparator BU alone.

The above clinical study showed that the administration of the combination of bupropion with dextromethorphan (DM/BU) provides greater efficacy than would otherwise be achieved by administering bupropion alone. This clinical study demonstrated that the combination of dextromethorphan and bupropion has an additive or synergistic efficacy in treating depression.

Example 4: Product Kit:

In some embodiments, a product kit comprises a combination of dextromethorphan and bupropion, for treating depression, wherein the product kit contains a dosage form containing about 30 mg to about 60 mg of dextromethorphan and about 100 mg to about 200 mg of bupropion, and wherein administration of the dosage form once daily or twice daily results in greater efficacy in the human being than that for administering bupropion alone. In some embodiments, the product kit contains 45 mg of dextromethorphan and 105 mg of bupropion.

In some embodiments, a product kit comprises an oral sustained release delivery system for dextromethorphan, comprising bupropion; dextromethorphan; and a water soluble vehicle in a dosage form, wherein the dosage form contains about 30 mg to about 60 mg of dextromethorphan and about 100 mg to about 200 mg of bupropion, and wherein the use of the dosage form once or twice daily for at least eight days results in the increase of elimination halflife (T1/2) of dextromethorphan than that for administration dextromethorphan alone on the eighth day.

Example 5: Nearly 40 million American adults smoke and around 70% of them report that they want to quit. Tobacco use results in approximately 500,000 premature deaths each year in the U.S. alone, according to the Centers for Disease Control and Prevention. Smoking is the single largest cause of premature deaths worldwide accounting for an estimated almost 20% of all deaths in developed countries [Dani JA and Heinemann S (1996) Neuron 16:5, pp. 905-8], Direct health care and lost productivity costs as a result of smoking total nearly $300 billion a year in the U.S. alone. It is estimated that only 3 to 5% of cigarette smokers who attempt to quit without assistance are successful for 6-12 months, and the relapse rate remains above 80% even with current treatments [Hughes JR, et al. (2004) Addiction 99:1, pp. 29-38], As the vast majority of smokers who attempt to quit fail to do so highlighting the need for new approaches. The combination of dextromethorphan and bupropion (DM/BU) has the potential to address this condition due to the novel mechanisms of action of DM/BU.

The dextromethorphan component of DM/BU is a sigma-1 receptor agonist, nicotinic acetylcholine receptor antagonist, and inhibitor of the serotonin and norepinephrine transporters. The bupropion component of DM/BU serves to increase the bioavailability of dextromethorphan, and is a norepinephrine and dopamine reuptake inhibitor, and a nicotinic acetylcholine receptor antagonist. Both components of DM/BU are nicotinic acetylcholine receptor antagonists, a mechanism that is relevant to nicotine dependence. Thus, DM/BU provides a potentially new mechanism of action for smoking cessation treatment.

Phase 2 clinical trial design:

The clinical trial was a Phase 2, randomized, double-blind, active-controlled study to evaluate the efficacy and safety of DM/BU for smoking cessation treatment. A total of 58 smokers were randomized in a 1:1 ratio to receive either DM/BU (45 mg dextromethorphan/105 mg bupropion) (n=31), or the active comparator bupropion (105 mg) (n=27), twice daily, and assessed over a 3-week period. Enrolled subjects were daily smokers using 10 or more cigarettes per day. The average number of cigarettes smoked per day at baseline was 20 for DM/BU and 17 for the bupropion treatment groups.

The primary outcome measure was the change in smoking intensity, measured using the number of cigarettes smoked per day, assessed via daily smoking diaries. Reduction in ad-lib smoking was selected as the primary endpoint in this trial because it has been shown to correlate with smoking abstinence.

Medication adherence was similar between the study arms for both the morning dose (97.1% for DM/BU and 96.6% for bupropion) and the evening dose (76.3% for DM/BU and 79.4% for bupropion). In the study, DM/BU was safe and well tolerated with no serious adverse events. The most commonly reported side effects were headache, dry mouth, and insomnia/vivid dreams, with similar incidences in both treatment arms.

Results:

Treatment with DM/BU resulted in a 25% greater reduction in the average number of cigarettes smoked per day over the 3-week period, the prespecified primary endpoint, as compared to bupropion (average reductions of 8.49 and 6.79 cigarettes per day for DM/BU and bupropion, respectively, p = 0.0016).

