Pharmaceutical for treating agitation associated with alzheimer disease

Abstract

To provide a method for treating major depressive disorder or agitation associated with Alzheimer disease.SOLUTION: The method comprises administering a combination of drugs once or twice a day to a human in need of treatment, where the human is approximately 41 years of age or older, and the combination of drugs includes: about 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion; and about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 002,132, filed March 30, 2020, U.S. Provisional Patent Application No. 63 / 016,178, filed April 27, 2020, and U.S. Provisional Patent Application No. 63 / 032,517, filed May 29, 2020, which is a continuation-in-part of U.S. Patent Application No. 16 / 894,713, filed June 5, 2020, the entire disclosures of which are incorporated herein by reference. Summary of the Invention [Means for solving the problem]

[0002] Some embodiments include a method of increasing dextromethorphan plasma levels in a human being comprising co-administering bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of these compounds with dextromethorphan.

[0003] Some embodiments include co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan to a human being, wherein the erythrohydroxybupropion, or a prodrug thereof, achieves an AUC of dextromethorphan that is at least about 40 ng·hr / mL. 0-12 The present invention includes a method for increasing dextromethorphan plasma concentrations in a human, wherein the dextromethorphan is administered in an amount that results in:

[0004] Some embodiments include co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan to a human being, wherein the erythrohydroxybupropion, or a prodrug thereof, achieves a C of dextromethorphan that is at least about 6 ng / mL. 最大 The present invention includes a method for increasing dextromethorphan plasma concentrations in a human, wherein the dextromethorphan is administered in an amount that results in:

[0005] Some embodiments include co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan to a human being, wherein the erythrohydroxybupropion, or a prodrug thereof, increases the C of dextromethorphan by at least about 5 ng / mL over a period between two separate but sequential administrations of dextromethorphan. 平均 The present invention includes a method for increasing dextromethorphan plasma concentrations in a human, wherein the dextromethorphan is administered in an amount that results in:

[0006] Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan comprising administering threohydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human body simultaneously with threohydroxybupropion.

[0007] Some embodiments include a method of reducing adverse events associated with treatment with dextromethorphan, comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of treatment with dextromethorphan, where the human patient is at risk of experiencing an adverse event as a result of being treated with dextromethorphan.

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

[0009] Some embodiments include a method of reducing the number of doses of dextromethorphan that can be administered without losing efficacy, comprising orally administering to a human being in need of treatment with dextromethorphan an effective amount of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any of these compounds.

[0010] Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the threohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, compared to the same amount of dextromethorphan administered without threohydroxybupropion or a prodrug thereof.

[0011] Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the hydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, compared to the same amount of dextromethorphan administered without hydroxybupropion or a prodrug thereof.

[0012] Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering bupropion and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein bupropion is administered on the first day of at least two days of treatment with dextromethorphan, wherein a reduction in dextrorphan plasma levels occurs on the first day that bupropion and dextromethorphan are co-administered, compared to the same amount of dextromethorphan administered without bupropion.

[0013] Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the erythrohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of treatment with dextromethorphan, wherein a reduction in the dextrorphan plasma level occurs on the first day that erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, compared to the same amount of dextromethorphan administered without erythrohydroxybupropion or a prodrug thereof.

[0014] Some embodiments include a method of reducing dextromethorphan plasma levels, comprising co-administering bupropion and dextromethorphan for at least eight consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion for eight consecutive days.

[0015] Some embodiments include a method of reducing dextromethorphan plasma levels, comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan for at least eight consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for eight consecutive days.

[0016] Some embodiments include a method of reducing dextromethorphan plasma levels, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan for at least eight consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for eight consecutive days.

[0017] Some embodiments include a method of reducing dextrorphan plasma levels, comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan for at least eight consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for eight consecutive days.

[0018] Some embodiments include a method of reducing dextrorphan plasma levels, comprising co-administering bupropiont and dextromethorphan for at least nine consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the ninth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion for nine consecutive days.

[0019] Some embodiments include a method of reducing dextrorphan plasma levels, comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan for at least nine consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the ninth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without hydroxybupropion for nine consecutive days.

[0020] Some embodiments include a method of reducing dextrorphan plasma levels, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan for at least nine consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the ninth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion for nine consecutive days.

[0021] Some embodiments include a method of reducing dextrorphan plasma levels, comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan for at least nine consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the ninth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion for nine consecutive days.

[0022] Some embodiments include a method of reducing dextrorphan plasma levels, comprising co-administering bupropion and dextromethorphan for at least nine consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the ninth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion for nine consecutive days.

[0023] Some embodiments include a method of reducing dextrorphan plasma levels, comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan for at least nine consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the ninth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for nine consecutive days.

[0024] Some embodiments include a method of reducing dextrorphan plasma levels, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan for at least nine consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the ninth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for nine consecutive days.

[0025] Some embodiments include a method of reducing dextrorphan plasma levels, comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan for at least nine consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the ninth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for nine consecutive days.

[0026] Some embodiments include a method of reducing dextrorphan plasma levels, comprising co-administering bupropion and dextromethorphan for at least nine consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the ninth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion for nine consecutive days.

[0027] Some embodiments include a method of reducing dextrorphan plasma levels, comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan for at least nine consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the ninth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for nine consecutive days.

[0028] Some embodiments include a method of reducing dextrorphan plasma levels, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan for at least nine consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the ninth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for nine consecutive days.

[0029] Some embodiments include a method of reducing dextrorphan plasma levels, comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan for at least nine consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the ninth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for nine consecutive days.

[0030] Some embodiments include a method of reducing dextrorphan plasma levels, comprising co-administering bupropion and dextromethorphan for at least 10 consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the 10th day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion for 10 consecutive days.

[0031] Some embodiments include a method of reducing dextrorphan plasma levels, comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan for at least 10 consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the 10th day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for 10 consecutive days.

[0032] Some embodiments include a method of reducing dextrorphan plasma levels, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan for at least 10 consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the 10th day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for 10 consecutive days.

[0033] Some embodiments include a method of reducing dextrorphan plasma levels, comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan for at least 10 consecutive days to a human being in need of treatment with dextromethorphan, wherein, on the 10th day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for 10 consecutive days.

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

[0035] Some embodiments include a method of treating a neurological disorder comprising administering to a human being in need thereof 1) dextromethorphan, or 2) a combination of an antidepressant and dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan.

[0036] Some embodiments include a method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering dextromethorphan and bupropion to the human being.

[0037] Some embodiments include a method of inhibiting the metabolism of dextromethorphan, comprising administering bupropion to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with bupropion.

[0038] Some embodiments include a method of increasing the metabolite lifetime of dextromethorphan, comprising administering bupropion to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human being's body simultaneously with bupropion.

[0039] Some embodiments include a method of correcting an extensive metabolite of dextromethorphan, comprising administering bupropion to a human being in need thereof.

[0040] Some embodiments include a method of improving the antitussive properties of dextromethorphan, comprising administering bupropion in combination with administration of dextromethorphan to a human being in need of treatment for cough.

[0041] Some embodiments include a method of treating cough comprising administering to a human being in need thereof a combination of bupropion or another active compound and dextromethorphan.

[0042] Some embodiments include a method of treating a neurological disorder comprising administering to a human being in need thereof 1) dextromethorphan, or 2) bupropion and dextromethorphan, wherein 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 a method of treating a neurological disorder comprising administering to a human being in need thereof 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 a method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.

[0045] Some embodiments include a method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.

[0046] Some embodiments include a method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.

[0047] Some embodiments include a method of inhibiting the metabolism of dextromethorphan, comprising administering bupropion to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with bupropion.

[0048] Some embodiments include a method of inhibiting the metabolism of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with hydroxybupropion.

[0049] Some embodiments include a method of inhibiting the metabolism of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with erythrohydroxybupropion.

[0050] Some embodiments include a method of inhibiting the metabolism of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human being's body simultaneously with threohydroxybupropion.

[0051] Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human being's body simultaneously with hydroxybupropion.

[0052] Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human being's body simultaneously with erythrohydroxybupropion.

[0053] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein bupropion is administered on the first day of at least two days of co-administration of dextromethorphan with bupropion (at least two days of co-administration), and wherein an increase in dextromethorphan plasma levels occurs on the first day that bupropion and dextromethorphan are co-administered compared to administration of the same amount of dextromethorphan without bupropion.

[0054] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the hydroxybupropion or a prodrug thereof is administered on the first day of at least two days of co-administration of dextromethorphan with hydroxybupropion or a prodrug thereof, and wherein an increase in dextromethorphan plasma levels occurs on the first day that hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered compared to administration of the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.

[0055] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the erythrohydroxybupropion or a prodrug thereof is administered on the first day of at least two days of co-administration of dextromethorphan with hydroxybupropion or a prodrug thereof, and wherein an increase in dextromethorphan plasma levels occurs on the first day that erythrohydroxybupropion or a prodrug thereof and dextromethorphan are co-administered compared to administration of the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.

[0056] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the threohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of co-administration of dextromethorphan with hydroxybupropion, or a prodrug thereof, and wherein an increase in dextromethorphan plasma levels occurs on the first day that threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered compared to administration of the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.

[0057] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the fifth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without bupropion for five consecutive days.

[0058] Some embodiments include a method of increasing dextromethorphan plasma levels, comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, for at least five consecutive days, wherein on the fifth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for five consecutive days.

[0059] Some embodiments include a method of increasing dextromethorphan plasma levels, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, for at least five consecutive days, wherein on the fifth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for five consecutive days.

[0060] Some embodiments include a method of increasing dextromethorphan plasma levels, comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, for at least five consecutive days, wherein on the fifth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for five consecutive days.

[0061] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the sixth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without bupropion for six consecutive days.

[0062] Some embodiments include a method of increasing dextromethorphan plasma levels, comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, for at least six consecutive days, wherein on the sixth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without hydroxybupropion or a prodrug thereof for six consecutive days.

[0063] Some embodiments include a method of increasing dextromethorphan plasma levels, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the sixth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for six consecutive days.

[0064] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, for at least six consecutive days, wherein on the sixth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for six consecutive days.

[0065] Some embodiments include a method of reducing the trough effect of dextromethorphan comprising co-administering bupropion with dextromethorphan to a human being in need of treatment with dextromethorphan, wherein 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 administration of the same amount of dextromethorphan without bupropion.

[0066] Some embodiments include a method of reducing the trough effect of dextromethorphan comprising co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein the dextromethorphan has a plasma concentration 12 hours after co-administration of hydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma concentration achieved by administration of the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.

[0067] Some embodiments include a method of reducing the trough effect of dextromethorphan comprising co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein the dextromethorphan has a plasma concentration 12 hours after co-administration of erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma concentration achieved by administration of the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.

[0068] Some embodiments include a method of reducing the trough effect of dextromethorphan comprising co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein the dextromethorphan has a plasma concentration 12 hours after co-administration of threohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.

[0069] Some embodiments include a method of reducing adverse events associated with treatment with dextromethorphan comprising co-administering bupropion and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing an adverse event as a result of treatment with dextromethorphan.

[0070] Some embodiments include a method of reducing adverse events associated with treatment with dextromethorphan comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing an adverse event as a result of treatment with dextromethorphan.

[0071] Some embodiments include a method of reducing adverse events associated with treatment with dextromethorphan comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing an adverse event as a result of treatment with dextromethorphan.

[0072] Some embodiments include a method of reducing adverse events associated with treatment with bupropion, comprising co-administering dextromethorphan and bupropion to a human patient in need of bupropion treatment, wherein the human patient is at risk of experiencing the same adverse events as a result of treatment with bupropion.

[0073] Some embodiments include a method of correcting an extensive metabolite of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human being in need thereof.

[0074] Some embodiments include a method of correcting an extensive metabolite of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human being in need thereof.

[0075] Some embodiments include a method of correcting an extensive metabolite of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, to a human being in need thereof.

[0076] Some embodiments include a method of improving the antitussive properties of dextromethorphan, comprising administering bupropion in combination with administration of dextromethorphan to a human being in need of treatment for cough.

[0077] Some embodiments include a method of improving the antitussive properties of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, in combination with administration of dextromethorphan to a human being in need of treatment for cough.

[0078] Some embodiments include a method of improving the antitussive properties of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, in combination with administration of dextromethorphan to a human being in need of treatment for cough.

[0079] Some embodiments include a method of improving the antitussive properties of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, in combination with administration of dextromethorphan to a human being in need of treatment for cough.

[0080] Some embodiments include a method of treating cough comprising administering to a human being in need thereof a combination of hydroxybupropion, or a prodrug thereof, and dextromethorphan.

[0081] Some embodiments include a method of treating cough comprising administering a combination of erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof.

[0082] Some embodiments include a method of treating cough comprising administering to a human being in need thereof a combination of threohydroxybupropion, or a prodrug thereof, and dextromethorphan.

[0083] Some embodiments include a method of treating a neurological disorder comprising administering bupropion and dextromethorphan to a human being in need thereof, wherein the 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 of treating a neurological disorder comprising administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof, wherein the 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 of treating a neurological disorder comprising administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof, wherein the 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 of treating a neurological disorder comprising administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof, wherein the 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 medicament comprising a therapeutically effective amount of dextromethorphan, an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any of these compounds, and a pharmaceutically acceptable excipient.

