A dosage form for treating agitation associated with Alzheimer's disease.

Abstract

This provides a method for treating agitation associated with major depressive disorder or Alzheimer's disease. [Solution] The method comprises administering a combination of drugs to a person in need of treatment once or twice a day, wherein the person is about 41 years of age or older, and the combination of drugs comprises about 105 mg of bupropion hydrochloride, or the molar equivalent of bupropion in the form of a free base or another salt, and about 45 mg of dextromethorphan hydrobromide, or the molar equivalent of dextromethorphan in the form of a free base or another salt.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims the benefits of U.S. Provisional Patent Application No. 63 / 002,132 filed on 30 March 2020, U.S. Provisional Patent Application No. 63 / 016,178 filed on 27 April 2020, and U.S. Provisional Patent Application No. 63 / 032,517 filed on 29 May 2020, which is a partial application of U.S. Patent Application No. 16 / 894,713 filed on 5 June 2020, and incorporates their full disclosures herein by reference. [Overview of the project] [Means for solving the problem]

[0002] Some embodiments include methods for increasing dextromethorphan plasma concentrations in humans, comprising co-administering bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of these compounds with dextromethorphan.

[0003] Some embodiments involve co-administering erythrohydroxybupropion or its prodrug to humans together with dextromethorphan, wherein the AUC of erythrohydroxybupropion or its prodrug is at least about 40 ng·hours / mL of dextromethorphan. 0-12 The present invention includes a method for increasing dextromethorphan plasma concentration in humans by administering a dose that results in [a specific outcome].

[0004] Some embodiments involve co-administering erythrohydroxybupropion or its prodrug to humans together with dextromethorphan, wherein the erythrohydroxybupropion or its prodrug is at least about 6 ng / mL of dextromethorphan. 最大 The present invention includes a method for increasing dextromethorphan plasma concentration in humans by administering a dose that results in [a specific outcome].

[0005] Some embodiments involve co-administering erythrohydroxybupropion or its prodrug to humans together with dextromethorphan, wherein erythrohydroxybupropion or its prodrug is present at a concentration of at least about 5 ng / mL of dextromethorphan over the period between two separate and consecutive doses of dextromethorphan. 平均 The present invention includes a method for increasing dextromethorphan plasma concentration in humans by administering a dose that results in [a specific outcome].

[0006] Some embodiments include administering threohydroxybupropion or its prodrug to a human requiring treatment with dextromethorphan, wherein the human is a high-metabolite group of dextromethorphan, and dextromethorphan is present in the human body simultaneously with threohydroxybupropion, and the method includes increasing the metabolic lifespan of dextromethorphan.

[0007] Some embodiments include co-administering threohydroxybupropion or its prodrug and dextromethorphan to human patients requiring treatment with dextromethorphan, and include methods for reducing adverse events associated with treatment with dextromethorphan, which the human patients are at risk of experiencing as a result of treatment with dextromethorphan.

[0008] Some embodiments include an oral sustained-release delivery system for dextromethorphan, comprising bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any of these compounds, dextromethorphan, and a water-soluble vehicle.

[0009] Some embodiments include methods for reducing the number of doses of dextromethorphan that can be administered without loss of efficacy, comprising orally administering an effective amount of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any of these compounds as a prodrug to a person requiring treatment with dextromethorphan.

[0010] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering threohydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan, wherein threohydroxybupropion or its prodrug is administered on the first day of at least two days of treatment with dextromethorphan, and a reduction in dextromethorphan plasma concentration occurs on the first day of co-administration of threohydroxybupropion or its prodrug and dextromethorphan compared to the same amount of dextromethorphan administered without threohydroxybupropion or its prodrug.

[0011] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering hydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan, wherein hydroxybupropion or its prodrug is administered on the first day of at least two days of treatment with dextromethorphan, and a reduction in dextromethorphan plasma concentration occurs on the first day of co-administration of hydroxybupropion or its prodrug and dextromethorphan compared to the same amount of dextromethorphan administered without hydroxybupropion or its prodrug.

[0012] Some embodiments include co-administering bupropion and dextromethorphan to a person requiring treatment with dextromethorphan, wherein bupropion is administered on the first day of at least two days of treatment with dextromethorphan, and the method for reducing dextromethorphan plasma concentration is such that a reduction in dextromethorphan plasma concentration occurs on the first day of co-administration of bupropion and dextromethorphan compared to the same amount of dextromethorphan administered without bupropion.

[0013] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering erythrohydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan, wherein erythrohydroxybupropion or its prodrug is administered on the first day of at least two days of treatment with dextromethorphan, and a reduction in dextromethorphan plasma concentration occurs on the first day of co-administration of erythrohydroxybupropion or its prodrug and dextromethorphan compared to the same amount of dextromethorphan administered without erythrohydroxybupropion or its prodrug.

[0014] Some embodiments include co-administering bupropion and dextromethorphan to a person requiring treatment with dextromethorphan for at least eight consecutive days, and include a method for reducing dextromethorphan plasma concentration such that on day eight the dextromethorphan plasma concentration is lower than the dextromethorphan plasma concentration that would have been achieved by administering the same amount of dextromethorphan for eight consecutive days without bupropion.

[0015] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering hydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least eight consecutive days, wherein on day eight, the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for eight consecutive days without hydroxybupropion or its prodrug.

[0016] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering erythrohydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least eight consecutive days, wherein on day eight the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for eight consecutive days without erythrohydroxybupropion or its prodrug.

[0017] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering threohydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least eight consecutive days, wherein on day eight the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for eight consecutive days without threohydroxybupropion or its prodrug.

[0018] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering bupropiont and dextromethorphan to a person requiring treatment with dextromethorphan for at least nine consecutive days, wherein on day 9, the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for nine consecutive days without bupropion.

[0019] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering hydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least nine consecutive days, wherein on day 9, the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for nine consecutive days without hydroxybupropion.

[0020] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering erythrohydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least nine consecutive days, wherein on day 9, the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for nine consecutive days without erythrohydroxybupropion.

[0021] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering hydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least nine consecutive days, wherein on day 9, the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for nine consecutive days without threohydroxybupropion.

[0022] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering bupropion and dextromethorphan to a person requiring treatment with dextromethorphan for at least nine consecutive days, wherein on day 9, the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for nine consecutive days without bupropion.

[0023] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering hydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least nine consecutive days, wherein on day 9, the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for nine consecutive days without hydroxybupropion or its prodrug.

[0024] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering erythrohydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least nine consecutive days, wherein on day 9, the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for nine consecutive days without erythrohydroxybupropion or its prodrug.

[0025] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering threohydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least nine consecutive days, wherein on day 9, the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for nine consecutive days without threohydroxybupropion or its prodrug.

[0026] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering bupropion and dextromethorphan to a person requiring treatment with dextromethorphan for at least nine consecutive days, wherein on day 9, the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for nine consecutive days without bupropion.

[0027] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering hydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least nine consecutive days, wherein on day 9, the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for nine consecutive days without hydroxybupropion or its prodrug.

[0028] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering erythrohydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least nine consecutive days, wherein on day 9, the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for nine consecutive days without erythrohydroxybupropion or its prodrug.

[0029] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering threohydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least nine consecutive days, wherein on day 9, the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for nine consecutive days without threohydroxybupropion or its prodrug.

[0030] Some embodiments include co-administering bupropion and dextromethorphan to a person requiring treatment with dextromethorphan for at least 10 consecutive days, and include a method for reducing dextromethorphan plasma concentration such that on day 10 the dextromethorphan plasma concentration is lower than the dextromethorphan plasma concentration that would have been achieved by administering the same amount of dextromethorphan for 10 consecutive days without bupropion.

[0031] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering hydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 10 consecutive days, wherein on day 10, the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for 10 consecutive days without hydroxybupropion or its prodrug.

[0032] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering erythrohydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 10 consecutive days, wherein on day 10, the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for 10 consecutive days without erythrohydroxybupropion or its prodrug.

[0033] Some embodiments include a method for reducing dextromethorphan plasma concentration, comprising co-administering threohydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 10 consecutive days, wherein on day 10, the dextromethorphan plasma concentration is lower than that which would have been achieved by administering the same amount of dextromethorphan for 10 consecutive days without threohydroxybupropion or its prodrug.

[0034] Antidepressant compounds such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or their metabolites, or prodrugs of any of these compounds, may be used to improve the therapeutic properties of dextromethorphan, such as the treatment of neurological disorders. Bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or their metabolites, or prodrugs of any of these compounds, regardless of stereochemistry, may be effective in inhibiting or reducing dextromethorphan metabolites in some individuals. This may be achieved by co-administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or their metabolites, or prodrugs of any of these compounds, with dextromethorphan.

[0035] Some embodiments include a method for treating neurological disorders, comprising administering to a person in need 1) dextromethorphan, or 2) a combination of an antidepressant and dextromethorphan, wherein the person is a high-metabolism group for dextromethorphan.

[0036] Some embodiments include methods for increasing dextromethorphan plasma concentrations in humans requiring treatment with dextromethorphan, wherein the humans are a high-metabolism group for dextromethorphan, and the methods include co-administration of dextromethorphan and bupropion to the humans.

[0037] Some embodiments include methods for inhibiting the metabolites of dextromethorphan, comprising administering bupropion to a human, where the human is a high-metabolite group of dextromethorphan, and dextromethorphan is present in the human body simultaneously with bupropion.

[0038] Some embodiments include methods for increasing the lifespan of dextromethorphan metabolites, comprising administering bupropion to a human being in need of treatment with dextromethorphan, the human being being a high-metabolite group of dextromethorphan, and dextromethorphan being present in the human body simultaneously with bupropion.

[0039] Some embodiments include methods for correcting high metabolites of dextromethorphan, including administering bupropion to a person in need.

[0040] Some embodiments include methods for improving the antitussive properties of dextromethorphan, which involve administering bupropion in combination with the administration of dextromethorphan to a person requiring treatment for a cough.

[0041] Some embodiments include a method for treating cough, which involves administering to a person in need a combination of bupropion or another active compound and dextromethorphan.

[0042] Some embodiments include a method for treating a neurological disorder, comprising administering to a person in need 1) dextromethorphan, or 2) bupropion and dextromethorphan, where 1) dextromethorphan, or 2) bupropion and dextromethorphan, is administered at least once daily for at least 8 days, at least 9 days, or at least 10 days.

[0043] Some embodiments include methods for treating neurological disorders, which involve administering to a person in need about 150 mg / day to about 300 mg / day of bupropion and about 15 mg / day to about 60 mg / day of dextromethorphan.

[0044] Some embodiments include methods for increasing dextromethorphan plasma concentrations in humans requiring treatment with dextromethorphan, wherein the humans are a high-metabolism group for dextromethorphan, and the methods include co-administration of hydroxybupropion or its prodrug with dextromethorphan to the humans.

[0045] Some embodiments include methods for increasing dextromethorphan plasma concentrations in humans requiring treatment with dextromethorphan, wherein the humans are a high-metabolism group for dextromethorphan, and the methods include co-administration of erythrohydroxybupropion or its prodrug with dextromethorphan to the humans.

[0046] Some embodiments include methods for increasing dextromethorphan plasma concentrations in humans requiring treatment with dextromethorphan, wherein the humans are a high-metabolism group for dextromethorphan, and the methods include co-administration of threohydroxybupropion or its prodrug with dextromethorphan to the humans.

[0047] Some embodiments include methods for inhibiting the metabolites of dextromethorphan, comprising administering bupropion to a human, where the human is a high-metabolite group of dextromethorphan, and dextromethorphan is present in the human body simultaneously with bupropion.

[0048] Some embodiments include methods for inhibiting the metabolites of dextromethorphan, comprising administering hydroxybupropion or its prodrug to a human, wherein the human is a high-metabolite group of dextromethorphan, and dextromethorphan is present in the human body simultaneously with hydroxybupropion.

[0049] Some embodiments include methods for inhibiting the metabolites of dextromethorphan, comprising administering erythrohydroxybupropion or its prodrug to a human, wherein the human is a high-metabolite group of dextromethorphan, and dextromethorphan is present in the human body simultaneously with erythrohydroxybupropion.

[0050] Some embodiments include methods for inhibiting the metabolites of dextromethorphan, comprising administering threohydroxybupropion or its prodrug to a human, wherein the human is a high-metabolite group of dextromethorphan, and dextromethorphan is present in the human body simultaneously with threohydroxybupropion.

[0051] Some embodiments include methods for increasing the metabolic lifespan of dextromethorphan, comprising administering hydroxybupropion or its prodrug to a person in need of treatment with dextromethorphan, where the person is a high-metabolism group for dextromethorphan, and dextromethorphan is present in the human body simultaneously with hydroxybupropion.

[0052] Some embodiments include methods for increasing the metabolic lifespan of dextromethorphan, comprising administering erythrohydroxybupropion or its prodrug to a person in need of treatment with dextromethorphan, wherein the person is a high-metabolism group for dextromethorphan, and dextromethorphan is present in the human body simultaneously with erythrohydroxybupropion.

[0053] Some embodiments include a method for increasing dextromethorphan plasma concentration, comprising co-administering bupropion and dextromethorphan to a person requiring treatment with dextromethorphan, wherein bupropion is administered on day 1 of at least two days (at least two days of co-administration) of co-administration of dextromethorphan and bupropion, and the increase in dextromethorphan plasma concentration occurs on day 1 of co-administration of bupropion and dextromethorphan compared to administration of the same amount of dextromethorphan without bupropion.

[0054] Some embodiments include a method for increasing dextromethorphan plasma concentration in a person requiring treatment with dextromethorphan, comprising co-administering hydroxybupropion or its prodrug and dextromethorphan, wherein hydroxybupropion or its prodrug is administered on the first day of at least two days of co-administration of dextromethorphan and hydroxybupropion or its prodrug, and the increase in dextromethorphan plasma concentration occurs on the first day of co-administration of hydroxybupropion or its prodrug and dextromethorphan compared to administration of the same amount of dextromethorphan without hydroxybupropion or its prodrug.

[0055] Some embodiments include a method for increasing dextromethorphan plasma concentration in a person requiring treatment with dextromethorphan, comprising co-administering erythrohydroxybupropion or its prodrug and dextromethorphan, wherein erythrohydroxybupropion or its prodrug is administered on the first day of at least two days of co-administration of dextromethorphan and hydroxybupropion or its prodrug, and the increase in dextromethorphan plasma concentration occurs on the first day of co-administration of erythrohydroxybupropion or its prodrug and dextromethorphan compared to administration of the same amount of dextromethorphan without erythrohydroxybupropion or its prodrug.

[0056] Some embodiments include a method for increasing dextromethorphan plasma concentration, comprising co-administering threohydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan, wherein threohydroxybupropion or its prodrug is administered on the first day of at least two days of co-administration of dextromethorphan and hydroxybupropion or its prodrug, and the increase in dextromethorphan plasma concentration occurs on the first day of co-administration of threohydroxybupropion or its prodrug and dextromethorphan compared to administration of the same amount of dextromethorphan without threohydroxybupropion or its prodrug.

[0057] Some embodiments include a method for increasing dextromethorphan plasma concentration in a person requiring treatment with dextromethorphan, comprising co-administering bupropion and dextromethorphan for at least 5 consecutive days, wherein on day 5, the dextromethorphan plasma concentration is higher than that achieved by administering the same amount of dextromethorphan for 5 consecutive days without bupropion.

[0058] Some embodiments include a method for increasing dextromethorphan plasma concentration in a person requiring treatment with dextromethorphan, comprising co-administering hydroxybupropion or its prodrug and dextromethorphan for at least 5 consecutive days, wherein on day 5, the dextromethorphan plasma concentration is higher than that achieved by administering the same amount of dextromethorphan for 5 consecutive days without hydroxybupropion or its prodrug.

[0059] Some embodiments include a method for increasing dextromethorphan plasma concentration in a person requiring treatment with dextromethorphan, comprising co-administering erythrohydroxybupropion or its prodrug and dextromethorphan for at least 5 consecutive days, wherein on day 5, the dextromethorphan plasma concentration is higher than that achieved by administering the same amount of dextromethorphan for 5 consecutive days without erythrohydroxybupropion or its prodrug.

[0060] Some embodiments include a method for increasing dextromethorphan plasma concentration in a person requiring treatment with dextromethorphan, comprising co-administering threohydroxybupropion or its prodrug and dextromethorphan for at least 5 consecutive days, wherein on day 5, the dextromethorphan plasma concentration is higher than that achieved by administering the same amount of dextromethorphan for 5 consecutive days without threohydroxybupropion or its prodrug.

[0061] Some embodiments include a method for increasing dextromethorphan plasma concentration in a person requiring treatment with dextromethorphan, comprising co-administering bupropion and dextromethorphan for at least six consecutive days, wherein on day 6, the dextromethorphan plasma concentration is higher than that achieved by administering the same amount of dextromethorphan for six consecutive days without bupropion.

[0062] Some embodiments include a method for increasing dextromethorphan plasma concentration in a person requiring treatment with dextromethorphan, comprising co-administering hydroxybupropion or its prodrug and dextromethorphan for at least 6 consecutive days, wherein on day 6, the dextromethorphan plasma concentration is higher than that achieved by administering the same amount of dextromethorphan for 6 consecutive days without hydroxybupropion or its prodrug.

[0063] Some embodiments include a method for increasing dextromethorphan plasma concentration in a person requiring treatment with dextromethorphan, comprising co-administering erythrohydroxybupropion or its prodrug and dextromethorphan for at least 6 consecutive days, wherein on day 6, the dextromethorphan plasma concentration is higher than that achieved by administering the same amount of dextromethorphan for 6 consecutive days without erythrohydroxybupropion or its prodrug.

[0064] Some embodiments include a method for increasing dextromethorphan plasma concentration in a person requiring treatment with dextromethorphan, comprising co-administering threohydroxybupropion or its prodrug and dextromethorphan for at least 6 consecutive days, wherein on day 6, the dextromethorphan plasma concentration is higher than that achieved by administering the same amount of dextromethorphan for 6 consecutive days without threohydroxybupropion or its prodrug.

[0065] Some embodiments include methods for reducing the trough effect of dextromethorphan, which involve co-administering bupropion with dextromethorphan to a person requiring treatment with dextromethorphan, such that the dextromethorphan has a plasma concentration 12 hours after co-administration of bupropion with dextromethorphan that is at least twice the plasma concentration achieved by administering the same amount of dextromethorphan without bupropion.

[0066] Some embodiments include methods for reducing the trough effect of dextromethorphan in human patients requiring treatment with dextromethorphan, comprising co-administering dextromethorphan with hydroxybupropion or its prodrug, wherein the plasma concentration of dextromethorphan 12 hours after co-administration of hydroxybupropion or its prodrug with dextromethorphan is at least twice the plasma concentration achieved by administration of the same amount of dextromethorphan without hydroxybupropion or its prodrug.

[0067] Some embodiments include methods for reducing the trough effect of dextromethorphan in human patients requiring treatment with dextromethorphan, comprising co-administering dextromethorphan with erythrohydroxybupropion or its prodrug, wherein the plasma concentration of dextromethorphan 12 hours after co-administration of erythrohydroxybupropion or its prodrug with dextromethorphan is at least twice the plasma concentration achieved by administration of the same amount of dextromethorphan without erythrohydroxybupropion or its prodrug.

[0068] Some embodiments include methods for reducing the trough effect of dextromethorphan in human patients requiring treatment with dextromethorphan, comprising co-administering dextromethorphan with threohydroxybupropion or its prodrug, wherein the plasma concentration of dextromethorphan 12 hours after co-administration of dextromethorphan with threohydroxybupropion or its prodrug is at least twice the plasma concentration achieved by administration of the same amount of dextromethorphan without threohydroxybupropion or its prodrug.

[0069] Some embodiments include methods for reducing adverse events associated with treatment with dextromethorphan, which involve co-administering bupropion and dextromethorphan to human patients who require dextromethorphan treatment, as human patients are at risk of experiencing adverse events such as those resulting from treatment with dextromethorphan.

[0070] Some embodiments include methods for reducing adverse events associated with treatment with dextromethorphan, which involve co-administering hydroxybupropion, or its prodrug, and dextromethorphan to human patients who require dextromethorphan treatment, as human patients are at risk of experiencing adverse events such as those resulting from treatment with dextromethorphan.

[0071] Some embodiments include methods for reducing adverse events associated with treatment with dextromethorphan, which involve co-administering erythrohydroxybupropion, or its prodrug, and dextromethorphan to human patients who require dextromethorphan treatment, as human patients are at risk of experiencing adverse events such as those resulting from treatment with dextromethorphan.

[0072] Some embodiments include methods for reducing adverse events associated with bupropion treatment, including co-administration of dextromethorphan and bupropion to human patients requiring bupropion treatment, where the human patients are at risk of experiencing the same adverse events as those resulting from bupropion treatment alone.

[0073] Some embodiments include methods for correcting high metabolites of dextromethorphan, and administering hydroxybupropion or its prodrugs to humans in need.

[0074] Some embodiments include methods for correcting high metabolites of dextromethorphan, and administering erythrohydroxybupropion or its prodrugs to humans in need.

[0075] Some embodiments include methods for correcting high metabolites of dextromethorphan, and administering threohydroxybupropion or its prodrugs to humans in need.

[0076] Some embodiments include methods for improving the cough-suppressant properties of dextromethorphan, which involve administering bupropion in combination with the administration of dextromethorphan to a person requiring treatment for a cough.

[0077] Some embodiments include methods for improving the cough-suppressant properties of dextromethorphan, which involve administering hydroxybupropion or a prodrug thereof in combination with the administration of dextromethorphan to a person in need of treatment for a cough.

[0078] Some embodiments include methods for improving the cough-suppressant properties of dextromethorphan, which involve administering erythrohydroxybupropion or a prodrug thereof in combination with the administration of dextromethorphan to a person in need of treatment for a cough.

[0079] Some embodiments include methods for improving the cough-suppressant properties of dextromethorphan, which involve administering threohydroxybupropion or a prodrug thereof in combination with the administration of dextromethorphan to a person in need of treatment for a cough.

[0080] Some embodiments include a method for treating a cough that involves administering hydroxybupropion, or a combination thereof with its prodrug and dextromethorphan, to a person in need.

[0081] Some embodiments include a method for treating a cough that involves administering erythrohydroxybupropion, or a combination thereof with dextromethorphan, to a person in need.

[0082] Some embodiments include a method for treating a cough that involves administering threohydroxybupropion, or a combination thereof with dextromethorphan, to a person in need.

[0083] Some embodiments include a method for treating a neurological disorder, comprising administering bupropion and dextromethorphan to a person in need, wherein bupropion and dextromethorphan are administered at least once daily for at least 8 days, at least 9 days, or at least 10 days.

[0084] Some embodiments include a method for treating a neurological disorder, comprising administering hydroxybupropion, or its prodrug and dextromethorphan, to a person in need, wherein bupropion and dextromethorphan are administered at least once daily for at least 8 days, at least 9 days, or at least 10 days.

[0085] Some embodiments include a method for treating a neurological disorder, comprising administering erythrohydroxybupropion, or its prodrug and dextromethorphan, to a person in need, wherein bupropion and dextromethorphan are administered at least once daily for at least 8 days, at least 9 days, or at least 10 days.

[0086] Some embodiments include a method for treating a neurological disorder, comprising administering threohydroxybupropion, or its prodrug and dextromethorphan, to a person in need, wherein threohydroxybupropion and dextromethorphan are administered at least once daily for at least 8 days, at least 9 days, or at least 10 days.

[0087] Some embodiments include a pharmaceutical composition, dosage form, or agent comprising a therapeutically effective amount of dextrotomethorphan, an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any prodrug of these compounds, and a pharmaceutically acceptable excipient.

[0088] Some embodiments include a method for reducing the risk of seizures associated with the use of bupropion to treat depression, comprising orally administering a dextromethorphan-bupropion combination twice daily, characterized in that, compared to orally administering 150 mg of bupropion alone to humans twice daily for the same number of days, 1) is effective in treating depression, and 2) reduces the risk of seizures in humans.

[0089] Some embodiments include a method to improve the therapeutic effect of bupropion in the treatment of depression, comprising co-administering dextromethorphan and bupropion orally twice daily to a person suffering from depression, characterized in that this method is more effective than treating the person's depression by orally administering 150 mg of bupropion alone twice daily for 5 weeks.

[0090] In some embodiments, the combination of dextromethorphan and bupropion is more effective than the oral administration of equal amounts of dextromethorphan or bupropion independently.

[0091] Some embodiments include methods for improving the efficacy of bupropion in the treatment of depression, comprising orally administering approximately 90 mg to approximately 125 g of bupropion in combination with approximately 0.3 mg / kg to approximately 1 mg / kg of dextromethorphan to a person suffering from depression once or twice daily for at least 23 days, characterized in that oral administration of bupropion in combination with dextromethorphan is more effective in the treatment of depression than oral administration of the same dose of bupropion without dextromethorphan.

[0092] Some embodiments include a method for treating treatment-resistant depression, comprising selecting a person suffering from depression for whom treatment with at least one antidepressant has been unsuccessful, and orally administering a dextromethorphan-bupropion combination therapy to the person once or twice daily for at least about five weeks, wherein the dextromethorphan-bupropion combination therapy comprises about 40 mg to about 70 mg of dextromethorphan and about 100 mg to about 140 mg of bupropion.

[0093] Some embodiments include a method for rapidly relieving symptoms of depression, comprising administering a combination of bupropion and dextromethorphan once or twice daily to a person in need, characterized in that the person feels the therapeutic effect within two weeks from the first day of administration of the bupropion and dextromethorphan combination.

[0094] Some embodiments include a method for treating depression, comprising administering a combination of bupropion and dextromethorphan once or twice daily to a person in need of treatment, characterized in that the person is of Asian descent.

[0095] Some embodiments include a method for treating nicotine addiction associated with tobacco smoking, comprising administering a combination of bupropion and dextromethorphan to a person suffering from nicotine addiction daily for at least 21 consecutive days, characterized in that the person is an ad-lib tobacco smoker, the person is administered a total dose of 200 mg to 250 mg of bupropion and 80 mg to 140 mg of dextromethorphan daily, and the method is more effective than administration of the same amount of bupropion alone.

[0096] In some embodiments, including the treatment of nicotine addiction, administration of a combination of bupropion and dextromethorphan results in a reduction of at least 20% greater in the intensity of nicotine self-administration compared to bupropion alone, as measured by a reduction in the average number of cigarettes smoked per day.

[0097] In some embodiments, including the treatment of nicotine addiction, administration of a combination of bupropion and dextromethorphan results in a reduction of at least 10% greater in exhaled carbon monoxide concentration compared to bupropion alone.