Consistent with this finding, a greater proportion of smokers receiving DM/BU experienced a more than 50% reduction in expired carbon monoxide levels, a biochemical marker of smoking intensity, as compared to those treated with bupropion (52.0% for DM/BU versus 30.4% for bupropion, p = 0.15).

In addition, the human subjects who took DM/BU as prescribed on a given day smoked 1.0 fewer cigarette on the day of medication use of DM/BU (p = 0.026) and 1.2 fewer cigarettes on the following day (p = 0.008) as compared to those who missed one or both doses of DM/BU.

The treatment with DM/BU achieves the prespecified primary endpoint in Phase 2 Trial in Smoking Cessation. The treatment with DM/BUdemonstrated statistically significant reduction in daily smoking compared to the active comparator bupropion alone (p = 0.0016). The findings in this phase 2 clinical trial are notable because DM/BU was compared to bupropion, which is an approved treatment for smoking cessation.

Furthermore, it is worth noting that the improvement of DM/BU over bupropion observed in this clinical trial in human beings is similar in magnitude to the improvement over placebo reported for the approved smoking cessation treatment varenicline in studies with a similar design. Varenicline is a prescription medication used to treat smoking addiction. This medication is the first approved nicotinic receptor partial agonist. Specifically, varenicline is a partial agonist of the alpha4/beta2 subtype of the nicotinic acetylcholine receptor.

Example 6

A Phase 3, randomized, double-blind, multicenter, placebo-controlled clinical trial of the combination of dextromethorphan (DM) and bupropion (BU or BUP) in patients with major depressive disorder (MDD) was conducted in the U.S. A total of 327 patients with a confirmed diagnosis of moderate to severe MDD were randomized in a 1:1 ratio to receive 45 mg dextromethorphan/105 mg bupropion (DM/BU) (n=163), or placebo (n=164) once daily for the first 3 days (day 1, day 2, and day 3) and twice daily thereafter (starting day 4) for a total of 6 weeks.

Baseline inclusion criteria included: Male or female 18-65 years of age, meeting DSM-5 criteria for current MDD without psychotic features, a Montgomery-Asberg Depression Rating Scale (MADRS) total score of at least 25, and CGI-S score of at least 4. Exclusion criteria included: a history of electroconvulsive therapy, vagusnerve stimulation, transcranial magnetic stimulation, or any experimental central nervous system treatment of, during the current episode or in the past 6 months, Schizophrenia, bipolar disorder, obsessive compulsive disorder, and Psychiatric symptoms secondary to any other general medical condition.

Patient demographics and baseline characteristics are shown in Table 6 below:

Table 6

Data are mean (SD) unless otherwise stated.

Abbreviations: BMI = Body Mass Index; BU = Bupropion; CGI-S = Clinical Global Impression - Severity; DM = Dextromethorphan; MADRS = Montgomery-Asberg Depression Rating Scale Demographics and baseline characteristics were similar across both treatment groups. Study completion rates were greater than 75% in both treatment groups.

The primary endpoint of the study was the change from baseline in the MADRS total score at Week 6. Secondary endpoints included MADRS change at Weeks 1 and 2, remission, response, Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity (CGI-S), Patient Global Impression-Improvement (PGI-I), MADRS-6, Sheehan Disability Scale (SDS), other quality of life measures, safety, and tolerability. P-values were calculated based on least square mean estimates.

DM/BU met the primary endpoint and rapidly and significantly improved symptoms of depression. Specifically, DM/BU demonstrated rapid, durable, and statistically significant improvement in depressive symptoms as measured by MADRS total score compared to placebo (p=0.002 on primary endpoint). DM/BU demonstrated a highly statistically significant reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) total score compared to placebo at Week 6, with mean reductions from baseline of 16.6 points for DM/BU and 11.9 points for placebo (p=0.002).