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

[0089] Some embodiments include a method of improving the therapeutic efficacy of bupropion in treating depression, comprising orally co-administering dextromethorphan and bupropion twice daily to a human suffering from depression, wherein the method is characterized as being more effective than treating the depression in the human by orally administering to the human 150 mg of bupropion alone twice daily for five weeks.

[0090] In some embodiments, the combination of dextromethorphan and bupropion is more effective than the same amount of dextromethorphan or bupropion administered orally independently.

[0091] Some embodiments include a method of improving the efficacy of bupropion in treating depression, comprising orally administering from about 90 mg to about 125 g of bupropion in combination with about 0.3 mg / kg to about 1 mg / kg of dextromethorphan once or twice daily for at least 23 days to a human being suffering from depression, wherein the oral administration of bupropion in combination with dextromethorphan is more effective in treating depression than the same dose of bupropion administered orally without dextromethorphan.

[0092] Some embodiments include a method of treating treatment-resistant depression, comprising: selecting a human suffering from depression who has previously been unsuccessfully treated with at least one antidepressant; and orally administering a dextromethorphan-bupropion combination treatment once or twice daily to the human for at least about 5 weeks, wherein the dextromethorphan-bupropion combination treatment comprises from about 40 mg to about 70 mg of dextromethorphan and from 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 daily or twice daily to a human being in need thereof, wherein the human being experiences a therapeutic effect within two weeks from the first day the combination of bupropion and dextromethorphan is administered.

[0094] Some embodiments include a method of treating depression, comprising administering a combination of bupropion and dextromethorphan once daily or twice daily to a human being in need thereof, wherein the human 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 daily for at least 21 consecutive days to a person suffering from nicotine addiction, wherein the person is an ad-lib cigarette smoker, and the person is administered a total amount of 200 mg to 250 mg of bupropion and 80 mg to 140 mg of dextromethorphan daily, wherein the method is more effective than administering an equivalent amount of bupropion alone.

[0096] In some embodiments involving the treatment of nicotine addiction, administration of the combination of bupropion and dextromethorphan results in at least a 20% greater decrease 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 involving the treatment of nicotine addiction, administration of the combination of bupropion and dextromethorphan results in at least a 10% greater decrease in exhaled carbon monoxide levels compared to bupropion alone.

[0098] In some embodiments, including the treatment of nicotine addiction, administering a combination of bupropion and dextromethorphan in two equal doses twice daily reduces the intensity of nicotine self-administration at a particular time point, such as 1 week, 2 weeks, 3 weeks, 4 weeks, or any other time point described herein, more than would have occurred by administering one of the two doses at the same time or by not administering the combination. [Brief explanation of the drawings]

[0099] [Figure 1] FIG. 1 is a plot of the mean plasma concentrations of dextromethorphan over time after administration on Day 8 for subjects receiving dextromethorphan alone or dextromethorphan and bupropion. [Figure 2]FIG. 2 shows the mean AUC of dextromethorphan on Day 8 for subjects receiving dextromethorphan alone or dextromethorphan and bupropion. [Figure 3] FIG. 3 shows the mean AUC of dextromethorphan on Day 8 for subjects receiving dextromethorphan alone or dextromethorphan and bupropion. [Figure 4] FIG. 4 shows the mean AUCO-inf of dextromethorphan on Day 8 for subjects receiving dextromethorphan alone or dextromethorphan and bupropion. [Figure 5] FIG. 5 shows the fold change in the AUC of dextromethorphan on Day 8 for subjects administered dextromethorphan alone compared to dextromethorphan and bupropion. [Figure 6] FIG. 6 shows the mean AUC of dextromethorphan on Days 1 and 8 for subjects receiving dextromethorphan alone or dextromethorphan and bupropion. [Figure 7] FIG. 7 shows the mean dextromethorphan in plasma concentrations for administration of dextromethorphan alone or dextromethorphan and bupropion to subjects. [Figure 8] FIG. 8 shows the mean maximum dextromethorphan plasma concentrations on days 1 and 8 for subjects receiving dextromethorphan alone, or dextromethorphan and bupropion. [Figure 9] FIG. 9 shows a plot of the mean plasma concentration of dextrorphan over time after dosing on day 8 for subjects receiving dextromethorphan alone, or dextromethorphan and bupropion. [Figure 10] FIG. 10 shows the mean maximum dextrorphan plasma concentrations after dosing on days 1 and 8 for subjects receiving dextromethorphan alone, or dextromethorphan and bupropion. [Figure 11]FIG. 11 shows the mean AUC of dextromethorphan on Days 1 and 8 for administration to subjects of dextromethorphan alone, or dextromethorphan and bupropion. [Figure 12] FIG. 12 shows the effect of various antidepressant compounds on inhibiting the metabolism of dextromethorphan in human liver microsomes. [Figure 13] FIG. 13 is a plot of the mean MADRS total score change from baseline over time during the 6-week treatment period for subjects receiving bupropion alone or the combination of dextromethorphan and bupropion. [Figure 14] FIG. 14 shows the percentage of subjects who achieved remission (MADRS≦10) over time during the 6-week treatment period for subjects receiving bupropion alone or the combination of dextromethorphan and bupropion. [Figure 15] FIG. 15 is a plot showing the reduction in MADRS total score over time for the subjects described in Example 6. [Figure 16] FIG. 16 is a plot of the percentage of responders over time for the subjects described in Example 6. [Figure 17] FIG. 17 is a plot of the percentage of subjects in remission over time for the subjects described in Example 6. [Figure 18] FIG. 18 is a plot of the change from baseline in MADRS total score over time for the subjects described in Example 7. [Figure 19] FIG. 19 is a plot of the change from baseline in QIDS-SR-16 total score over time for the subjects described in Example 7. [Figure 20] FIG. 20 is a plot of the percentage of subjects in remission (QIDS-SR-16 score≦5) over time for the subjects described in Example 7. [Figure 21] FIG. 21 is a plot of the change from baseline over time in the cognitive components of the MGH-CPFQ for the subjects described in Example 7. [Figure 22] FIG. 22 is a plot of the change from baseline in CMAI total score over time for the subjects described in Example 8. [Figure 23] FIG. 23 is a plot of the percent decrease in CMAI from baseline over time for the subjects described in Example 8. [Figure 24] FIG. 24 is a plot of the percentage of responders with a CMAI decrease of ≧30% from baseline over time for subjects described in Example 8. [Figure 25] FIG. 25 shows the reduction from baseline in MADRS scores from a clinical trial of DM / BU in Example 10 compared to a combination of dextromethorphan and quinidine (DM / Q), as reported by Murrough (Journal of Affective Disorders 218 (2017) 277-283, FIG. 3A). DETAILED DESCRIPTION OF THE INVENTION

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

[0101] Some embodiments include a method of enhancing the therapeutic properties of dextromethorphan in treating a neurological disorder, comprising co-administering dextromethorphan with an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of these compounds.

[0102] Some embodiments include a method of increasing dextromethorphan plasma levels in a human being who is an extensive metabolizer of dextromethorphan, comprising co-administering to the human being an antidepressant compound, such as bupropion, and dextromethorphan.

[0103] Some embodiments include a method of inhibiting the metabolism of dextromethorphan, comprising administering an antidepressant compound, such as bupropion, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with the antidepressant.

[0104] Some embodiments provide a dextromethorphan elimination half-life (T 1 / 2 These embodiments can include methods of increasing the metabolic lifetime of dextromethorphan, including methods of increasing the metabolic lifetime of dextromethorphan. These embodiments can include administering an antidepressant compound, such as bupropion, to a human, where the human is an extensive metabolizer of dextromethorphan, and where dextromethorphan is present in the human's body simultaneously with the antidepressant compound.

[0105] Some embodiments include a method of correcting an advanced metabolite of dextromethorphan, comprising administering an antidepressant compound, such as bupropion, to a human in need thereof, such as a human in need of treatment for pain.

[0106] Some embodiments include a method of improving the therapeutic properties of dextromethorphan in the treatment of neurological disorders, comprising administering an antidepressant compound, such as bupropion, in combination with administration of dextromethorphan to a human being in need of such treatment.

[0107] Some embodiments include a method of treating a neurological disorder comprising administering to a human being in need of treatment an antidepressant compound, such as bupropion, and dextromethorphan in combination.

[0108] Co-administration of dextromethorphan with an antidepressant compound, such as bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a prodrug of an antidepressant compound, occurs one or more times for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, or more consecutive days. In some embodiments, co-administration is at least daily for at least two consecutive days.

[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 occur once daily for 1, 2, 3, 4, 5, 6, or 7 days prior to twice-daily co-administration.

[0110] Dextromethorphan has 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 [21 CFR 341.74], dextromethorphan should be administered six times daily (every four hours), four times daily (every six hours), or three times daily (every eight hours). The OTC monograph [21 CFR 341.74] also states, "Dosage regimens are equivalent to those for dextromethorphan hydrobromide... Oral doses should be 10 to 20 milligrams every four hours, 30 milligrams every six to eight hours, or not to exceed 120 milligrams in 24 hours, or as directed by a physician."

[0112] Dextromethorphan is metabolized very rapidly in the human liver. This very rapid hepatic metabolism can limit systemic drug exposure in individuals who are extensive metabolizers. Humans can be 1) extensive dextromethorphan metabolizers—those who metabolize dextromethorphan very rapidly; 2) poor dextromethorphan metabolizers—those who metabolize dextromethorphan only slightly; or 3) intermediate dextromethorphan metabolizers—those whose metabolism of dextromethorphan falls somewhere between extensive and poor metabolizers. Extensive dextromethorphan metabolizers can also be very rapid metabolizers. Extensive dextromethorphan metabolizers represent a significant portion of the population. For example, dextromethorphan can be metabolized to dextrorphan.

[0113] Given the same oral dose of dextromethorphan, plasma concentrations of dextromethorphan are significantly higher in poor or intermediate metabolizers than in extensive metabolizers. Low dextromethorphan plasma concentrations can limit its clinical usefulness as a single agent for extensive and, in some cases, intermediate metabolizers of dextromethorphan. Therapeutically active compounds, including some antidepressants such as bupropion, can inhibit the metabolism of dextromethorphan and increase its plasma concentration, thereby enhancing its therapeutic efficacy. Similarly, antidepressants can allow dextromethorphan to be given less frequently, such as once daily instead of twice daily, once daily instead of three times daily, once daily instead of four times daily, twice daily instead of three times daily, or twice daily instead of four times daily, without loss of therapeutic efficacy.

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

[0115] Some embodiments include co-administration of dextromethorphan or dextrorphan with an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, to agonize, antagonize, or modulate sigma-1 receptors or NMDA receptors, block calcium channels, bind to muscarinic receptors, inhibit the serotonin transporter (5HTT), or potentiate mu receptors.

[0116] The pharmacological properties of dextromethorphan and dextrorphan may include NMDA high-affinity sites, NMDR-2A, and functional NMDR-2B receptor antagonism, sigma-1 stimulation, putative mTOR activation (via sigma-1 stimulation, mu potentiation, beta-adrenergic receptor stimulation, and 5HTT inhibition), putative AMPA receptor trafficking (via mTOR activation, PCP antagonism, sigma-1 stimulation, beta-stimulation, mu potentiation, and 5HTT inhibition), and effects on dendritogenesis, spindle formation, synaptogenesis, and neuronal survival via NMDA antagonism and sigma-1 and mTOR signaling. Some embodiments include co-administration of dextromethorphan or dextrorphan with an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, to bind to, agonize, antagonize, stimulate, activate, inhibit, affect trafficking of, or modulate an NMDA high affinity site, an NMDR-2A, a functional NMDR-2B receptor, a sigma-1 receptor, a putative mTOR receptor (such as by stimulating sigma-1, potentiating mu receptors, stimulating beta adrenergic receptors, or inhibiting 5HTT), or a putative AMPA receptor (such as by activating mTOR, antagonizing PCP activity, stimulating sigma-1 receptors, stimulating beta adrenergic receptors, potentiating mu receptors, or inhibiting 5HTT). Some embodiments include co-administration of dextromethorphan or dextrorphan with an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, to cause, increase, decrease, or modulate dendritogenesis, spindle formation, or synaptogenesis.Some embodiments include co-administration of dextromethorphan or dextrorphan with an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, to cause, 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 can include 5HTT and norepinephrine transporter inhibition, sigma-1 stimulation, NMDA and PCP antagonism, and stimulation of serotonin 5HT1b / d receptors, if present. Some embodiments include co-administration of dextromethorphan or dextrorphan with an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, to bind to, agonize, antagonize, stimulate, activate, inhibit, affect the transport of, or modulate 5HTT and / or norepinephrine transporters, sigma-1 receptors, NMDA and / or PCP receptors, and / or stimulate serotonin 5HT1b / d receptors.

[0118] Additional properties of dextromethorphan and dextrorphan may include presynaptic alpha-2 adrenergic receptor antagonism, if present, or postsynaptic alpha-2 agonism, beta agonism, and possible muscarinic and mu antagonism. Some embodiments include co-administration of dextromethorphan or dextrorphan with an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, to bind to, agonize, antagonize, stimulate, activate, inhibit, affect trafficking, or modulate presynaptic alpha-2 adrenergic receptors, postsynaptic alpha-2 receptors, beta adrenergic receptors, muscarinic receptors, or mu receptors. Dextromethorphan and dextrorphan may be glial cell modulators. Some embodiments include co-administration of dextromethorphan or dextrorphan with an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, to modulate glial cells.