[0098] In some embodiments, including the treatment of nicotine addiction, administering the combination of bupropion and dextromethorphan twice daily in two equal doses results in a greater reduction in the intensity of nicotine self-administration at a specific point in time, such as one week, two weeks, three weeks, four weeks, or another point in time as described herein, than would have occurred by administering one of the two divided doses at the same time or by not administering the combination. [Brief explanation of the drawing]

[0099] [Figure 1] Figure 1 plots the mean plasma concentration of dextromethorphan over time after administration on day 8 to subjects receiving dextromethorphan alone or dextromethorphan and bupropion. [Figure 2]Figure 2 shows the mean AUC0-12 of dextromethorphan on day 8 for subjects treated with dextromethorphan alone or with dextromethorphan and bupropion. [Figure 3] Figure 3 shows the mean AUC0-24 of dextromethorphan on day 8 for subjects treated with dextromethorphan alone or with dextromethorphan and bupropion. [Figure 4] Figure 4 shows the mean AUC0-inf of dextromethorphan on day 8 for subjects treated with dextromethorphan alone or with dextromethorphan and bupropion. [Figure 5] Figure 5 shows the metric change in AUC of dextromethorphan on day 8 when administered to subjects with dextromethorphan alone compared to dextromethorphan and bupropion. [Figure 6] Figure 6 shows the mean AUC0-12 of dextromethorphan on days 1 and 8 for subjects treated with dextromethorphan alone or with dextromethorphan and bupropion. [Figure 7] Figure 7 shows the mean plasma concentration of dextromethorphan for administration of dextromethorphan alone or dextromethorphan and bupropion to the target population. [Figure 8] Figure 8 shows the mean maximum plasma concentrations of dextromethorphan on days 1 and 8 for patients treated with dextromethorphan alone or with dextromethorphan and bupropion. [Figure 9] Figure 9 shows a plot of mean plasma concentrations of dextromethorphan over time after day 8 administration for subjects receiving dextromethorphan alone or dextromethorphan and bupropion. [Figure 10] Figure 10 shows the mean maximum dextromethorphan plasma concentrations after administration on day 1 and day 8 for subjects receiving dextromethorphan alone or dextromethorphan and bupropion. [Figure 11]Figure 11 shows the mean AUC0-12 of dextromethorphan on days 1 and 8 for subjects treated with dextromethorphan alone or with dextromethorphan and bupropion. [Figure 12] Figure 12 shows the effects of various antidepressant compounds on inhibiting the metabolism of dextromethorphan in human liver microsomes. [Figure 13] Figure 13 is a time-course plot of the mean change in MADRS total score from baseline during a 6-week treatment period for subjects treated with bupropion alone or in combination with dextromethorphan and bupropion. [Figure 14] Figure 14 shows the percentage of subjects who achieved remission (MADRS ≤ 10) over a 6-week treatment period, either with bupropion alone or in combination with dextromethorphan. [Figure 15] Figure 15 is a plot showing the decrease in the total MADRS score over time for the subjects described in Example 6. [Figure 16] Figure 16 is a plot of the percentage of respondents over time for the subjects described in Example 6. [Figure 17] Figure 17 is a plot of the percentage of subjects in remission over time for the subjects described in Example 6. [Figure 18] Figure 18 is a plot of the change in the total MADRS score over time from baseline for the subjects described in Example 7. [Figure 19] Figure 19 is a plot of the change in the total QIDS-SR-16 score over time from baseline for the subjects described in Example 7. [Figure 20] Figure 20 is a time-course plot of the percentage of subjects in remission (QIDS-SR-16 score ≤ 5) among the subjects described in Example 7. [Figure 21] Figure 21 is a plot of the changes over time in cognitive items of the MGH-CPFQ from baseline for the subjects described in Example 7. [Figure 22] Figure 22 is a plot of the change in the total CMAI score over time from baseline for the subjects described in Example 8. [Figure 23] Figure 23 is a plot of the percentage decrease in CMAI from baseline over time for the subjects described in Example 8. [Figure 24] Figure 24 is a plot of the percentage of respondents who showed a CMAI decrease of ≥30% from baseline over time for the subjects described in Example 8. [Figure 25] Figure 25 shows the reduction from baseline in MADRS scores from a clinical trial of DM / BU in Example 10 compared to the combination of dextromethorphan and quinidine (DM / Q), as reported by Murrough (Journal of Affective Disorders 218(2017)277-283, Figure 3A). [Modes for carrying out the invention]

[0100] Some embodiments include a method for treating a neurological disorder, comprising administering to a person in need of treatment for the neurological disorder a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of these compounds.

[0101] Some embodiments include methods for enhancing the therapeutic properties of dextromethorphan in the treatment of neurological disorders, including co-administration of dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of these compounds.

[0102] Some embodiments include methods for increasing dextromethorphan plasma concentrations in humans who are high metabolites of dextromethorphan, and include co-administering dextromethorphan to humans with an antidepressant compound such as bupropion.

[0103] Some embodiments include methods for inhibiting the metabolites of dextromethorphan, comprising administering an antidepressant compound such as bupropion to a human, where the human is a high-metabolite group of dextromethorphan, and where dextromethorphan is present in the human body simultaneously with the antidepressant.

[0104] Some embodiments describe the emission half-life (T) of dextromethorphan. 1 / 2 The present invention includes methods for increasing the lifespan of dextromethorphan metabolites, including methods for increasing the amount of dextromethorphan present in the human body. These embodiments may include administering an antidepressant compound such as bupropion to a human, where the human is a high-metabolite group of dextromethorphan, and where dextromethorphan is present in the human body simultaneously with the antidepressant compound.

[0105] Some embodiments include methods for correcting high metabolites of dextromethorphan, which include administering an antidepressant compound such as bupropion to a person in need of such correction, such as a person in need of pain treatment.

[0106] Some embodiments include methods for improving the therapeutic properties of dextromethorphan in the treatment of neurological disorders, which include administering an antidepressant compound such as bupropion in combination with the administration of dextromethorphan to a person requiring treatment for a neurological disorder.

[0107] Some embodiments include methods for treating neurological disorders, which involve administering a combination of an antidepressant compound such as bupropion and dextromethorphan to a person in need of treatment for a neurological disorder.

[0108] Co-administration of dextromethorphan with an antidepressant compound such as bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a prodrug of an antidepressant compound occurs once or more consecutively for 1 day, or 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 days, or longer. In some embodiments, co-administration occurs at least daily for at least 2 consecutive days.

[0109] In some embodiments, co-administration of an antidepressant compound such as bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a prodrug of an antidepressant compound with dextromethorphan may be performed once daily for 1, 2, 3, 4, 5, 6, or 7 days prior to twice-daily co-administration.

[0110] Dextromethorphan includes the following structure: [ka]

[0111] Dextromethorphan is used as a cough suppressant. According to the FDA's labeling requirements for dextromethorphan products under the OTC monograph [21CFR341.74], dextromethorphan should be administered six times a day (every four hours), four times a day (every six hours), or three times a day (every eight hours). The OTC monograph [21CFR341.74] also states that "the dosage is equivalent to that of dextromethorphan hydrobromide...the oral dose should not exceed 10-20 milligrams every four hours, 30 milligrams every six- to eight hours, or 120 milligrams in 24 hours, or as directed by a physician."

[0112] Dextromethorphan is metabolized very rapidly in the human liver. This rapid hepatic metabolism can limit systemic drug exposure in individuals with high metabolism. Humans can be 1) high-metabolism dextromethorphan individuals—those who metabolize dextromethorphan very rapidly, 2) low-metabolism dextromethorphan individuals—those who metabolize dextromethorphan very little, or 3) intermediate-metabolism dextromethorphan individuals—those whose dextromethorphan metabolism falls somewhere between high-metabolism and low-metabolism groups. High-metabolism dextromethorphan individuals can also be hyperfast-metabolizing individuals. High-metabolism dextromethorphan individuals constitute a significant portion of the population. For example, dextromethorphan can be metabolized to dextrorphan.

[0113] When the same oral dose of dextromethorphan is administered, plasma concentrations of dextromethorphan are significantly higher in the low-metabolism or intermediate-metabolism groups compared to the high-metabolism group. Low plasma concentrations of dextromethorphan may limit the clinical utility of dextromethorphan as a monotherapy for the high-metabolism group, and possibly for intermediate metabolism. Therapeutic compounds, including several antidepressants such as bupropion, can inhibit the metabolism of dextromethorphan and increase its plasma concentration, thereby enhancing its therapeutic effect. Similarly, antidepressants may allow dextromethorphan to be administered at a lower frequency, such as once daily instead of twice daily, once daily instead of three daily, once daily instead of four daily, twice daily instead of three daily, or twice daily instead of four daily, without loss of therapeutic effect.

[0114] Co-administration of dextromethorphan or dextrorphan with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds may enhance the mechanism of action or pharmacological properties of dextromethorphan and dextrorphan. Possible mechanisms of action of dextromethorphan and dextrorphan include sigma-1 agonist and NMDA antagonist properties, calcium channel blockade, muscarinic binding, serotonin transporter (5HTT) inhibition, and mu receptor enhancement.

[0115] Some embodiments involve co-administration of dextromethorphan or dextrorphan for activating, antagonizing, or modulating sigma-1 receptors or NMDA receptors, blocking calcium channels, binding to muscarinic receptors, inhibiting serotonin transporters (5HTT), or enhancing mu receptors, with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds.

[0116] The pharmacological properties of dextromethorphan and dextrorphan may include high affinity for NMDA sites, NMDR-2A and functional NMDR-2B receptor antagonism, sigma-1 stimulation, putative mTOR activation (by sigma-1 stimulation, mu-enhancement, beta-adrenergic receptor stimulation, and 5HTT inhibition), putative AMPA receptor transport (by mTOR activation, PCP antagonism, sigma-1 stimulation, beta stimulation, mu-enhancement, and 5HTT inhibition), and neuronal survival through dendritic formation, spindle formation, synapse formation, NMDA antagonism, and sigma-1 and mTOR signaling. Some embodiments involve co-administration of dextromethorphan or dextrorphan for binding to, activating, antagonizing, stimulating, activating, inhibiting, affecting the transport of, or modulating an NMDA high-affinity site, NMDR-2A, functional NMDR-2B receptor, sigma-1 receptor, putative mTOR receptor (by sigma-1 stimulation, mu receptor enhancement, beta-adrenergic receptor stimulation, or 5HTT inhibition, etc.), or putative AMPA receptor (by mTOR activation, PCP activity antagonism, sigma-1 receptor stimulation, beta-adrenergic receptor stimulation, mu receptor enhancement, or 5HTT inhibition, etc.), and antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds. Some embodiments involve co-administration of dextromethorphan or dextrorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds to induce, increase, decrease, or modulate dendritic formation, spindle formation, or synapse formation.Some embodiments involve co-administration of dextromethorphan or dextrorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds to induce, increase, decrease, or modulate neuronal survival through NMDA antagonism and / or sigma-1 and / or mTOR signaling.

[0117] The pharmacological properties of dextromethorphan and dextrorphan may include inhibition of 5HTT and norepinephrine transporters, sigma-1 stimulation, NMDA and PCP antagonism, and stimulation of serotonin 5HT1b / d receptors, if present. Some embodiments involve co-administration of dextromethorphan or dextrorphan with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds, for binding to, activating, antagonizing, stimulating, activating, inhibiting, affecting or modulating the transport of, and / or serotonin 5HT1b / d receptors.

[0118] Further properties of dextromethorphan and dextrophan may include antagonistic or postsynaptic alpha-2 adrenergic receptor stimuli, postsynaptic alpha-2 stimuli, and possible muscarinic and muon antagonism, if present with presynaptic alpha-2 adrenergic receptors. Some embodiments involve co-administration of dextromethorphan or dextrorphan for binding to, activating, antagonizing, stimulating, activating, inhibiting, influencing the transport of, or modulating presynaptic alpha-2 adrenergic receptors, postsynaptic alpha-2 receptors, beta-adrenergic receptors, muscarinic receptors, or muon receptors with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds. Dextromethorphan and dextrorphan may be glial cell modulators. Some embodiments involve co-administration of dextromethorphan or dextrorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds for modulating glial cells.

[0119] Pain or other neurological disorders may be treated by increasing the plasma concentration of dextromethorphan or by increasing the bioavailability of dextromethorphan, for example, by administering a therapeutically effective dose of dextromethorphan and a therapeutically effective dose of an antidepressant compound such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds to a person in need of treatment for pain or other neurological disorders.

[0120] Examples of neurological disorders that can be treated or treated with increased efficacy by elevated dextromethorphan concentrations, such as those obtained by combining dextromethorphan with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds, include, but are not limited to, mood disorders, psychiatric disorders, brain dysfunction, motor disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[0121] Affective disorders that can be treated by increased dextromethorphan concentrations, or by combinations of dextromethorphan with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds, include, but are not limited to, depression, major depressive disorder, treatment-resistant depression and treatment-resistant bipolar depression, bipolar disorder including cyclothymic disorder, seasonal affective disorder, and mood disorders. Harm, including chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADDH), attention deficit / hyperactivity disorder (ADHD), bipolar disorder and manic episodes, obsessive-compulsive disorder, bulimia nervosa, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance intoxication or abuse, nicotine addiction, psychosexual dysfunction, pseudoinfluence, and emotional instability.

[0122] Depression can manifest through symptoms of depression. These symptoms may include mood swings, intense feelings of sadness, despair, impaired mental functioning, difficulty concentrating, 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, loss of appetite, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, pain, headaches, seizures, indigestion, and / or disturbances in the circadian rhythm of hormone secretion.

[0123] Some patients experience insufficient or no therapeutic effect even with drug therapy such as antidepressants. Treatment-resistant depression (TRD), or treatment-refractory depression, is a condition commonly associated with patients who have failed to treat with at least two different antidepressants. Part of the diagnosis of TRD is the failure to achieve sufficient therapeutic effect with adequate doses and duration of antidepressants in the current depressive episode, for example. TRD may be more difficult to treat due to co-occurring medical or psychological disorders such as drug / alcohol abuse or eating disorders, or because TRD is misdiagnosed. Some TRD patients have not responded adequately to one, two, three, or more attempts at appropriate antidepressant treatment, or have failed or not responded adequately to one, two, three, or more prior antidepressant treatments. In some embodiments, patients being treated for treatment-resistant depression have failed to treat with at least one, two, three, four, five, six, seven, eight, nine, ten, or more antidepressant treatments.

[0124] Therapeutic efficacy can be improved by treatment that enhances the bioavailability or plasma concentration of dextromethorphan, or by combining dextromethorphan with antidepressants (such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of these compounds), and is not limited to the following: Montgomery-Asberg Depression Rating Scale (MADRS), Life Enjoyment and Satisfaction Questionnaire Short Form, Functional Impairment Scale, Sheehan's Disorder Scale, Patient Assessment Adverse Event Inventory (PRISE), Columbia Suicide Severity Rating Scale (C-SSRS), Quick Depressive Symptom Scale - Self-Report (QIDS-SR), Clinical Global Impression (CGI) Scale, Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), Hamilton Depression Rating Scale 17-item version (HAM-D17), Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGF). ATRQ), Quick Depressive Symptom Scale (QIDS-SR16), Sheehan's Disorder Scale (SDS), Clinical Global Impression Severity (CGI-S), Clinical Global Impression Change (CGI-C), Euro Quality of Life 5-point 5-level (EQ-5D-5L), Patient Global Impression Change (PGIC), Generalized Anxiety Disorder 7-item (GAD-7), Clinical Global Impression Improvement (CGI-I), Sheehan's Disorder Scale (SDS), Quick Depressive Symptom Scale (QIDS-SR16SDS), Quick Depressive Impression Severity (CGI-S), Quick Depressive Impression Change (CGI-C), Quick Depressive Impression Change (EQ-5D-5L), Quick Depressive Impression Change (PGIC), Quick Depressive Impression Change (GAD-SR1 These include the S-SR16, Hamilton Anxiety Scale (HAM-A), Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), CPFQ-Cognitive Subscales (4-7 items), Brief Psychiatric Symptom Rating Scale (BPRS), etc., Number-Symptom Substitution Test (DSST), Ray Auditory Verbal Learning Task (RAVLT), Trailmaking Test (TMT), Stroop Color Naming Test (STROOP), Simple Reaction Time (SRT), Choice Reaction Time (CRT), etc.In some embodiments, treating a person with a combination of dextromethorphan and bupropion may improve (e.g., reduce) that 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%, and about 90-100% compared to baseline or placebo. In some embodiments, the improvement is compared to baseline. In some embodiments, the improvement is compared to placebo.

[0125] The combination of bupropion and dextromethorphan may produce rapid therapeutic effects, for example, within approximately one week, two weeks, three weeks, or four weeks after the start of treatment. Improvements in any of the assessments described herein, including but not limited to MADRS, Quality of Life Enjoyment and Satisfaction Questionnaire Short Form, Disability Assessment Questionnaire, PRISE, C-SSSR, QIDS-SR, CGI, CPFQ, HAM-D17, MGH ATRQ, CGI-S, CGI-C, EQ-5D-5L, PGIC, GAD-7, CGI-I, ADS, QIDS-SR16, HAM-A, CPFQ, CPFQ-Cognitive Subscales (items 4-7), BPRS, DSST, RAVLT, TMT, STROOP, SRT, CRT, etc., may be observed within these periods.

[0126] In some embodiments, the enhanced bioavailability of dextromethorphan, or the combination of dextromethorphan with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any of these compounds' metabolites or prodrugs, may begin within 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 6-8 hours, 8-12 hours, 12 hours, 1 day, 1-7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks.

[0127] Patients who may benefit from the treatments described herein include pediatric patients such as those under approximately 18 years of age, approximately 0–5 years, approximately 5–10 years, approximately 10–12 years, or approximately 12–18 years; adult patients such as those approximately 18–70 years, approximately 18–65 years, approximately 18–30 years, approximately 10–20 years, approximately 20–30 years, approximately 30–40 years, approximately 40–50 years, approximately 50–60 years, approximately 60–70 years, approximately 70–80 years, approximately 80–90 years, approximately 30–50 years, or approximately 50–65 years; elderly patients such as those over 65 years of age, 65–75 years, approximately 75–90 years, or over 90 years of age; and patients aged approximately 41 years or older.

[0128] In some embodiments, a person treated with the combination of dextromethorphan and bupropion for, for example, a type of depression, is of Asian descent or selected to be of Asian descent. In some embodiments, a person treated with the combination of dextromethorphan and bupropion for, for example, a type of depression, is of Japanese descent or selected to be of Japanese descent. In some embodiments, a person treated with the combination of dextromethorphan and bupropion for, for example, a type of depression, is of Korean descent or selected to be of Korean descent. In some embodiments, a person treated with the combination of dextromethorphan and bupropion for, for example, a type of depression, is of Chinese descent or selected to be Chinese descent. An individual's attribution as Asian, Chinese, Japanese, or Korean may be based on self-declaration by the individual. In these Asian patients, the combination of dextromethorphan and bupropion may be effective in treating depression that is not responsive to bupropion alone. This may be particularly important because Asian patients may have more severe depression than patients of other ethnic or cultural backgrounds.

[0129] In some embodiments, the human being may not have, or may be selected not to have, depressive episodes having psychotic or catatonic characteristics.

[0130] In some embodiments, the human being is selected to be free from or without bipolar disorder (type 1 or type 2) and mania, hypomania, or mixed episodes, including substance-induced (e.g., antidepressant-induced) mania.

[0131] In some embodiments, the human being may not have, or may not have, schizophrenia, schizoaffectiveness, or another psychotic disorder.

[0132] In some embodiments, the human being may or may not have a panic disorder with or without agoraphobia.

[0133] In some embodiments, the human being may or may not have obsessive-compulsive disorder.

[0134] In some embodiments, the human being is selected to not have or not have bulimia or anorexia nervosa.

[0135] In some embodiments, the human being may or may not have persistent neurocognitive impairment.

[0136] In some embodiments, the human being is selected to have not had an anxiety disorder in the six months prior to treatment.

[0137] In some embodiments, a person being treated with a combination of dextromethorphan and bupropion for, for example, a type of depression, is selected to have been diagnosed with or be diagnosed with major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) or Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Clinical Trials Version SCID-5-CT. In some embodiments, the person currently meets the DSM-5 criteria for MDD without psychotic features, based on SCID-5-CT.

[0138] In some embodiments, a person treated with the combination of dextromethorphan and bupropion is selected to have suffered or be suffering from a major depressive episode that lasted for a period of time of approximately 8 weeks to 24 months, approximately 1 to 6 months, approximately 6 to 12 months, approximately 1 to 2 years, at least approximately 1 week, at least approximately 2 weeks, at least approximately 3 weeks, at least approximately 4 weeks, at least approximately 6 weeks, at least approximately 2 months, at least approximately 3 months, at least approximately 4 months, at least approximately 6 months, at least approximately 9 months, at least approximately 1 year, at least approximately 18 months, at least approximately 2 years, approximately 1 to 12 weeks, approximately 3 to 6 months, approximately 6 to 9 months, approximately 9 to 12 months, approximately 12 to 18 months, approximately 18 to 24 months, approximately 2 to 4 years, approximately 4 to 6 years, approximately 6 to 10 years, approximately 10 to 20 years, or longer, for example, due to the type of depression.

[0139] In some embodiments, a person treated with the combination of dextromethorphan and bupropion has, or is selected to have, major depressive episodes comprising, for example, 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, and has at least about 20, at least about 20, at least about 30, or more major depressive episodes, for example, at least about 10, at least about 40, at least about 40, at least about 40, at least about 30, or more major depressive episodes, for example, at least about 15, at least about 15, at least about 40, at least about 40, at least about 30, or more. Having or having had approximately 1 to 100 or more lifetime depressive episodes, such as major depressive episodes, including at least approximately 40, at least approximately 50, at least approximately 60, at least approximately 70, at least approximately 80, at least approximately 90, at least approximately 100, approximately 1 to 5, approximately 5 to 10, approximately 10 to 20, approximately 20 to 30, approximately 30 to 40, approximately 40 to 50, approximately 50 to 60, approximately 60 to 70, approximately 70 to 80, approximately 80 to 90, approximately 90 to 100, or approximately 4 to 7 lifetime depressive episodes.

[0140] In some embodiments, for a type of depression, for example, treated with a combination of dextromethorphan and bupropion, the subject has or is selected to have an inadequate response to one or more prior antidepressant therapies, including prior antidepressant therapy in a current depressive episode (e.g., a current major depressive episode), such as 1, 2, 3, 4, 5 or more prior antidepressant therapies.

[0141] In some embodiments, a human subject treated with a combination of dextromethorphan and bupropion, for example for a type of depression, is selected to have received or be receiving background antidepressant therapy with, for example, a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI), or bupropion, at an appropriate dose for at least 8 weeks, and at a stable dose for at least 4 weeks prior to entering a double-blind treatment period. In some embodiments, the antidepressant therapy is continued in combination with treatment with the combination of bupropion and dextromethorphan.

[0142] In some embodiments, for example, a human subject treated with a combination of dextromethorphan and bupropion for a type of depression is or is selected to be male. In some embodiments, for example, a human subject treated with a combination of dextromethorphan and bupropion for a type of depression is or is selected to be female.

[0143] In some embodiments, for example for a type of depression, a human subject treated with a combination of dextromethorphan and bupropion has a body mass index of from about 18 to 40 kg / m 2 , about 18.5 kg / m 2 2, about 18.5 kg / m 2 or less, about 19 kg / m 2 , about 19 to 24.9 kg / m 2 , about 25 kg / m 2 , about 25 to 29 kg / m 2 , about 29 kg / m 2 , about 29 kg / m2 A larger amount, approximately 18-22 kg / m³ 2 , about 22~24kg / m 2 , about 24~26kg / m 2 , about 26~28kg / m 2 , about 28~30kg / m 2 , about 30~32kg / m 2 , about 32~34kg / m 2 , about 34~36kg / m 2 , about 36~38kg / m 2 , about 38~40kg / m 2 , about 18~26kg / m 2 , about 26~34kg / m 2 , or approximately 34-40 kg / m 2 The body mass index is, or is selected to be, of the specified value.

[0144] The MADRS is a scale used by clinicians to assess depressive symptoms in the past week. Participants rate 10 items, evaluating feelings of guilt, sadness, fatigue, pessimism, entrenched tension, suicidal thoughts, decreased sleep or appetite, restlessness, anxiety, weight loss, physical symptoms, difficulty concentrating, and lack of interest. Each item is scored out of 7 points. 0 indicates no symptoms, and 6 indicates the most severe symptoms.

[0145] In some embodiments, a person treated with the combination of dextromethorphan and bupropion has, or is selected to have, a MADRS score of at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 55, about 20-25, about 25-30, about 30-35, about 35-40, about 40-45, about 45-50, about 50-55, about 55-60, about 25-35, about 35-45, about 45-60, about 25-40, or about 40-60, for example, a type of depression.

[0146] In some embodiments, treatment with the combination of dextromethorphan and bupropion results in humans having a MADRS score reduced 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 50-60%, about 60-80%, about 80-90%, or about 90-100% compared to baseline or placebo. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0147] In some embodiments, treatment with a combination of dextromethorphan and bupropion resulted in humans having a blood count of less than 34, about 20-34, about 7-19, about 0-6, about 30 or less, about 26 or less, about 25 or less, about 20 or less, about 17 or less, about 14 or less, about 12 or less, about 10 or less, about 8 or less, about 6 or less, about 5 or less, about 4 or less, about 3 or less, about 2 or less, about 1 or less, about 0 or less, about 0.1-6, about 0.1-1, about 1-2, The results will have a MADRS score of approximately 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15-16, 16-17, 17-18, 18-19, 19-20, 18-20, 0.1-3, 3-6, 6-9, 9-12, 12-14, 12-15, or 15-20.

[0148] The MADRS-6 subscale is the sum of responses to six items from the 10 MADRS items, which are considered to represent the core symptoms of depression: reported sadness, apparent sadness, inner tension, fatigue, inability to feel, and pessimistic thoughts. The MADRS items not included in the MADRS-6 score are decreased sleep, decreased appetite, difficulty concentrating, and suicidal ideation. A higher MADRS score indicates more severe depression, with each item scored from 0 to 6. The overall score ranges from 0 to 60. The questionnaire items are questions about the following symptoms: 1. apparent sadness, 2. reported sadness, 3. inner tension, 4. decreased sleep, 5. decreased appetite, 6. difficulty concentrating, 7. fatigue, 8. inability to feel, 9. pessimistic thoughts, and 10. suicidal ideation. The usual cutoff points are: a) 0-6: normal / asymptomatic, b) 7-19: mild depression, c) 20-34: moderate depression, d) 34 or above: severe depression.

[0149] In some embodiments, a person treated with the combination of dextromethorphan and bupropion has, or is selected to have, a MADRS-6 score of at least about 15, at least about 18, at least about 20, at least about 21, at least about 24, at least about 27, at least about 30, at least about 33, about 15-18, about 18-21, about 21-24, about 24-27, about 27-30, about 30-33, about 30-34, about 33-36, at least about 34, about 7-19, about 15-19, about 15-24, about 24-30, about 20-34, or about 30-36 prior to the initiation of treatment, for example, for a type of depression.

[0150] In some embodiments, treatment with the combination of dextromethorphan and bupropion results in humans having a MADRS-6 score reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-80%, about 80-90%, or about 90-100%, compared to baseline or placebo. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0151] In some embodiments, treatment with a combination of dextromethorphan and bupropion results in humans having a MADRS-6 score of approximately 17 or less, approximately 15 or less, approximately 10 or less, approximately 8 or less, approximately 6 or less, approximately 5 or less, approximately 4 or less, approximately 3 or less, approximately 2 or less, approximately 1 or less, approximately 0.1 to 6, approximately 0.1 to 1, approximately 1 to 2, approximately 2 to 3, approximately 3 to 4, approximately 4 to 5, approximately 5 to 6, approximately 6 to 7, approximately 7 to 8, approximately 8 to 9, approximately 9 to 12, approximately 12 to 15, approximately 0.1 to 3, approximately 3 to 6, approximately 6 to 8, approximately 6 to 9, or approximately 9 to 15.

[0152] In some embodiments, for example, a person being treated with a combination of dextromethorphan and bupropion for a type of depression, has, or is selected to have, a score of 2, 4, or 6 on item 1 (obvious sadness) on the MADRS before initiating treatment.