Additionally, a statistically significant improvement was observed at Week 1, or only 4 days after the start of twice daily dosing. As depicted in FIG. 15, statistically significant improvements at Week 1 were observed for MADRS total score, with a reduction in MADRS total score of 7.3 points for DM/BU compared to the reduction of 4.9 points for placebo (key secondary endpoint, p=0.007) , with statistical significance for this measure maintained at all time points thereafter (e.g., Week 2, 3, 4, 5, or 6). Statistically significant improvements for Patient Global Impression- Improvement (PGI-I) (p=0.008); Clinical Global Impression-Severity (CGI-S) (p=0.013); Clinical Global Impression-Improvement (CGI-I) (p=0.035); Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR-16) (p=0.016); Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) (p=0.031); and other endpoints were also observed at Week 1 and at every time point thereafter (e.g., Week 2, 3, 4, 5, or 6).

As shown in FIG. 16, response, defined as a >50% improvement in the MADRS total score, was seen at Week 6 in 54.0% of patients who received DM/BU, compared to 34.0% of patients who received placebo (p<0.001).

As shown in FIG. 17, rates of remission from depression (defined as MADRS <10) were statistically significantly greater for DM/BU compared to placebo at Week 2 (p=0.013) and at every time point thereafter (e.g., Week 3, 4, or 6), being achieved by 39.5% of DM/BU patients compared to 17.3% of placebo patients at Week 6 (p<0.001).

DM/BU was also associated with a statistically significant reduction in functional impairment, as measured by the Sheehan Disability Scale (SDS), compared to placebo at Week 2 (p=0.003), and at every time point thereafter (p=0.002, at Week 6).

On all secondary endpoints including the following, DM/BU demonstrated statistically significant improvement at Week 6 compared to placebo, reflecting increasing treatment effects over time: clinical response on the MADRS total score (defined as >50%) (p<0.001); PGI-I (p=0.007); CGI-S (p=0.002); CGI-I (p=0.016); QIDS-SR-16 (p=0.001); Sheehan Disability Scale (SDS) (p=0.002); and Q-LES-Q-SF (p=0.011).

DM/BU was well tolerated in the phase 3 clinical trial. The most commonly reported adverse events in the DM/BU arm were dizziness, nausea, headache, diarrhea, somnolence, and dry mouth. There was one serious adverse event in the DM/BU arm which was deemed by the investigator not to be study-drug related. The rates of discontinuation due to adverse events were low in both treatment groups (6.2% for DM/BU and 0.6% for placebo). Treatment with DM/BU was not associated with psychotomimetic effects or weight gain.

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as amounts, percentage, and so forth used in the specification and claims are to be understood in all instances as indicating both the exact values as shown and as being modified by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

The terms "a," "an," "the" and similar referents used in the context of describing the embodiments (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the claims.

Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or to expedite prosecution. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups if used in the appended claims.

Certain embodiments are described herein, including the best mode known to the inventors for carrying out the claimed embodiments. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the claimed embodiments to be practiced otherwise than specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

In closing, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, but not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to embodiments precisely as shown and described.

Claims

1. A method of treating depression, comprising administering a combination of an antidepressant and dextromethorphan to a human being in need thereof, wherein the antidepressant comprises levomilnacipran, vilazodone, vortioxetine, atomoxetine, reboxetine, teniloxazine, viloxazine, amitriptylinoxide, dimetacrine, melitracen, nitroxazepine, noxiptiline, pipofezine, setiptiline, caroxazone, metralindole, pirlindole, eprobemide, minaprine, bifemelane, agomelatine, esketamine, tandospirone, tianeptine, a-methyltryptamine, etryptamine, a- ethyltryptamine, indeloxazine, medifoxamine, oxaflozane, pivagabine, ademetionine, S-adenosyl- L-methionine, hypericum perforatum, oxitriptan, 5-hydroxytryptophan, rubidium chloride, tryptophan, magnesium, acetylcarnitine, saffron, amisulpride, aripiprazole, brexpiprazole, lurasidone, olanzapine, quetiapine, risperidone, buspirone, lithium, modafinil, thyroxine, triiodothyronine, minocycline, a combination of amitriptyline and chlordiazepoxide, a combination of amitriptyline and perphenazine, flupentixol and melitracen, a combination of olanzapine and fluoxetine, a combination of tranylcypromine and trifluoperazine, 4- chlorokynurenine, AGN-241751, apimostinel, arketamine, dextromethadone, EVT-101, rislenemdaz, basimglurant, AN-788, toludesvenlafaxine, PDC-1421, MIN-117, TGBA01AD, gepirone, pimavanserin, psilocybin, brilaroxazine, lumateperone, ademetionine, ganaxolone, zuranolone, 3|3-methoxypregnenolone, PH-10 - vomeropherine, aticaprant, BTRX-335140, a combination of buprenorphine and samidorphan, BTRX-246040, hydroxynorketamine , JNJ- 39393406, JNJ-54175446, JNJ-61393215, NNI-351, NSI-189, NV-5138, onabotulinumtoxin A , pramipexole, seltorexant , sirukumab, SUVN-911, TS-121, tramadol, a combination of cycloserine and lurasidone, 7,8-dihydroxyflavone (7,8-dhf), minocycline, nitrous oxide, pramipexole, R13, or a combination thereof.