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

[0120] Examples of neurological disorders that can be treated or treated with increased efficacy by increased dextromethorphan concentrations, such as may be obtained by combining dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, include, but are not limited to, affective disorders, psychiatric disorders, brain function disorders, movement disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[0121] Affective disorders that may be treated with increased dextromethorphan concentrations or with 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, depression, major depression, treatment-resistant depression and treatment-resistant bipolar depression, bipolar disorder including cyclothymia, seasonal affective disorder, mood disorders, Harm, 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) including hyperactivity, attention deficit / hyperactivity disorder (AD / HD), bipolar and manic states, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychosexual dysfunction, pseudo-affect, and mood lability.

[0122] Depression may manifest itself through depressive symptoms. These symptoms may include psychological changes such as mood changes, intense feelings of sadness, hopelessness, decreased mental function, difficulty concentrating, pessimistic worry, restlessness, 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, aches and pains, headaches, cramps, indigestion, and / or abnormalities in the circadian rhythm of hormone secretion.

[0123] Some patients experience inadequate or no therapeutic benefit from medications such as antidepressants. Treatment-resistant depression (TRD), or treatment-refractory depression, is a condition commonly associated with patients who have failed treatment with at least two antidepressants. Part of the diagnosis of TRD is the failure to achieve adequate therapeutic benefit, even with sufficient doses and sufficient course of antidepressants, for example, in the current depressive episode. TRD may be more difficult to treat due to the presence of other medical or psychological disorders, such as drug / alcohol abuse or eating disorders, or because TRD has been misdiagnosed. Some TRD patients have failed to adequately respond to one, two, three, or more attempts at appropriate antidepressant treatment, or have failed or failed to adequately respond to one, two, three, or more prior antidepressant treatments. In some embodiments, patients being treated for treatment-resistant depression have failed at least one, two, three, four, five, six, seven, eight, nine, ten, or more antidepressant treatments.

[0124] Measures of therapeutic efficacy that may be improved by treatments that increase the bioavailability or plasma concentrations of dextromethorphan or by the combination of dextromethorphan with an antidepressant (e.g., bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of these compounds) include, but are not limited to, the Montgomery-Asberg Depression Rating Scale (MADRS), the Questionnaire on Enjoyment and Satisfaction with Life Short Form, Functional Impairment Spectrum Tool, Sheehan Disability Scale, Patient-Rated Side Effect Inventory (PRISE), Columbia-Suicide Severity Rating Scale (C-SSRS), Brief 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), Brief Depressive Symptom Scale 16-item Self-Report (QIDS-SR16), Sheehan Disability Scale (SDS), Clinical Global Impression-Severity (CGI-S), Clinical Global Impression-Change (CGI-C), Euro Quality of Life 5-item 5-level (EQ-5D-5L), Patient Global Impression of Change (PGIC), Generalized Anxiety Disorder 7-item (GAD-7), Clinical Global Impression-Improvement (CGI-I), Sheehan Disability Scale (SDS), Brief Depressive Symptom Scale 16-item Self-Report (QID S-SR16), Hamilton Anxiety Scale (HAM-A), Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), CPFQ-cognitive subscale (4-7 items), Brief Psychiatric Rating Scale (BPRS), Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Task (RAVLT), Trail Making Test (TMT), Stroop Color Naming Test (STROOP), Simple Reaction Time (SRT), Choice Reaction Time (CRT), etc.In some embodiments, treating a person with the combination of dextromethorphan and bupropion may improve (e.g., reduce) the person's score on 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%, or 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] Administration of the combination of bupropion and dextromethorphan may result in rapid therapeutic effects, e.g., within about 1 week, 2 weeks, 3 weeks, or 4 weeks after initiation of treatment. For example, improvements in any of the assessments described herein, including, but not limited to, the MADRS, the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form, the Functional Impairment Spectrum Inventory, 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 Subscale (items 4-7), BPRS, DSST, RAVLT, TMT, STROOP, SRT, CRT, etc., may be observed within these time periods.

[0126] In some embodiments, the enhanced bioavailability of dextromethorphan, or a combination of dextromethorphan and an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, may have an onset of action within 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 6-8 hours, 8-12 hours, 12 hours, 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 patients under about 18 years of age, about 0-5 years of age, about 5-10 years of age, about 10-12 years of age, or about 12-18 years of age; adult patients, such as patients about 18-70 years of age, about 18-65 years of age, about 18-30 years of age, about 10-20 years of age, about 20-30 years of age, about 30-40 years of age, about 40-50 years of age, about 50-60 years of age, about 60-70 years of age, about 70-80 years of age, about 80-90 years of age, about 30-50 years of age, about 50-65 years of age; elderly patients, such as patients over 65 years of age, 65-75 years of age, about 75-90 years of age, or over 90 years of age; and patients about 41 years of age or older.

[0128] In some embodiments, a person being treated with a combination of dextromethorphan and bupropion, for example, for a type of depression, is of Asian descent or is selected to be of Asian descent. In some embodiments, a person being treated with a combination of dextromethorphan and bupropion, for example, for a type of depression, is of Japanese descent or is selected to be of Japanese descent. In some embodiments, a person being treated with a combination of dextromethorphan and bupropion, for example, for a type of depression, is of Korean descent or is selected to be of Korean descent. In some embodiments, a person being treated with a combination of dextromethorphan and bupropion, for example, for a type of depression, is of Chinese descent or is selected to be of Chinese descent. An individual's attribution of Asian, Chinese, Japanese, or Korean descent may be based on the individual's self-report. In these Asian patients, the combination of dextromethorphan and bupropion may be effective in treating depression for which bupropion alone is ineffective. This may be particularly important because patients of Asian descent may suffer from more severe depression than patients of other ethnicities or cultures.

[0129] In some embodiments, the human does not have, or is selected to not have, depressive episodes with psychotic or catatonic features.

[0130] In some embodiments, the human does not have, or is selected to not have, bipolar disorder (type 1 or type 2) and manic, hypomanic, or mixed episodes, including substance-induced (e.g., antidepressant-induced) mania, or hypomanic / mixed episodes.

[0131] In some embodiments, the human does not have, or is selected to not have, schizophrenia, schizoaffective, or another psychotic disorder.

[0132] In some embodiments, the human does not have, or is selected to not have, a panic disorder with or without agoraphobia.

[0133] In some embodiments, the human does not have, or is selected to not have, obsessive-compulsive disorder.

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

[0135] In some embodiments, the human does not have, or is selected to not have, a persistent neurocognitive disorder.

[0136] In some embodiments, the human does not have, or is selected to not have, an anxiety disorder for six months prior to treatment.

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

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

[0139] In some embodiments, the person being treated with the combination of dextromethorphan and bupropion has, or is selected to have, major depressive episodes, e.g., including at least 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 10, at least about 15, at least about 20, at least about 30, e.g., due to the type of depression, at least about 20, at least about 20, at least about 30, or more major depressive episodes, e.g., at least about 10, at least about 40, at least about 40, at least about 30, or more major depressive episodes, e.g., at least about 15, at least about 15, at least about 40, at least about 40, at least about 30, or more major depressive episodes. The patient has or is selected to have had about 1 to 100 or more lifetime depressive episodes, such as major depressive episodes, including at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, about 1 to 5, about 5 to 10, about 10 to 20, about 20 to 30, about 30 to 40, about 40 to 50, about 50 to 60, about 60 to 70, about 70 to 80, about 80 to 90, about 90 to 100, or about 4 to 7 lifetime depressive episodes.

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

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

[0142] In some embodiments, the person being treated with a combination of dextromethorphan and bupropion, e.g., for a type of depression, is male or selected to be male. In some embodiments, the person being treated with a combination of dextromethorphan and bupropion, e.g., for a type of depression, is female or selected to be female.

[0143] In some embodiments, a human being treated with a combination of dextromethorphan and bupropion, e.g., for any type of depression, has a body mass index of about 18 to 40 kg / m 2 , about 18.5kg / m 2 2, about 18.5kg / m 2 Less than 19 kg / m 2 , about 19~24.9kg / m 2 , about 25kg / m 2 , about 25~29kg / m 2 , about 29kg / m 2 , about 29kg / m2 More than 18-22 kg / m 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 have or are selected to have a body mass index of

[0144] The MADRS is a clinician-rated scale. It is used to assess depressive symptoms over the past week. Participants are rated on 10 items that assess feelings of guilt, sadness, fatigue, pessimism, inner tension, suicidal thoughts, loss of sleep or appetite, agitation, anxiety, weight loss, physical symptoms, difficulty concentrating, and lack of interest. Each item is scored out of 7 points, with 0 indicating no symptoms and 6 indicating maximum severity of symptoms.

[0145] In some embodiments, a human being treated with a 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, for the type of depression.

[0146] In some embodiments, treatment with the combination of dextromethorphan and bupropion results in the human having an MADRS score that is 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 the combination of dextromethorphan and bupropion may provide a human with an increased risk of: less than 34, about 20 to 34, about 7 to 19, about 0 to 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 to 6, about 0.1 to 1, about 1 to 2, The result is a MADRS score of about 2-3, about 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 10-11, about 11-12, about 12-13, about 13-14, about 14-15, about 15-16, about 16-17, about 17-18, about 18-19, about 19-20, about 18-20, about 0.1-3, about 3-6, about 6-9, about 9-12, about 12-14, about 12-15, or about 15-20.

[0148] The MADRS-6 subscale is the sum of responses to six of the 10 MADRS items considered to represent core symptoms of depression: reported sadness, apparent sadness, inner tension, fatigue, inability to feel, and pessimistic thoughts. MADRS items not included in the MADRS-6 score are decreased sleep, decreased appetite, difficulty concentrating, and suicidal ideation. Higher MADRS scores indicate more severe depression, and each item is scored from 0 to 6. The overall score ranges from 0 to 60. The questionnaire questions address 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. Usual cut-off points are: a) 0-6: normal / no symptoms, b) 7-19: mild depression, c) 20-34: moderate depression, d) 34 or above: severe depression.

[0149] In some embodiments, a human being treated with a 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 start of treatment, e.g., due to the type of depression.

[0150] In some embodiments, treatment with the combination of dextromethorphan and bupropion results in a human having a MADRS-6 score that is 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 the combination of dextromethorphan and bupropion results in the human having a MADRS-6 score that is about 17 or less, about 15 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 0.1 to 6, about 0.1 to 1, about 1 to 2, about 2 to 3, about 3 to 4, about 4 to 5, about 5 to 6, about 6 to 7, about 7 to 8, about 8 to 9, about 9 to 12, about 12 to 15, about 0.1 to 3, about 3 to 6, about 6 to 8, about 6 to 9, or about 9 to 15.

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

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

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

[0155] The therapeutic effect can be assessed at any appropriate time, e.g., 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 time point. In some embodiments, the therapeutic effect is assessed weekly using the MADRS.

[0156] The CGI-S scale is a clinician-rated scale used to assess the severity of a subject's current psychiatric condition compared to a population of MDD subjects. Subjects are rated on a scale of 1 to 7, with 1 indicating "normal" and 7 indicating "among the most severely ill subjects." The CGI-S can be administered by individuals with extensive specialized training and experience in assessing psychiatric disorders. Possible ratings are: 1) normal, not ill at all; 2) borderline psychopathological; 3) mildly ill; 4) moderately ill; 5) markedly ill; 6) severely ill; and 7) among the most severely ill.

[0157] In some embodiments, a human being treated with a combination of dextromethorphan and bupropion, e.g., for a type of depression, has, or is selected to have, a Clinical Global Index of Severity (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 human experiencing a reduction in CGI-S score of at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% 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 the combination of dextromethorphan and bupropion to a human results in a reduction in CGI-S 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 about 2, about 3 to about 3, about 4 to about 5, about 5 to about 6, about 0.1 to 3, or about 3 to about 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, 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 weeks, the beginning or 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 time point.

[0161] The 16-item patient-rated scale, QID-SR-16, 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 symptom domains that are 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 their symptoms across 10 categories: sleep, sadness, appetite, weight change, concentration, self-esteem, suicidality, general interest level, energy level, psychomotor retardation, and restlessness. Each category is rated on a four-point scale, with 0 representing no symptoms and 3 representing maximum symptom severity.

[0163] The total score on the QIDS ranges from 0 to 27, with a score of 5 or less indicating no depression, 6 to 10 indicating mild depression, 11 to 15 indicating moderate depression, 16 to 20 indicating severe depression, and a total score of more than 21 indicating 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 prior to initiating treatment.