[0153] In some embodiments, treatment with the combination of dextromethorphan and bupropion results in a reduction of at least approximately 10%, at least approximately 20%, at least approximately 30%, at least approximately 40%, or at least approximately 50% in the score of item 1 of the MADRS compared to baseline or placebo. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0154] In some embodiments, treatment with a combination of dextromethorphan and bupropion results in a score of approximately 2 or less on item 1 of the MADRS in humans.

[0155] The therapeutic effect can be evaluated at any appropriate time, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, the end of week 1, the beginning or end of week 2, the beginning or end of week 3, the beginning or end of week 4, the beginning or end of week 5, the beginning or end of week 6, the beginning or end of week 7, the beginning or end of week 8, the beginning or end of week 9, the beginning or end of week 10, the beginning or end of week 11, the beginning or end of week 12, the beginning or end of week 13, the beginning or end of week 14, the beginning or end of week 15, the beginning or end of week 16, or any other point in time. In some embodiments, the therapeutic effect is evaluated weekly using MADRS.

[0156] The CGI-S scale is a clinician-administered scale used to assess the severity of a subject's current mental illness status compared to a target population with MDD. Subjects are evaluated on a scale from 1 to 7, where 1 indicates "normal state" and 7 indicates "among the most severely ill subjects." The CGI-S can be administered by individuals with extensive professional training and experience in mental illness assessment. Possible evaluations include: 1) normal, no illness at all, 2) borderline psychotic state, 3) mild illness, 4) moderate illness, 5) marked illness, 6) severe illness, and 7) among the most severely ill patients.

[0157] In some embodiments, for example, a person treated with the combination of dextromethorphan and bupropion for a type of depression has, or is selected to have, a Clinical Global Severity-S (CGI-S) score of at least about 3, at least about 4, at least about 5, at least about 6, about 7, about 3-7, about 4-7, about 3-4, about 4-5, about 5-6, or about 6-7.

[0158] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction of CGI-S scores of at least approximately 10%, at least approximately 20%, at least approximately 30%, at least approximately 40%, or at least approximately 50% in humans compared to baseline or placebo. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0159] In some embodiments, administration of a combination of dextromethorphan and bupropion results in humans exhibiting a reduction in the CGI-S score of at least approximately 1, at least approximately 2, at least approximately 3, at least approximately 4, at least approximately 5, approximately 0.1 to approximately 6, approximately 0.1 to approximately 1, approximately 1 to approximately 2, approximately 3 to approximately 3, approximately 4 to approximately 5, approximately 5 to approximately 6, approximately 0.1 to approximately 3, or approximately 3 to approximately 6. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0160] The therapeutic effect can be evaluated at any appropriate time, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-6, weeks 2-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, the start or end of week 1, the start or end of week 2, the start or end of week 3, the start or end of week 4, the start or end of week 5, the start or end of week 6, the start or end of week 7, the start or end of week 8, the start or end of week 9, the start or end of week 10, the start or end of week 11, the start or end of week 12, the start or end of week 13, the start or end of week 14, the start or end of week 15, the start or end of week 16, or any other point in time.

[0161] The 16-item QID-SR-16 patient assessment scale is a shortened version of the 30-item Depressive Symptom Scale (IDS) and is designed to assess the severity of depressive symptoms. The QID-SR-16 assesses the symptom domains that serve as criteria for diagnosing a major depressive episode.

[0162] The QID-SR can be used to assess a subject's depressive symptoms over the past seven days. Subjects report the severity of symptoms on 10 items: sleep, feelings of sadness, appetite, weight change, concentration, self-esteem, suicidal tendencies, general interest levels, energy levels, psychomotor lag, and restlessness. Each item is rated on a 4-point scale, with 0 representing no symptoms and 3 representing the maximum severity of symptoms.

[0163] The total QIDS score ranges from 0 to 27 points. A score of 5 or less indicates no depression, 6 to 10 indicates mild depression, 11 to 15 indicates moderate depression, 16 to 20 indicates severe depression, and a total score of 21 or more indicates very severe depression.

[0164] In some embodiments, for example, a person being treated with a combination of dextromethorphan and bupropion for a type of depression has, or is selected to have, a QID-SR-16 score of at least about 16, at least about 18, at least about 21, at least about 24, at least about 27, at least about 30, at least about 33, about 16-18, about 16-19, about 16-20, about 18-21, about 21-24, about 24-27, about 15-21, or about 21-27 before initiating treatment.

[0165] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction of QID-SR-16 score by at least approximately 10%, at least approximately 20%, at least approximately 30%, at least approximately 40%, or at least approximately 50% compared to baseline or placebo. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0166] In some embodiments, treatment with a combination of dextromethorphan and bupropion results in humans having QID-SR-16 scores of approximately 6 or less, approximately 5 or less, approximately 4 or less, approximately 3 or less, approximately 2 or less, approximately 1 or less, approximately 0.1 to 6, approximately 0.1 to 5, approximately 0.1 to 1, approximately 1 to 2, approximately 2 to 3, approximately 3 to 4, approximately 4 to 5, approximately 5 to 6, approximately 0.1 to 3, or approximately 3 to 6. The therapeutic effect can be evaluated at any appropriate time, for example, weeks 1-2, weeks 1-3, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, the start or end of week 1, the start or end of week 2, the start or end of week 3, the start or end of week 4, the start or end of week 5, the start or end of week 6, the start or end of week 7, the start or end of week 8, the start or end of week 9, the start or end of week 10, the start or end of week 11, the start or end of week 12, the start or end of week 13, the start or end of week 14, the start or end of week 15, the start or end of week 16, or at any other time.

[0167] The CGI-I is a clinician-administered scale used to assess the sum of improvement or worsening of mental illness, regardless of whether the principal investigator considers it to be a result of drug treatment. Participants are evaluated on a scale from 1 to 7, where 1 indicates significant improvement and 7 indicates significant deterioration. The CGI-I should be administered by individuals with extensive professional training and experience in assessing mental illness.

[0168] In some embodiments, treatment with a combination of dextromethorphan and bupropion results in humans having a CGI-I score of approximately 3 or less, approximately 2 or less, approximately 1, approximately 1-2, or approximately 2-3.

[0169] The therapeutic effect can be evaluated at any appropriate time, for example, weeks 1-2, weeks 1-3, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, the start or end of week 1, the start or end of week 2, the start or end of week 3, the start or end of week 4, the start or end of week 5, the start or end of week 6, the start or end of week 7, the start or end of week 8, the start or end of week 9, the start or end of week 10, the start or end of week 11, the start or end of week 12, the start or end of week 13, the start or end of week 14, the start or end of week 15, the start or end of week 16, or at any other time.

[0170] The VAMS is a patient-assessed mood scale consisting of a 100mm line, where the extremes of mood, such as happiness and sadness, are represented graphically, diagrammatically, or pictorially, such as a sad face and a happy face. The ends of the line may also be further fixed with words representing the opposite extremes of mood. Participants are asked to rate their mood as marks on the line. The distance on the line is measured and calculated as a numerical value between 0 and 100. Participants may be asked to complete the VAMS daily.

[0171] In some embodiments, for example, for a type of depression, a person treated with a combination of dextromethorphan and bupropion is selected to have, or to have, a VAMS score of at least about 40 mm, at least about 50 mm, at least about 60 mm, at least about 70 mm, at least about 80 mm, at least about 90 mm, about 40-50 mm, about 50-60 mm, about 60-70 mm, about 70-80 mm, about 80-90 mm, about 90-100 mm, about 40-60 mm, about 60-80 mm, or about 80-100 mm.

[0172] In some embodiments, administration of the combination of dextromethorphan and bupropion results in humans having at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% reduction in the VAMS score compared to baseline or placebo. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0173] In some embodiments, treatment with a combination of dextromethorphan and bupropion results in humans having VAMS scores of approximately 50 mm, 40 mm, 30 mm, 20 mm, 10 mm, 0-10 mm, 10-20 mm, 20-30 mm, 30-40 mm, 40-50 mm, 0-25 mm, or 25-50 mm.

[0174] The therapeutic effect can be evaluated at any appropriate time, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, the start or end of week 1, the start or end of week 2, the start or end of week 3, the start or end of week 4, the start or end of week 5, the start or end of week 6, the start or end of week 7, the start or end of week 8, the start or end of week 9, the start or end of week 10, the start or end of week 11, the start or end of week 12, the start or end of week 13, the start or end of week 14, the start or end of week 15, the start or end of week 16, or at any other time.

[0175] The Columbia Suicide Severity Rating Scale (C-SSRS) is a clinician assessment scale that reports the severity of suicidal ideation and suicidal behavior. Suicidal ideation is classified into five categories: 1 (desire to die), 2 (vague, active suicidal ideation), 3 (active suicidal ideation with an idea of ​​how to commit suicide (but no plan), but no intention to carry it out), 4 (active suicidal ideation with some intention to carry it out, but no concrete plan), and 5 (active suicidal ideation with a concrete plan and intention to carry it out). The C-SSRS also collects information on the intensity of ideas, including frequency, duration, controllability, deterrent effect, and reasons for the most severe type of ideation. Suicidal behavior is classified into five categories: 0 (no suicidal behavior), 1 (preparatory behavior or action), 2 (interrupted suicide attempt), 3 (interrupted suicide attempt), and 4 (actual suicide attempt). Multiple classifications can be selected if they represent separate episodes. For actual suicide attempts only, the actual lethality or potential lethality is classified for the first attempt, the most fatal attempt, and the most recent attempt.

[0176] The C-SSRS may be administered each time the person receiving treatment meets with a healthcare professional. The C-SSRS may include a complete life history of the subject's suicidal thoughts and behaviors, chronologically aligned with the most recent period of recollection.

[0177] In some embodiments, administration of the combination of dextromethorphan and bupropion results in humans having a reduction of at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% in their Columbia Suicide Severity Scale (C-SSRS) score compared to baseline or placebo. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0178] The therapeutic effect can be evaluated at any appropriate time, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, the start or end of week 1, the start or end of week 2, the start or end of week 3, the start or end of week 4, the start or end of week 5, the start or end of week 6, the start or end of week 7, the start or end of week 8, the start or end of week 9, the start or end of week 10, the start or end of week 11, the start or end of week 12, the start or end of week 13, the start or end of week 14, the start or end of week 15, the start or end of week 16, or at any other time.

[0179] The Sheehan's Disability Scale (SDS) is a self-assessment tool used to measure the impact of a patient's symptoms on three areas: work / school, social life, and family / home responsibilities. Each of the three items has a score ranging from 0 to 10. The number that best represents the degree to which each area is disrupted by symptoms is marked on a line from 0 (not at all) to 10 (very much). Adding the scores of each of the three items or areas results in a global SDS score ranging from 0 (no disability) to 30 (severe disability), allowing for an aggregated assessment of global functional impairment across the three items or areas.

[0180] In some embodiments, for example, for a type of depression, a person treated with the combination of dextromethorphan and bupropion has, or is selected to have, a Sheehan's Disorder Scale (SDS) score of at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9 for each item of the SDS (0-10 scale), and at least about 5, at least 10, at least about 20, about 10-15, about 15-20, about 20-25, or about 25-30 for the total SDS score.

[0181] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction of SDS score of at least approximately 10%, at least approximately 20%, at least approximately 30%, at least approximately 40%, or at least approximately 50% in humans compared to baseline or placebo. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0182] The therapeutic effect can be evaluated at any appropriate time, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, the start or end of week 1, the start or end of week 2, the start or end of week 3, the start or end of week 4, the start or end of week 5, the start or end of week 6, the start or end of week 7, the start or end of week 8, the start or end of week 9, the start or end of week 10, the start or end of week 11, the start or end of week 12, the start or end of week 13, the start or end of week 14, the start or end of week 15, the start or end of week 16, or at any other time.

[0183] The Hamilton Depression Rating Scale (HAM-D, HRSD, HDRS, HAMD-17) is a clinician-administered scale consisting of 17 items used to assess a person's depressive state based on the degree of depression, guilt, suicidal tendencies, anxiety, agitation, level of insight, insomnia patterns, loss of interest in work and other activities, weight loss, hypochondria, and psychomotor retardation. It can also be used to check for genital and physical symptoms. Items are rated on a 0-2 or 0-4 scale. Higher scores indicate greater severity. For example, a HAM-D score of 10-13 for depression is understood as mild, 14-17 as mild to moderate, and >17 as moderate to severe.

[0184] In some embodiments, for example, a person to be treated with the combination of dextromethorphan and bupropion for a type of depression has, or is selected to have, a HAM-D score of at least about 16, at least about 19, at least about 21, at least about 24, at least about 27, at least about 30, at least about 33, at least about 36, about 16-19, about 18-21, about 21-24, about 24-27, about 27-30, about 30-33, about 33-36, about 36-40, about 15-24, about 24-33, or about 33-40, or greater than 40, prior to initiating treatment.

[0185] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction of at least approximately 10%, at least approximately 20%, at least approximately 30%, at least approximately 40%, or at least approximately 50% in HAM-D scores compared to baseline or placebo. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0186] The therapeutic effect can be evaluated at any appropriate time, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, the start or end of week 1, the start or end of week 2, the start or end of week 3, the start or end of week 4, the start or end of week 5, the start or end of week 6, the start or end of week 7, the start or end of week 8, the start or end of week 9, the start or end of week 10, the start or end of week 11, the start or end of week 12, the start or end of week 13, the start or end of week 14, the start or end of week 15, the start or end of week 16, or at any other time. In some embodiments, the therapeutic effect is evaluated weekly using HAM-D.

[0187] The conversion from MADRS scores to HAM-D scores, or vice versa, can be performed using the table below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0188] The Hamilton Anxiety Scale (HAM-A) is a clinician-administered scale consisting of 14 items, each rated on a 5-point scale from 0 (no anxiety) to 4 (very anxious). The highest possible total score is 56, representing the most severe anxiety, while the lowest possible score is 0, representing no anxiety.

[0189] In some embodiments, for example, for a type of depression, a person treated with the combination of dextromethorphan and bupropion has, or is selected to have, a Hamilton Anxiety Scale (HAM-A) score of at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 55, about 20-25, about 25-30, about 30-35, about 35-40, about 40-45, about 45-50, about 50-56, about 25-35, about 35-45, about 45-56, about 25-40, or about 40-56.

[0190] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction of at least approximately 10%, at least approximately 20%, at least approximately 30%, at least approximately 40%, or at least approximately 50% in HAM-A scores compared to baseline or placebo. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0191] The therapeutic effect can be evaluated at any appropriate time, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, the start or end of week 1, the start or end of week 2, the start or end of week 3, the start or end of week 4, the start or end of week 5, the start or end of week 6, the start or end of week 7, the start or end of week 8, the start or end of week 9, the start or end of week 10, the start or end of week 11, the start or end of week 12, the start or end of week 13, the start or end of week 14, the start or end of week 15, the start or end of week 16, or at any other time.

[0192] The Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) is a seven-item patient-assessed scale used to measure cognitive and executive function impairments in mood and anxiety disorders. It was developed to assess clinically relevant cognitive and physical symptoms that may appear or persist during long-term treatment for depression. Participants rate the perceived quality of their own physical and cognitive functioning. The CPFQ assesses seven items individually: motivation / enthusiasm, arousal / attention, energy, focus / attention, recall, word-finding ability, and sharpness / quick thinking, with scores ranging from 1 to 6, increasing in severity. The physical aspect of the CPFQ assesses sleepiness and fatigue, while the cognitive aspect assesses apathy, inattention, forgetfulness, word-finding difficulty, and mental lag. Higher scores indicate a greater degree of impairment.

[0193] In some embodiments, administration of a combination of dextromethorphan and bupropion results in a reduction of at least approximately 10%, at least approximately 20%, at least approximately 30%, at least approximately 40%, or at least approximately 50% in CPFQ scores compared to baseline or placebo. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0194] In some embodiments, administration of a combination of dextromethorphan and bupropion results in a reduction of at least approximately 10%, at least approximately 20%, at least approximately 30%, at least approximately 40%, or at least approximately 50% in CPFQ-cognitive subscale (4-7 items) scores compared to baseline or placebo. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0195] The therapeutic effect can be evaluated at any appropriate time, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, the start or end of week 1, the start or end of week 2, the start or end of week 3, the start or end of week 4, the start or end of week 5, the start or end of week 6, the start or end of week 7, the start or end of week 8, the start or end of week 9, the start or end of week 10, the start or end of week 11, the start or end of week 12, the start or end of week 13, the start or end of week 14, the start or end of week 15, the start or end of week 16, or at any other time.

[0196] The Brief Psychiatric Symptom Rating Scale (BPRS) is a clinician-administered scale developed to measure psychiatric symptoms such as depression, anxiety, hallucinations, and abnormal behavior. Each symptom is rated on a scale from 1 (absent) to 7 (very severe). If an item is not rated, a value of 0 is entered and it is excluded from the analysis. This scale should be administered by a clinician who is familiar with psychotic disorders and can interpret the constructs used in the assessment. The items in Factor I (reality distortion) are suspicion, hallucinatory behavior, and abnormal thought content.

[0197] In some embodiments, for example, for a type of depression, a person treated with a combination of dextromethorphan and bupropion has, or is selected to have, a baseline score of at least about 3, at least about 4, at least about 5, at least about 6, about 7, about 3–7, about 4–7, about 4–5, about 5–6, or about 6–7 on the Brief Psychiatric Rating Scale-Factor I score.

[0198] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a decrease in the BPRS-Factor I score of at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, about 0.1 to about 6, about 0.1 to about 1, about 1 to 2, about 2 to 3, about 3 to about 4, about 4 to about 5, about 5 to about 6, about 0.1 to 3, or about 3 to 6 compared to baseline or placebo. In some embodiments, the decrease is compared to baseline. In some embodiments, the decrease is compared to placebo.

[0199] The therapeutic effect can be evaluated at any appropriate time, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, the start or end of week 1, the start or end of week 2, the start or end of week 3, the start or end of week 4, the start or end of week 5, the start or end of week 6, the start or end of week 7, the start or end of week 8, the start or end of week 9, the start or end of week 10, the start or end of week 11, the start or end of week 12, the start or end of week 13, the start or end of week 14, the start or end of week 15, the start or end of week 16, or at any other time.

[0200] In some embodiments, for example, for a type of depression, a person treated with the combination of dextromethorphan and bupropion has, or is selected to have, a Beck Depression Inventory (BDI) score of at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 55, at least about 60, about 20-25, about 25-30, about 30-35, about 35-40, about 40-45, about 45-50, about 50-55, about 55-60, about 60-63, about 25-35, about 35-45, about 45-55, about 55-63, about 25-40, or about 40-63.

[0201] The Beck Depression Inventory (BDI, BDI-1A, BDI-II) is a 21-question, multiple-choice self-report questionnaire about how individuals have felt in the past week. Each question has four possible responses ranging in intensity. When the test is scored, each response is assigned a value from 0 to 3, and the total score is compared to the explanation to determine the severity of depression. A higher total score indicates more severe depressive symptoms. The standard cutoff scores are as follows: 0-9: very mild depression, 10-18: mild depression, 19-29: moderate depression, 30-63: severe depression.

[0202] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction of at least approximately 10%, at least approximately 20%, at least approximately 30%, at least approximately 40%, or at least approximately 50% in the BDI score compared to baseline or placebo. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0203] The therapeutic effect can be evaluated at any appropriate time, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, the start or end of week 1, the start or end of week 2, the start or end of week 3, the start or end of week 4, the start or end of week 5, the start or end of week 6, the start or end of week 7, the start or end of week 8, the start or end of week 9, the start or end of week 10, the start or end of week 11, the start or end of week 12, the start or end of week 13, the start or end of week 14, the start or end of week 15, the start or end of week 16, or at any other time.

[0204] In some embodiments, for example, for a type of depression, a person treated with a combination of dextromethorphan and bupropion has, or is selected to have, a C-reactive protein (CRP) level of at least 0.5 mg / L, at least 1 mg / L, at least 2 mg / L, or higher.

[0205] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction of CRP levels of at least approximately 10%, at least approximately 20%, at least approximately 30%, at least approximately 40%, or at least approximately 50% in humans compared to baseline or placebo. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0206] The therapeutic effect can be evaluated at any appropriate time, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, the start or end of week 1, the start or end of week 2, the start or end of week 3, the start or end of week 4, the start or end of week 5, the start or end of week 6, the start or end of week 7, the start or end of week 8, the start or end of week 9, the start or end of week 10, the start or end of week 11, the start or end of week 12, the start or end of week 13, the start or end of week 14, the start or end of week 15, the start or end of week 16, or at any other time.

[0207] The conversion between the scores of the above evaluations can be performed according to the table below. [Table 2-1] [Table 2-2] [Table 2-3] [Table 3-1] [Table 3-2] [Table 4-1] [Table 4-2] [Table 5-1] [Table 5-2] [Table 5-3]

[0208] In some embodiments, the combination of dextromethorphan and bupropion is a novel oral NMDA receptor antagonist with multimodal activity for the treatment of central nervous system (CNS) disorders. Dextromethorphan is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, also known as a glutamate receptor modulator, and is a novel drug that acts through a mechanism of action different from that of currently available antidepressants.

[0209] Dextromethorphan is also a sigma-1 receptor agonist, a nicotinic acetylcholine receptor antagonist, and an inhibitor of serotonin and norepinephrine transporters. Bupropion can increase the bioavailability of dextromethorphan, and is a norepinephrine and dopamine reuptake inhibitor, as well as a nicotinic acetylcholine receptor antagonist. Both dextromethorphan and bupropion are nicotinic acetylcholine receptor antagonists, and share a mechanism associated with nicotine dependence. Therefore, the combination of dextromethorphan and bupropion may provide a novel mechanism of action for smoking cessation treatment.

[0210] In some embodiments, the combination of dextromethorphan and bupropion may be used for treating nicotine addiction. In some embodiments, the combination of dextromethorphan and bupropion may be administered to a human once or twice daily. In some embodiments, the combination of dextromethorphan and bupropion may be administered to a human twice daily. In some embodiments, the combination of dextromethorphan and bupropion may be administered to a human once or twice daily 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 to 12 months, about 1 year, about 2 years, or longer. In some embodiments, the combination of dextromethorphan and bupropion may be administered to a human twice daily for at least 1 week, at least 2 weeks, at least 3 weeks, or longer.

[0211] In some embodiments, the smoker may be an ad-lib smoker, or may be selected as being an ad-lib smoker. In some embodiments, prior to administration of the combination of dextromethorphan and bupropion, the smoker may, on average per day, for example, smoke about 10, about 10 to 15, about 10 to 17, about 10 to 20, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 20 to 25, about 25 to 30, about 30 to 40, about 40 to 50, or more cigarettes, or may be selected to smoke such a number of cigarettes.

[0212] In some embodiments, a combination of dextromethorphan and bupropion can 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 55 mg, about 65 mg, about 75 mg, about 85 mg, or about 95 mg of dextromethorphan in free base form or salt form. In some embodiments, the dextromethorphan is in the form of an HBr salt.

[0213] In some embodiments, a combination of dextromethorphan and bupropion may be used to treat nicotine addiction, with dosages of approximately 100-200 mg, approximately 100-150 mg, approximately 150-200 mg, approximately 100-110 mg, approximately 110-120 mg, approximately 120-130 mg, approximately 130-140 mg, approximately 140-150 mg, approximately 150- It contains 160 mg, approximately 160-170 mg, approximately 170-180 mg, approximately 180-190 mg, approximately 190-200 mg, approximately 105 mg, approximately 115 mg, approximately 125 mg, approximately 135 mg, approximately 145 mg, approximately 150 mg, approximately 155-165 mg, approximately 165-175 mg, approximately 175-185 mg, or approximately 185-195 mg of bupropion, either in free radical form or salt form. In some embodiments, bupropion is in the form of an HCl salt.

[0214] In some embodiments, administration of a combination of dextromethorphan and bupropion to humans results in a reduction of smoking intensity, measured using the number of cigarettes smoked per day, as assessed through a daily smoking diary.

[0215] Treatment of humans with the combination of dextromethorphan and bupropion reduces the average number of cigarettes smoked per day by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, approximately 5-10%, approximately 10-15%, approximately 15-20%, approximately 20-25%, approximately 25-30%, approximately 10-20%, approximately 20-30%, approximately 30-40%, approximately 40-50%, approximately 50-60%, approximately 60-80%, approximately 80-100%, approximately 20%, approximately 25%, approximately 30%, or approximately 50% compared to bupropion alone, over periods of, for example, 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.

[0216] Human treatment with the combination of dextromethorphan and bupropion results in an 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.

[0217] Treatment of humans with the combination of dextromethorphan and bupropion increases the proportion of smokers who experience a 50% or greater reduction in exhaled carbon monoxide levels, a biochemical marker of smoking intensity, compared to those treated with bupropion alone, by, for example, 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%, approximately 35%, approximately 50%, approximately 60%, approximately 60-80%, approximately 80-90%, and approximately 90-100%.

[0218] Treatment of humans with the combination of dextromethorphan and bupropion resulted in a reduction of at least one cigarette, or about one to two cigarettes, on the day of administration, and at least one cigarette, at least two, about one to two, or about two to three cigarettes, on the following day, compared to those who did not receive either or both of the combination.

[0219] Human smoking cessation treatment using a combination of dextromethorphan and bupropion yielded results where the magnitude of improvement compared to bupropion alone was comparable to the improvement reported to placebo for varenicline, an approved smoking cessation medication, in trials of a similar design.

[0220] In some embodiments, the bioavailability of dextromethorphan, or combinations of dextromethorphan with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of these compounds, may be used as adjunctive therapy for the treatment of any condition described herein, including TRD. For example, adjunctive therapy may be used in combination with another antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarbazide, tranylcypromine, paroxetine. Examples include trazodone, citalopram, sertraline, aliloxyindanamine, benactidine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensin, brasofensin, moclobemide, rasaziline, niramide, iproniazid, iproclozid, troxatone, butriptyline, dosulepin, dibenzepine, iprendol, lofepramine, opopiramol, norfluoxetine, dapoxetine, ketamine, or metabolites or prodrugs of these compounds, or pharmaceutically acceptable salts of these compounds.

[0221] In some embodiments, TRD may be treated by enhancing the bioavailability or plasma concentration of dextromethorphan, or by a combination of dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any of these metabolites or prodrugs, resulting 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 other reductions within any of these ranges.

[0222] Mental disorders that can be treated by elevated plasma concentrations of dextromethorphan, such as those obtained by combination of dextromethorphan with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds, include, but are not limited to, anxiety disorders including, 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, schizotypal tendencies, aggression, aggression in Alzheimer's disease, restlessness, and restlessness in Alzheimer's disease.

[0223] In Alzheimer's disease, agitation develops as the disease progresses. Agitation may manifest as inappropriate verbal, emotional, and / or physical behaviors. Inappropriate behaviors may include, but are not limited to, incoherent babbling, inappropriate emotional responses, attention-seeking demands, threats, irritability, frustration, shouting, repetitive questioning, mood swings, swearing, verbal abuse, physical outbursts, emotional distress, restlessness, fragmentation, sleep disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body movements, hoarding, shadowing, hitting, scratching, biting, aggressive, hyperactivity, and / or kicking.

[0224] In some embodiments, agitation in Alzheimer's disease may be treated by increasing the plasma concentration of dextromethorphan, or by a combination of dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, which 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 other reductions within a range delimited by any of these values.