2. The method of claim 1, wherein the antidepressant comprises levomilnacipran.

3. The method of claim 1, wherein the antidepressant comprises vilazodone.

4. The method of claim 1, wherein the antidepressant comprises vortioxetine.

5. The method of claim 1, wherein the antidepressant comprises atomoxetine.

6. The method of claim 1, wherein the antidepressant comprises reboxetine.

7. The method of claim 1, wherein the antidepressant comprises teniloxazine.

8. The method of claim 1, wherein the antidepressant comprises viloxazine.

9. The method of claim 1, wherein the antidepressant comprises amitriptylinoxide.

10. The method of claim 1, wherein the antidepressant comprises dimetacrine.

11. The method of claim 1, wherein the antidepressant comprises melitracen.

12. The method of claim 1, wherein the antidepressant comprises nitroxazepine.

13. The method of claim 1, wherein the antidepressant comprises noxiptiline.

14. The method of claim 1, wherein the antidepressant comprises pipofezine.

15. The method of claim 1, wherein the antidepressant comprises setiptiline.

16. The method of claim 1, wherein the antidepressant comprises caroxazone.

17. The method of claim 1, wherein the antidepressant comprises metralindole.

18. The method of claim 1, wherein the antidepressant comprises pi rl indole.

19. The method of claim 1, wherein the antidepressant comprises eprobemide.

20. The method of claim 1, wherein the antidepressant comprises minaprine.

21. The method of claim 1, wherein the antidepressant comprises bifemelane.

22. The method of claim 1, wherein the antidepressant comprises agomelatine.

23. The method of claim 1, wherein the antidepressant comprises esketamine.

24. The method of claim 1, wherein the antidepressant comprises tandospirone.

25. The method of claim 1, wherein the antidepressant comprises tianeptine.

26. The method of claim 1, wherein the antidepressant comprises a-methyltryptamine.

27. The method of claim 1, wherein the antidepressant comprises etryptamine.

28. The method of claim 1, wherein the antidepressant comprises indeloxazine.

29. The method of claim 1, wherein the antidepressant comprises medifoxamine.

30. The method of claim 1, wherein the antidepressant comprises oxaflozane.

31. The method of claim 1, wherein the antidepressant comprises pivagabine.

32. The method of claim 1, wherein the antidepressant comprises ademetionine.

33. The method of claim 1, wherein the antidepressant comprises hypericum perforatum.

34. The method of claim 1, wherein the antidepressant comprises oxitriptan.

35. The method of claim 1, wherein the antidepressant comprises 5-hydroxytryptophan.

36. The method of claim 1, wherein the antidepressant comprises rubidium chloride.

37. The method of claim 1, wherein the antidepressant comprises tryptophan.

38. The method of claim 1, wherein the antidepressant comprises magnesium.

39. The method of claim 1, wherein the antidepressant comprises acetylcarnitine.

40. The method of claim 1, wherein the antidepressant comprises saffron.

41. The method of claim 1, wherein the antidepressant comprises amisulpride.

42. The method of claim 1, wherein the antidepressant comprises aripiprazole.

43. The method of claim 1, wherein the antidepressant comprises brexpiprazole.

44. The method of claim 1, wherein the antidepressant comprises lurasidone.

45. The method of claim 1, wherein the antidepressant comprises olanzapine.

46. The method of claim 1, wherein the antidepressant comprises quetiapine.

47. The method of claim 1, wherein the antidepressant comprises risperidone.

48. The method of claim 1, wherein the antidepressant comprises buspirone.

49. The method of claim 1, wherein the antidepressant comprises lithium.

50. The method of claim 1, wherein the antidepressant comprises modafinil.

51. The method of claim 1, wherein the antidepressant comprises thyroxine.

52. The method of claim 1, wherein the antidepressant comprises triiodothyronine.

53. The method of claim 1, wherein the antidepressant comprises minocycline.

54. The method of claim 1, wherein the antidepressant comprises a combination of amitriptyline and chlordiazepoxide.