[0165] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a human experiencing at least about a 10%, at least about a 20%, at least about a 30%, at least about a 40%, or at least about a 50% reduction in QID-SR-16 score 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 the combination of dextromethorphan and bupropion results in the human having a QID-SR-16 score of 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 0.1 to 6, about 0.1 to 5, about 0.1 to 1, about 1 to 2, about 2 to 3, about 3 to 4, about 4 to 5, about 5 to 6, about 0.1 to 3, or about 3 to 6. The therapeutic effect can be evaluated at any appropriate time, for example, 1-2 weeks, 1-3 weeks, 1-5 weeks, 1-6 weeks, 4-6 weeks, 6-8 weeks, 8-12 weeks, 12-16 weeks, at the beginning or end of week 1, at the beginning or end of week 2, at the beginning or end of week 3, at the beginning or end of week 4, at the beginning or end of week 5, at the beginning or end of week 6, at the beginning or end of week 7, at the beginning or end of week 8, at the beginning or end of week 9, at the beginning or end of week 10, at the beginning or end of week 11, at the beginning or end of week 12, at the beginning or end of week 13, at the beginning or end of week 14, at the beginning or end of week 15, at the beginning or end of week 16, or any other time.

[0167] The CGI scale is a clinician-rated scale used to assess the total improvement or worsening of psychiatric disorders, whether or not the investigator believes it is due to medication. Subjects are rated on a scale of 1 to 7, with 1 indicating the subject has improved greatly and 7 indicating the subject has deteriorated greatly. The CGI-I can be administered by anyone with extensive specialized training and experience in the assessment of psychiatric disorders.

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

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

[0170] The VAMS is a patient-rated mood scale consisting of a 100 mm line at each end of which the extremes of mood, e.g., happiness and sadness, are represented graphically, diagrammatically, or pictorially, such as sad and happy faces. The ends of the line may be further anchored with words representing the extremes of mood. Subjects are asked to rate their mood as a mark on the line. The distance along the line is measured and calculated as a number between 0 and 100. Subjects may be asked to complete the VAMS daily.

[0171] In some embodiments, for example, for a type of depression, a human being treated with a combination of dextromethorphan and bupropion has, or is selected 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 a human having at least about a 10%, at least about a 20%, at least about a 30%, at least about a 40%, or at least about a 50% reduction in 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 the combination of dextromethorphan and bupropion results in the human having a VAMS score of less than about 50 mm, less than about 40 mm, less than about 30 mm, less than about 20 mm, less than about 10 mm, between about 0 and 10 mm, between about 10 and 20 mm, between about 20 and 30 mm, between about 30 and 40 mm, between about 40 and 50 mm, between about 0 and 25 mm, or between about 25 and 50 mm.

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

[0175] The Columbia-Suicide Severity Rating Scale (C-SSRS) is a clinician-rated scale that reports the severity of suicidal ideation and suicidal behavior. Suicidal ideation is categorized into five categories: 1 (wish to die), 2 (active suicidal ideation without specificity), 3 (active suicidal ideation with some idea of ​​a method (but no plan) but no intention to carry it out), 4 (active suicidal ideation with some intention to carry it out but no specific plan), and 5 (active suicidal ideation with specific plan and intention to carry it out). The C-SSRS also collects information on the intensity of ideation, including frequency, duration, controllability, deterrence, and reasons for the most severe types of ideation. Suicidal behavior is categorized into five categories: 0 (no suicidal attempt), 1 (preparatory act or action), 2 (interrupted suicide attempt), 3 (interrupted suicide attempt), and 4 (actual suicide attempt). Multiple categories can be selected if they represent separate episodes. For actual suicide attempts only, the first attempt, the most fatal attempt, and the most recent attempt are classified as actual or potential lethal.

[0176] The C-SSRS may be administered to a person receiving treatment at each visit with a healthcare professional. The C-SSRS may be completed regarding the subject's lifetime history of suicidal thoughts and behaviors along with a recent recall period.

[0177] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a human having at least about a 10%, at least about a 20%, at least about a 30%, at least about a 40%, or at least about a 50% reduction in Columbia-Suicide Severity Rating 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, 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 weeks, at the beginning or end of week 1, at the beginning or end of week 2, at the beginning or end of week 3, at the beginning or end of week 4, at the beginning or end of week 5, at the beginning or end of week 6, at the beginning or end of week 7, at the beginning or end of week 8, at the beginning or end of week 9, at the beginning or end of week 10, at the beginning or end of week 11, at the beginning or end of week 12, at the beginning or end of week 13, at the beginning or end of week 14, at the beginning or end of week 15, at the beginning or end of week 16, or any other time.

[0179] The Sheehan Disability Scale (SDS) is a self-rating instrument 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 placed on a line ranging from 0 (not at all) to 10 (very much). The scores for each of the three items or areas are added together to arrive at a global SDS score ranging from 0 (no impairment) to 30 (severe impairment), and the three items or areas can be combined to assess global impairment.

[0180] In some embodiments, for example, for a type of depression, a person being treated with a combination of dextromethorphan and bupropion has, or is selected to have, a Sheehan Disability Scale (SDS) score of at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, or at least about 9 for each item on the SDS (0 to 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 SDS total score.

[0181] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a human experiencing at least about a 10%, at least about a 20%, at least about a 30%, at least about a 40%, or at least about a 50% reduction in SDS score 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, 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 weeks, at the beginning or end of week 1, at the beginning or end of week 2, at the beginning or end of week 3, at the beginning or end of week 4, at the beginning or end of week 5, at the beginning or end of week 6, at the beginning or end of week 7, at the beginning or end of week 8, at the beginning or end of week 9, at the beginning or end of week 10, at the beginning or end of week 11, at the beginning or end of week 12, at the beginning or end of week 13, at the beginning or end of week 14, at the beginning or end of week 15, at the beginning or end of week 16, or any other time.

[0183] The Hamilton Depression Rating Scale (HAM-D, HRSD, HDRS, HAMD-17) is a clinician-rated scale. This 17-item scale is used to assess a subject's depression based on the level of depression, guilt, suicidality, anxiety, agitation, level of insight, sleep patterns, loss of interest in work and other activities, weight loss, hypochondriasis, and psychomotor retardation. It can also be used to identify genital and physical symptoms. Items are rated on a 0-2 or 0-4 scale. Higher scores indicate more severe symptoms. For example, a HAM-D score of 10-13 for depression is considered mild, 14-17 is considered mild to moderate, and >17 is considered moderate to severe.

[0184] In some embodiments, for example, a human being treated with a 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 human experiencing at least about a 10%, at least about a 20%, at least about a 30%, at least about a 40%, or at least about a 50% reduction in HAM-D score 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 assessed at any appropriate time, e.g., 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, at the beginning or end of week 1, at the beginning or end of week 2, at the beginning or end of week 3, at the beginning or end of week 4, at the beginning or end of week 5, at the beginning or end of week 6, at the beginning or end of week 7, at the beginning or end of week 8, at the beginning or end of week 9, at the beginning or end of week 10, at the beginning or end of week 11, at the beginning or end of week 12, at the beginning or end of week 13, at the beginning or end of week 14, at the beginning or end of week 15, at the beginning or end of week 16, or any other time. In some embodiments, the therapeutic effect is assessed weekly using the HAM-D.

[0187] Conversion of MADRS scores to HAM-D scores, and vice versa, can be done using the following table. [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 ranging from 0 (no anxiety) to 4 (very strong anxiety). The highest possible total score is 56, representing the most severe anxiety, and the lowest possible score is 0, representing no anxiety.

[0189] In some embodiments, for example, for a type of depression, a person being treated with a 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 human experiencing at least about a 10%, at least about a 20%, at least about a 30%, at least about a 40%, or at least about a 50% reduction in HAM-A score 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, 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 weeks, at the beginning or end of week 1, at the beginning or end of week 2, at the beginning or end of week 3, at the beginning or end of week 4, at the beginning or end of week 5, at the beginning or end of week 6, at the beginning or end of week 7, at the beginning or end of week 8, at the beginning or end of week 9, at the beginning or end of week 10, at the beginning or end of week 11, at the beginning or end of week 12, at the beginning or end of week 13, at the beginning or end of week 14, at the beginning or end of week 15, at the beginning or end of week 16, or any other time.

[0192] The Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) is a seven-item, patient-rated scale used to measure cognitive and executive dysfunction in mood and anxiety disorders. It was developed to assess clinically relevant cognitive and physical symptoms that may emerge or persist during long-term treatment for depression. Subjects rate the perceived quality of their physical and cognitive functioning. The CPFQ assesses seven separate items—motivation / engagement, alertness / attention, energy, concentration / attention, recall, word-finding ability, and alertness / mental acuity—scored from 1 to 6 with increasing severity. The physical component of the CPFQ assesses sleepiness and fatigue, while the cognitive component assesses lethargy, inattention, forgetfulness, word-finding difficulty, and mental slowing. Higher scores indicate more impairment.

[0193] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a human experiencing at least about a 10%, at least about a 20%, at least about a 30%, at least about a 40%, or at least about a 50% reduction in CPFQ score 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 the combination of dextromethorphan and bupropion results in a human experiencing at least about a 10%, at least about a 20%, at least about a 30%, at least about a 40%, or at least about a 50% reduction in CPFQ-Cognitive subscale (items 4-7) score 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, 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 weeks, at the beginning or end of week 1, at the beginning or end of week 2, at the beginning or end of week 3, at the beginning or end of week 4, at the beginning or end of week 5, at the beginning or end of week 6, at the beginning or end of week 7, at the beginning or end of week 8, at the beginning or end of week 9, at the beginning or end of week 10, at the beginning or end of week 11, at the beginning or end of week 12, at the beginning or end of week 13, at the beginning or end of week 14, at the beginning or end of week 15, at the beginning or end of week 16, or any other time.

[0196] The Brief Psychiatric 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 from 1 (not present) to 7 (extremely severe). If an item is not rated, a 0 is entered and it is excluded from the analysis. This scale should be administered by a clinician familiar with psychotic disorders and able to interpret the constructs used to assess it. Items in Factor 1 (reality distortion) are suspiciousness, hallucinatory behavior, and unusual thought content.

[0197] 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 Brief Psychiatric Rating Scale (BPRS)-Factor 1 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 at the start of treatment.

[0198] In some embodiments, administration of the combination of dextromethorphan and bupropion to a human results in a decrease in BPRS-Factor 1 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, 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 weeks, at the beginning or end of week 1, at the beginning or end of week 2, at the beginning or end of week 3, at the beginning or end of week 4, at the beginning or end of week 5, at the beginning or end of week 6, at the beginning or end of week 7, at the beginning or end of week 8, at the beginning or end of week 9, at the beginning or end of week 10, at the beginning or end of week 11, at the beginning or end of week 12, at the beginning or end of week 13, at the beginning or end of week 14, at the beginning or end of week 15, at the beginning or end of week 16, or any other time.

[0200] In some embodiments, for example, for a type of depression, a person being treated with a 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 subjects have felt over 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 with the scale to determine the severity of depression. A higher total score indicates more severe depressive symptoms. Standard cutoff scores are as follows: 0-9 indicates very mild depression, 10-18 indicates mild depression, 19-29 indicates moderate depression, and 30-63 indicates severe depression.

[0202] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a human experiencing at least about a 10%, at least about a 20%, at least about a 30%, at least about a 40%, or at least about a 50% reduction in 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, 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 weeks, at the beginning or end of week 1, at the beginning or end of week 2, at the beginning or end of week 3, at the beginning or end of week 4, at the beginning or end of week 5, at the beginning or end of week 6, at the beginning or end of week 7, at the beginning or end of week 8, at the beginning or end of week 9, at the beginning or end of week 10, at the beginning or end of week 11, at the beginning or end of week 12, at the beginning or end of week 13, at the beginning or end of week 14, at the beginning or end of week 15, at the beginning or end of week 16, or any other time.

[0204] In some embodiments, for example, for a type of depression, a human being 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 human experiencing at least about a 10%, at least about a 20%, at least about a 30%, at least about a 40%, or at least about a 50% improvement in CRP levels 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, 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 weeks, at the beginning or end of week 1, at the beginning or end of week 2, at the beginning or end of week 3, at the beginning or end of week 4, at the beginning or end of week 5, at the beginning or end of week 6, at the beginning or end of week 7, at the beginning or end of week 8, at the beginning or end of week 9, at the beginning or end of week 10, at the beginning or end of week 11, at the beginning or end of week 12, at the beginning or end of week 13, at the beginning or end of week 14, at the beginning or end of week 15, at the beginning or end of week 16, or any other time.

[0207] Conversions between scores for some of the above assessments can be made 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 noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, also known as a glutamate receptor modulator, and is a novel agent that acts by a different mechanism of action than currently available antidepressants.

[0209] Dextromethorphan is a sigma-1 receptor agonist, a nicotinic acetylcholine receptor antagonist, and a serotonin and norepinephrine transporter inhibitor. Bupropion can enhance the bioavailability of dextromethorphan and is a norepinephrine and dopamine reuptake inhibitor and a nicotinic acetylcholine receptor antagonist. Both dextromethorphan and bupropion are nicotinic acetylcholine receptor antagonists and have mechanisms related to nicotine addiction. Therefore, the combination of dextromethorphan and bupropion may provide a new mechanism of action for smoking cessation treatment.

[0210] In some embodiments, the combination of dextromethorphan and bupropion may be used to treat 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 6-12 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 or may choose to be an ad-lib smoker. In some embodiments, prior to administration of the combination of dextromethorphan and bupropion, the smoker may smoke or choose to smoke, on average, about 10, about 10-15, about 10-17, about 10-20, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 20-25, about 25-30, about 30-40, about 40-50, or more cigarettes per day.