[0225] Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and behavioral and psychological symptoms, including agitation. AD is the most common form of dementia, affecting an estimated 6 million people in the United States, a number projected to increase to approximately 14 million by 2050. Agitation, present in up to 70% of AD patients, is characterized by emotional distress, aggressive behavior, destructive irritability, and disinhibition. Managing agitation is a priority in AD patients. Agitation in AD patients is associated with increased caregiver burden, functional decline, accelerated cognitive decline, early placement in nursing homes, and increased mortality. Currently, there are no FDA-approved treatments for agitation in AD patients.

[0226] The indicators of therapeutic efficacy that can be improved by treatment that enhances the bioavailability or plasma concentration of dextromethorphan, or by the combined use of dextromethorphan with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of these compounds, are not limited to the following: the overall and all domains of the Neuropsychiatric Inventory-Clinical (NPI-C) assessment scale, and the Neuropsychiatric Symptom Assessment-Clinical The following are included in the assessment scales for agitation (NPI-C), the Cohen-Mansfield Agitation Scale (CMAI), the Cornell Dementia Scale for Depression (CSDD), the Neuropsychiatric Symptom Assessment (NPI agitation / aggression domain), concomitant medications (frequency of concomitant medication use), the Alzheimer's Disease Collaborative Study - Activities of Daily Living (ADCS-ADL), the Neuropsychiatric Symptom Assessment (NPI) including the domain of indifference, individual domains and the NPI total score, NPI agitation / aggression caregiver distress, and the Modified Alzheimer's Disease Collaborative Study - Clinical Global Impression Agitation Variation (mADCS-CGIC). This includes Agitation, Global Patient Impression Change (PGIC) (caregiver assessment), Quality of Life with Dementia (DEMQOL), Quality of Life-Alzheimer's Disease Scale (AoL-AD), Zelit Burden Scale, Resource Utilization with Dementia (RUDE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Mini-Mental Estate Study (MMSE), Caregiver Stress Index (CSI), individual domains of the Neuropsychiatric Symptom Assessment (NPI), total score of the Neuropsychiatric Symptom Assessment (NPI), Neuropsychiatric Symptom Assessment (NPI agitation / aggression domain), Neuropsychiatric Symptom Assessment (NPI domain caregiver distress), etc.

[0227] Substance intoxication and abuse that can be treated by the enhanced bioavailability or plasma concentration of dextromethorphan, or by combination of dextromethorphan with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds, include, but are not limited to, drug dependence on and addiction to cocaine, psychostimulants (e.g., crack, cocaine, speed, meta), nicotine, alcohol, opioids, anxiolytics and hypnotics, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as smoking tobacco, cigars and / or pipes, as well as chewing tobacco addiction.

[0228] Brain dysfunctions that can be treated by the enhanced bioavailability or plasma concentration of dextromethorphan, or by combination of dextromethorphan with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds, include, but are not limited to, disorders including senile dementia, Alzheimer's disease, amnesia, amnesia / amnesic syndrome, epilepsy, impaired consciousness, coma, decreased attention, speech disorders, voice spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperactivity syndrome, and intellectual disabilities such as schizophrenia. Brain dysfunctions also include, but are not limited to, disorders caused by cerebrovascular diseases such as stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, and head trauma, whose symptoms include, but are not limited to, symptoms such as impaired consciousness, senile dementia, coma, decreased attention, and speech disorders.

[0229] Movement disorders that can be treated by the enhanced bioavailability or plasma concentration of dextromethorphan, or by combination of dextromethorphan with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds, include, but are not limited to, akathisia, akinesia, related movements, athetosis, ataxia, ballism, hemiballism, bradykinetics, 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 leg syndrome (RLS), tremor, essential tremor, Tourette's syndrome, and Wilson's disease.

[0230] Dementia that can be treated by the enhanced bioavailability or plasma concentration of dextromethorphan, or by combination of dextromethorphan with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds, include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff syndrome, and Pick's disease.

[0231] Motor neuron diseases that can be treated by the enhanced bioavailability or plasma concentration of dextromethorphan, or by combination with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds, 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 muscular atrophy, Tay-Sachs disease, Sandhoff disease, and hereditary spastic paraplegia.

[0232] Neurodegenerative diseases that can be treated by increased bioavailability or plasma concentration of dextromethorphan, or by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedreich'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 dystrophy, Charcot-Marie-Tooth (CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0233] Seizure disorders that can be treated by increased bioavailability or plasma concentration of dextromethorphan, or by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, include, but are not limited to, partial seizures including, but not limited to, epileptic seizures, non-epileptic seizures, epilepsy, febrile convulsions, simple partial seizures, Jacksonian seizures, complex partial seizures, and continuous partial epilepsy, 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.

[0234] The types of headaches that can be treated by the enhanced bioavailability or plasma concentration of dextromethorphan, or by combination with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds, include, but are not limited to, migraines, tension headaches, and cluster headaches.

[0235] Other neurological disorders that may be treated by the enhanced bioavailability or plasma concentration of dextromethorphan, or by combination of dextromethorphan with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds, include Rett syndrome, autism, tinnitus, disturbance of consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy, abductor spasmodic dysphonia, adductor spasmodic dysphonia, muscle tone dysphonia, and voice disorders due to uncontrolled laryngeal muscle spasms, including but not limited to vocal tremor, diabetic neuropathy, chemotherapy-induced neurotoxicity such as methotrexate neurotoxicity, incontinence including but not limited to stress urinary incontinence, urge urinary incontinence, and fecal incontinence, and erectile dysfunction.

[0236] In some embodiments, combinations of dextromethorphan with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds may be used to treat pain, arthralgia, pain associated with sickle cell disease, emotional dysregulation, depression (including treatment-resistant depression), impairments associated with memory and dementia, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, seizures, and cough (including chronic cough).

[0237] In some embodiments, dextromethorphan can be used in combination with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds to treat treatment-refractory depression.

[0238] In some embodiments, combinations of dextromethorphan with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds may be used to treat allodynia.

[0239] In some embodiments, dextromethorphan can be used in combination with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds to treat treatment-refractory hyperalgesia.

[0240] In some embodiments, dextromethorphan can be used in combination with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds to treat dermatitis.

[0241] The pain-relieving properties of dextromethorphan may be enhanced by co-administering dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0242] The analgesic properties of bupropion may be enhanced by co-administration of dextromethorphan with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0243] In some embodiments, ketamine or other NMDA receptor antagonists may be administered with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds.

[0244] In some embodiments, dextromethorphan and quinidine may be co-administered with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds.

[0245] These methods may be used to treat or alleviate any type of pain, including, but not limited to, musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive pain, inflammatory pain, arthritis pain, and complex regional pain syndrome.

[0246] In some embodiments, co-administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of these compounds with dextromethorphan may be used to treat or alleviate inflammation or inflammatory conditions such as Crohn's disease, including inflammation-related pain.

[0247] In some embodiments, co-administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of these compounds with dextromethorphan can be used for the treatment of psoriasis, cancer, viral infections, or as adjuvant therapy for multiple myeloma.

[0248] Examples of musculoskeletal pain include lower back pain (i.e., lumbosacral pain), primary dysmenorrhea, and pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, arthralgia such as axial spondyloarthritis including ankylosing spondylitis, pain associated with vertebral crush fractures, fibrous dysplasia, osteogenesis imperfecta, Paget's disease of the bone, transient osteoporosis, and transient osteoporosis of the hip, among others.

[0249] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion may be administered orally to relieve musculoskeletal pain, including lower back pain, pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid-like) arthropathy, non-rheumatoid arthritis, periarthritis, axonal spondyloarthritis including ankylosing spondylitis, Paget's disease, fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip, vertebral crush fractures, and osteoporosis.

[0250] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion may be administered to relieve inflammatory pain, including musculoskeletal pain, arthritis pain, and complex regional pain syndrome.

[0251] Arthritis refers to inflammatory joint diseases that may be associated with pain. Examples of arthritis pain include osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatoid-like) arthropathy, non-rheumatoid arthritis, periarthritis, neurogenic arthropathy including Charcot's foot, axonal spondyloarthropathy including ankylosing spondylitis, and pain associated with SAPHO syndrome.

[0252] In some embodiments, a combination of dextrorphan and an antidepressant such as bupropion may be used to treat chronic musculoskeletal pain.

[0253] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion may be administered to alleviate complex regional pain syndromes such as complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or other types of CRPS. CRPS is a type of inflammatory pain. CRPS may also have a neuropathic component. Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain in the extremities, which may be accompanied by edema, autonomic, motor, and sensory alterations.

[0254] In some embodiments, a combination of dextromethorphan and an antidepressant such as buplepion may be administered orally to relieve neuropathic pain.

[0255] Examples of neuropathic pain include diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, and central pain. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy, and radiation therapy or chemotherapy-related neuropathy.

[0256] In some embodiments, a combination of dextromethorphan and an antidepressant such as buplepion may be administered orally to alleviate fibromyalgia.

[0257] The term “to treat” or “to cure” includes any activity that diagnoses, cures, alleviates, treats or prevents disease in humans or other animals, or otherwise affects the structure or any function of the body of a human or other animal.

[0258] Any antidepressant may be used in combination with dextromethorphan to enhance its therapeutic properties. Dextromethorphan and antidepressant compounds may be administered in separate compositions or dosage forms, or in a single composition or dosage form containing both.

[0259] Quinidine can be co-administered with dextromethorphan to enhance its plasma concentration. For combinations of quinidine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily doses of quinidine are approximately 1-1000 mg, 1-10 mg, 10 mg, approximately 5 mg, approximately 4.5 mg, approximately 1-3 mg, approximately 2-4 mg, approximately 3-5 mg, approximately 4-6 mg, approximately 5-7 mg, approximately 6-8 mg, approximately 7-9 mg, approximately 8-10 mg, approximately 9-11 mg, approximately 10-12 mg, and approximately 4. Dosages of 5 mg, 20 mg, 30 mg, 30-100 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 10-30 mg, approximately 30-50 mg, 50-70 mg, approximately 10-90 mg, or any dosage within these ranges.

[0260] Antidepressant compositions that can be co-administered with dextrorphan include, but are not limited to, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-clomipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazide, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyindanamine, benactidine, escitalopram, and fluboxamine. This includes venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, brasofensine, moclobemide, rasagiline, nyalamide, iproniazid, iproclozid, troxatone, butriptyline, dosulepin, dibenzepine, iprindol, lofepramine, opipramol, norfluoxetine, dapoxetine, ketamine, or any metabolite or prodrug of these compounds, or any pharmaceutically acceptable salt of these compounds.

[0261] For combinations of ketamine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily recommended dosages of ketamine are approximately 0.01-0.2 mg, 0.2-0.4 mg, 0.4-0.6 mg, 0.6-0.8 mg, 0.8-1 mg, 1-1.2 mg, 1.2-1.4 mg, 1.4-1.6 mg, 1.6-1.8 mg, 1.8-2 mg, 2-2.2 mg, 2.2-2.4 mg, and 2.4-2.6 mg. mg, about 2.6-2.8 mg, about 2.8-3 mg, about 3-3.2 mg, about 3.2-3.4 mg, about 3.4-3.6 mg, about 3.6-3.8 mg, about 3.8-4 mg, about 3.9-4.1 mg, about 4-4.2 mg, about 0.2-0.4 mg, about 0.2-0.6 mg , about 0.2-0.8 mg, about 0.2-1 mg, about 0.2-1.2 mg, about 0.2-1.4 mg, about 0.2-1.6 mg, about 0.2-1.8 mg, about 0.2-2.0 mg, 0.2-2.5 mg, about 0.2-3.0 mg, about 0.2-3.5 mg, about 0.2-4.0mg, about 5-10mg, about 10-15mg, about 15-20mg, about 20-25mg, about 25-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 6 0~70mg, approx. 70~80mg, approx. 80~90mg, approx. 90~100mg, approx. 100~120mg, approx. 120~140mg, approx. 140~150mg, approx. 150~160m g, about 160-180mg, about 180-200mg, about 200-220mg, about 220-240, about 10-500mg, about 50-400mg, about 50-300mg, about 10 0~250mg, approx. 1~10mg, approx. 10~200mg, approx. 10~150mg, approx. 10~100mg, approx. 10~180mg, approx. 10~160mg, approx. 10~140mg, approx. 1 0~120mg, approx. 10~100mg, approx. 10~20mg, approx. 20~30mg, approx. 30~40mg, approx. 40~50mg, approx. 50~60mg, approx. 60~70mg, approx. 70~8 0mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg It can be administered in doses of approximately 200-220 mg, 220-240 mg, 240-250 mg, 250-260 mg, 260-280 mg, 280-300 mg, 300-350 mg, 350-400 mg, 25 mg, 50 mg, 100 mg, or 250 mg, or any dose within any of these ranges.

[0262] Regarding the combination of tesofensin and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of tesofensin is approximately 0.1-0.2 mg, 0.1-0.3 mg, 0.1-0.4 mg, 0.1-0.5 mg, 0.1-0.6 mg, 0.1-0.7 mg, 0.1-0.8 mg, and 0.1 mg. The drug can be administered in doses of ~0.9 mg, approximately 0.1~0.1 mg, approximately 0.1~0.12 mg, approximately 0.01~0.2 mg, approximately 0.1~0.3 mg, approximately 0.2~0.4 mg, approximately 0.3~0.5 mg, approximately 0.4~0.6 mg, approximately 0.5~0.7 mg, approximately 0.6~0.8 mg, approximately 0.7~0.9 mg, approximately 0.8~1 mg, approximately 0.9~1.1 mg, or any dose within any of these ranges.

[0263] For combinations of prasofensin and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily doses of prasofensin are approximately 0.01-0.2 mg, 0.2-0.4 mg, 0.4-0.6 mg, 0.6-0.8 mg, 0.8-1 mg, 1-1.2 mg, 1.2-1.4 mg, and 1.4-1.6 mg. mg, approximately 1.6~1.8mg, approximately 1.8~2mg, approximately 2~2.2mg, approximately 2.2~2.4mg, approximately 2.4~2.6mg, approximately 2.6~2.8mg, approximately 2.8~3mg, approximately 3~3.2mg, Approx. 3.2~3.4mg, approx. 3.4~3.6mg, approx. 3.6~3.8mg, approx. 3.8~4mg, approx. 3.9~4.1mg, approx. 4~4.2mg, approx. 0.2~0.4mg, approx. 0.2~0.6mg It can be administered in doses of approximately 0.2-0.8 mg, approximately 0.2-1 mg, approximately 0.2-1.2 mg, approximately 0.2-1.4 mg, approximately 0.2-1.6 mg, approximately 0.2-1.8 mg, approximately 0.2-2.0 mg, 0.2-2.5 mg, approximately 0.2-3.0 mg, approximately 0.2-3.5 mg, or approximately 0.2-4.0 mg, or within any of these ranges.

[0264] For combinations of clomipramine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of clomipramine is approximately 10-500 mg, approximately 50-400 mg, approximately 50-300 mg, approximately 100-250 mg, approximately 1-10 mg, approximately 10-200 mg, approximately 10-150 mg, approximately 10-100 mg, approximately 10-180 mg, approximately 10-160 mg, approximately 10-140 mg, approximately 10-120 mg, approximately 10-100 mg, approximately 10-20 mg, approximately 20-30 mg, approximately 30-40 mg, approximately It can be administered in doses of 40-50 mg, approximately 50-60 mg, approximately 60-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-350 mg, approximately 350-400 mg, approximately 25 mg, approximately 50 mg, approximately 100 mg, or approximately 250 mg, or within any range defined by these values.

[0265] For combinations of doxepin and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of doxepin is approximately 1-500 mg, 1-10 mg, 1-40 mg, 1-30 mg, 1-20 mg, 1-18 mg, 1-16 mg, 1-14 mg, 1-12 mg, 1-10 mg, 10-150 mg, 10-125 mg, 10-100 mg, 10-75 mg, 10-70 mg, 10-60 mg, 10-50 mg, 10-40 mg, 10-30 mg, 10-20 mg, 20-30 mg, 30-40 mg, and 40-5 mg. 0mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 14 0~160mg, approx. 160~180mg, approx. 180~200mg, approx. 200~220mg, approx. 220~240, approx. 240~250mg, approx. 250~260mg, approx. 26 It can be administered in doses of 0-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-500 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, and approximately 300 mg, or within any range defined by these values.

[0266] For combinations of fluoxetine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), fluoxetine can be administered in doses of approximately 1-10 mg, 5-15 mg, 10-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-120 mg, 120-140 mg, 140-160 mg, 160-180 mg, 180-200 mg, 10 mg, 20 mg, 60 mg, 100 mg, or 150 mg per day, or within any of these ranges.

[0267] Regarding the combination of mianserin and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, non-deuterium-modified dextromethorphan), the daily dose of mianserin is approximately 1-300 mg, 1-90 mg, 1-60 mg, 1-30 mg, 1-25 mg, 1-20 mg, 1-15 mg, 1-10 mg, 10-20 mg, 20-30 mg, and 30 mg. It can be administered in doses of 40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 30 mg, approximately 60 mg, approximately 90 mg, approximately 120 mg, approximately 150 mg, or any dose within a range defined by these values.

[0268] Regarding the combination of imipramine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the recommended daily dose of imipramine is approximately 1-10 mg, 5-150 mg, 5-125 mg, 5-100 mg, 5-75 mg, 5-60 mg, 5-50 mg, 5-40 mg, 5-30 mg, 5-25 mg, 5-20 mg, 5-15 mg, 10-20 mg, 20-25 mg, 25-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, and 70-80 mg. It can be administered in doses of approximately 80-90 mg, 90-100 mg, 100-120 mg, 120-140 mg, 140-160 mg, 160-180 mg, 180-200 mg, 200-220 mg, 220-240 mg, 240-250 mg, 250-260 mg, 260-280 mg, 280-300 mg, 300-320 mg, 320-350 mg, 350-400 mg, 400-500 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 250 mg, or 300 mg, or any dose within a range defined by these values.

[0269] Regarding the combination of 2-chloroimipramine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of 2-chloroimipramine is approximately 0.1-0.25 mg, approximately 0.25-0.5 mg, approximately 0.5-0.75 mg, and approximately 0.75-1 mg. , about 1-5 mg, about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg , about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-150mg, about 150-16 0mg, approx. 160~180mg, approx. 180~200mg, approx. 200~220mg, approx. 220~240, approx. 240~250mg, approx. 250~260mg, approx. 260~280mg , about 280-300mg, about 300-320mg, about 320-350mg, about 350-400mg, about 400-450mg, about 450-500mg, about 500-550mg, The drug can be administered in doses of approximately 550-600 mg, 600-650 mg, 650-700 mg, 700-800 mg, 800-1000 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 250 mg, 300 mg, 400 mg, or 600 mg, or any range defined by these values.

[0270] Regarding the combination of amitriptyline and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of amitriptyline is approximately 1-10 mg, 5-100 mg, 5-70 mg, 5-60 mg, 5-50 mg, 5-40 mg, 5-35 mg, 5-30 mg, 5-25 mg, 5-20 mg, 10-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, and 90- It can be administered in doses of 100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-500 mg, approximately 10 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, or doses within any range defined by these values.

[0271] Regarding amoxapine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), amoxapine is prescribed in the following daily doses: approximately 1-10 mg, approximately 10-20 mg, approximately 10-300 mg, approximately 10-250 mg, approximately 10-200 mg, approximately 10-150 mg, approximately 10-120 mg, approximately 10-100 mg, approximately 10-80 mg, approximately 10-60 mg, approximately 10-40 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, and approximately 10 It can be administered in doses of 0-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-500 mg, approximately 500-600 mg, approximately 600-700 mg, approximately 700-800 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, or any dose within a range defined by these values.

[0272] Regarding the combination of desipramine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of desipramine is approximately 1-10 mg, 1-15 mg, 10-20 mg, 10-25 mg, 10-30 mg, 10-40 mg, 10-50 mg, 10-60 mg, 10-70 mg, 10-80 mg, 10-90 mg, 10-100 mg, 10-120 mg, 10-140 mg, 10-150 mg, 10-180 mg, 10-200 mg, 20-30 mg, 20-40 mg, 30-40 mg, 40-50 mg, 40-60 mg, and 50-6 0mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 90-110mg, about 100-120mg, about 120-140mg, about 140 ~160mg, approx. 160~180mg, approx. 180~200mg, approx. 180~220mg, approx. 200~220mg, approx. 220~240, approx. 240~250mg, approx. 250~2 The drug can be administered in doses of 60 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 280-320 mg, approximately 300-350 mg, approximately 350-400 mg, approximately 100-200 mg, approximately 25-100 mg, approximately 25 mg, approximately 50 mg, approximately 100 mg, approximately 200 mg, approximately 250 mg, or any dose within a range defined by these values.

[0273] For combinations of protriptyline and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the recommended daily doses of protriptyline are approximately 5-100 mg, 2-5 mg, 2-6 mg, 2-7 mg, 2-8 mg, 2-9 mg, 2-10 mg, 2-11 mg, 2-12 mg, 2-13 mg, 2-14 mg, 2-15 mg, 2-20 mg, 2-21 mg, 2-22 mg, 2-23 mg, 2-24 mg, 2-25 mg, 2-26 mg, 2-27 mg, 2-28 mg, 2-29 mg, 2-30 mg, 2-35 mg, and 2-4 mg. 0mg, about 15-60mg, about 1-5mg, about 5-10mg, about 10-15mg, about 15-20mg, about 20-25mg, about 25-30mg, about 30-35mg, about 35-40mg, about 40-45mg, about 45-50mg, about 50-55mg, about 55-60mg, about 60-65mg, about 65-70mg, about 70-80mg, about 80 The drug can be administered in doses of ~90mg, approximately 90~100mg, approximately 100~120mg, approximately 120~140mg, approximately 140~160mg, approximately 160~180mg, approximately 180~200mg, approximately 10mg, approximately 20mg, approximately 30mg, approximately 60mg, approximately 100mg, approximately 150mg, or any dose within a range defined by these values.

[0274] When trimipramine is combined with dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of trimipramine is approximately 20-300 mg, 1-10 mg, 5-20 mg, 5-25 mg, 5-30 mg, 5-35 mg, 5-40 mg, 5-45 mg, 5-50 mg, 5-55 mg, 5-60 mg, 5-65 mg, 5-70 mg, 5-75 mg, 5-100 mg, 5-125 mg, 5-150 mg, 10-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, and 70- 80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 100-200mg, about 120-140mg, about 140-160mg, about 160-18 0mg, approx. 180~200mg, approx. 180~220mg, approx. 200~220mg, approx. 220~240mg, approx. 240~250mg, approx. 250~260mg, approx. 260~2 The drug can be administered in doses of 80 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-500 mg, approximately 10 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, or any dose within a range defined by these values.

[0275] Regarding the combination of nortriptyline and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of nortriptyline is approximately 1-5 mg, 5-10 mg, 5-20 mg, 5-25 mg, 5-30 mg, 5-35 mg, 5-40 mg, 5-45 mg, 5-50 mg, 5-55 mg, 5-60 mg, 5-65 mg, 5-70 mg, 5-75 mg, 5-100 mg, 5-125 mg, 5-150 mg, 10-15 mg, 15-20 mg, 20-25 mg, and 20-3 mg. It can be administered in doses of 0 mg, approximately 25-30 mg, approximately 30-35 mg, approximately 30-50 mg, approximately 35-40 mg, approximately 40-45 mg, approximately 45-50 mg, approximately 50-150 mg, approximately 50-55 mg, approximately 55-60 mg, approximately 60-65 mg, approximately 65-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 80-120 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 60 mg, approximately 100 mg, approximately 150 mg, or any dose within a range defined by these values.

[0276] Regarding the combination of maprotiline and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the daily dose of maprotiline should be approximately 1-5 mg, 5-10 mg, 5-20 mg, 5-25 mg, 5-30 mg, 5-35 mg, 5-40 mg, or 5-45 mg. mg, about 5-50 mg, about 5-55 mg, about 5-60 mg, about 5-65 mg, about 5-70 mg, about 5-75 mg, about 5-100 mg, about 5-125 mg, about 5-150 mg, about 10- 15mg, about 10-250mg, about 10-75mg, about 10-50mg, about 15-20mg, about 20-25mg, about 25-30mg, about 30-35mg, about 35-40mg, about 40- 45mg, about 45-50mg, about 50-55mg, about 55-60mg, about 60-65mg, about 60-90mg, about 65-70mg, about 70-75mg, about 75-80mg, about 80- 85mg, about 80-120mg, about 85-90mg, about 90-100mg, about 100-120mg, about 100-150mg, about 120-125mg, about 125-140mg, about 140 The drug can be administered in doses of ~150 mg, approximately 150~160 mg, approximately 160~180 mg, approximately 180~200 mg, approximately 200~225 mg, approximately 210~240 mg, approximately 200~250 mg, approximately 10 mg, approximately 25 mg, approximately 30 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 225 mg, or any dose within a range defined by these values.

[0277] Regarding the combination of phenelzine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, non-deuterium-modified dextromethorphan), the daily dose of phenelzine is approximately 1-5 mg, 5-10 mg, 5-20 mg, 5-25 mg, 5-30 mg, 5-35 mg, 5-40 mg, 5-45 mg, 5-50 mg, 5-55 mg, 5-60 mg, 5-65 mg, 5-70 mg, 5-75 mg, 5-90 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, and 35-40 mg. The drug can be administered in doses of approximately 40-45 mg, 40-50 mg, 45-50 mg, 50-55 mg, 50-70 mg, 50-200 mg, 55-60 mg, 60-65 mg, 60-90 mg, 65-70 mg, 70-80 mg, 80-90 mg, 80-120 mg, 90-100 mg, 100-120 mg, 100-150 mg, 120-140 mg, 140-160 mg, 160-180 mg, 180-200 mg, 10 mg, 15 mg, 30 mg, 60 mg, 100 mg, or 150 mg, or any dose within these ranges.

[0278] Regarding the combination of isocarboxazide and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, non-deuterium-modified dextromethorphan), the daily dose of isocarboxazide is approximately 1-5 mg, 2-5 mg, 2-6 mg, 2-7 mg, 2-8 mg, 2-9 mg, 2-10 mg, 2-11 mg, and 2-1 2mg, about 2-13mg, about 2-14mg, about 2-15mg, about 2-16mg, about 2-17mg, about 2-18mg, about 2-19mg, about 2-20mg, about 2-21mg, about 2-22mg, Approx. 2~23mg, approx. 2~24mg, approx. 2~25mg, approx. 2~26mg, approx. 2~27mg, approx. 2~28mg, approx. 2~29mg, approx. 2~30mg, approx. 2~35mg, approx. 2~40mg, approx. 2~45 mg, about 2-50 mg, about 2-55 mg, about 2-60 mg, about 5-10 mg, about 5-15 mg, about 10-15 mg, about 10-60 mg, about 15-20 mg, about 20-25 mg, about 25-3 0mg, about 30-35mg, about 30-50mg, about 35-40mg, about 40-45mg, about 45-50mg, about 50-55mg, about 50-70mg, about 55-60mg, about 60-65mg, The drug can be administered in doses of approximately 65-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-120 mg, 120-140 mg, 140-160 mg, 160-180 mg, 180-200 mg, 10 mg, 15 mg, 30 mg, 60 mg, 100 mg, or 150 mg, or any dose within these ranges.