55. The method of claim 1, wherein the antidepressant comprises a combination of amitriptyline and perphenazine.

56. The method of claim 1, wherein the antidepressant comprises a combination of flupentixol and melitracen.

57. The method of claim 1, wherein the antidepressant comprises a combination of olanzapine and fluoxetine.

58. The method of claim 1, wherein the antidepressant comprises a combination of tranylcypromine and trifluoperazine.

59. The method of claim 1, wherein the antidepressant comprises 4-chlorokynurenine.

60. The method of claim 1, wherein the antidepressant comprises AGN-241751.

61. The method of claim 1, wherein the antidepressant comprises apimostinel.

62. The method of claim 1, wherein the antidepressant comprises arketamine.

63. The method of claim 1, wherein the antidepressant comprises dextromethadone.

64. The method of claim 1, wherein the antidepressant comprises EVT-101.

65. The method of claim 1, wherein the antidepressant comprises rislenemdaz.

66. The method of claim 1, wherein the antidepressant comprises basimglurant.

67. The method of claim 1, wherein the antidepressant comprises AN-788.

68. The method of claim 1, wherein the antidepressant comprises toludesvenlafaxine.

69. The method of claim 1, wherein the antidepressant comprises PDC-1421.

70. The method of claim 1, wherein the antidepressant comprises MIN-117.

71. The method of claim 1, wherein the antidepressant comprises TGBA01AD.

72. The method of claim 1, wherein the antidepressant comprises gepirone.

73. The method of claim 1, wherein the antidepressant comprises pimavanserin.

74. The method of claim 1, wherein the antidepressant comprises psilocybin.

75. The method of claim 1, wherein the antidepressant comprises brilaroxazine.

76. The method of claim 1, wherein the antidepressant comprises lumateperone.

77. The method of claim 1, wherein the antidepressant comprises ademetionine.

78. The method of claim 1, wherein the antidepressant comprises ganaxolone.

79. The method of claim 1, wherein the antidepressant comprises zuranolone.

80. The method of claim 1, wherein the antidepressant comprises 3|3-methoxypregnenolone.

81. The method of claim 1, wherein the antidepressant comprises PH-10 - vomeropherine.

82. The method of claim 1, wherein the antidepressant comprises aticaprant.

83. The method of claim 1, wherein the antidepressant comprises BTRX-335140.

84. The method of claim 1, wherein the antidepressant comprises a combination of buprenorphine and samidorphan.

85. The method of claim 1, wherein the antidepressant comprises hydroxynorketamine.

86. The method of claim 1, wherein the antidepressant comprises JNJ-39393406.

87. The method of claim 1, wherein the antidepressant comprises JNJ-54175446.

88. The method of claim 1, wherein the antidepressant comprises JNJ-61393215.

89. The method of claim 1, wherein the antidepressant comprises NNI-351.

90. The method of claim 1, wherein the antidepressant comprises NSI-189.

91. The method of claim 1, wherein the antidepressant comprises NV-5138.

92. The method of claim 1, wherein the antidepressant comprises onabotulinumtoxin A.

93. The method of claim 1, wherein the antidepressant comprises pramipexole.

94. The method of claim 1, wherein the antidepressant comprises seltorexant.

95. The method of claim 1, wherein the antidepressant comprises sirukumab.

96. The method of claim 1, wherein the antidepressant comprises SUVN-911.

97. The method of claim 1, wherein the antidepressant comprises TS-121.

98. The method of claim 1, wherein the antidepressant comprises tramadol.

99. The method of claim 1, wherein the antidepressant comprises a combination of cycloserine and lurasidone.

100. The method of claim 1, wherein the antidepressant comprises 7,8-dihydroxyflavone.

101. The method of claim 1, wherein the antidepressant comprises minocycline.

102. The method of claim 1, wherein the antidepressant comprises nitrous oxide.

103. The method of claim 1, wherein the antidepressant comprises pramipexole.

104. The method of claim 1, wherein the antidepressant comprises R13.