[0212] In some embodiments, a combination of dextromethorphan and bupropion can be used to treat nicotine addiction, and the combination includes 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 or salt form. In some embodiments, the dextromethorphan is in the form of its HBr salt.

[0213] In some embodiments, a combination of dextromethorphan and bupropion may be used to treat nicotine addiction, and this combination may be administered at a dose of about 100-200 mg, about 100-150 mg, about 150-200 mg, about 100-110 mg, about 110-120 mg, about 120-130 mg, about 130-140 mg, about 140-150 mg, about 150- The formulation contains 160 mg, about 160-170 mg, about 170-180 mg, about 180-190 mg, about 190-200 mg, about 105 mg, about 115 mg, about 125 mg, about 135 mg, about 145 mg, about 150 mg, about 155-165 mg, about 165-175 mg, about 175-185 mg, or about 185-195 mg of bupropion in free base or salt form. In some embodiments, the bupropion is in the form of the HCl salt.

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

[0215] Treatment of a human 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%, about 5-10%, about 10-15%, about 15-20%, about 20-25%, about 25-30%, 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-80%, about 80-100%, about 20%, about 25% greater, about 30%, or about 50% compared to bupropion alone, for example, over a period of 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] Treatment of a human 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 results in, 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%, about 35%, about 50%, about 60%, about 60-80%, about 80-90%, or about 90-100% more smokers experiencing a 50% or greater reduction in exhaled carbon monoxide levels, a biochemical marker of smoking intensity, compared to smokers treated with bupropion alone.

[0218] Treatment of a human with the combination of dextromethorphan and bupropion results in a reduction of at least one, or about one to two cigarettes, on the day of administration and a reduction of at least one, at least two, about one to two, or about two to three cigarettes on the next day, compared to a person who misses out on one or both doses of the combination of dextromethorphan and bupropion.

[0219] Human smoking cessation treatment with a combination of dextromethorphan and bupropion results in improvements over bupropion alone that are similar in magnitude to the improvements over placebo reported for varenicline, an approved smoking cessation medication, in similarly designed trials.

[0220] In some embodiments, the enhanced bioavailability of dextromethorphan or the combination of dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of these compounds can be used as an adjunctive therapy for the treatment of any of the conditions described herein, including TRD. For example, the adjunctive therapy can 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, or paroxetine. Trazodone, citalopram, sertraline, allyloxyindanamine, benactyzine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, brasofensine, moclobemide, rasagiline, niramide, iproniazid, iproclozide, toloxatone, butriptyline, dosulepin, dibenzepin, iprindole, 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 concentrations 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, which can result in a reduction in depressive symptoms of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100%, or any other reduction within a range bounded by any of these values.

[0222] Psychiatric disorders that may be treated by enhanced plasma concentrations of dextromethorphan, such as those obtained by combining dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, include, but are not limited to, anxiety disorders including, but not limited to, phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD), mania, manic-depressive illness, hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform tendencies, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease.

[0223] As Alzheimer's disease progresses, agitation may occur. Agitation may manifest as inappropriate verbal, emotional, and / or physical behavior. Inappropriate behavior may include, but is not limited to, incoherent babbling, inappropriate emotional responses, demands for attention, threats, irritability, frustration, shouting, repetitive questioning, mood swings, swearing, verbal abuse, physical outbursts, emotional distress, restlessness, fragmented sleep, sleep disturbances, delusions, hallucinations, pacing, wandering, searching, scavenging, repetitive body movements, hoarding, shadowing, hitting, scratching, biting, combativeness, hyperactivity, and / or kicking.

[0224] In some embodiments, agitation in Alzheimer's disease may be treated by enhancing the 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, which may result in a reduction in symptoms associated with agitation 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 reduction within a range bounded 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 predicted to increase to approximately 14 million by 2050. Agitation is present in up to 70% of AD patients and is characterized by emotional distress, aggressive behavior, disruptive irritability, and disinhibition. Managing agitation in AD patients is a priority. Agitation in AD patients is associated with increased caregiver burden, functional decline, accelerated cognitive decline, earlier nursing home placement, and increased mortality. There are currently no FDA-approved treatments for agitation in AD patients.

[0226] Indicators of therapeutic efficacy that may be improved by treatments that increase the bioavailability or plasma concentrations of dextromethorphan or by the combination of dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of these compounds include, but are not limited to, the Neuropsychiatric Inventory-Clinician (NPI-C) overall and all domains of the Neuropsychiatric Symptom Assessment-Clinician (NPI-C) scale. Neuropsychiatric Inventory-C rating scale agitation domain, Cohen-Mansfield Agitation Inventory (CMAI), Cornell Dementia Scale for Dementia (CSDD), Neuropsychiatric Symptom Assessment (NPI agitation / aggression domain), concomitant medications (frequency of concomitant medication use), Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), Neuropsychiatric Inventory (NPI) individual domains and NPI total score including the apathy domain, NPI agitation / aggression caregiver distress, modified Alzheimer's Disease Cooperative Study-Clinical Global Impression Scale agitation variation (mADCS-CGIC) Agitation), Patient Global Impression of Life (PGIC) (caregiver rating), Quality of Life in Dementia (DEMQOL), Quality of Life - Alzheimer's Disease Scale (AoL-AD), Zerritt Burden Scale, Resource Utilization in Dementia (RUDE), Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog), Mini-Mental State Examination (MMSE), Caregiver Strain Index (CSI), Neuropsychiatric Symptom Assessment (NPI) individual domains, Neuropsychiatric Symptom Assessment (NPI) total score, Neuropsychiatric Symptom Assessment (NPI agitation / aggression domain), Neuropsychiatric Symptom Assessment (NPI domain caregiver distress), etc.

[0227] Substance addictions that may be treated by increased bioavailability or plasma concentrations 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, drug dependence and addiction to cocaine, psychostimulants (e.g., crack, cocaine, speed, meth), 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 cigarettes, cigars, and / or pipes, as well as chewing tobacco.

[0228] Brain dysfunctions that may be treated by increased bioavailability or plasma concentrations of dextromethorphan or by the combination of dextromethorphan with an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, include, but are not limited to, disorders involving senile dementia, Alzheimer's disease, memory loss, amnesia / amnestic syndrome, epilepsy, impaired consciousness, coma, decreased attention, speech impairment, vocal spasms, and intellectual disabilities such as Parkinson's disease, Lennox-Gastaut syndrome, autism, attention deficit hyperactivity syndrome, and schizophrenia. Brain dysfunctions also include disorders caused by cerebrovascular disease, including, but not limited to, stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head trauma, etc., whose symptoms include impaired consciousness, senile dementia, coma, decreased attention, and speech impairment.

[0229] Movement disorders that may be treated by enhanced bioavailability or plasma concentrations 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, akathisia, akinesia, associated movements, athetosis, ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea, Huntington's disease, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, and Tourette's syndrome, and Wilson's disease.

[0230] Dementias that may be treated by enhanced bioavailability or plasma concentrations 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, 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 may be treated by enhanced bioavailability or plasma concentrations 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, 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 may be treated by enhanced bioavailability or plasma concentrations 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 degeneration (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedreich's ataxia, Huntington's disease, and the like. These include: Tony'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 may be treated by enhanced bioavailability or plasma concentrations 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, epileptic seizures, nonepileptic seizures, epilepsy, febrile convulsions, partial seizures including, but not limited to, simple partial seizures, Jacksonian seizures, complex partial seizures, and epilepsy partialis continua, generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and generalized seizures including, but not limited to, infantile spasms, and status epilepticus.

[0234] Types of headaches that may be treated by enhanced bioavailability or plasma concentrations 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, migraine, tension, and cluster headaches.

[0235] Other neurological disorders that may be treated by enhanced bioavailability or plasma concentrations 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 Rett syndrome, autism, tinnitus, disturbances of consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy, voice disorders due to uncontrolled laryngeal muscle spasms, including, but not limited to, abductor spasmodic dysphonia, adductor spasmodic dysphonia, muscle tension dysphonia, and 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, the combination of dextromethorphan and an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, may be used to treat pain, joint pain, pain associated with sickle cell disease, emotional dysregulation, depression (including treatment-resistant depression), memory and dementia-related disorders, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, seizures, cough (including chronic cough), and the like.

[0237] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds can be used to treat treatment-refractory depression.

[0238] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds may be used to treat allodynia.

[0239] In some embodiments, a combination of dextromethorphan and an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, can be used to treat treatment-refractory hyperalgesia.

[0240] In some embodiments, a combination of dextromethorphan and an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, can be used to treat dermatitis.

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

[0242] The pain-relieving properties of bupropion may be enhanced by methods including co-administering 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 an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0244] In some embodiments, dextromethorphan and quinidine may be co-administered with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.

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

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

[0247] In some embodiments, co-administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of these compounds with dextromethorphan can be used to treat psoriasis, cancer, viral infections, or as an adjuvant treatment for multiple myeloma.

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

[0249] In some embodiments, the 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) arthropathies, non-articular rheumatism, periarticular disorders, axonal spondyloarthropathy including ankylosing spondylitis, Paget's disease, fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip, vertebral crush fractures, osteoporosis, and the like.

[0250] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion may be administered to relieve musculoskeletal pain, arthritis pain, and inflammatory pain, including 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) arthropathy, non-articular rheumatism, periarticular disorders, neuropathic arthropathy including Charcot's foot, axial 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 can be administered to relieve complex regional pain syndrome, such as complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or 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 changes.

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

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

[0256] In some embodiments, a combination of dextromethorphan and an antidepressant such as buprepion can be administered orally to relieve fibromyalgia.

[0257] The terms "treating" or "treatment" include the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals, or any activity that otherwise affects the structure or any function of the human or other animal body.

[0258] Any antidepressant may be used in combination with dextromethorphan to improve the therapeutic properties of dextromethorphan. The dextromethorphan and antidepressant compound 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 plasma concentrations of dextromethorphan. For combinations of quinidine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the quinidine doses per day are about 1-1000 mg, 1-10 mg, 10 mg, about 5 mg, about 4.5 mg, about 1-3 mg, about 2-4 mg, about 3-5 mg, about 4-6 mg, about 5-7 mg, about 6-8 mg, about 7-9 mg, about 8-10 mg, about 9-11 mg, about 10-12 mg, and about 4 mg. Dosages include 5 mg, 20 mg, 30 mg, 30 to 100 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 10 to 30 mg, about 30 to 50 mg, 50 to 70 mg, and about 10 to 90 mg, or any dosage within a range bounded by these values.

[0260] Antidepressant compositions that may 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, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyindanamines, benactyzine, escitalopram, fluvoxamine benzodiazepine, benzodiazepine, benzophenone, benzodiazepines, benzodiazepines containing ...

[0261] For combinations of ketamine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the dose of ketamine per day is about 0.01 to 0.2 mg, about 0.2 to 0.4 mg, about 0.4 to 0.6 mg, about 0.6 to 0.8 mg, about 0.8 to 1 mg, about 1 to 1.2 mg, about 1.2 to 1.4 mg, about 1.4 to 1.6 mg, about 1.6 to 1.8 mg, about 1.8 to 2 mg, about 2 to 2.2 mg, about 2.2 to 2.4 mg, and about 2.4 to 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, approx. 80~90mg, approx. 90~100mg, approx. 100~120mg, approx. 120~140mg, approx. 140~160mg, approx. 160~180mg, approx. 180~200mg It can be administered in a dose of about 200-220 mg, about 220-240, about 240-250 mg, about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-350 mg, about 350-400 mg, about 25 mg, about 50 mg, about 100 mg, about 250 mg, or any dose within a range delimited by any of these values.

[0262] For combinations of tesofensine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the dose of tesofensine per day is about 0.1 to 0.2 mg, about 0.1 to 0.3 mg, about 0.1 to 0.4 mg, about 0.1 to 0.5 mg, about 0.1 to 0.6 mg, about 0.1 to 0.7 mg, about 0.1 to 0.8 mg, or about 0.1 The drug can be administered at a dose of about 0.9 mg, about 0.1 to 0.1 mg, about 0.1 to 0.12 mg, about 0.01 to 0.2 mg, about 0.1 to 0.3 mg, about 0.2 to 0.4 mg, about 0.3 to 0.5 mg, about 0.4 to 0.6 mg, about 0.5 to 0.7 mg, about 0.6 to 0.8 mg, about 0.7 to 0.9 mg, about 0.8 to 1 mg, about 0.9 to 1.1 mg, or any dose within a range delimited by any of these values.

[0263] For combinations of brasofensine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the dose of brasofensine per day is about 0.01 to 0.2 mg, about 0.2 to 0.4 mg, about 0.4 to 0.6 mg, about 0.6 to 0.8 mg, about 0.8 to 1 mg, about 1 to 1.2 mg, about 1.2 to 1.4 mg, or about 1.4 to 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 , about 0.2 to 0.8 mg, about 0.2 to 1 mg, about 0.2 to 1.2 mg, about 0.2 to 1.4 mg, about 0.2 to 1.6 mg, about 0.2 to 1.8 mg, about 0.2 to 2.0 mg, 0.2 to 2.5 mg, about 0.2 to 3.0 mg, about 0.2 to 3.5 mg, about 0.2 to 4.0 mg, or a range bounded by any of these values.