[0279] For combinations of tranylcypromine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the recommended daily dose of tranylcypromine is approximately 1-5 mg, 1-30 mg, 1-25 mg, 1-20 mg, 2-5 mg, 2-6 mg, 2-7 mg, and 2-8 mg. , about 2-9mg, about 2-10mg, about 2-11mg, about 2-12mg, about 2-13mg, about 2-14mg, about 2-15mg, about 2-16mg, about 2-17mg, about 2-18mg, about 2- 19mg, about 2-20mg, about 2-21mg, about 2-22mg, about 2-23mg, about 2-24mg, about 2-25mg, about 2-26mg, about 2-27mg, about 2-28mg, about 2-29mg , about 2-30mg, about 2-35mg, about 2-40mg, about 2-45mg, about 2-50mg, about 2-55mg, about 2-60mg, about 5-10mg, about 10-15mg, about 15-20mg, Approx. 20~25mg, approx. 25~30mg, approx. 30~35mg, approx. 35~40mg, approx. 40~45mg, approx. 45~50mg, approx. 50~55mg, approx. 55~60mg, approx. 60~65mg, approx. 65 The drug can be administered in doses of ~70mg, approximately 70~80mg, approximately 80~90mg, approximately 90~100mg, approximately 100~120mg, approximately 120~140mg, approximately 140~160mg, approximately 160~180mg, approximately 180~200mg, approximately 10mg, approximately 15mg, approximately 30mg, approximately 60mg, approximately 100mg, approximately 150mg, or any dose within a range defined by these values.

[0280] For combinations of paroxetine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the recommended daily dose of paroxetine is approximately 1-5 mg, 1-50 mg, 1-20 mg, 1-15 mg, 1-10 mg, 2-5 mg, 2-6 mg, 2-7 mg, 2-8 mg, 2-9 mg, 2-10 mg, 2-11 mg, 2-12 mg, 2-13 mg, 2-14 mg, 2-15 mg, 2-16 mg, 2-17 mg, 2-18 mg, 2-19 mg, 2-20 mg, 2-30 mg, 2-40 mg, and 2-50 mg. The drug can be administered in doses of mg, approximately 5-10 mg, approximately 10-15 mg, approximately 15-20 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-35 mg, approximately 35-40 mg, approximately 40-45 mg, approximately 45-50 mg, approximately 50-55 mg, approximately 55-60 mg, approximately 60-65 mg, approximately 65-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, approximately 60 mg, approximately 100 mg, approximately 150 mg, or any dose within a range defined by these values.

[0281] Regarding the combination of trazodone and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, non-deuterium-modified dextromethorphan), the recommended daily dose of trazodone is approximately 1-10 mg, 10-20 mg, 10-30 mg, 10-40 mg, 10-50 mg, 10-60 mg, 10-70 mg, and 10-80 mg. mg, about 10-90mg, about 10-100mg, about 10-120mg, about 10-140mg, about 10-150mg, about 10-180mg, about 10-200mg, about 10-250mg, about 1 0~300mg, approx. 20~25mg, approx. 25~30mg, approx. 30~40mg, approx. 40~50mg, approx. 50~60mg, approx. 60~70mg, approx. 70~80mg, approx. 80~90mg, approx. 90~ 100mg, about 100-120mg, about 120-140mg, about 140-150mg, about 150-160mg, about 160-180mg, about 180-200mg, about 200-220mg, Approx. 220~240, Approx. 240~250mg, Approx. 250~260mg, Approx. 260~280mg, Approx. 280~300mg, Approx. 300~320mg, Approx. 320~350mg, Approx. 350~400m It can be administered in doses of approximately 400-450 mg, 450-500 mg, 500-550 mg, 550-600 mg, 600-650 mg, 650-700 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 250 mg, 300 mg, 400 mg, or 600 mg, or any range of these values.

[0282] Regarding the combination of citalopram and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of citalopram is approximately 1-5 mg, 1-20 mg, 1-15 mg, 1-10 mg, 2-5 mg, 2-6 mg, 2-7 mg, 2-8 mg, 2-9 mg, 2-10 mg, 2-11 mg, 2-12 mg, 2-13 mg, 2-14 mg, 2-15 mg, 2-20 mg, 2-25 mg, 2-30 mg, 2-35 mg, 2-40 mg, 5-10 mg, and 10-15 mg. The drug can be administered in doses of approximately 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 45-50 mg, 50-55 mg, 55-60 mg, 60-65 mg, 65-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-120 mg, 120-140 mg, 140-160 mg, 160-180 mg, 180-200 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, 100 mg, or 150 mg, or any dose within these ranges.

[0283] For combinations of sertraline and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the recommended daily dose of sertraline is approximately 1-5 mg, 1-50 mg, 1-45 mg, 1-40 mg, 1-30 mg, 1-20 mg, 2-5 mg, 2-6 mg, 2-7 mg, 2-8 mg, and 2-9 mg. , about 2-10mg, about 2-11mg, about 2-12mg, about 2-13mg, about 2-14mg, about 2-15mg, about 2-16mg, about 2-17mg, about 2-18mg, about 2-19mg, about 2-20mg, about 2 ~21mg, approx. 2~22mg, approx. 2~23mg, approx. 2~24mg, approx. 2~25mg, approx. 2~26mg, approx. 2~27mg, approx. 2~28mg, approx. 2~29mg, approx. 2~30mg, approx. 2~35mg, approx. 2~40m g, about 2-45 mg, about 2-50 mg, about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg, about 30-35 mg, about 35-40 mg, about 40-45 mg, about 4 5-50mg, about 50-55mg, about 55-60mg, about 60-65mg, about 65-70mg, about 70-75mg, about 75-80mg, about 80-85mg, about 85-90mg, about 90-100mg, about 10 The drug can be administered in doses of 0-120 mg, approximately 120-125 mg, approximately 125-140 mg, approximately 140-150 mg, approximately 150-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 200-300 mg, approximately 10 mg, approximately 25 mg, approximately 30 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 225 mg, or any dose within a range defined by these values.

[0284] Regarding the combination of aryloxyindanamine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the recommended daily dosage of aryloxyindanamine is approximately 0.1-0.25 mg, 0.25-0.5 mg, 0.5-0.75 mg, 0.75-1 mg, 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-120 mg, 120-140 mg, 140-150 mg, and 150 mg. 160mg, about 160-180mg, about 180-200mg, about 200-220mg, about 220-240, about 240-250mg, about 250-260mg, about 260-280 mg, approx. 280~300mg, approx. 300~320mg, approx. 320~350mg, approx. 350~400mg, approx. 400~450mg, approx. 450~500mg, approx. 500~550mg It can be administered in doses of approximately 550-600 mg, 600-650 mg, 650-700 mg, 700-800 mg, 800-1000 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 250 mg, 300 mg, 400 mg, or 600 mg, or any range defined by these values.

[0285] Regarding the combination of benactidine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the recommended daily doses of benactidine are approximately 0.1-0.25 mg, 0.25-0.5 mg, 0.5-0.75 mg, 0.75-1 mg, and 1-5 mg. Approx. 5~10mg, approx. 10~15mg, approx. 15~20mg, approx. 20~25mg, approx. 25~30mg, approx. 30~40mg, approx. 40~50mg, approx. 50~60mg, approx. 60~7 0mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-150mg, about 150-160mg, about 160~180mg, approx. 180~200mg, approx. 200~220mg, approx. 220~240, approx. 240~250mg, approx. 250~260mg, approx. 260~280mg, approx. 2 80~300mg, approx. 300~320mg, approx. 320~350mg, approx. 350~400mg, approx. 400~450mg, approx. 450~500mg, approx. 500~550mg, approx. 5 The drug can be administered in doses of 50-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg, or any range defined by these values.

[0286] Regarding the combination of escitalopram and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of escitalopram is approximately 1-5 mg, 2-5 mg, 2-6 mg, 2-7 mg, 2-8 mg, 2-9 mg, 2-10 mg, 2-12 mg, 2-14 mg, 2-15 mg, 2-20 mg, 5-10 mg, 5-15 mg, 10-15 mg, 10-30 mg, 15-20 mg, and approximately It can be administered in doses of 15-30 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-35 mg, approximately 35-40 mg, approximately 40-45 mg, approximately 45-50 mg, approximately 50-55 mg, approximately 55-60 mg, approximately 60-65 mg, approximately 65-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-200 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 50 mg, or any dose within a range defined by these values.

[0287] Regarding the combination of fluvoxamine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the daily dose of fluvoxamine is 50-300 mg, 1-10 mg, approximately 10-20 mg, approximately 10-30 mg, approximately 10-40 mg, approximately 10-50 mg, approximately 10- 60mg, about 10-70mg, about 10-80mg, about 10-90mg, about 10-100mg, about 10-120mg, about 10-140mg, about 10-150mg, about 10-180m g, approximately 10~200mg, approximately 10~250mg, approximately 10~300mg, approximately 20~30mg, approximately 30~40mg, approximately 40~50mg, approximately 50~60mg, approximately 60~70mg, approximately 70~ 80mg, about 80-90mg, about 90-100mg, about 90-110mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 1 80~200mg, approx. 180~220mg, approx. 200~220mg, approx. 220~240, approx. 240~250mg, approx. 240~260mg, approx. 250~260mg, approx. 260~280 The drug can be administered in doses of mg, approximately 280-300 mg, approximately 280-320 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-500 mg, approximately 10 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, or any dose within a range defined by these values.

[0288] Regarding the combination of venlafaxine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the daily dose of venlafaxine is approximately 1-10 mg, approximately 5-20 mg, approximately 5-25 mg, approximately 5-30 mg, approximately 5-35 mg, approximately 5-40 mg, approximately 5-45 mg, and approximately 5~50mg, approx. 5~55mg, approx. 5~60mg, approx. 5~65mg, approx. 5~70mg, approx. 5~75mg, approx. 5~100mg, approx. 5~125mg, approx. 5~150mg, approx. 10~20m g, about 20-25mg, about 25-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100m g, about 100-120mg, about 120-140mg, about 140-150mg, about 120-180mg, about 150-160mg, about 160-180mg, about 180-200mg, about 2 00~220mg, approx. 220~240, approx. 240~250mg, approx. 250~260mg, approx. 260~280mg, approx. 280~300mg, approx. 300~320mg, approx. 320~350 The dosage can be in the following ranges: mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 225 mg, approximately 250 mg, approximately 375 mg, approximately 400 mg, approximately 600 mg, or any of these ranges.

[0289] For combinations of desvenlafaxine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of desvenlafaxine is approximately 2-5 mg, 2-6 mg, 2-7 mg, 2-8 mg, 2-9 mg, 2-10 mg, 2-11 mg, 2-12 mg, 2-13 mg, 2-14 mg, 2-15 mg, 2-20 mg, 2-21 mg, 2-22 mg, 2-23 mg, 2-24 mg, 2-25 mg, 2-30 mg, 2-35 mg, 2-40 mg, 2-45 mg, 2-50 mg, 2-75 mg, 2-100 mg, 1-5 mg, and 5-10 mg. g, about 10-15 mg, about 15-20 mg, about 20-25 mg, about 20-30 mg, about 25-30 mg, about 30-35 mg, about 35-40 mg, about 40-45 mg, about 40 ~60mg, approx. 45~50mg, approx. 50~55mg, approx. 55~60mg, approx. 60~65mg, approx. 65~70mg, approx. 70~80mg, approx. 80~90mg, approx. 80~120mg It can be administered in doses of approximately 90-100 mg, 100-120 mg, 120-140 mg, 140-160 mg, 160-180 mg, 180-200 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, 100 mg, or 150 mg, or any dose within a range defined by these values.

[0290] Regarding the combination of duloxetine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of duloxetine is approximately 1-5 mg, 2-5 mg, 2-6 mg, 2-7 mg, 2-8 mg, 2-9 mg, 2-10 mg, and 2-11 mg. Approx. 2~12mg, approx. 2~13mg, approx. 2~14mg, approx. 2~15mg, approx. 2~20mg, approx. 2~21mg, approx. 2~22mg, approx. 2~23mg, approx. 2~24mg, approx. 2~25mg, approx. 2-26mg, about 2-27mg, about 2-28mg, about 2-29mg, about 2-30mg, about 2-35mg, about 2-40mg, about 2-45mg, about 2-60mg, about 2-90mg, about 2 ~120mg, approximately 5~10mg, approximately 10~15mg, approximately 15~20mg, approximately 20~25mg, approximately 20~40mg, approximately 25~30mg, approximately 30~35mg, approximately 30~50mg, approximately 3 5-40mg, about 40-45mg, about 45-50mg, about 50-55mg, about 50-70mg, about 55-60mg, about 60-65mg, about 65-70mg, about 70-80mg, about 8 The drug can be administered in doses of 0-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 60 mg, approximately 100 mg, approximately 120 mg, or any dose within a range defined by these values.

[0291] For combinations of mirtazapine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the daily dose of mirtazapine is approximately 2-5 mg, 2-6 mg, 2-7 mg, 2-8 mg, 2-9 mg, 2-10 mg, 2-11 mg, 2-12 mg, 2-13 mg, 2-14 mg, 2-15 mg, 2-20 mg, 2-25 mg, 2-30 mg, 2-35 mg, 2-40 mg, 2-45 mg, 1-5 mg, 5-10 mg, 5-100 mg, 10-15 mg, 10-50 mg, and 1 It can be administered in doses of 5-20 mg, approximately 15-45 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-35 mg, approximately 35-40 mg, approximately 40-45 mg, approximately 45-50 mg, approximately 50-55 mg, approximately 55-60 mg, approximately 60-65 mg, approximately 65-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 45 mg, approximately 60 mg, approximately 75 mg, or any dose within a range defined by these values.

[0292] Regarding the combination of nefazodone and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, non-deuterium-modified dextromethorphan), the daily dose of nefazodone is approximately 1-10 mg, 10-20 mg, 20-40 mg, 20-50 mg, 20-60 mg, 20-70 mg, 20-80 mg, 20-90 mg, and 20-100 mg. Approx. 20~120mg, Approx. 20~140mg, Approx. 20~160mg, Approx. 20~180mg, Approx. 20~200mg, Approx. 20~250mg, Approx. 20~300mg, Approx. 20~450mg, Approx. 20~600mg, Approx. 20-25mg, about 25-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 80-120mg, about 90-100mg, about 100~120mg, approx. 120~140mg, approx. 140~150mg, approx. 150~160mg, approx. 160~180mg, approx. 160~240mg, approx. 180~200mg, approx. 200~220mg, approx. 220 ~240mg, approx. 240~250mg, approx. 250~260mg, approx. 260~280mg, approx. 280~300mg, approx. 300~320mg, approx. 320~350mg, approx. 350~400mg, approx. 400~450 The dosage can be in the following ranges: mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-1000 mg, approximately 1000-1500 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg, or any of these ranges.

[0293] For combinations of selegiline and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), selegiline can be administered in doses of approximately 0.5-2 mg, 2-5 mg, 1-10 mg, 1-9 mg, 1-8 mg, 1-7 mg, 1-6 mg, 1-5 mg, 1-3 mg, 3-5 mg, 5-10 mg, 5-15 mg, 10-15 mg, 15-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 45-50 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, or 40 mg per day, or within any range defined by these values.

[0294] In combination with sibutramine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of sibutramine is approximately 1-5 mg, 1-15 mg, 1-10 mg, 1-8 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, and 40 mg. The drug can be administered in doses of ~45mg, approximately 45~50mg, approximately 50~55mg, approximately 55~60mg, approximately 60~65mg, approximately 65~70mg, approximately 70~80mg, approximately 80~90mg, approximately 90~100mg, approximately 100~120mg, approximately 120~140mg, approximately 5mg, approximately 10mg, approximately 15mg, approximately 20mg, approximately 30mg, approximately 40mg, approximately 60mg, approximately 100mg, approximately 120mg, or any dose within a range defined by these values.

[0295] Regarding the combination of rasaziline and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), rasaziline can be administered in doses of approximately 0.1-0.3 mg, 0.3-0.5 mg, 0.3-0.7 mg, 0.5-0.7 mg, 0.5-1.5 mg, 0.7-0.9 mg, 0.9-1.0 mg, 1.0-1.5 mg, 1.5-2.0 mg, 2.0-3.0 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, or 2 mg per day, or any dose within these ranges.

[0296] Regarding the combination of milnacipran and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dosage of milnacipran is approximately 1-7.5 mg, 7.5-12.5 mg, 5-20 mg, 5-100 mg, 5-90 mg, 5-80 mg, 5-70 mg, 5-60 mg, 5-50 mg, 5-40 mg, 12.5-15 mg, 15-20 mg, 20-30 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, and 45-5 mg. It can be administered in doses of 0 mg, approximately 50-55 mg, approximately 40-60 mg, approximately 55-60 mg, approximately 60-65 mg, approximately 65-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 80-120 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 180-220 mg, approximately 200-300 mg, approximately 300-400 mg, approximately 7.5 mg, approximately 12.5 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 60 mg, approximately 100 mg, approximately 200 mg, or any dose within a range defined by these values.

[0297] Regarding the combination of moclobemide and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dosage of moclobemide is approximately 1-10 mg, 10-20 mg, 20-25 mg, 20-450 mg, 20-300 mg, 20-250 mg, 20-200 mg, 20-150 mg, 20-100 mg, 25-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-120 mg, 120-140 mg, 140-150 mg, 150-160 mg, and approximately 160~180mg, approx. 180~200mg, approx. 200~220mg, approx. 220~240, approx. 240~250mg, approx. 250~260mg, approx. 260~280mg, approx. 2 80~320mg, approx. 280~300mg, approx. 300~320mg, approx. 320~350mg, approx. 350~400mg, approx. 430~470mg, approx. 400~450mg, approx. 4 The drug can be administered in doses of 50-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg, or any dose within a range defined by these values.

[0298] Regarding the combination of nyaramide and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of nyaramide is approximately 0.1-0.25 mg, 0.25-0.5 mg, 0.5-0.75 mg, 0.75-1 mg, 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-120 mg, 120-140 mg, 140-150 mg, 150-160 mg, and 16 mg. 0~180mg, approx. 180~200mg, approx. 200~220mg, approx. 220~240mg, approx. 240~250mg, approx. 250~260mg, approx. 260~280mg, approx. 2 80~300mg, approx. 300~320mg, approx. 320~350mg, approx. 350~400mg, approx. 400~450mg, approx. 450~500mg, approx. 500~550mg, approx. 5 The drug can be administered in doses of 50-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg, or any range defined by these values.

[0299] Regarding the combination of iproniazid and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of iproniazid is approximately 0.1-0.25 mg, approximately 0.25-0.5 mg, approximately 0.5-0.75 mg, approximately 0.75-1 mg, approximately 1-5 mg, approximately 5-10 mg, approximately 10-15 mg, approximately 15-20 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-150 mg, approximately 150-160 mg, approximately 160~180mg, approx. 180~200mg, approx. 200~220mg, approx. 220~240mg, approx. 240~250mg, approx. 250~260mg, approx. 260~280mg, approx. 280~300mg, approx. 300~320mg, approx. 320~350mg, approx. 350~400mg, approx. 400~450mg, approx. 450~500mg, approx. 500~550mg, approx. The drug can be administered in doses of 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg, or any range defined by these values.

[0300] For combinations of iproclozide and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of iproclozide is approximately 0.1-0.25 mg, 0.25-0.5 mg, 0.5-0.75 mg, 0.75-1 mg, 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-120 mg, 120-140 mg, 140-150 mg, 150-160 mg, and approximately 160~180mg, approx. 180~200mg, approx. 200~220mg, approx. 220~240mg, approx. 240~250mg, approx. 250~260mg, approx. 260~280mg, approx. 280~300mg, approx. 300~320mg, approx. 320~350mg, approx. 350~400mg, approx. 400~450mg, approx. 450~500mg, approx. 500~550mg, approx. The drug can be administered in doses of 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg, or any range defined by these values.

[0301] For combinations of troxatone and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the recommended daily doses of troxatone are approximately 0.1-0.25 mg, 0.25-0.5 mg, 0.5-0.75 mg, 0.75-1 mg, 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-120 mg, 120-140 mg, 140-150 mg, 150-160 mg, and 1 60~180mg, approx. 180~200mg, approx. 200~220mg, approx. 220~240mg, approx. 240~250mg, approx. 250~260mg, approx. 260~280mg, approx. 2 80~300mg, approx. 300~320mg, approx. 320~350mg, approx. 350~400mg, approx. 400~450mg, approx. 450~500mg, approx. 500~550mg, approx. 5 The drug can be administered in doses of 50-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg, or any range defined by these values.

[0302] Regarding the combination of butriptyline and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of butriptyline is approximately 0.1-0.25 mg, 0.25-0.5 mg, 0.5-0.75 mg, 0.75-1 mg, and 1-5 mg. , about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-7 0mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-150mg, about 150-160mg, about 160~180mg, approx. 180~200mg, approx. 200~220mg, approx. 220~240mg, approx. 240~250mg, approx. 250~260mg, approx. 260~280mg, approx. 280~300mg, approx. 300~320mg, approx. 320~350mg, approx. 350~400mg, approx. 400~450mg, approx. 450~500mg, approx. 500~550mg, approx. The drug can be administered in doses of 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg, or any range defined by these values.

[0303] Regarding the combination of dosulepin and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of dosulepin is approximately 0.1-0.25 mg, 0.25-0.5 mg, 0.5-0.75 mg, 0.75-1 mg, 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-120 mg, 120-140 mg, 140-150 mg, 150-160 mg, and 16 mg. 0~180mg, approx. 180~200mg, approx. 200~220mg, approx. 220~240mg, approx. 240~250mg, approx. 250~260mg, approx. 260~280mg, approx. 2 80~300mg, approx. 300~320mg, approx. 320~350mg, approx. 350~400mg, approx. 400~450mg, approx. 450~500mg, approx. 500~550mg, approx. 5 The drug can be administered in doses of 50-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg, or any range defined by these values.

[0304] Regarding the combination of dibenzepine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of dibenzepine is approximately 0.1-0.25 mg, 0.25-0.5 mg, 0.5-0.75 mg, 0.75-1 mg, 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-120 mg, 120-140 mg, 140-150 mg, 150-160 mg, and 1 60~180mg, approx. 180~200mg, approx. 200~220mg, approx. 220~240mg, approx. 240~250mg, approx. 250~260mg, approx. 260~280mg, approx. 2 80~300mg, approx. 300~320mg, approx. 320~350mg, approx. 350~400mg, approx. 400~450mg, approx. 450~500mg, approx. 500~550mg, approx. 5 The drug can be administered in doses of 50-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg, or any range defined by these values.

[0305] Regarding the combination of iprendol and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of iprendol is approximately 0.1-0.25 mg, 0.25-0.5 mg, 0.5-0.75 mg, 0.75-1 mg, 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-120 mg, 120-140 mg, 140-150 mg, 150-160 mg, and approximately 160~180mg, approx. 180~200mg, approx. 200~220mg, approx. 220~240mg, approx. 240~250mg, approx. 250~260mg, approx. 260~280mg, approx. 280~300mg, approx. 300~320mg, approx. 320~350mg, approx. 350~400mg, approx. 400~450mg, approx. 450~500mg, approx. 500~550mg, approx. The drug can be administered in doses of 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg, or any range defined by these values.

[0306] Regarding the combination of lofepramine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of lofepramine is approximately 0.1-0.25 mg, approximately 0.25-0.5 mg, approximately 0.5-0.75 mg, approximately 0.75-1 mg, approximately 1-5 mg, approximately 5-10 mg, approximately 10-15 mg, approximately 15-20 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-150 mg, approximately 150-160 mg, approximately 160~180mg, approx. 180~200mg, approx. 200~220mg, approx. 220~240mg, approx. 240~250mg, approx. 250~260mg, approx. 260~280mg, approx. 280~300mg, approx. 300~320mg, approx. 320~350mg, approx. 350~400mg, approx. 400~450mg, approx. 450~500mg, approx. 500~550mg, approx. The drug can be administered in doses of 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg, or any range defined by these values.

[0307] Regarding the combination of opipramol and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of opipramol is approximately 0.1-0.25 mg, 0.25-0.5 mg, 0.5-0.75 mg, 0.75-1 mg, 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-120 mg, 120-140 mg, 140-150 mg, 150-160 mg, and approximately 160~180mg, approx. 180~200mg, approx. 200~220mg, approx. 220~240mg, approx. 240~250mg, approx. 250~260mg, approx. 260~280mg, approx. 280~300mg, approx. 300~320mg, approx. 320~350mg, approx. 350~400mg, approx. 400~450mg, approx. 450~500mg, approx. 500~550mg, approx. The drug can be administered in doses of 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg, or any range defined by these values.

[0308] Regarding the combination of norfluoxetine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of norfluoxetine is approximately 0.1-0.25 mg, approximately 0.25-0.5 mg, approximately 0.5-0.75 mg, approximately 0.75-1 mg, and approximately 1 mg. 5mg, about 5-10mg, about 10-15mg, about 15-20mg, about 20-25mg, about 25-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 6 0~70mg, approx. 70~80mg, approx. 80~90mg, approx. 90~100mg, approx. 100~120mg, approx. 120~140mg, approx. 140~150mg, approx. 150~160mg , about 160-180mg, about 180-200mg, about 200-220mg, about 220-240mg, about 240-250mg, about 250-260mg, about 260-280mg , about 280-300mg, about 300-320mg, about 320-350mg, about 350-400mg, about 400-450mg, about 450-500mg, about 500-550mg, The drug can be administered in doses of approximately 550-600 mg, 600-650 mg, 650-700 mg, 700-800 mg, 800-1000 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 250 mg, 300 mg, 400 mg, or 600 mg, or any range defined by these values.

[0309] Regarding the combination of dapoxetine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the daily dose of dapoxetine is approximately 0.1-0.25 mg, approximately 0.25-0.5 mg, approximately 0.5-0.75 mg, approximately 0.75-1 mg, and approximately 1-5 mg. Approx. 5~10mg, approx. 10~15mg, approx. 15~20mg, approx. 20~25mg, approx. 25~30mg, approx. 30~40mg, approx. 40~50mg, approx. 50~60mg, approx. 60~70 mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-150mg, about 150-160mg, about 1 60~180mg, approx. 180~200mg, approx. 200~220mg, approx. 220~240mg, approx. 240~250mg, approx. 250~260mg, approx. 260~280mg, approx. 2 80~300mg, approx. 300~320mg, approx. 320~350mg, approx. 350~400mg, approx. 400~450mg, approx. 450~500mg, approx. 500~550mg, approx. 5 The drug can be administered in doses of 50-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg, or any range defined by these values.

[0310] Bupropion has the structure shown below (the bupropion hydrochloride form is shown). [ka]

[0311] The combination of dextromethorphan and bupropion may provide greater effects, such as greater pain relief, than when either component is administered alone. In high-metabolism groups, dextromethorphan can be rapidly and broadly metabolized, resulting in low systemic exposure even at high doses. Bupropion, in addition to having antidepressant and analgesic properties, is an inhibitor of dextromethorphan metabolism. Bupropion is a dopamine and norepinephrine reuptake inhibitor. It can also be a nicotinic acetylcholine receptor antagonist, which can modulate cytokines associated with inflammatory diseases. Bupropion may affect the concentrations of tumor necrosis factor-alpha and interferon-γ. Metabolites of bupropion, including hydroxybupropion, threohydroxybupropion (also known as threohydrobupropion or threodihydrobupropion), and erythrohydroxybupropion (also known as erythrohydrobupropion or erythrodihydrobupropion), are also inhibitors of dextromethorphan metabolism. Therefore, bupropion, including forms that are rapidly converted in the body (e.g., salts, hydrates, solvates, polymorphs, etc.), are prodrugs of propion, hydroxybupropion, threohydroxybupropion, and erythrohydroxybupropion. Prodrugs of bupropion may include N-methylbupropion and N-benzylbupropion.

[0312] As mentioned above, this inhibition can increase plasma concentrations of dextromethorphan, resulting in additive or synergistic effects such as the alleviation of neurological disorders including pain, depression, and smoking cessation. Therefore, while inhibition of dextromethorphan metabolism is only one of many potential benefits of the combination, co-administration of bupropion and dextromethorphan can thereby enhance the efficacy of bupropion in many individuals. Co-administration of bupropion and dextromethorphan can enhance the analgesic properties of bupropion in many individuals. Co-administration of bupropion and dextromethorphan can also enhance the antidepressant properties of bupropion in many individuals, including a faster onset of action.

[0313] Another potential benefit of co-administration of dextromethorphan and bupropion is that it may be useful in reducing the likelihood of adverse events such as somnolence associated with treatment with dextromethorphan. This may be useful, for example, in human patients who are at risk of experiencing adverse events as a result of treatment with dextromethorphan.

[0314] Another potential benefit of co-administration of dextromethorphan and bupropion is that it may be useful in reducing the likelihood of seizure-like adverse events associated with treatment with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of any of these compounds. This may be useful, for example, in human patients at risk of experiencing adverse events as a result of treatment with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of any of these compounds.

[0315] With respect to dextromethorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds, co-administration may reduce central nervous system adverse events, gastrointestinal events, or other types of adverse events associated with any of these compounds. Adverse events of the central nervous system (CNS) include, but are not limited to, nervousness, dizziness, insomnia, unsteadiness, tremor, hallucinations, seizures, CNS depression, fear, anxiety, headache, increased irritability or agitation, tinnitus, drowsiness, vertigo, sedation, somnolence, confusion, disorientation, malaise, incoordination, fatigue, euphoria, nervousness, insomnia, sleep disturbance, seizures, agitation, tension-like conditions, hysteria, hallucinations, delusions, paranoia, headache and / or migraine, as well as extrapyramidal symptoms such as oculomotor crisis, torticollis, hyperexcitability, increased muscle tone, ataxia and / or tongue thrust.

[0316] Gastrointestinal adverse events include, but are not limited to, nausea, vomiting, abdominal pain, dysphagia, indigestion, diarrhea, abdominal distension, flatulence, peptic ulcers with bleeding, loose stools, constipation, stomach pain, heartburn, gas, loss of appetite, bloating, indigestion, bloating, excessive stomach acid, dry mouth, gastrointestinal disorders, and stomach pain.

[0317] Co-administration of dextromethorphan with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds does not necessarily require the two compounds to 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. Furthermore, the two compounds may be administered simultaneously, but this is not mandatory. The compounds may be administered at different times, as long as both are present in the human body at the same time for at least a portion of the time the co-administration treatment is being performed.

[0318] Side effects of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, and / or dextromethorphan may be reduced by administering bupropion, hydroxybupropion, erythrohydroxybupropion, or threohydroxybupropion together with dextromethorphan. Examples of side effects that may be reduced include: paresthesia of rotation and movement, restlessness, weakness of the arms, bloating, blurred vision, burning of the eyes, tinnitus, changes in vital signs (including, but not limited to, heart rate, respiratory rate, body temperature, and blood pressure), coldness, constipation, difficulty concentrating, difficulty sleeping, difficulty falling asleep, difficulty urinating, difficulty defecating, ear discomfort, eye discomfort, stomach discomfort, dizziness, dry lips, dry mouth, dry throat, dysmenorrhea, fatigue, feverishness, heavy head, increased agitation, feeling more tired than usual, fatigue, and hand tremors. These side effects include weakness in the hands, headache, heartburn, hot flashes, increased blood pressure, skin hypersensitivity, skin hypersensitivity of the head and face, involuntary muscle contractions, generalized involuntary muscle contractions, knee pain, beriberi, dizziness, loose stools, loss of appetite, lower back pain, menstrual irregularities, metallic taste, increased saliva production, dry mucous membranes, nasal congestion, nausea, runny nose, mild eye pressure, tremors when stretching or yawning, skin hypersensitivity, skin hypersensitivity of the arms, face and / or head, sleep disturbances, loose stools, stomach pain, stomach discomfort, sweating of the hands and / or feet, throat inflammation, sore throat, tinnitus, tremors, and / or weakness. These side effects may also be referenced or grouped according to the corresponding terms, equivalent terms, or other relevant terms listed in the MedRA (Medical Regulatory Terminology) Glossary.

[0319] In some embodiments, co-administration consisting of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds with dextromethorphan results in both bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan contributing to the pain-relieving properties of the combination. For example, compared to bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds alone or dextromethorphan alone, the combination may improve pain-relieving properties, including potentially faster onset of action.

[0320] In some embodiments, the combination is 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 about 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 30%. The pain relief properties can be improved for any amount of pain relief within the range bounded by approximately 50%, approximately 50% to approximately 60%, approximately 60% to approximately 70%, approximately 70% to approximately 80%, approximately 80% to approximately 90%, approximately 90% to approximately 100%, approximately 100% to approximately 110%, approximately 110% to approximately 120%, approximately 120% to approximately 130%, approximately 130% to approximately 140%, approximately 140% to approximately 150%, approximately 150% to approximately 160%, approximately 160% to approximately 170%, approximately 170% to approximately 180%, approximately 180% to approximately 190%, approximately 190% to approximately 200%, or any amount of pain relief within the range bounded by any of these values.

[0321] In some embodiments, the combination, compared to dextrolphan alone, is 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 about 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%, The pain relief properties can be improved for any amount of pain relief within the range bounded by approximately 80% to 90%, 90% to 100%, 100% to 110%, 110% to 120%, 120% to 130%, 130% to 140%, 140% to 150%, 150% to 160%, 160% to 170%, 170% to 180%, 180% to 190%, 190% to 200%, or any amount of pain relief between any of these values.

[0322] Unless otherwise specified, references to compounds described herein, such as dextromethorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion, by structure, name, or any other means, include alternative solid forms such as pharmaceutically acceptable salts, polymorphs, solvates, hydrates, tautomers, deuterium-modified compounds such as deuterium-modified dextromethorphan, and any chemical species that can rapidly convert the compound to a compound described herein under conditions in which the compound is used as described herein.

[0323] In some embodiments, an excess amount of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or one stereoisomer of any metabolite or prodrug of these compounds may be administered. In other embodiments, an excess of the S-enantiomer (e.g., 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 an optically isomerically pure S-enantiomer) or an excess of the R-enantiomer (e.g., 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 an optically isomerically pure R-enantiomer) of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds may be administered.

[0324] Examples of deuterium-enriched bupropion and / or enantiopurine deuterium-enriched bupropion include, but are not limited to, the following: [ka] [ka] [ka]

[0325] In some embodiments, both dextromethorphan and bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds are formulated for immediate release, while in other embodiments, both bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds are formulated for sustained release.

[0326] Examples of deuterium-modified dextromethorphan include, but are not limited to, the following: [ka] Contains d6-dextromethorphan.

[0327] The dosage form or composition may be a combination or mixture of dextromethorphan alone or within a vehicle with a compound that inhibits the metabolism of dextromethorphan, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, dextromethorphan and bupropion may be dispersed amongst themselves or together within a vehicle. The dispersion contains a mixture of solid materials, where the small individual particles are substantially one compound, but the small particles are dispersed amongst themselves, as can happen when two powders of two different drugs are compounded with a solid vehicle material, and the compounding takes place in solid form. In some embodiments, dextromethorphan and bupropion may be dispersed substantially uniformly within the composition or dosage form. Alternatively, dextromethorphan and bupropion may be in separate domains or phases within the composition or dosage form. For example, one drug may be in a coating, and the other drug may be in the core within the coating. For example, one drug may be prescribed for sustained release, while the other may be prescribed for immediate release.

[0328] Some embodiments involve the administration of tablets containing bupropion in a dosage form that provides sustained release and dextromethorphan in a dosage form that provides immediate release. While there are various ways to achieve sustained release of bupropion, in some embodiments, bupropion is combined with hydroxypropyl methylcellulose. For example, particles of bupropion hydrochloride may be compounded with microcrystalline cellulose and hydroxypropyl methylcellulose (e.g., METHOCEL®) to form a mixture of compound powders. This may be combined with dextromethorphan for immediate release in a single tablet.

[0329] Dextromethorphan and / or antidepressants such as bupropion, hydroxybupropion, threohydroxybupropion, and erythrohydroxybupropion, or non-bupropion antidepressants (collectively referred to herein as “therapeutic compounds” for convenience) may be combined with a pharmaceutical carrier selected based on the selected route of administration and standard pharmacovigilance described, for example, in Remington's Pharmaceutical Sciences, 2005. The relative proportions of the active ingredient and carrier may be determined, for example, by the solubility and chemical properties of the compounds, the selected route of administration, and standard pharmacovigilance.

[0330] Therapeutic compounds may be administered by any means that brings the activator into contact with a desired site or site of action (one or more) in the patient's body. The compounds may be administered by any conventional means that can be used in conjunction with pharmaceuticals, either as individual therapeutic agents or as a combination of therapeutic agents. For example, they may be administered as the sole activator in a pharmaceutical composition, or they may be used in combination with other therapeutically active ingredients.

[0331] Therapeutic compounds may be administered to human patients in various forms suitable for a selected route of administration, for example, orally or parenterally. In this regard, parenteral administration includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrabursal, transdermal, ocular, sublingual, and buccal transepithelial; and topical administration including ophthalmic, cutaneous, ocular, rectal, and nasal inhalation via air, aerosol, and rectal systemic inhalation.

[0332] The ratio of dextromethorphan to bupropion can vary. In some embodiments, the weight ratio of dextromethorphan to bupropion is 0.1 to about 10, about 0.1 to about 2, about 0.2 to about 1, about 0.1 to about 0.5, about 0.1 to about 0.3, about 0.2 to about 0.4, about 0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1, about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or any ratio within the range bounded by any of these values, or any ratio between any of these values. A ratio of 0.1 indicates that the weight of dextromethorphan is 1 / 10 of that of bupropion. A ratio of 10 indicates that the weight of dextromethorphan is 10 times that of bupropion.

[0333] The amount of dextromethorphan in the therapeutic composition may vary. For example, some liquid compositions contain 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), and about 3% (w / v) to about 5% (w / v). It may contain approximately 5% (w / v) to 7% (w / v), approximately 7% (w / v) to 10% (w / v), approximately 10% (w / v) to 15% (w / v), approximately 15% (w / v) to 20% (w / v), approximately 20% (w / v) to 30% (w / v), approximately 30% (w / v) to 40% (w / v), or approximately 40% (w / v) to 50% (w / v) of dextromethorphan.

[0334] Some liquid dosage forms may contain dextromethorphan in amounts of approximately 10 mg to approximately 500 mg, approximately 30 mg to approximately 350 mg, approximately 50 mg to approximately 200 mg, approximately 50 mg to approximately 70 mg, approximately 20 mg to approximately 50 mg, approximately 30 mg to approximately 60 mg, approximately 40 mg to approximately 50 mg, approximately 40 mg to approximately 55 mg, approximately 40 mg to approximately 42 mg, approximately 42 mg to approximately 44 mg, approximately 44 mg to approximately 46 mg, approximately 46 mg to approximately 48 mg, approximately 48 mg to approximately 50 mg, approximately 80 mg to approximately 100 mg, approximately 110 mg to approximately 130 mg, approximately 170 mg to approximately 190 mg, approximately 45 mg, approximately 60 mg, approximately 90 mg, approximately 120 mg, or approximately 180 mg, or any amount of dextromethorphan within the range bounded by any of these values, or any amount of dextromethorphan between any of these values.

[0335] Some solid compositions contain 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), and about 30% It may contain approximately 50% (w / w) to 40% (w / w), approximately 30% (w / w) to 40% (w / w), approximately 40% (w / w) to 50% (w / w), approximately 50% (w / w) to 80% (w / w), approximately 50% (w / w) to 60% (w / w), approximately 70% (w / w) to 80% (w / w), or approximately 80% (w / w) to 90% (w / w) of dextromethorphan.

[0336] Some solid dosage forms may contain dextromethorphan in amounts of approximately 10 mg to approximately 500 mg, approximately 30 mg to approximately 350 mg, approximately 20 mg to approximately 50 mg, approximately 30 mg to approximately 60 mg, approximately 40 mg to approximately 50 mg, approximately 40 mg to approximately 42 mg, approximately 42 mg to approximately 44 mg, approximately 44 mg to approximately 46 mg, approximately 46 mg to approximately 48 mg, approximately 48 mg to approximately 50 mg, approximately 50 mg to approximately 200 mg, approximately 50 mg to approximately 70 mg, approximately 80 mg to approximately 100 mg, approximately 110 mg to approximately 130 mg, approximately 170 mg to approximately 190 mg, approximately 60 mg, approximately 90 mg, approximately 120 mg, or approximately 180 mg, or any amount of dextromethorphan within the range bounded by any of these values, or any amount of dextromethorphan between any of these values.

[0337] In some embodiments, the amount of dextromethorphan is based on the patient's body weight and ranges from approximately 0.1 mg / kg to approximately 20 mg / kg, approximately 0.75 mg / kg to approximately 7.5 mg / kg, approximately 0.1 mg / kg to approximately 5 mg / kg, approximately 0.1 mg / kg to approximately 3 mg / kg, approximately 0.3 mg / kg to approximately 0.9 mg / kg, approximately 0.3 mg / kg to approximately 1 mg / kg, approximately 0.6 mg / kg to approximately 0.8 mg / kg, and approximately 0.7 mg / kg. The ranges are approximately 0.8 mg / kg, 0.75 mg / kg, 0.4 mg / kg to 1.5 mg / kg, 1 mg / kg to 2 mg / kg, 10 mg / kg to 20 mg / kg, 12 mg / kg to 17 mg / kg, 15 mg / kg to 20 mg / kg, 1 mg / kg, and 1 mg / kg to 10 mg / kg, or any value that is separated by these ranges or any value that lies between them.

[0338] The amounts of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds in the therapeutic composition may vary. If an increase in the plasma concentration of dextromethorphan is desired, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds should be administered in amounts that increase the plasma concentration of dextromethorphan. For example, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds may be administered in amounts that result in a plasma concentration of dextromethorphan in humans 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 higher on day 8, day 9, or day 10 than the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds.

[0339] In some embodiments, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of any of these compounds, at day 8, day 9, or day 10, the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of any of these compounds 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 in the 12-hour region (AUC) under the curve from the time of administration.0-12 ) or 12 hours after administration (C 平均 Dextromethorphan can be administered to humans in amounts that yield the mean plasma concentration in humans for )

[0340] In some embodiments, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of any of these compounds results in a maximum plasma concentration (C) in humans 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 higher on day 8, day 9, or day 10 than the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of any of these compounds. 最大 Dextromethorphan can be administered to humans in amounts that produce the following effects:

[0341] Increased plasma dextromethorphan concentrations due to co-administration of bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or metabolites or prodrugs of any of these compounds may occur on day 1 of administration of bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or metabolites or prodrugs of any of these compounds, compared to the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or metabolites or prodrugs of any of these compounds. For example, the plasma concentration of dextromethorphan on day 1 when bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered may be at least about 1.5 times, at least about 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 higher than the level that can be achieved with the same dose of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0342] In some embodiments, for example, by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, the dextromethorphan AUC on day 1, with increased plasma dextromethorphan concentrations, may be at least twice the AUC that can be achieved with the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0343] In some embodiments, dextromethorphan AUC on the first day was increased by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds. 0-12 This includes at least approximately 15 ng·hours / mL, at least approximately 17 ng·hours / mL, at least approximately 19 ng·hours / mL, at least approximately 20 ng·hours / mL, at least approximately 22 ng·hours / mL, at least approximately 23 ng·hours / mL, at least approximately 24 ng·hours / mL, at least approximately 25 ng·hours / mL, at least approximately 26 ng·hours / mL, at least approximately 27 ng·hours / mL, at least approximately 28 ng·hours / mL, at least approximately 29 ng·hours / mL, at least approximately 30 ng·hours / mL, at least approximately 31 ng·hours / mL, at least approximately 32 ng·hours / mL, at least approximately 33 ng·hours / mL, at least approximately 34 ng·hours / mL, at least approximately 35 ng·hours / mL, at least approximately 36 ng·hours / mL, at least approximately 37 ng·hours / mL, and at least approximately 38 ng·hours / mL. It may be between 10,000 ng·hours / mL, at least about 39 ng·hours / mL, at least about 40 ng·hours / mL, at least about 41 ng·hours / mL, at least about 42 ng·hours / mL, at least about 43 ng·hours / mL, at least about 44 ng·hours / mL, at least about 45 ng·hours / mL, at least about 46 ng·hours / mL, at least about 47 ng·hours / mL, at least about 48 ng·hours / mL, at least about 49 ng·hours / mL, at least about 50 ng·hours / mL, at least about 51 ng·hours / mL, at least about 52 ng·hours / mL, at least about 53 ng·hours / mL, at least about 54 ng·hours / mL, at least about 55 ng·hours / mL, at least about 56 ng·hours / mL, at least about 56.7 ng·hours / mL, and up to 10,000 ng·hours / mL.

[0344] In some embodiments, dextromethorphan AUC on day 8 was increased by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, thereby increasing dextromethorphan plasma concentration. 0-12This includes at least approximately 40 ng·hours / mL, at least approximately 50 ng·hours / mL, at least approximately 60 ng·hours / mL, at least approximately 70 ng·hours / mL, at least approximately 80 ng·hours / mL, at least approximately 90 ng·hours / mL, at least approximately 100 ng·hours / mL, at least approximately 150 ng·hours / mL, at least approximately 200 ng·hours / mL, at least approximately 250 ng·hours / mL, at least approximately 300 ng·hours / mL, at least approximately 350 ng·hours / mL, at least approximately 400 ng·hours / mL, and at least approximately 450 ng·hours / mL. , at least about 500 ng·hours / mL, at least about 550 ng·hours / mL, about 500 ng·hours / mL to about 600 ng·hours / mL, about 500 ng·hours / mL to about 550 ng·hours / mL, about 500 ng·hours / mL to about 525 ng·hours / mL, about 525 ng·hours / mL to about 600 ng·hours / mL, at least about 600 ng·hours / mL, at least about 650 ng·hours / mL, at least about 700 ng·hours / mL, at least about 750 ng·hours / mL, at least about 800 ng·hours / mL, about 800 ng·hours / mL to about 900 ng·hr / mL, approximately 850ng·hr / mL to approximately 900ng·hr / mL, approximately 850ng·hr / mL to approximately 875ng·hr / mL, approximately 875ng·hr / mL to approximately 900ng·hr / mL, approximately 900ng·hr / mL to approximately 1000ng·hr / mL, approximately 1000ng·hr / mL ~ approx. 1100ng · h / mL, approx. 1100ng · h / mL ~ approx. 1200ng · h / mL, approx. 1200ng · h / mL ~ approx. 1300ng · h / mL, approx. 1300ng · h / mL ~ approx. 1400ng · h / mL, approx. 1400ng · h / mL ~ approx. 1500ng · hour / mL, approximately 1500 ng·hour / mL to approximately 1600 ng·hour / mL, approximately 1600 ng·hour / mL to approximately 1700 ng·hour / mL, approximately 1700 ng·hour / mL to approximately 1800 ng·hour / mL, approximately 1800 ng·hour / mL to approximately 2000 ng·hour / mL, at least approximately 850 ng·hour / mL, at least approximately 900 ng·hour / mL, at least approximately 950 ng·hour / mL, at least approximately 1000 ng·hour / mL, at least approximately 1050 ng·hour / mL, at least approximately 1100 ng·hour / mL, at least approximately 1150 ng·hour / mL,It may be at least about 1200 ng·hours / mL, at least about 1250 ng·hours / mL, at least about 1300 ng·hours / mL, at least about 1350 ng·hours / mL, at least about 1400 ng·hours / mL, at least about 1450 ng·hours / mL, at least about 1500 ng·hours / mL, at least about 1550 ng·hours / mL, at least about 1600 ng·hours / mL, at least about 1625 ng·hours / mL, at least about 1650 ng·hours / mL, at least about 1675 ng·hours / mL, or at least about 1686.3 ng·hours / mL, and in some embodiments, it may be up to about 50,000 ng·hours / mL.

[0345] In some embodiments, dextromethorphan AUC on day 8 was increased by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, thereby increasing dextromethorphan plasma concentration. 0-24This includes at least approximately 50 ng·hours / mL, at least approximately 75 ng·hours / mL, at least approximately 100 ng·hours / mL, at least approximately 200 ng·hours / mL, at least approximately 300 ng·hours / mL, at least approximately 400 ng·hours / mL, at least approximately 500 ng·hours / mL, at least approximately 600 ng·hours / mL, at least approximately 700 ng·hours / mL, at least approximately 800 ng·hours / mL, at least approximately 900 ng·hours / mL, at least approximately 1000 ng·hours / mL, at least approximately 1100 ng·hours / mL, at least approximately 1200 ng·hours / mL, at least approximately 1300 ng·hours / mL, at least approximately 1400 ng·hours / mL, at least approximately 1500 ng·hours / mL, at least approximately 1600 ng·hours / mL, and at least approximately 1700 It may be ng·hours / mL, at least about 1800 ng·hours / mL, at least about 1900 ng·hours / mL, at least about 2000 ng·hours / mL, at least about 2100 ng·hours / mL, at least about 2200 ng·hours / mL, at least about 2300 ng·hours / mL, at least about 2400 ng·hours / mL, at least about 2500 ng·hours / mL, at least about 2600 ng·hours / mL, at least about 2700 ng·hours / mL, at least about 2800 ng·hours / mL, at least about 1850 ng·hours / mL, at least about 2900 ng·hours / mL, at least about 2950 ng·hours / mL, or at least about 2975.3 ng·hours / mL, and in some embodiments it may be up to about 100,000 ng·hours / mL.

[0346] In some embodiments, dextromethorphan AUC on day 8 was increased by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, thereby increasing dextromethorphan plasma concentration. 0-infThis includes at least approximately 75 ng·hours / mL, at least approximately 100 ng·hours / mL, at least approximately 200 ng·hours / mL, at least approximately 300 ng·hours / mL, at least approximately 400 ng·hours / mL, at least approximately 500 ng·hours / mL, at least approximately 600 ng·hours / mL, at least approximately 700 ng·hours / mL, at least approximately 800 ng·hours / mL, at least approximately 900 ng·hours / mL, at least approximately 1000 ng·hours / mL, at least approximately 1100 ng·hours / mL, at least approximately 1200 ng·hours / mL, and at least approximately 1300 ng·hours / mL. g·hours / mL, at least about 1400 ng·hours / mL, at least about 1500 ng·hours / mL, at least about 1600 ng·hours / mL, at least about 1700 ng·hours / mL, at least about 1800 ng·hours / mL, at least about 1900 ng·hours / mL, at least about 2000 ng·hours / mL, at least about 2100 ng·hours / mL, at least about 2200 ng·hours / mL, at least about 2300 ng·hours / mL, at least about 2400 ng·hours / mL, at least about 2500 ng·hours / mL, at least about 2600 ng·hours hours / mL, at least about 2700 ng·hours / mL, at least about 2800 ng·hours / mL, at least about 2900 ng·hours / mL, at least about 3000 ng·hours / mL, at least about 3100 ng·hours / mL, at least about 3200 ng·hours / mL, at least about 3300 ng·hours / mL, at least about 3400 ng·hours / mL, at least about 3500 ng·hours / mL, at least about 3600 ng·hours / mL, at least about 3700 ng·hours / mL, at least about 3800 ng·hours / mL, at least about 3900 ng·hours / mL mL, at least about 4000 ng·hours / mL, at least about 4100 ng·hours / mL, at least about 4200 ng·hours / mL, at least about 4300 ng·hours / mL, at least about 4400 ng·hours / mL, at least about 4500 ng·hours / mL, at least about 4600 ng·hours / mL, at least about 4700 ng·hours / mL, at least about 4800 ng·hours / mL, at least about 4900 ng·hours / mL, at least about 5000 ng·hours / mL, at least about 5100 ng·hours / mL, at least about 5200 ng·hours / mL,At least approximately 5300 ng·hours / mL, at least approximately 5400 ng·hours / mL, at least approximately 5500 ng·hours / mL, at least approximately 5600 ng·hours / mL, at least approximately 5700 ng·hours / mL, at least approximately 5800 ng·hours / mL, at least approximately 5900 ng·hours / mL, at least approximately 6000 ng·hours / mL, at least approximately 6100 ng·hours / mL, at least approximately 6200 ng·hours / mL, at least approximately 6300 ng·hours / mL, at least approximately 6400 ng·hours / mL, and at least It may be approximately 6500 ng·hours / mL, at least approximately 6600 ng·hours / mL, at least approximately 6700 ng·hours / mL, at least approximately 6800 ng·hours / mL, at least approximately 6900 ng·hours / mL, at least approximately 7000 ng·hours / mL, at least approximately 7100 ng·hours / mL, at least approximately 7150 ng·hours / mL, at least approximately 7200 ng·hours / mL, or at least approximately 7237.3 ng·hours / mL, and in some embodiments, it may be up to approximately 100,000 ng·hours / mL.

[0347] In some embodiments, dextromethorphan AUC on day 9 was increased by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, thereby increasing dextromethorphan plasma concentration. 0-12This includes at least approximately 40 ng·hours / mL, at least approximately 50 ng·hours / mL, at least approximately 60 ng·hours / mL, at least approximately 70 ng·hours / mL, at least approximately 80 ng·hours / mL, at least approximately 90 ng·hours / mL, at least approximately 100 ng·hours / mL, at least approximately 150 ng·hours / mL, at least approximately 200 ng·hours / mL, at least approximately 250 ng·hours / mL, at least approximately 300 ng·hours / mL, at least approximately 350 ng·hours / mL, and at least Approximately 400 ng·hours / mL, at least approximately 450 ng·hours / mL, at least approximately 500 ng·hours / mL, at least approximately 550 ng·hours / mL, approximately 500 ng·hours / mL to approximately 600 ng·hours / mL, approximately 500 ng·hours / mL to approximately 550 ng·hours / mL, approximately 500 ng·hours / mL to approximately 525 ng·hours / mL, approximately 525 ng·hours / mL to approximately 600 ng·hours / mL, at least approximately 600 ng·hours / mL, at least approximately 650 ng·hours / mL, at least approximately 700 ng·hours / mL g·hours / mL, at least about 750 ng·hours / mL, at least about 800 ng·hours / mL, about 800 ng·hours / mL to about 900 ng·hours / mL, about 850 ng·hours / mL to about 900 ng·hours / mL, about 850 ng·hours / mL to about 875 ng·hours / mL, about 875 ng·hours / mL to about 900 ng·hours / mL, about 900 ng·hours / mL to about 1,000 ng·hours / mL, about 1,000 ng·hours / mL to about 1,100 ng·hours / mL, about 1,100 ng·hours / mL~approx. 1,200ng·hr / mL, approx. 1,200ng·hr / mL~approx. 1,300ng·hr / mL, approx. 1,300ng·hr / mL~approx. 1,400ng·hr / mL, approx. 1,400ng·hr / mL~approx. 1,500ng·hr / mL , about 1,500ng·hr / mL to about 1,600ng·hr / mL, about 1,600ng·hr / mL to about 1,700ng·hr / mL, about 1,700ng·hr / mL to about 1,800ng·hr / mL, about 1,800ng·hr / mL to about 2,000 ng·hour / mL, at least about 850 ng·hour / mL, at least about 900 ng·hour / mL, at least about 950 ng·hour / mL, at least about 1000 ng·hour / mL, at least about 1050 ng·hour / mL, at least about 1100 ng·hour / mL, at least about 1150 ng·hour / mL, at least about 1200 ng·hour / mL, at least about 1250 ng·hour / mL, at least about 1300 ng·hour / mL, at least about 1350 ng·hour / mL It may be at least about 1400 ng·hours / mL, at least about 1450 ng·hours / mL, at least about 1500 ng·hours / mL, at least about 1550 ng·hours / mL, at least about 1600 ng·hours / mL, at least about 1625 ng·hours / mL, at least about 1650 ng·hours / mL, at least about 1675 ng·hours / mL, or at least about 1686.3 ng·hours / mL, and in some embodiments, it may be up to about 50,000 ng·hours / mL.