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

[0265] For combinations of doxepin and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), doxepin is administered at doses of about 1 to 500 mg, about 1 to 10 mg, about 1 to 40 mg, about 1 to 30 mg, about 1 to 20 mg, about 1 to 18 mg, about 1 to 16 mg, about 1 to 14 mg, about 1 to 12 mg, about 1 to 10 mg, about 10 to 150 mg, about 10 to 125 mg, about 10 to 100 mg, about 10 to 75 mg, about 10 to 70 mg, about 10 to 60 mg, about 10 to 50 mg, about 10 to 40 mg, about 10 to 30 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 75 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 10 to 150 mg, about 10 to 125 mg, about 1 ... 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 a dose of 0 to 280 mg, about 280 to 300 mg, about 300 to 320 mg, about 320 to 350 mg, about 350 to 400 mg, about 400 to 500 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, or any range of doses delimited by these numerical 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 at a dosage of about 1-10 mg, about 5-15 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 10 mg, about 20 mg, about 60 mg, about 100 mg, about 150 mg per day, or any range of dosages delimited by these numerical values.

[0267] For combinations of mianserin and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the dose of mianserin is about 1 to 300 mg, about 1 to 90 mg, about 1 to 60 mg, about 1 to 30 mg, about 1 to 25 mg, about 1 to 20 mg, about 1 to 15 mg, about 1 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, and about 30 to 40 mg per day. It can be administered at a dose of 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, or any range of doses separated by these numerical values.

[0268] For combinations of imipramine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the imipramine dose is about 1 to 10 mg, about 5 to 150 mg, about 5 to 125 mg, about 5 to 100 mg, about 5 to 75 mg, about 5 to 60 mg, about 5 to 50 mg, about 5 to 40 mg, about 5 to 30 mg, about 5 to 25 mg, about 5 to 20 mg, about 5 to 15 mg, about 10 to 20 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, or about 70 to 80 mg per day. g, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-220 mg, about 220-240, about 240-250 mg, about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-320 mg, about 320-350 mg, about 350-400 mg, about 400-500 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, or a range of doses separated by any of these numerical values.

[0269] For the combination of 2-chloroimipramine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the 2-chloroimipramine dose is about 0.1 to 0.25 mg, about 0.25 to 0.5 mg, about 0.5 to 0.75 mg, or about 0.75 to 1 mg per day. , 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, It can be administered at a dose of about 550 to 600 mg, about 600 to 650 mg, about 650 to 700 mg, about 700 to 800 mg, about 800 to 1000 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or any range of doses delimited by these numerical values.

[0270] For combinations of amitriptyline and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), amitriptyline should be administered at a dose of about 1 to 10 mg, about 5 to 100 mg, about 5 to 70 mg, about 5 to 60 mg, about 5 to 50 mg, about 5 to 40 mg, about 5 to 35 mg, about 5 to 30 mg, about 5 to 25 mg, about 5 to 20 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, or about 90 to 100 mg per day. It can be administered in a dose of 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 220 mg, about 220 to 240, about 240 to 250 mg, about 250 to 260 mg, about 260 to 280 mg, about 280 to 300 mg, about 300 to 320 mg, about 320 to 350 mg, about 350 to 400 mg, about 400 to 500 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, or a range of doses separated by any of these numerical values.

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

[0272] For combinations of desipramine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the dose of desipramine is about 1 to 10 mg, about 1 to 15 mg, about 10 to 20 mg, about 10 to 25 mg, about 10 to 30 mg, about 10 to 40 mg, about 10 to 50 mg, about 10 to 60 mg, about 10 to 70 mg, about 10 to 80 mg, about 10 to 90 mg, about 10 to 100 mg, about 10 to 120 mg, about 10 to 140 mg, about 10 to 150 mg, about 10 to 180 mg, about 10 to 200 mg, about 20 to 30 mg, about 20 to 40 mg, about 30 to 40 mg, about 40 to 50 mg, about 40 to 60 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 10 to 100 mg, about 10 to 120 mg, about 10 to 140 mg, about 10 to 150 mg, about 10 to 180 mg, about 10 to 200 mg, about 20 to 30 mg, about 20 to 40 mg, about 30 to 40 mg, about 40 to 50 mg, about 40 to 60 mg, about 50 to 60 mg, about 70 to 80 mg, about 80 to 90 mg, about 10 to 120 mg, about 10 to 140 mg, about 10 to 15 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 It can be administered at a dose of 60 mg, about 260 to 280 mg, about 280 to 300 mg, about 280 to 320 mg, about 300 to 350 mg, about 350 to 400 mg, about 100 to 200 mg, about 25 to 100 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, or any range of doses delimited by these numerical values.

[0273] For combinations of protriptyline and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, non-deuterium-modified dextromethorphan), the protriptyline dose is about 5 to 100 mg, about 2 to 5 mg, about 2 to 6 mg, about 2 to 7 mg, about 2 to 8 mg, about 2 to 9 mg, about 2 to 10 mg, about 2 to 11 mg, about 2 to 12 mg, about 2 to 13 mg, about 2 to 14 mg, about 2 to 15 mg, about 2 to 20 mg, about 2 to 21 mg, about 2 to 22 mg, about 2 to 23 mg, about 2 to 24 mg, about 2 to 25 mg, about 2 to 26 mg, about 2 to 27 mg, about 2 to 28 mg, about 2 to 29 mg, about 2 to 30 mg, about 2 to 35 mg, about 2 to 40 mg, about 2 to 41 mg, about 2 to 42 mg, about 2 to 43 mg, about 2 to 44 mg, about 2 to 45 mg, about 2 to 46 mg, about 2 to 47 mg, about 2 to 48 mg, about 2 to 49 mg, about 2 to 50 mg, about 2 to 51 mg, about 2 to 52 mg, about 2 to 53 mg, about 2 to 54 mg, about 2 to 55 mg, about 2 to 56 mg, about 2 to 57 mg, about 2 to 58 mg, about 2 to 59 mg, about 2 to 60 mg, about 2 to 61 mg, about 2 to 62 mg, about 2 to 63 mg, about 2 to 64 mg, about 2 to 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 It can be administered at a dose of about 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 10 mg, about 20 mg, about 30 mg, about 60 mg, about 100 mg, about 150 mg, or any range of doses delimited by these numerical values.

[0274] For combinations of trimipramine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the daily dose of trimipramine is about 20 to 300 mg, about 1 to 10 mg, about 5 to 20 mg, about 5 to 25 mg, about 5 to 30 mg, about 5 to 35 mg, about 5 to 40 mg, about 5 to 45 mg, about 5 to 50 mg, about 5 to 55 mg, about 5 to 60 mg, about 5 to 65 mg, about 5 to 70 mg, about 5 to 75 mg, about 5 to 100 mg, about 5 to 125 mg, about 5 to 150 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 125 mg, about 10 to 150 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 100 mg, about 100 to 125 mg, about 10 to 150 mg 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 It can be administered at a dose of 80 mg, about 280 to 300 mg, about 300 to 320 mg, about 320 to 350 mg, about 350 to 400 mg, about 400 to 500 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, or a range of doses delimited by any of these numerical values.

[0275] For combinations of nortriptyline and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the dose of nortriptyline per day is about 1 to 5 mg, about 5 to 10 mg, about 5 to 20 mg, about 5 to 25 mg, about 5 to 30 mg, about 5 to 35 mg, about 5 to 40 mg, about 5 to 45 mg, about 5 to 50 mg, about 5 to 55 mg, about 5 to 60 mg, about 5 to 65 mg, about 5 to 70 mg, about 5 to 75 mg, about 5 to 100 mg, about 5 to 125 mg, about 5 to 150 mg, about 10 to 15 mg, about 15 to 20 mg, about 20 to 30 mg, about 25 to 35 mg, about 30 to 40 mg, about 35 to 45 mg, about 35 to 50 mg, about 35 to 5 ... The dosage may be about 0 mg, about 25 to 30 mg, about 30 to 35 mg, about 30 to 50 mg, about 35 to 40 mg, about 40 to 45 mg, about 45 to 50 mg, about 50 to 150 mg, about 50 to 55 mg, about 55 to 60 mg, about 60 to 65 mg, about 65 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 80 to 120 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 10 mg, about 20 mg, about 30 mg, about 60 mg, about 100 mg, about 150 mg, or any range of dosages separated by these numerical values.

[0276] For combinations of maprotiline and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the dose of maprotiline per day is about 1 to 5 mg, about 5 to 10 mg, about 5 to 20 mg, about 5 to 25 mg, about 5 to 30 mg, about 5 to 35 mg, about 5 to 40 mg, about 5 to 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 It can be administered at a dose of about 150 mg, about 150 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 225 mg, about 210 to 240 mg, about 200 to 250 mg, about 10 mg, about 25 mg, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 225 mg, or a range of doses separated by any of these numerical values.

[0277] For combinations of phenelzine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the phenelzine dose is about 1 to 5 mg, about 5 to 10 mg, about 5 to 20 mg, about 5 to 25 mg, about 5 to 30 mg, about 5 to 35 mg, about 5 to 40 mg, about 5 to 45 mg, about 5 to 50 mg, about 5 to 55 mg, about 5 to 60 mg, about 5 to 65 mg, about 5 to 70 mg, about 5 to 75 mg, about 5 to 90 mg, about 10 to 15 mg, about 15 to 20 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 35 mg, and about 35 to 40 mg per day. It can be administered in a dose of about 40 to 45 mg, about 40 to 50 mg, about 45 to 50 mg, about 50 to 55 mg, about 50 to 70 mg, about 50 to 200 mg, about 55 to 60 mg, about 60 to 65 mg, about 60 to 90 mg, about 65 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, 80 to 120 mg, about 90 to 100 mg, about 100 to 120 mg, about 100 to 150 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 100 mg, about 150 mg, or a range of doses separated by any of these numerical values.

[0278] For combinations of isocarboxazid and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, non-deuterium-modified dextromethorphan), the dose of isocarboxazid is about 1 to 5 mg, about 2 to 5 mg, about 2 to 6 mg, about 2 to 7 mg, about 2 to 8 mg, about 2 to 9 mg, about 2 to 10 mg, about 2 to 11 mg, or about 2 to 12 mg per day. 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, It can be administered at a dose of about 65 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 100 mg, about 150 mg, or any range of doses delimited by these numerical values.

[0279] For combinations of tranylcypromine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the tranylcypromine dose is about 1 to 5 mg, about 1 to 30 mg, about 1 to 25 mg, about 1 to 20 mg, about 2 to 5 mg, about 2 to 6 mg, about 2 to 7 mg, or about 2 to 8 mg per day. , 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 It can be administered at a dose of about 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 100 mg, about 150 mg, or a range of doses separated by any of these numerical values.

[0280] For combinations of paroxetine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), paroxetine may be administered at doses of about 1 to 5 mg, about 1 to 50 mg, about 1 to 20 mg, about 1 to 15 mg, about 1 to 10 mg, about 2 to 5 mg, about 2 to 6 mg, about 2 to 7 mg, about 2 to 8 mg, about 2 to 9 mg, about 2 to 10 mg, about 2 to 11 mg, about 2 to 12 mg, about 2 to 13 mg, about 2 to 14 mg, about 2 to 15 mg, about 2 to 16 mg, about 2 to 17 mg, about 2 to 18 mg, about 2 to 19 mg, about 2 to 20 mg, about 2 to 30 mg, about 2 to 40 mg, about 2 to 50 mg, about 2 to 50 mg, about 2 to 60 mg, about 2 to 70 mg, about 2 to 80 mg, about 2 to 90 mg, about 2 to 100 mg, about 2 to 11 mg, about 2 to 12 mg, about 2 to 13 mg, about 2 to 14 mg, about 2 to 15 mg, about 2 to 16 mg, about 2 to 17 mg, about 2 to 18 mg, about 2 to 19 mg, about 2 to 20 mg, about 2 to 30 mg, about 2 to 40 mg, about 2 to 50 mg, about 2 to 60 mg, about 2 to 70 mg, about 2 to 80 mg, about 2 to 90 mg, about 3 to 40 mg, about 3 to 50 mg, It can be administered in a dose of about 5 to 10 mg, about 10 to 15 mg, about 15 to 20 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 35 mg, about 35 to 40 mg, about 40 to 45 mg, about 45 to 50 mg, about 50 to 55 mg, about 55 to 60 mg, about 60 to 65 mg, about 65 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 60 mg, about 100 mg, about 150 mg, or a range of doses separated by any of these numerical values.

[0281] For combinations of trazodone and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), trazodone is administered at doses of about 1 to 10 mg, about 10 to 20 mg, about 10 to 30 mg, about 10 to 40 mg, about 10 to 50 mg, about 10 to 60 mg, about 10 to 70 mg, and about 10 to 80 mg per day. 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 g, about 400-450 mg, about 450-500 mg, about 500-550 mg, about 550-600 mg, about 600-650 mg, about 650-700 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or a range of doses delimited by any of these numerical values.