[0348] In some embodiments, dextromethorphan AUC on day 9 was increased by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, thereby increasing dextromethorphan plasma concentration. 0-24This includes at least approximately 50 ng·hours / mL, at least approximately 75 ng·hours / mL, at least approximately 100 ng·hours / mL, at least approximately 200 ng·hours / mL, at least approximately 300 ng·hours / mL, at least approximately 400 ng·hours / mL, at least approximately 500 ng·hours / mL, at least approximately 600 ng·hours / mL, at least approximately 700 ng·hours / mL, at least approximately 800 ng·hours / mL, at least approximately 900 ng·hours / mL, at least approximately 1000 ng·hours / mL, at least approximately 1100 ng·hours / mL, at least approximately 1200 ng·hours / mL, at least approximately 1300 ng·hours / mL, at least approximately 1400 ng·hours / mL, at least approximately 1500 ng·hours / mL, at least approximately 1600 ng·hours / mL, and at least approximately 1700 It may be ng·hours / mL, at least about 1800 ng·hours / mL, at least about 1900 ng·hours / mL, at least about 2000 ng·hours / mL, at least about 2100 ng·hours / mL, at least about 2200 ng·hours / mL, at least about 2300 ng·hours / mL, at least about 2400 ng·hours / mL, at least about 2500 ng·hours / mL, at least about 2600 ng·hours / mL, at least about 2700 ng·hours / mL, at least about 2800 ng·hours / mL, at least about 1850 ng·hours / mL, at least about 2900 ng·hours / mL, at least about 2950 ng·hours / mL, or at least about 2975.3 ng·hours / mL, and in some embodiments it may be up to about 100,000 ng·hours / mL.

[0349] In some embodiments, dextromethorphan AUC on day 9 was increased by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, thereby increasing dextromethorphan plasma concentration. 0-infThis includes at least approximately 75 ng·hours / mL, at least approximately 100 ng·hours / mL, at least approximately 200 ng·hours / mL, at least approximately 300 ng·hours / mL, at least approximately 400 ng·hours / mL, at least approximately 500 ng·hours / mL, at least approximately 600 ng·hours / mL, at least approximately 700 ng·hours / mL, at least approximately 800 ng·hours / mL, at least approximately 900 ng·hours / mL, at least approximately 1000 ng·hours / mL, at least approximately 1100 ng·hours / mL, at least approximately 1200 ng·hours / mL, and at least approximately 1300 ng·hours / mL. g·hours / mL, at least about 1400 ng·hours / mL, at least about 1500 ng·hours / mL, at least about 1600 ng·hours / mL, at least about 1700 ng·hours / mL, at least about 1800 ng·hours / mL, at least about 1900 ng·hours / mL, at least about 2000 ng·hours / mL, at least about 2100 ng·hours / mL, at least about 2200 ng·hours / mL, at least about 2300 ng·hours / mL, at least about 2400 ng·hours / mL, at least about 2500 ng·hours / mL, at least about 2600 ng·hours hours / mL, at least about 2700 ng·hours / mL, at least about 2800 ng·hours / mL, at least about 2900 ng·hours / mL, at least about 3000 ng·hours / mL, at least about 3100 ng·hours / mL, at least about 3200 ng·hours / mL, at least about 3300 ng·hours / mL, at least about 3400 ng·hours / mL, at least about 3500 ng·hours / mL, at least about 3600 ng·hours / mL, at least about 3700 ng·hours / mL, at least about 3800 ng·hours / mL, at least about 3900 ng·hours / mL mL, at least about 4000 ng·hours / mL, at least about 4100 ng·hours / mL, at least about 4200 ng·hours / mL, at least about 4300 ng·hours / mL, at least about 4400 ng·hours / mL, at least about 4500 ng·hours / mL, at least about 4600 ng·hours / mL, at least about 4700 ng·hours / mL, at least about 4800 ng·hours / mL, at least about 4900 ng·hours / mL, at least about 5000 ng·hours / mL, at least about 5100 ng·hours / mL, at least about 5200 ng·hours / mL,At least approximately 5300 ng·hours / mL, at least approximately 5400 ng·hours / mL, at least approximately 5500 ng·hours / mL, at least approximately 5600 ng·hours / mL, at least approximately 5700 ng·hours / mL, at least approximately 5800 ng·hours / mL, at least approximately 5900 ng·hours / mL, at least approximately 6000 ng·hours / mL, at least approximately 6100 ng·hours / mL, at least approximately 6200 ng·hours / mL, at least approximately 6300 ng·hours / mL, at least approximately 6400 ng·hours / mL, and at least It may be approximately 6500 ng·hours / mL, at least approximately 6600 ng·hours / mL, at least approximately 6700 ng·hours / mL, at least approximately 6800 ng·hours / mL, at least approximately 6900 ng·hours / mL, at least approximately 7000 ng·hours / mL, at least approximately 7100 ng·hours / mL, at least approximately 7150 ng·hours / mL, at least approximately 7200 ng·hours / mL, or at least approximately 7237.3 ng·hours / mL, and in some embodiments, it may be up to approximately 100,000 ng·hours / mL.

[0350] In some embodiments, dextromethorphan AUC on day 10 was increased by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, thereby increasing dextromethorphan plasma concentration. 0-12This includes at least approximately 40 ng·hours / mL, at least approximately 50 ng·hours / mL, at least approximately 60 ng·hours / mL, at least approximately 70 ng·hours / mL, at least approximately 80 ng·hours / mL, at least approximately 90 ng·hours / mL, at least approximately 100 ng·hours / mL, at least approximately 150 ng·hours / mL, at least approximately 200 ng·hours / mL, at least approximately 250 ng·hours / mL, at least approximately 300 ng·hours / mL, at least approximately 350 ng·hours / mL, and at least Approximately 400 ng·hours / mL, at least approximately 450 ng·hours / mL, at least approximately 500 ng·hours / mL, at least approximately 550 ng·hours / mL, approximately 500 ng·hours / mL to approximately 600 ng·hours / mL, approximately 500 ng·hours / mL to approximately 550 ng·hours / mL, approximately 500 ng·hours / mL to approximately 525 ng·hours / mL, approximately 525 ng·hours / mL to approximately 600 ng·hours / mL, at least approximately 600 ng·hours / mL, at least approximately 650 ng·hours / mL, at least approximately 700 ng·hours / mL g·hours / mL, at least about 750 ng·hours / mL, at least about 800 ng·hours / mL, about 800 ng·hours / mL to about 900 ng·hours / mL, about 850 ng·hours / mL to about 900 ng·hours / mL, about 850 ng·hours / mL to about 875 ng·hours / mL, about 875 ng·hours / mL to about 900 ng·hours / mL, about 900 ng·hours / mL to about 1,000 ng·hours / mL, about 1,000 ng·hours / mL to about 1,100 ng·hours / mL, about 1,100 ng·hours / mL~approx. 1,200ng·hr / mL, approx. 1,200ng·hr / mL~approx. 1,300ng·hr / mL, approx. 1,300ng·hr / mL~approx. 1,400ng·hr / mL, approx. 1,400ng·hr / mL~approx. 1,500ng·hr / mL , about 1,500ng·hr / mL to about 1,600ng·hr / mL, about 1,600ng·hr / mL to about 1,700ng·hr / mL, about 1,700ng·hr / mL to about 1,800ng·hr / mL, about 1,800ng·hr / mL to about 2,000 ng·hour / mL, at least about 850 ng·hour / mL, at least about 900 ng·hour / mL, at least about 950 ng·hour / mL, at least about 1000 ng·hour / mL, at least about 1050 ng·hour / mL, at least about 1100 ng·hour / mL, at least about 1150 ng·hour / mL, at least about 1200 ng·hour / mL, at least about 1250 ng·hour / mL, at least about 1300 ng·hour / mL, at least about 1350 ng·hour / mL, at least about 1400 ng·hour / mL, at least about 1450 ng·hour / mL, at least about 1500 ng·hour / mL, at least about 1550 ng·hour / mL, at least about 1600 ng·hour / mL, at least about 1625 ng·hour / mL, at least about 1650 ng·hour / mL, at least about 1675 It may be ng·time / mL, or at least about 1686.3 ng·time / mL, and in some embodiments, it may be up to about 50,000 ng·time / mL.

[0351] In some embodiments, dextromethorphan AUC on day 10 was increased by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, thereby increasing dextromethorphan plasma concentration. 0-24This includes at least approximately 50 ng·hours / mL, at least approximately 75 ng·hours / mL, at least approximately 100 ng·hours / mL, at least approximately 200 ng·hours / mL, at least approximately 300 ng·hours / mL, at least approximately 400 ng·hours / mL, at least approximately 500 ng·hours / mL, at least approximately 600 ng·hours / mL, at least approximately 700 ng·hours / mL, at least approximately 800 ng·hours / mL, at least approximately 900 ng·hours / mL, at least approximately 1000 ng·hours / mL, at least approximately 1100 ng·hours / mL, at least approximately 1200 ng·hours / mL, at least approximately 1300 ng·hours / mL, at least approximately 1400 ng·hours / mL, at least approximately 1500 ng·hours / mL, at least approximately 1600 ng·hours / mL, and at least approximately 1700 It may be ng·hours / mL, at least about 1800 ng·hours / mL, at least about 1900 ng·hours / mL, at least about 2000 ng·hours / mL, at least about 2100 ng·hours / mL, at least about 2200 ng·hours / mL, at least about 2300 ng·hours / mL, at least about 2400 ng·hours / mL, at least about 2500 ng·hours / mL, at least about 2600 ng·hours / mL, at least about 2700 ng·hours / mL, at least about 2800 ng·hours / mL, at least about 1850 ng·hours / mL, at least about 2900 ng·hours / mL, at least about 2950 ng·hours / mL, or at least about 2975.3 ng·hours / mL, and in some embodiments it may be up to about 100,000 ng·hours / mL.

[0352] In some embodiments, dextromethorphan AUC on day 10 was increased by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, thereby increasing dextromethorphan plasma concentration. 0-infThis includes at least approximately 75 ng·hours / mL, at least approximately 100 ng·hours / mL, at least approximately 200 ng·hours / mL, at least approximately 300 ng·hours / mL, at least approximately 400 ng·hours / mL, at least approximately 500 ng·hours / mL, at least approximately 600 ng·hours / mL, at least approximately 700 ng·hours / mL, at least approximately 800 ng·hours / mL, at least approximately 900 ng·hours / mL, at least approximately 1000 ng·hours / mL, at least approximately 1100 ng·hours / mL, at least approximately 1200 ng·hours / mL, and at least approximately 1300 ng·hours / mL. g·hours / mL, at least about 1400 ng·hours / mL, at least about 1500 ng·hours / mL, at least about 1600 ng·hours / mL, at least about 1700 ng·hours / mL, at least about 1800 ng·hours / mL, at least about 1900 ng·hours / mL, at least about 2000 ng·hours / mL, at least about 2100 ng·hours / mL, at least about 2200 ng·hours / mL, at least about 2300 ng·hours / mL, at least about 2400 ng·hours / mL, at least about 2500 ng·hours / mL, at least about 2600 ng·hours hours / mL, at least about 2700 ng·hours / mL, at least about 2800 ng·hours / mL, at least about 2900 ng·hours / mL, at least about 3000 ng·hours / mL, at least about 3100 ng·hours / mL, at least about 3200 ng·hours / mL, at least about 3300 ng·hours / mL, at least about 3400 ng·hours / mL, at least about 3500 ng·hours / mL, at least about 3600 ng·hours / mL, at least about 3700 ng·hours / mL, at least about 3800 ng·hours / mL, at least about 3900 ng·hours / mL mL, at least about 4000 ng·hours / mL, at least about 4100 ng·hours / mL, at least about 4200 ng·hours / mL, at least about 4300 ng·hours / mL, at least about 4400 ng·hours / mL, at least about 4500 ng·hours / mL, at least about 4600 ng·hours / mL, at least about 4700 ng·hours / mL, at least about 4800 ng·hours / mL, at least about 4900 ng·hours / mL, at least about 5000 ng·hours / mL, at least about 5100 ng·hours / mL, at least about 5200 ng·hours / mL,At least approximately 5300 ng·hours / mL, at least approximately 5400 ng·hours / mL, at least approximately 5500 ng·hours / mL, at least approximately 5600 ng·hours / mL, at least approximately 5700 ng·hours / mL, at least approximately 5800 ng·hours / mL, at least approximately 5900 ng·hours / mL, at least approximately 6000 ng·hours / mL, at least approximately 6100 ng·hours / mL, at least approximately 6200 ng·hours / mL, at least approximately 6300 ng·hours / mL, at least approximately 6400 ng·hours / mL, and at least It may be approximately 6500 ng·hours / mL, at least approximately 6600 ng·hours / mL, at least approximately 6700 ng·hours / mL, at least approximately 6800 ng·hours / mL, at least approximately 6900 ng·hours / mL, at least approximately 7000 ng·hours / mL, at least approximately 7100 ng·hours / mL, at least approximately 7150 ng·hours / mL, at least approximately 7200 ng·hours / mL, or at least approximately 7237.3 ng·hours / mL, and in some embodiments, it may be up to approximately 100,000 ng·hours / mL.

[0353] In some embodiments, dextromethorphan C1 plasma concentrations were elevated by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or metabolites or prodrugs of any of these compounds. 最大 This can be achieved by administering the same amount of bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite of any of these compounds or dextromethorphan without a prodrug. 最大 It could be at least twice that amount.

[0354] In some embodiments, dextromethorphan C on the first day of increased dextromethorphan plasma concentration is achieved by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds. 最大This includes 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, and at least Approximately 4.2 ng / mL, at least approximately 4.3 ng / mL, at least approximately 4.4 ng / mL, at least approximately 4.5 ng / mL, at least approximately 4.6 ng / mL, at least approximately 4.7 ng / mL, at least approximately 4.8 ng / mL, at least approximately 4.9 ng / mL, at least approximately 5.0 ng / mL, at least approximately 5.1 ng / mL, at least approximately 5.2 ng / mL, at least approximately 5.3 ng / mL, at least approximately 5.4 ng / mL, at least approximately 5.5 ng / mL, at least approximately 5.6 ng / mL, at least approximately 5.7 ng / mL, at least approximately 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, and at least It may be approximately 7.4 ng / mL, at least approximately 7.5 ng / mL, at least approximately 7.6 ng / mL, at least approximately 7.7 ng / mL, at least approximately 7.8 ng / mL, at least approximately 7.9 ng / mL, at least approximately 8.0 ng / mL, at least approximately 8.1 ng / mL, at least approximately 8.2 ng / mL, at least approximately 8.3 ng / mL, at least approximately 8.4 ng / mL, at least approximately 8.5 ng / mL, at least approximately 8.6 ng / mL, or at least approximately 8.7 ng / mL, and in some embodiments, it may be up to approximately 1000 ng·hour / mL.

[0355] In some embodiments, dextromethorphan C2 was co-administered with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, resulting in elevated dextromethorphan plasma concentrations on day 8. 最大This includes approximately 50 ng / mL to 60 ng / mL, approximately 50 ng / mL to 55 ng / mL, approximately 55 ng / mL to 60 ng / mL, approximately 80 ng / mL to 90 ng / mL, approximately 80 ng / mL to 85 ng / mL, approximately 85 ng / mL to 90 ng / mL, approximately 90 ng / mL to 95 ng / mL, approximately 95 ng / mL to 100 ng / mL, approximately 100 ng / mL to 105 ng / mL, approximately 105 ng / mL to 110 ng / mL, approximately 110 ng / mL to 115 ng / mL, approximately 115 ng / mL to 120 ng / mL, and approximately 120 ng / mL to 1 30 ng / mL, approximately 130 ng / mL to approximately 135 ng / mL, approximately 135 ng / mL to approximately 140 ng / mL, approximately 140 ng / mL to approximately 145 ng / mL, approximately 145 ng / mL to approximately 150 ng / mL, approximately 150 ng / mL to approximately 155 ng / mL, approximately 155 ng / mL to approximately 160 ng / mL, approximately 160 ng / mL to approximately 170 ng / mL, approximately 170 ng / mL to approximately 200 ng / mL, at least approximately 6.0 ng / mL, at least approximately 7.0 ng / mL, at least approximately 8.0 ng / mL, at least approximately 9.0 ng / mL, at least approximately 10 ng / mL 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 L may be 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 may be up to about 10,000 ng / mL in some embodiments.

[0356] In some embodiments, dextromethorphan C2 was co-administered with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, resulting in elevated dextromethorphan plasma concentrations on day 9. 最大This ranges from approximately 50 ng / mL to 60 ng / mL, 50 ng / mL to 55 ng / mL, 55 ng / mL to 60 ng / mL, 80 ng / mL to 90 ng / mL, 80 ng / mL to 85 ng / mL, 85 ng / mL to 90 ng / mL, 90 ng / mL to 95 ng / mL, 95 ng / mL to 100 ng / mL, 100 ng / mL to 105 ng / mL, 105 ng / mL to 110 ng / mL, 110 ng / mL to 115 ng / mL, and 115 ng / mL to 120 ng / mL, approximately 120 ng / mL to approximately 130 ng / mL, approximately 130 ng / mL to approximately 135 ng / mL, approximately 135 ng / mL to approximately 140 ng / mL, approximately 140 ng / mL to approximately 145 ng / mL, approximately 145 ng / mL to approximately 150 ng / mL, approximately 150 ng / mL to approximately 155 ng / mL, approximately 155 ng / mL to approximately 160 ng / mL, approximately 160 ng / mL to approximately 170 ng / mL, approximately 170 ng / mL to approximately 200 ng / mL, at least approximately 6.0 ng / mL, at least approximately 7.0 ng / mL, at least approximately 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 It can be 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 it can be up to about 10,000 ng / mL.

[0357] In some embodiments, dextromethorphan C10 plasma concentrations were elevated by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds. 最大This includes approximately 50 ng / mL to 60 ng / mL, approximately 50 ng / mL to 55 ng / mL, approximately 55 ng / mL to 60 ng / mL, approximately 80 ng / mL to 90 ng / mL, approximately 80 ng / mL to 85 ng / mL, approximately 85 ng / mL to 90 ng / mL, approximately 90 ng / mL to 95 ng / mL, approximately 95 ng / mL to 100 ng / mL, approximately 100 ng / mL to 105 ng / mL, approximately 105 ng / mL to 110 ng / mL, approximately 110 ng / mL to 115 ng / mL, approximately 115 ng / mL to 120 ng / mL, and approximately 120 ng / mL to 1 30 ng / mL, approximately 130 ng / mL to approximately 135 ng / mL, approximately 135 ng / mL to approximately 140 ng / mL, approximately 140 ng / mL to approximately 145 ng / mL, approximately 145 ng / mL to approximately 150 ng / mL, approximately 150 ng / mL to approximately 155 ng / mL, approximately 155 ng / mL to approximately 160 ng / mL, approximately 160 ng / mL to approximately 170 ng / mL, approximately 170 ng / mL to approximately 200 ng / mL, at least approximately 6.0 ng / mL, at least approximately 7.0 ng / mL, at least approximately 8.0 ng / mL, at least approximately 9.0 ng / mL, at least approximately 10 ng / mL 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 L may be 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 may be up to about 10,000 ng / mL in some embodiments.

[0358] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of any of these compounds is administered over the period between two separate and consecutive doses of dextromethorphan in amounts of 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, and 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 140.5ng / mL, about 20ng / mL to about 30ng / mL, about 30ng / mL to about 40ng / mL, about 40ng / mL to about 50ng / mL, about 50ng / mL to about 55ng / mL, about 55ng / mL to about 60ng / mL, about 80ng / mL to about 90ng / mL, about 80ng / mL Approximately 85ng / mL, approximately 85ng / mL to approximately 90ng / mL, approximately 90ng / mL to approximately 95ng / mL, approximately 95ng / mL to approximately 100ng / mL, approximately 100ng / mL to approximately 105ng / mL, approximately 105ng / mL to approximately 110ng / mL, approximately 110ng / mL to approximately 115ng / mL, The possible concentrations of dextromethorphan C are approximately 115 ng / mL to 120 ng / mL, 120 ng / mL to 130 ng / mL, 130 ng / mL to 135 ng / mL, 135 ng / mL to 140 ng / mL, 140 ng / mL to 145 ng / mL, 145 ng / mL to 150 ng / mL, 150 ng / mL to 155 ng / mL, 155 ng / mL to 160 ng / mL, 160 ng / mL to 170 ng / mL, and 170 ng / mL to 200 ng / mL, and in some embodiments up to approximately 10,000 ng / mL. 平均 It is administered in an amount that produces the desired effect. For example, if dextromethorphan is administered at 8:00 a.m. and 8:00 p.m. on day 1, but not after 8:00 a.m. and before 8:00 p.m. on day 1, the period between the two separate and consecutive administrations of dextromethorphan is from immediately after 8:00 a.m. on day 1 to immediately before 8:00 p.m.

[0359] In some embodiments, dextromethorphan C2 was co-administered with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, resulting in elevated dextromethorphan plasma concentrations on day 8. 平均This includes at least approximately 4.0 ng / mL, at least approximately 5.0 ng / mL, at least approximately 6.0 ng / mL, at least approximately 7.0 ng / mL, at least approximately 8.0 ng / mL, at least approximately 9.0 ng / mL, at least approximately 10 ng / mL, at least approximately 15 ng / mL, at least approximately 20 ng / mL, at least approximately 25 ng / mL, at least approximately 30 ng / mL, at least approximately 35 ng / mL, at least approximately 40 ng / mL, at least approximately 45 ng / mL, at least approximately 50 ng / mL, at least approximately 55 ng / mL, and at least approximately 60 ng / mL. L, 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 1 40.5ng / mL, about 20ng / mL to about 30ng / mL, about 30ng / mL to about 40ng / mL, about 40ng / mL to about 50ng / mL, about 50ng / mL to about 55ng / mL, about 55ng / mL to about 60ng / mL, about 80ng / mL to about 90ng / mL, about 80n g / mL~about 85ng / mL, about 85ng / mL~about 90ng / mL, about 90ng / mL~about 95ng / mL, about 95ng / mL~about 100ng / mL, about 100ng / mL~about 105ng / mL, about 105ng / mL~about 110ng / mL, about 110ng / mL~about 11 It can be 5 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, and about 170 ng / mL to about 200 ng / mL, and in some embodiments it can be up to about 10,000 ng / mL. 平均The value is C, which is the period between two separate and consecutive doses of dextromethorphan, or when dextromethorphan is administered only once on day 8. 平均 This may be in reference to the 12 hours following the first dose of dextromethorphan.

[0360] In some embodiments, dextromethorphan C2 was co-administered with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, resulting in elevated dextromethorphan plasma concentrations on day 9. 平均This includes at least approximately 4.0 ng / mL, at least approximately 5.0 ng / mL, at least approximately 6.0 ng / mL, at least approximately 7.0 ng / mL, at least approximately 8.0 ng / mL, at least approximately 9.0 ng / mL, at least approximately 10 ng / mL, at least approximately 15 ng / mL, at least approximately 20 ng / mL, at least approximately 25 ng / mL, at least approximately 30 ng / mL, at least approximately 35 ng / mL, at least approximately 40 ng / mL, at least approximately 45 ng / mL, at least approximately 50 ng / mL, at least approximately 55 ng / mL, and at least approximately 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 20ng / mL to about 30ng / mL, about 30ng / mL to about 40ng / mL, about 40ng / mL to about 50ng / mL, about 50ng / mL to about 55ng / mL, about 55ng / mL to about 60ng / mL, about 80ng / mL to about 90ng / mL, about 80ng / m L ~ about 85ng / mL, about 85ng / mL - about 90ng / mL, about 90ng / mL - about 95ng / mL, about 95ng / mL - about 100ng / mL, about 100ng / mL - about 105ng / mL, about 105ng / mL - about 110ng / mL, about 110ng / mL - about 115n The values ​​can range from g / mL, approximately 115 ng / mL to approximately 120 ng / mL, approximately 120 ng / mL to approximately 130 ng / mL, approximately 130 ng / mL to approximately 135 ng / mL, approximately 135 ng / mL to approximately 140 ng / mL, approximately 140 ng / mL to approximately 145 ng / mL, approximately 145 ng / mL to approximately 150 ng / mL, approximately 150 ng / mL to approximately 155 ng / mL, approximately 155 ng / mL to approximately 160 ng / mL, approximately 160 ng / mL to approximately 170 ng / mL, and approximately 170 ng / mL to approximately 200 ng / mL, and in some embodiments, up to approximately 10,000 ng / mL. 平均The value is the period between two separate and consecutive doses of dextromethorphan, or if dextromethorphan is administered only once on day 9, C 平均 This may be in reference to the 12 hours following the first dose of dextromethorphan.

[0361] In some embodiments, dextromethorphan C10 plasma concentrations were elevated by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds. 平均This includes at least approximately 4.0 ng / mL, at least approximately 5.0 ng / mL, at least approximately 6.0 ng / mL, at least approximately 7.0 ng / mL, at least approximately 8.0 ng / mL, at least approximately 9.0 ng / mL, at least approximately 10 ng / mL, at least approximately 15 ng / mL, at least approximately 20 ng / mL, at least approximately 25 ng / mL, at least approximately 30 ng / mL, at least approximately 35 ng / mL, at least approximately 40 ng / mL, at least approximately 45 ng / mL, at least approximately 50 ng / mL, at least approximately 55 ng / mL, and at least approximately 60 ng / mL. L, 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 1 40.5ng / mL, about 20ng / mL to about 30ng / mL, about 30ng / mL to about 40ng / mL, about 40ng / mL to about 50ng / mL, about 50ng / mL to about 55ng / mL, about 55ng / mL to about 60ng / mL, about 80ng / mL to about 90ng / mL, about 80n g / mL~about 85ng / mL, about 85ng / mL~about 90ng / mL, about 90ng / mL~about 95ng / mL, about 95ng / mL~about 100ng / mL, about 100ng / mL~about 105ng / mL, about 105ng / mL~about 110ng / mL, about 110ng / mL~about 11 It can be 5 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, and about 170 ng / mL to about 200 ng / mL, and in some embodiments it can be up to about 10,000 ng / mL. 平均The value is the period between two separate and consecutive doses of dextromethorphan, or if dextromethorphan is administered only once on day 10, C 平均 This may be in reference to the 12 hours following the first dose of dextromethorphan.

[0362] The variation index value FI(%) of dextromethorphan can be calculated using the following formula.

number

[0363] In some embodiments, for example, by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, the dextromethorphan FI (%) on day 8, when the plasma concentration of dextromethorphan is increased, is at least 1.5 times or at least 2 times lower compared to when dextromethorphan is administered for 8 days without increasing the plasma concentration by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of these compounds.