[0282] For combinations of citalopram and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the dose of citalopram per day is about 1 to 5 mg, about 1 to 20 mg, about 1 to 15 mg, about 1 to 10 mg, about 2 to 5 mg, about 2 to 6 mg, about 2 to 7 mg, about 2 to 8 mg, about 2 to 9 mg, about 2 to 10 mg, about 2 to 11 mg, about 2 to 12 mg, about 2 to 13 mg, about 2 to 14 mg, about 2 to 15 mg, about 2 to 20 mg, about 2 to 25 mg, about 2 to 30 mg, about 2 to 35 mg, about 2 to 40 mg, about 5 to 10 mg, about 10 to 15 mg, It can be administered in a dose of about 15 to 20 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 35 mg, about 35 to 40 mg, about 40 to 45 mg, about 45 to 50 mg, about 50 to 55 mg, about 55 to 60 mg, about 60 to 65 mg, about 65 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 100 mg, about 150 mg, or a range of doses separated by any of these numerical values.

[0283] For combinations of sertraline and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the dose of sertraline is about 1 to 5 mg, about 1 to 50 mg, about 1 to 45 mg, about 1 to 40 mg, about 1 to 30 mg, about 1 to 20 mg, about 2 to 5 mg, about 2 to 6 mg, about 2 to 7 mg, about 2 to 8 mg, or about 2 to 9 mg per day. , 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 It can be administered at a dose of 0 to 120 mg, about 120 to 125 mg, about 125 to 140 mg, about 140 to 150 mg, about 150 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 300 mg, about 10 mg, about 25 mg, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 225 mg, or any range of doses separated by these numerical values.

[0284] For combinations of aryloxyindanamine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the aryloxyindanamine should be administered at a dose of about 0.1 to 0.25 mg, about 0.25 to 0.5 mg, about 0.5 to 0.75 mg, about 0.75 to 1 mg, about 1 to 5 mg, about 5 to 10 mg, about 10 to 15 mg, about 15 to 20 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 150 mg, or about 150 to 200 mg per day. 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 , about 550 to 600 mg, about 600 to 650 mg, about 650 to 700 mg, about 700 to 800 mg, about 800 to 1000 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or a range of doses delimited by any of these numerical values.

[0285] For a combination of benactyzine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the dose of benactyzine is about 0.1 to 0.25 mg, about 0.25 to 0.5 mg, about 0.5 to 0.75 mg, about 0.75 to 1 mg, or about 1 to 5 mg per day. 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 It can be administered at a dose of 50 to 600 mg, about 600 to 650 mg, about 650 to 700 mg, about 700 to 800 mg, about 800 to 1000 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or any range of doses delimited by these numerical values.

[0286] For combinations of escitalopram and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the dose of escitalopram per day is about 1 to 5 mg, about 2 to 5 mg, about 2 to 6 mg, about 2 to 7 mg, about 2 to 8 mg, about 2 to 9 mg, about 2 to 10 mg, about 2 to 12 mg, about 2 to 14 mg, about 2 to 15 mg, about 2 to 20 mg, about 5 to 10 mg, about 5 to 15 mg, about 10 to 15 mg, about 10 to 30 mg, about 15 to 20 mg, about It can be administered at a dose of 15 to 30 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 35 mg, about 35 to 40 mg, about 40 to 45 mg, about 45 to 50 mg, about 50 to 55 mg, about 55 to 60 mg, about 60 to 65 mg, about 65 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 200 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, or any range of doses separated by these numerical values.

[0287] For combinations of fluvoxamine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), fluvoxamine is administered at doses of 50 to 300 mg, 1 to 10 mg, about 10 to 20 mg, about 10 to 30 mg, about 10 to 40 mg, about 10 to 50 mg, or about 10 to 60 mg per day. 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 dose may be about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, or a range of doses delimited by any of these numerical values.

[0288] For combinations of venlafaxine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), venlafaxine is administered at doses of about 1 to 10 mg, about 5 to 20 mg, about 5 to 25 mg, about 5 to 30 mg, about 5 to 35 mg, about 5 to 40 mg, about 5 to 45 mg, or about 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 dose may be about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 225 mg, about 250 mg, about 375 mg, about 400 mg, about 600 mg, or any range of doses delimited by these numerical values.

[0289] For combinations of desvenlafaxine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), desvenlafaxine is administered at doses of about 2 to 5 mg, about 2 to 6 mg, about 2 to 7 mg, about 2 to 8 mg, about 2 to 9 mg, about 2 to 10 mg, about 2 to 11 mg, about 2 to 12 mg, about 2 to 13 mg, about 2 to 14 mg, about 2 to 15 mg, about 2 to 20 mg, about 2 to 21 mg, about 2 to 22 mg, about 2 to 23 mg, about 2 to 24 mg, about 2 to 25 mg, about 2 to 30 mg, about 2 to 35 mg, about 2 to 40 mg, about 2 to 45 mg, about 2 to 50 mg, about 2 to 75 mg, about 2 to 100 mg, about 1 to 5 mg, and about 5 to 10 mg per day. 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 , about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 100 mg, about 150 mg, or a range of doses delimited by any of these numerical values.

[0290] For combinations of duloxetine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the dose of duloxetine is about 1 to 5 mg, about 2 to 5 mg, about 2 to 6 mg, about 2 to 7 mg, about 2 to 8 mg, about 2 to 9 mg, about 2 to 10 mg, or about 2 to 11 mg per day. 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 It can be administered at a dose of 0 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 100 mg, about 120 mg, or any range of doses delimited by these numerical values.

[0291] For combinations of mirtazapine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), mirtazapine may be administered at doses of about 2 to 5 mg, about 2 to 6 mg, about 2 to 7 mg, about 2 to 8 mg, about 2 to 9 mg, about 2 to 10 mg, about 2 to 11 mg, about 2 to 12 mg, about 2 to 13 mg, about 2 to 14 mg, about 2 to 15 mg, about 2 to 20 mg, about 2 to 25 mg, about 2 to 30 mg, about 2 to 35 mg, about 2 to 40 mg, about 2 to 45 mg, about 1 to 5 mg, about 5 to 10 mg, about 5 to 100 mg, about 10 to 15 mg, about 10 to 50 mg, about 15 to 200 mg, about 25 to 260 mg, about 26 to 280 mg, about 27 to 290 mg, about 30 to 350 mg, about 31 to 320 mg, about 32 to 330 mg, about 33 to 340 mg, about 34 to 350 mg, about 35 to 400 mg, about 35 to 450 mg, about 40 to 450 mg, about 45 to 50 ... It can be administered in a dose of 5 to 20 mg, about 15 to 45 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 35 mg, about 35 to 40 mg, about 40 to 45 mg, about 45 to 50 mg, about 50 to 55 mg, about 55 to 60 mg, about 60 to 65 mg, about 65 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 45 mg, about 60 mg, about 75 mg, or any range of doses separated by these numerical values.

[0292] For combinations of nefazodone and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the nefazodone dose is about 1 to 10 mg, about 10 to 20 mg, about 20 to 40 mg, about 20 to 50 mg, about 20 to 60 mg, about 20 to 70 mg, about 20 to 80 mg, about 20 to 90 mg, or about 20 to 100 mg per day. 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 It can be administered at a dose of about 450 to 500 mg, about 500 to 550 mg, about 550 to 600 mg, about 600 to 650 mg, about 650 to 700 mg, about 700 to 1000 mg, about 1000 to 1500 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or a range of doses delimited by any of these numerical values.

[0293] For combinations of selegiline and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), selegiline can be administered at a dose of about 0.5 to 2 mg, about 2 to 5 mg, about 1 to 10 mg, about 1 to 9 mg, about 1 to 8 mg, about 1 to 7 mg, about 1 to 6 mg, about 1 to 5 mg, about 1 to 3 mg, about 3 to 5 mg, about 5 to 10 mg, about 5 to 15 mg, about 10 to 15 mg, about 15 to 25 mg, about 25 to 30 mg, about 30 to 35 mg, about 35 to 40 mg, about 40 to 45 mg, about 45 to 50 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, or any range of doses delimited by these numerical values.

[0294] In the case of a combination of sibutramine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the dose of sibutramine should be about 1 to 5 mg, about 1 to 15 mg, about 1 to 10 mg, about 1 to 8 mg, about 5 to 10 mg, about 10 to 15 mg, about 15 to 20 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 35 mg, about 35 to 40 mg, or about 40 mg per day. It can be administered at a dose of about 45 mg, about 45 to 50 mg, about 50 to 55 mg, about 55 to 60 mg, about 60 to 65 mg, about 65 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 100 mg, about 120 mg, or a range of doses separated by any of these numerical values.

[0295] For combinations of rasagiline and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), rasagiline can be administered at a dose of about 0.1-0.3 mg, about 0.3-0.5 mg, about 0.3-0.7 mg, about 0.5-0.7 mg, about 0.5-1.5 mg, about 0.7-0.9 mg, about 0.9-1.0 mg, about 1.0-1.5 mg, about 1.5-2.0 mg, about 2.0-3.0 mg, about 0.1 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, or about 2 mg per day, or any range of doses delimited by these numerical values.

[0296] For combinations of milnacipran and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the dose of milnacipran per day is about 1 to 7.5 mg, about 7.5 to 12.5 mg, about 5 to 20 mg, about 5 to 100 mg, about 5 to 90 mg, about 5 to 80 mg, about 5 to 70 mg, about 5 to 60 mg, about 5 to 50 mg, about 5 to 40 mg, about 12.5 to 15 mg, about 15 to 20 mg, about 20 to 30 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 35 mg, about 35 to 40 mg, about 40 to 45 mg, and about 45 to 50 mg. The dosage may be about 0 mg, about 50 to 55 mg, about 40 to 60 mg, about 55 to 60 mg, about 60 to 65 mg, about 65 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 80 to 120 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 180 to 220 mg, about 200 to 300 mg, about 300 to 400 mg, about 7.5 mg, about 12.5 mg, about 25 mg, about 50 mg, about 75 mg, about 60 mg, about 100 mg, about 200 mg, or a range of dosages separated by any of these numerical values.

[0297] For combinations of moclobemide and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the dose of moclobemide per day is about 1 to 10 mg, about 10 to 20 mg, about 20 to 25 mg, about 20 to 450 mg, about 20 to 300 mg, about 20 to 250 mg, about 20 to 200 mg, about 20 to 150 mg, about 20 to 100 mg, about 25 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 150 mg, about 150 to 160 mg, or about 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 It can be administered at a dose of 50 to 500 mg, about 500 to 550 mg, about 550 to 600 mg, about 600 to 650 mg, about 650 to 700 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or any range of doses delimited by these numerical values.

[0298] For combinations of nyaramide and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the dose of nyaramide per day is about 0.1 to 0.25 mg, about 0.25 to 0.5 mg, about 0.5 to 0.75 mg, about 0.75 to 1 mg, about 1 to 5 mg, about 5 to 10 mg, about 10 to 15 mg, about 15 to 20 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 150 mg, about 150 to 160 mg, and about 160 to 200 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 It can be administered at a dose of 50 to 600 mg, about 600 to 650 mg, about 650 to 700 mg, about 700 to 800 mg, about 800 to 1000 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or any range of doses delimited by these numerical values.

[0299] For combinations of iproniazid and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the dose of iproniazid per day is about 0.1 to 0.25 mg, about 0.25 to 0.5 mg, about 0.5 to 0.75 mg, about 0.75 to 1 mg, about 1 to 5 mg, about 5 to 10 mg, about 10 to 15 mg, about 15 to 20 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 150 mg, about 150 to 160 mg, 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. It can be administered at a dose of 550 to 600 mg, about 600 to 650 mg, about 650 to 700 mg, about 700 to 800 mg, about 800 to 1000 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or any range of doses delimited by these numerical values.

[0300] For combinations of iproclozide and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the dose of iproclozide per day is about 0.1 to 0.25 mg, about 0.25 to 0.5 mg, about 0.5 to 0.75 mg, about 0.75 to 1 mg, about 1 to 5 mg, about 5 to 10 mg, about 10 to 15 mg, about 15 to 20 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 150 mg, about 150 to 160 mg, 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. It can be administered at a dose of 550 to 600 mg, about 600 to 650 mg, about 650 to 700 mg, about 700 to 800 mg, about 800 to 1000 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or any range of doses delimited by these numerical values.

[0301] For combinations of toloxatone and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the dose of toloxatone is about 0.1 to 0.25 mg, about 0.25 to 0.5 mg, about 0.5 to 0.75 mg, about 0.75 to 1 mg, about 1 to 5 mg, about 5 to 10 mg, about 10 to 15 mg, about 15 to 20 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 150 mg, about 150 to 160 mg, or about 170 to 210 mg per day. 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 It can be administered at a dose of 50 to 600 mg, about 600 to 650 mg, about 650 to 700 mg, about 700 to 800 mg, about 800 to 1000 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or any range of doses delimited by these numerical values.

[0302] For the combination of butriptyline and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), butriptyline should be administered at a dose of about 0.1 to 0.25 mg, about 0.25 to 0.5 mg, about 0.5 to 0.75 mg, about 0.75 to 1 mg, or about 1 to 5 mg per day. , 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. It can be administered at a dose of 550 to 600 mg, about 600 to 650 mg, about 650 to 700 mg, about 700 to 800 mg, about 800 to 1000 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or any range of doses delimited by these numerical values.