[0364] In some embodiments, for example, by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, the dextromethorphan FI (%) on day 9, when the plasma concentration of dextromethorphan is increased, is at least 1.5 times or at least 2 times lower compared to when dextromethorphan is administered for 9 days without increasing the plasma concentration by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of these compounds.

[0365] In some embodiments, for example, by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, the dextromethorphan FI (%) on day 10, with increased plasma concentrations of dextromethorphan, is reduced by at least 1.5 times or at least 2 times compared to when dextromethorphan is administered for 10 days without increasing plasma concentrations by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of these compounds.

[0366] In some embodiments, the dextromethorphan FI(%) on day 8, after increased plasma concentrations of dextromethorphan by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, is any FI(%) value within the range of less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any FI(%) value within any of these ranges.

[0367] In some embodiments, the plasma concentration of dextromethorphan is increased by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, and the dextromethorphan FI(%) on day 9 is less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any FI(%) value within the range defined by any of these values.

[0368] In some embodiments, the dextromethorphan FI(%) on day 10, in which the plasma concentration of dextromethorphan is increased by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, is any FI(%) value within the range of less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any FI(%) value within any of these ranges.

[0369] In some embodiments, for example, co-administration of dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds results in an increased plasma concentration of dextromethorphan, and the dextromethorphan FI (%) on day 8 is reduced by at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, or at least 6 times compared to the case where dextromethorphan is administered for 8 days without increasing plasma concentration by co-administration of bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds.

[0370] In some embodiments, for example, co-administration of dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds results in an increased plasma concentration of dextromethorphan, and the dextromethorphan FI (%) on day 9 is reduced by at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, or at least 6 times compared to the case where dextromethorphan is administered for 9 days without increasing plasma concentration by co-administration of bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds.

[0371] In some embodiments, for example, co-administration of dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds results in a dextromethorphan FI (%) on day 10 with increased plasma concentrations of dextromethorphan, which is reduced by at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, or at least 6 times compared to the case where dextromethorphan is administered for 10 days without increasing plasma concentrations by co-administration of bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds.

[0372] In some embodiments, the dextromethorphan FI(%) on day 8, after increased plasma concentrations of dextromethorphan by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, is any FI(%) value within the range of less than 100%, less than 70%, less than 60%, less than 50%, about 30-70%, about 30-60%, about 30-50%, or any FI(%) value within these ranges.

[0373] In some embodiments, the dextromethorphan FI(%) on day 9, in which the plasma concentration of dextromethorphan is increased by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, is any FI(%) value within the range of less than 100%, less than 70%, less than 60%, less than 50%, about 30-70%, about 30-60%, about 30-50%, or any FI(%) value within any of these ranges.

[0374] In some embodiments, the dextromethorphan FI(%) on day 9, in which the plasma concentration of dextromethorphan is increased by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, is any FI(%) value within the range of less than 100%, less than 70%, less than 60%, less than 50%, about 30-70%, about 30-60%, about 30-50%, or any FI(%) value within any of these ranges.

[0375] In some embodiments, the trough concentration of dextromethorphan on day 1 after administration of bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds (e.g., the plasma concentration 12 hours post-administration; also called the "minimum C") may be at least twice the trough level that can be achieved with the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0376] In some embodiments, for example, co-administration of dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds increases the dextromethorphan plasma concentration, with the minimum dextromethorphan C on the first day being 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, and at least about 1.2 ng / mL. / mL, which may be 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.

[0377] In some embodiments, for example, co-administration of dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds increases the plasma concentration of dextromethorphan. The minimum dextromethorphan C on day 5 is 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, and at least It could be approximately 8.0 ng / mL, at least approximately 9.0 ng / mL, at least approximately 10 ng / mL, at least approximately 15 ng / mL, at least approximately 20 ng / mL, at least approximately 25 mL, at least approximately 30 ng / mL, at least approximately 35 ng / mL, at least approximately 40 ng / mL, at least approximately 45 ng / mL, at least approximately 50 ng / mL, at least approximately 55 ng / mL, at least approximately 60 ng / mL, at least approximately 65 ng / mL, at least approximately 70 ng / mL, at least approximately 75 ng / mL, at least approximately 80 ng / mL, or at least approximately 80.9 ng / mL, and could be up to approximately 10,000 ng / mL.

[0378] In some embodiments, for example, co-administration of dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds increases the plasma concentration of dextromethorphan. The minimum dextromethorphan C on day 6 is 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, and at least It can be approximately 10 ng / mL, at least approximately 15 ng / mL, at least approximately 20 ng / mL, at least approximately 25 ng / mL, at least approximately 30 ng / mL, at least approximately 35 ng / mL, at least approximately 40 ng / mL, at least approximately 45 ng / mL, at least approximately 50 ng / mL, at least approximately 55 ng / mL, at least approximately 60 ng / mL, at least approximately 65 ng / mL, at least approximately 70 ng / mL, at least approximately 75 ng / mL, at least approximately 80 ng / mL, at least approximately 85 ng / mL, at least approximately 90 ng / mL, at least approximately 95 ng / mL, at least approximately 100 ng / mL, or at least approximately 102.2 ng / mL, and can be up to approximately 10,000 ng / mL.

[0379] In some embodiments, for example, co-administration of dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds increases the plasma concentration of dextromethorphan. The minimum dextromethorphan C on day 7 is 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 It can be 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 can be up to about 10,000 ng / mL.

[0380] In some embodiments, dextromethorphan C18 plasma concentrations are increased by co-administration of dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds. 最小This includes at least approximately 1.5 ng / mL, at least approximately 2.0 ng / mL, at least approximately 3.0 ng / mL, at least approximately 4.0 ng / mL, at least approximately 5.0 ng / mL, at least approximately 6.0 ng / mL, at least approximately 7.0 ng / mL, at least approximately 8.0 ng / mL, at least approximately 9.0 ng / mL, at least approximately 10 ng / mL, at least approximately 15 ng / mL, at least approximately 20 ng / mL, at least approximately 25 ng / mL, at least approximately 30 ng / mL, at least approximately 35 ng / mL, and at least approximately 40 ng / mL. L, 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, approximately 20ng / mL~about 30ng / mL, about 30ng / mL~about 40ng / mL, about 40ng / mL~about 50ng / mL, about 50ng / mL~about 55ng / mL, about 55ng / mL~about 60ng / mL, about 80ng / mL~about 90ng / mL, about 80ng / mL~ Approximately 85ng / mL, approximately 85ng / mL to approximately 90ng / mL, approximately 90ng / mL to approximately 95ng / mL, approximately 95ng / mL to approximately 100ng / mL, approximately 100ng / mL to approximately 105ng / mL, approximately 105ng / mL to approximately 110ng / mL, approximately 110ng / mL to approximately 11 It can range from 5 ng / mL, approximately 115 ng / mL to 120 ng / mL, approximately 120 ng / mL to 130 ng / mL, approximately 130 ng / mL to 135 ng / mL, approximately 135 ng / mL to 140 ng / mL, approximately 140 ng / mL to 145 ng / mL, approximately 145 ng / mL to 150 ng / mL, approximately 150 ng / mL to 155 ng / mL, approximately 155 ng / mL to 160 ng / mL, approximately 160 ng / mL to 170 ng / mL, or approximately 170 ng / mL to 200 ng / mL, and can reach up to approximately 10,000 ng / mL.

[0381] In some embodiments, dextromethorphan C24 is co-administered with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds, thereby increasing the plasma concentration of dextromethorphan C24 on day 9. 最小This includes at least approximately 1.5 ng / mL, at least approximately 2.0 ng / mL, at least approximately 3.0 ng / mL, at least approximately 4.0 ng / mL, at least approximately 5.0 ng / mL, at least approximately 6.0 ng / mL, at least approximately 7.0 ng / mL, at least approximately 8.0 ng / mL, at least approximately 9.0 ng / mL, at least approximately 10 ng / mL, at least approximately 15 ng / mL, at least approximately 20 ng / mL, at least approximately 25 ng / mL, at least approximately 30 ng / mL, at least approximately 35 ng / mL, and at least approximately 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, or at least about 119.3 ng / mL , about 20ng / mL to about 30ng / mL, about 30ng / mL to about 40ng / mL, about 40ng / mL to about 50ng / mL, about 50ng / mL to about 55ng / mL, about 55ng / mL to about 60ng / mL, about 80ng / mL to about 90ng / mL, about 80ng / mL ~about 85ng / mL, about 85ng / mL to about 90ng / mL, about 90ng / mL to about 95ng / mL, about 95ng / mL to about 100ng / mL, about 100ng / mL to about 105ng / mL, about 105ng / mL to about 110ng / mL, about 110ng / mL to about 1 It can range from 15 ng / mL, approximately 115 ng / mL to 120 ng / mL, approximately 120 ng / mL to 130 ng / mL, approximately 130 ng / mL to 135 ng / mL, approximately 135 ng / mL to 140 ng / mL, approximately 140 ng / mL to 145 ng / mL, approximately 145 ng / mL to 150 ng / mL, approximately 150 ng / mL to 155 ng / mL, approximately 155 ng / mL to 160 ng / mL, approximately 160 ng / mL to 170 ng / mL, or approximately 170 ng / mL to 200 ng / mL, and can reach up to approximately 10,000 ng / mL.

[0382] In some embodiments, dextromethorphan plasma concentrations are increased on day 10 by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds. 最小This includes at least approximately 1.5 ng / mL, at least approximately 2.0 ng / mL, at least approximately 3.0 ng / mL, at least approximately 4.0 ng / mL, at least approximately 5.0 ng / mL, at least approximately 6.0 ng / mL, at least approximately 7.0 ng / mL, at least approximately 8.0 ng / mL, at least approximately 9.0 ng / mL, at least approximately 10 ng / mL, at least approximately 15 ng / mL, at least approximately 20 ng / mL, at least approximately 25 ng / mL, at least approximately 30 ng / mL, at least approximately 35 ng / mL, and at least approximately 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, or at least about 119.3 ng / mL , about 20ng / mL to about 30ng / mL, about 30ng / mL to about 40ng / mL, about 40ng / mL to about 50ng / mL, about 50ng / mL to about 55ng / mL, about 55ng / mL to about 60ng / mL, about 80ng / mL to about 90ng / mL, about 80ng / mL ~about 85ng / mL, about 85ng / mL to about 90ng / mL, about 90ng / mL to about 95ng / mL, about 95ng / mL to about 100ng / mL, about 100ng / mL to about 105ng / mL, about 105ng / mL to about 110ng / mL, about 110ng / mL to about 1 It can range from 15 ng / mL, approximately 115 ng / mL to 120 ng / mL, approximately 120 ng / mL to 130 ng / mL, approximately 130 ng / mL to 135 ng / mL, approximately 135 ng / mL to 140 ng / mL, approximately 140 ng / mL to 145 ng / mL, approximately 145 ng / mL to 150 ng / mL, approximately 150 ng / mL to 155 ng / mL, approximately 155 ng / mL to 160 ng / mL, approximately 160 ng / mL to 170 ng / mL, or approximately 170 ng / mL to 200 ng / mL, and can reach up to approximately 10,000 ng / mL.

[0383] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered on day 1 of at least two days of treatment with dextromethorphan, and the reduction in dextromethorphan plasma concentration occurs on day 1 when bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is co-administered with dextromethorphan, compared to the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the plasma concentration of dextromethorphan on day 1 may be reduced by at least 5% compared to the plasma concentration of dextromethorphan that can be achieved by administering the same amount of dextromethorphan without bupropion.

[0384] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is co-administered with dextromethorphan to a person requiring treatment with dextromethorphan for at least 5 consecutive days, and the plasma dextromethorphan concentration on day 5 is higher than the plasma dextromethorphan concentration that could be achieved with the same dose administered for 5 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the plasma concentration of dextromethorphan on day 5 (e.g., at 0, 1, 3, 6, or 12 hours post-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 approximately 500 times higher than the level that could be achieved with the same dose of dextromethorphan administered for 5 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of any of these compounds.

[0385] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan are co-administered to a person requiring treatment with dextromethorphan for at least six consecutive days, and the plasma dextromethorphan concentration on day six is ​​higher than the plasma dextromethorphan concentration that could be achieved with the same dose of dextromethorphan administered for six consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the plasma concentration of dextromethorphan on day 6 (e.g., at 0, 1, 3, 6, or 12 hours post-administration) may be at least 5, 10, 20, 30, 50, 60, 70, 75, or up to approximately 500 times higher than the level that could be achieved with the same dose of dextromethorphan administered for 6 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of any of these compounds.

[0386] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan are co-administered to a person requiring treatment with dextromethorphan for at least 7 consecutive days, and the plasma dextromethorphan concentration on day 7 is higher than the plasma dextromethorphan concentration that could be achieved with the same dose of dextromethorphan administered for 7 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the plasma concentration of dextromethorphan on day 7 (e.g., at 0, 1, 3, 6, or 12 hours post-administration) may be at least 5, 10, 20, 30, 50, 70, 80, 90, or up to approximately 500 times higher than the level that could be achieved with the same dose of dextromethorphan administered continuously for 7 days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of any of these compounds.

[0387] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan are co-administered for at least 8 consecutive days, and on day 8, dextromethorphan has a plasma concentration, for example, at 0, 1, 3, 6, or 12 hours after co-administration, 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 1000 times the plasma concentration that could be achieved with the same dose of dextromethorphan administered for 8 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0388] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan are co-administered to a person requiring treatment with dextromethorphan for at least eight consecutive days, and the plasma dextromethorphan concentration on day eight is lower than the plasma dextromethorphan concentration that could be achieved with the same dose of dextromethorphan administered for eight consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the plasma dextromethorphan concentration on day 8 (e.g., at 0, 1, 3, 6, or 12 hours post-administration) may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to the plasma dextromethorphan concentration that could be achieved with the same dose of dextromethorphan administered continuously for 8 days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of any of these compounds.

[0389] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan are co-administered for at least 9 consecutive days, and on day 9, dextromethorphan has a plasma concentration, for example, at 0, 1, 3, 6, or 12 hours after co-administration, 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 1000 times the plasma concentration that could be achieved with the same dose of dextromethorphan administered for 9 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0390] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan are co-administered to a person requiring treatment with dextromethorphan for at least nine consecutive days, and the plasma dextromethorphan concentration on day nine is lower than the plasma dextromethorphan concentration that could be achieved with the same dose of dextromethorphan administered for nine consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the plasma dextromethorphan concentration on day 9 (e.g., at 0, 1, 3, 6, or 12 hours post-administration) may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to the plasma dextromethorphan concentration that could be achieved with the same dose of dextromethorphan administered continuously for 9 days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of any of these compounds.

[0391] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan are co-administered for at least 10 consecutive days, and on day 10, dextromethorphan has a plasma concentration, for example, at 0, 1, 3, 6, or 12 hours after co-administration, 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 1000 times the plasma concentration that could be achieved with the same dose of dextromethorphan administered for 10 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0392] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan are co-administered to a person requiring treatment with dextromethorphan for at least 10 consecutive days, and the plasma dextromethorphan concentration on day 10 is lower than the plasma dextromethorphan concentration that could be achieved with the same dose of dextromethorphan administered for 10 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the plasma dextromethorphan concentration on day 10 (e.g., at 0, 1, 3, 6, or 12 hours post-administration) may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to the plasma dextromethorphan concentration that could be achieved with the same dose of dextromethorphan administered continuously for 10 days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of any of these compounds.

[0393] In some embodiments, the AUC of bupropion in humans on day 8 is at least about 100 ng·hour / mL, at least about 200 ng·hour / mL, at least about 500 ng·hour / mL, at least about 600 ng·hour / mL, at least about 700 ng·hour / mL, at least about 800 ng·hour / mL, at least about 900 ng·hour / mL, at least about 1,000 ng·hour / mL, at least about 1,200 ng·hour / mL, at least 1,600 ng·hour / mL, or up to about 15,000 ng·hour / mL. 0-12 It can be administered to humans in amounts that produce the desired effect.

[0394] In some embodiments, bupropion has a C1c level in humans of at least about 10 ng / mL, at least about 20 ng / mL, at least about 40 ng / mL, at least about 50 ng / mL, at least about 60 ng / mL, at least about 70 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, at least 120 ng / mL, or up to about 1,500 ng / mL on day 8. 平均 It can be administered to humans in amounts that produce the desired effect.

[0395] In some embodiments, bupropion is administered at a concentration of at least about 10 ng / mL, at least about 20 ng / mL, at least about 50 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, at least about 110 ng / mL, at least about 120 ng / mL, at least about 130 ng / mL, at least about 140 ng / mL, at least 200 ng / mL, or up to about 1,500 ng / mL in humans. 最大 It can be administered to humans in amounts that produce the desired effect.

[0396] Some liquid compositions are approximately 0.0001% (w / v) to approximately 50% (w / v), approximately 0.01% (w / v) to approximately 20% (w / v), approximately 0.01% to approximately 10% (w / v), approximately 1% (w / v) to approximately 3% (w / v), approximately 3% (w / v) to approximately 5% (w / v), approximately 5% (w / v) to approximately 7% (w / v), approximately 5% (w / v) to approximately 15% (w / v), approximately 7% (w / v) to approximately 10% (w / v), and approximately 10% This may include bupropion from (w / v) to approximately 15%(w / v), from approximately 15%(w / v) to approximately 20%(w / v), from approximately 20%(w / v) to approximately 30%(w / v), from approximately 30%(w / v) to approximately 40%(w / v), or from approximately 40%(w / v) to approximately 50%(w / v), or any amount of bupropion within the range bounded by any of these values, or any amount of bupropion between any of these values.

[0397] Some liquid dosage forms may contain bupropion, such as bupropion chloride, in amounts ranging from approximately 10 mg to approximately 1000 mg, approximately 50 mg to approximately 1000 mg, approximately 10 mg to approximately 50 mg, approximately 50 mg to approximately 100 mg, approximately 40 mg to approximately 90 mg, approximately 200 mg to approximately 300 mg, approximately 70 mg to approximately 95 mg, approximately 100 mg to approximately 200 mg, approximately 100 mg to approximately 105 mg, approximately 105 mg to approximately 200 mg, approximately 110 mg to approximately 140 mg, approximately 180 mg to approximately 220 mg, approximately 280 mg to approximately 320 mg, approximately 105 mg, approximately 200 mg, approximately 150 mg, or approximately 300 mg, or any amount of bupropion within the range bounded by any of these values, or any amount of bupropion between any of these values.

[0398] Some solid compositions contain 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), and about 30% (w / w) to about This may include bupropion at 40% (w / w), approximately 40% (w / w) to approximately 50% (w / w), approximately 50% (w / w) to approximately 80% (w / w), approximately 50% (w / w) to approximately 60% (w / w), approximately 70% (w / w) to approximately 80% (w / w), or approximately 80% (w / w) to approximately 90% (w / w), or any amount of bupropion within the range bounded by any of these values, or any amount of bupropion between any of these values.

[0399] Several solid dosage forms are available in approximately 10 mg to 1000 mg, 50 mg to 1000 mg, 10 mg to 50 mg, 50 mg to 100 mg, 40 mg to 90 mg, 200 mg to 300 mg, 70 mg to 95 mg, 100 mg to 200 mg, 100 mg to 120 mg, 105 mg to 200 mg, 90 mg to 120 mg, and 100 mg to 110 mg. This may include mg, approximately 110 mg to approximately 140 mg, approximately 50 mg to approximately 150 mg, approximately 180 mg to approximately 220 mg, approximately 280 mg to approximately 320 mg, approximately 105 mg, approximately 200 mg, approximately 150 mg, or approximately 300 mg of bupropion, such as bupropion chloride, or any amount of bupropion within the range bounded by any of these values, or any amount of bupropion between any of these values.

[0400] In some embodiments, bupropion is administered in doses that result in plasma concentrations of bupropion of approximately 0.1 μM to 10 μM, approximately 0.1 μM to 5 μM, approximately 0.2 μM to 3 μM, approximately 0.1 μM to 1 μM, approximately 0.2 μM to 2 μM, approximately 1 μM to 10 μM, approximately 1 μM to 5 μM, approximately 2 μM to 3 μM, or approximately 2.8 μM to 3 μM, approximately 1.5 μM to 2 μM, approximately 4.5 μM to 5 μM, approximately 2.5 μM to 3 μM, approximately 1.8 μM, approximately 4.8 μM, approximately 2.9 μM, or approximately 2.8 μM, or any plasma concentration within the range bounded by any of these values, or any plasma concentration between any of these values.

[0401] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion is administered in doses that result in plasma concentrations of hydroxybupropion of approximately 0.1 μM to approximately 10 μM, approximately 0.1 μM to approximately 5 μM, approximately 0.2 μM to approximately 3 μM, approximately 0.1 μM to approximately 1 μM, approximately 0.2 μM to approximately 2 μM, 1 μM to approximately 10 μM, approximately 1 μM to approximately 5 μM, approximately 2 μM to approximately 3 μM, or approximately 2.8 μM to approximately 3 μM, approximately 1.5 μM to approximately 2 μM, approximately 4.5 μM to approximately 5 μM, approximately 2.5 μM to approximately 3 μM, approximately 1.8 μM, approximately 4.8 μM, approximately 2.9 μM, or approximately 2.8 μM, or any plasma concentration within the range bounded by any of these values, or any plasma concentration between any of these values.

[0402] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion has an AUC of at least about 3,000 ng·hours / mL, at least about 7,000 ng·hours / mL, at least about 10,000 ng·hours / mL, at least about 15,000 ng·hours / mL, at least about 20,000 ng·hours / mL, at least about 30,000 ng·hours / mL, upper limit about 50,000 ng·hours / mL, upper limit about 150,000 ng·hours / mL, or any AUC within a range bounded by any of these values, or any AUC between any of these values, in humans. 0-12 It can be administered to humans in amounts that produce the desired effect.

[0403] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion has a C content of at least about 300 ng / mL, at least about 700 ng / mL, at least about 1,000 ng / mL, at least about 1,500 ng / mL, at least about 2,000 ng / mL, at least about 4,000 ng / mL, upper limit about 10,000 ng / mL, upper limit about 50,000 ng / mL, or any range bounded by any of these values ​​on day 8. 最大 , or any C between any of these values最大 The C of hydroxybupropion in humans is 最大 It can be administered to humans in amounts that produce the desired effect.

[0404] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion has a C content of at least about 200 ng / mL, at least about 300 ng / mL, at least about 700 ng / mL, at least about 1,000 ng / mL, at least about 1,500 ng / mL, at least about 2,000 ng / mL, at least about 4,000 ng / mL, upper limit about 10,000 ng / mL, upper limit about 50,000 ng / mL, or any range bounded by any of these values ​​on day 8. 平均 , or any C between any of these values 平均 The C of hydroxybupropion in humans is 平均 It can be administered to humans in amounts that produce the desired effect.

[0405] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion is administered in doses that result in threohydroxybupropion plasma concentrations of approximately 0.1 μM to 10 μM, approximately 0.1 μM to 5 μM, approximately 0.2 μM to 3 μM, approximately 0.1 μM to 1 μM, approximately 0.2 μM to 2 μM, approximately 1 μM to 10 μM, approximately 1 μM to 5 μM, approximately 2 μM to 3 μM, or approximately 2.8 μM to 3 μM, approximately 1.5 μM to 2 μM, approximately 4.5 μM to 5 μM, approximately 2.5 μM to 3 μM, approximately 1.8 μM, approximately 4.8 μM, approximately 2.9 μM, or approximately 2.8 μM, or any plasma concentration within the range bounded by any of these values, or any plasma concentration between any of these values.

[0406] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion has an AUC in humans that, on day 8, is at least about 1,000 ng·hour / mL, at least about 2,000 ng·hour / mL, at least about 4,000 ng·hour / mL, at least about 5,000 ng·hour / mL, at least about 8,000 ng·hour / mL, upper limit about 10,000 ng·hour / mL, upper limit about 40,000 ng·hour / mL, or any AUC within a range bounded by any of these values, or any AUC between any of these values. 0-12 It can be administered to humans in amounts that produce the desired effect.

[0407] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion has a C content of at least about 100 ng / mL, at least about 200 ng / mL, at least about 400 ng / mL, at least about 500 ng / mL, at least about 600 ng / mL, at least about 800 ng / mL, upper limit about 2,000 ng / mL, upper limit about 10,000 ng / mL, or any range bounded by any of these values ​​on day 8. 最大 , or any C between any of these values 最大 The C of threohydroxybupropion in humans is 最大 It can be administered to humans in amounts that produce the desired effect.

[0408] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion has a C content of at least about 100 ng / mL, at least about 300 ng / mL, at least about 400 ng / mL, at least about 600 ng / mL, at least about 800 ng / mL, upper limit about 2,000 ng / mL, upper limit about 10,000 ng / mL,...

Claims

1. A dosage form for treating agitation associated with Alzheimer's disease, Approximately 105 mg of bupropion hydrochloride or a molar equivalent of bupropion in another salt form or free base form, Approximately 45 mg of dextromethorphan hydrobromide or a molar equivalent of another salt form or free base form of dextromethorphan, Includes, It is a solid oral dosage form administered to individuals who require treatment once or twice daily for at least three weeks. The administration of the aforementioned dosage form is characterized by a more significant reduction in the total score on the Cohen-Mansfield Agitation Scale (CMAI) compared to baseline compared to administration of placebo or the same amount of bupropion hydrochloride or a molar equivalent of another salt form or free base form of bupropion. Dosage form.

2. The dosage form according to claim 1, which is administered to the human being twice a day for at least three weeks.

3. The dosage form according to claim 1, wherein before the first administration of the dosage form, another dosage form comprising about 30 mg of dextromethorphan hydrobromide or another salt form or free base form of dextromethorphan by molar equivalent and about 105 mg of bupropion hydrochloride or another salt form or free base form of bupropion by molar equivalent is administered to the person once daily for one week, and thereafter administered to the person twice daily.

4. The dosage form according to claim 1, wherein the dextromethorphan hydrobromide salt or dextromethorphan in the form of another salt or free base in molar equivalent is an immediate-release formulation.

5. The dosage form according to claim 1, wherein the bupropion hydrochloride or bupropion in the form of another salt or free base in molar equivalent is a sustained-release formulation.

6. The dosage form according to claim 1 or 3, wherein the person is 65 to 90 years old.

7. The dosage form according to claim 1 or 3, wherein the person has been diagnosed with presumptive Alzheimer's disease according to the 2011 NIA-AA criteria.

8. The dosage form according to claim 1 or 3, wherein the person has been diagnosed with agitation according to the provisional definition of agitation of IPA.

9. The dosage form according to claim 1 or 3, wherein the human has a Mini-Mental State Examination (MMSE) score of 10 to 24.

10. The dosage form according to claim 1 or 3, wherein the human has a neuropsychiatric symptom assessment agitation / aggression area (NPI-AA) score of 4 or more.

11. The dosage form according to claim 1 or 3, wherein the human is a cohabitant.

12. The dosage form according to claim 1 or 3, wherein the human is not receiving a selective serotonin reuptake inhibitor concomitantly.

13. The dosage form according to claim 1 or 3, wherein the person is not currently receiving a concomitant serotonin-norepinephrine inhibitor.

14. The dosage form according to claim 1 or 3, wherein the person is not currently suffering from non-Alzheimer's disease.

15. The dosage form according to claim 1, comprising 45 mg of dextromethorphan hydrobromide.

16. The dosage form according to claim 14, comprising 105 mg of bupropion hydrochloride.

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