[0303] For combinations of dosulepin and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the dose of dosulepin per day is about 0.1 to 0.25 mg, about 0.25 to 0.5 mg, about 0.5 to 0.75 mg, about 0.75 to 1 mg, about 1 to 5 mg, about 5 to 10 mg, about 10 to 15 mg, about 15 to 20 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 150 mg, about 150 to 160 mg, and about 160 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 It can be administered at a dose of 50 to 600 mg, about 600 to 650 mg, about 650 to 700 mg, about 700 to 800 mg, about 800 to 1000 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or any range of doses delimited by these numerical values.

[0304] For combinations of dibenzepine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the dibenzepine dose is about 0.1 to 0.25 mg, about 0.25 to 0.5 mg, about 0.5 to 0.75 mg, about 0.75 to 1 mg, about 1 to 5 mg, about 5 to 10 mg, about 10 to 15 mg, about 15 to 20 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 150 mg, about 150 to 160 mg, or about 170 to 210 mg per day. 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 It can be administered at a dose of 50 to 600 mg, about 600 to 650 mg, about 650 to 700 mg, about 700 to 800 mg, about 800 to 1000 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or any range of doses delimited by these numerical values.

[0305] For combinations of iprindole and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), the dose of iprindole per day is about 0.1 to 0.25 mg, about 0.25 to 0.5 mg, about 0.5 to 0.75 mg, about 0.75 to 1 mg, about 1 to 5 mg, about 5 to 10 mg, about 10 to 15 mg, about 15 to 20 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 150 mg, about 150 to 160 mg, or 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. It can be administered at a dose of 550 to 600 mg, about 600 to 650 mg, about 650 to 700 mg, about 700 to 800 mg, about 800 to 1000 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or any range of doses delimited by these numerical values.

[0306] For combinations of lofepramine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the daily dose of lofepramine is about 0.1 to 0.25 mg, about 0.25 to 0.5 mg, about 0.5 to 0.75 mg, about 0.75 to 1 mg, about 1 to 5 mg, about 5 to 10 mg, about 10 to 15 mg, about 15 to 20 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 150 mg, about 150 to 160 mg, 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. It can be administered at a dose of 550 to 600 mg, about 600 to 650 mg, about 650 to 700 mg, about 700 to 800 mg, about 800 to 1000 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or any range of doses delimited by these numerical values.

[0307] For a combination of opipramol and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan, and non-deuterium-modified dextromethorphan), opipramol should be administered at a dose of about 0.1 to 0.25 mg, about 0.25 to 0.5 mg, about 0.5 to 0.75 mg, about 0.75 to 1 mg, about 1 to 5 mg, about 5 to 10 mg, about 10 to 15 mg, about 15 to 20 mg, about 20 to 25 mg, about 25 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 150 mg, about 150 to 160 mg, or 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. It can be administered at a dose of 550 to 600 mg, about 600 to 650 mg, about 650 to 700 mg, about 700 to 800 mg, about 800 to 1000 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or any range of doses delimited by these numerical values.

[0308] For combinations of norfluoxetine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), norfluoxetine is administered at a dose of about 0.1 to 0.25 mg, about 0.25 to 0.5 mg, about 0.5 to 0.75 mg, about 0.75 to 1 mg, or about 1 to 1 mg per day. 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, It can be administered at a dose of about 550 to 600 mg, about 600 to 650 mg, about 650 to 700 mg, about 700 to 800 mg, about 800 to 1000 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or any range of doses delimited by these numerical values.

[0309] For combinations of dapoxetine and dextromethorphan (including deuterium-modified dextromethorphan, e.g., d6-dextromethorphan and non-deuterium-modified dextromethorphan), the dose of dapoxetine is about 0.1 to 0.25 mg, about 0.25 to 0.5 mg, about 0.5 to 0.75 mg, about 0.75 to 1 mg, or about 1 to 5 mg per day. 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 It can be administered at a dose of 50 to 600 mg, about 600 to 650 mg, about 650 to 700 mg, about 700 to 800 mg, about 800 to 1000 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg, or any range of doses delimited by these numerical values.

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

[0311] The combination of dextromethorphan and bupropion can provide greater benefits, such as greater pain relief, than can be achieved by administering either component alone. In extensive metabolizers, dextromethorphan can be rapidly and extensively metabolized, resulting in low systemic exposure even at high doses. In addition to its antidepressant and analgesic properties, bupropion is an inhibitor of dextromethorphan metabolism. It is also a dopamine and norepinephrine reuptake inhibitor. It can also act as a nicotinic acetylcholine receptor antagonist and regulate cytokines associated with inflammatory diseases. Bupropion can affect tumor necrosis factor-alpha and interferon-gamma concentrations. Bupropion metabolites, 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 of bupropion that are rapidly converted in the body (e.g., salts, hydrates, solvates, polymorphs, etc.), are prodrugs of propion, hydroxybupropion, threohydroxybupropion, and erythrohydroxybupropion. Bupropion prodrugs may include N-methylbupropion and N-benzylbupropion.

[0312] As discussed above, this inhibition may increase plasma concentrations of dextromethorphan, resulting in additive or synergistic effects such as relief of neurological disorders, including pain, depression, smoking cessation, etc. Thus, while inhibition of dextromethorphan metabolism is only one of many potential benefits of the combination, co-administration of bupropion with dextromethorphan may thereby enhance the efficacy of bupropion in many individuals. Co-administration of bupropion with dextromethorphan may enhance the analgesic properties of bupropion in many individuals. Co-administration of bupropion with dextromethorphan may also enhance the antidepressant properties of bupropion in many individuals, including a more rapid onset of action.

[0313] Another potential advantage 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 dextromethorphan treatment, which may be useful, for example, in human patients at risk of experiencing adverse events as a result of being treated with dextromethorphan.

[0314] Another potential advantage of co-administering dextromethorphan and bupropion is that it may be useful for reducing the likelihood of adverse events, such as seizures, associated with treatment with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a 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 a metabolite or prodrug of any of these compounds.

[0315] With respect to dextromethorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, co-administration may reduce central nervous system adverse events, gastrointestinal events, or another type of adverse event associated with any of these compounds. Central nervous system (CNS) adverse events include, but are not limited to, nervousness, dizziness, insomnia, lightheadedness, tremors, hallucinations, convulsions, CNS depression, fear, anxiety, headache, increased irritability or agitation, tinnitus, drowsiness, vertigo, sedation, somnolence, confusion, disorientation, malaise, incoordination, fatigue, euphoria, irritability, insomnia, sleep disturbances, seizures, agitation, catatonic states, hysteria, hallucinations, delusions, paranoia, headache and / or migraine, and extrapyramidal symptoms such as oculomotor crises, torticollis, hyperexcitability, increased muscle tone, ataxia and / or tongue protrusion.

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

[0317] Co-administration of dextromethorphan with an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, does not necessarily require that the two compounds be administered in the same dosage form. For example, the two compounds can be administered in a single dosage form, or they can be administered in two separate dosage forms. Furthermore, the two compounds can be administered simultaneously, although this is not required. The compounds can be administered at different times, as long as both are present in the human body at the same time for at least part of the time that 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 with dextromethorphan. Examples of side effects that may be reduced include paresthesia of rotation and movement, agitation, weakness in the arms, feeling full, blurred vision, burning eyes, tinnitus, changes in vital signs (including but not limited to heart rate, respiratory rate, body temperature, and blood pressure), feeling cold, constipation, difficulty concentrating, difficulty sleeping, difficulty falling asleep, difficulty urinating, difficulty having a bowel movement, ear discomfort, eye discomfort, stomach discomfort, dizziness, dry lips, dry mouth, dry throat, dysmenorrhea, fatigue, feeling feverish, heavy headed, feeling more irritable than usual, feeling more tired than usual, feeling fatigued, and hand tremors. Side effects include: weakness in hands, headache, heartburn, hot flashes, increased blood pressure, skin sensitivity, skin sensitivity of head and face, involuntary muscle contractions, involuntary muscle contractions of the whole body, knee pain, beriberi, dizziness, loose stools, loss of appetite, lower back pain, menstrual irregularities, metallic taste, increased saliva, dry mucous membranes, stuffy nose, nausea, runny nose, mild eye pressure, trembling when stretching or yawning, skin sensitivity, skin sensitivity of arms, face and / or head, sleep disturbance, loose stools, stomach pain, stomach discomfort, sweaty hands and / or feet, throat irritation, sore throat, tinnitus, trembling, and / or weakness. These side effects may also be referenced or grouped according to corresponding, equivalent, or other related terms found in the Medicines and Regulatory Affairs Dictionary (MedRA).

[0319] In some embodiments, co-administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds in combination 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 have improved pain-relieving properties, including a potentially faster onset of action.

[0320] In some embodiments, the combination has an improvement of at least about 0.5%, at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 100%, up to about 500%, or up to 1000%, between about 0.5% and about 1000%, between about 10% and about 20%, between about 20% and about 30%, between about 30% and about 40%, between about 40% and about 500%, or up to 1000%, compared to bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds alone. The pain relief properties may be improved by about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100% to about 110%, about 110% to about 120%, about 120% to about 130%, about 130% to about 140%, about 140% to about 150%, about 150% to about 160%, about 160% to about 170%, about 170% to about 180%, about 180% to about 190%, about 190% to about 200%, or any amount of pain relief in a range bounded by any of these values, or any amount of pain relief between any of these values.

[0321] In some embodiments, the combination provides a reduction in serotonin levels compared to dextrorphan alone by 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%, between about 0.5% and about 1000%, between about 10% and about 20%, between about 20% and about 30%, between about 30% and about 40%, between about 40% and about 50%, between about 50% and about 60%, between about 60% and about 70%, between about 70% and about 80%, The pain relief properties may be improved by about 80% to about 90%, about 90% to about 100%, about 100% to about 110%, about 110% to about 120%, about 120% to about 130%, about 130% to about 140%, about 140% to about 150%, about 150% to about 160%, about 160% to about 170%, about 170% to about 180%, about 180% to about 190%, about 190% to about 200%, or any amount of pain relief in a range bounded by any of these values, or any amount of pain relief between any of these values.

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

[0323] In some embodiments, an excess of one stereoisomer of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds can 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 enantiomerically 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 enantiomerically pure R-enantiomer) of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of these compounds can be administered.

[0324] Examples of deuterium-enriched bupropion and / or enantiopure deuterium-enriched bupropion include, but are not limited to, those shown below. [ka] [ka] [ka]

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

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

[0327] The dosage form or composition may be a blend or mixture of dextromethorphan alone or in 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 together in a vehicle, or may be dispersed together in a vehicle. A dispersion comprises a mixture of solid materials, with small individual particles that are essentially one compound, but are dispersed together in a solid form, such as may occur when two powders of two different drugs are blended with a solid vehicle material. In some embodiments, dextromethorphan and bupropion may be substantially uniformly dispersed 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 the coating, and the other drug may be in the core within the coating. For example, one agent may be formulated for sustained release and the other for immediate release.

[0328] Some embodiments involve administering a tablet containing bupropion in a dosage form providing sustained release and dextromethorphan in a dosage form providing immediate release. While there are various ways in which sustained release of bupropion can be achieved, in some embodiments, bupropion is combined with hydroxypropyl methylcellulose. For example, particles of bupropion hydrochloride can be blended with microcrystalline cellulose and hydroxypropyl methylcellulose (e.g., METHOCEL®) to form a blended powder mixture. This can be combined with immediate-release dextromethorphan in a single tablet.

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

[0330] Therapeutic compounds can be administered by any means that results in contact of the active agent with the desired site or sites of action in the patient's body. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. For example, they can be administered as the sole active agent in a pharmaceutical composition, or they can be used in combination with other therapeutically active ingredients.

[0331] Therapeutic compounds can be administered to human patients in a variety of forms compatible with the chosen route of administration, for example, orally or parenterally. In this regard, parenteral administration includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transdermal, transepithelial, including ophthalmic, sublingual, and buccal; topical administration, including ophthalmic, cutaneous, ophthalmic, rectal, and nasal inhalation, insufflation, aerosol, and rectal systemic.

[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 in a range bounded by any of these values, or any ratio therebetween. 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 can vary. For example, some liquid compositions contain from about 0.0001% (w / v) to about 50% (w / v), from about 0.01% (w / v) to about 20% (w / v), from about 0.01% (w / v) to about 10% (w / v), from about 0.001% (w / v) to about 1% (w / v), from about 0.1% (w / v) to about 0.5% (w / v), from about 1% (w / v) to about 3% (w / v), or from about 3% (w / v) to about 5% (w / v). , about 5% (w / v) to about 7% (w / v), about 7% (w / v) to about 10% (w / v), about 10% (w / v) to about 15% (w / v), about 15% (w / v) to about 20% (w / v), about 20% (w / v) to about 30% (w / v), about 30% (w / v) to about 40% (w / v), or about 40% (w / v) to about 50% (w / v) of dextromethorphan.

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

[0335] Some solid compositions have a solubility of at least about 5% (w / w), at least about 10% (w / w), at least about 20% (w / w), at least about 50% (w / w), at least about 70% (w / w), at least about 80%, about 10% (w / w) to about 30% (w / w), about 10% (w / w) to about 20% (w / w), about 20% (w / w) to about 30% (w / w), about 30% (w / w) to about 50% (w / w), about 30% (w / w) to about 40% (w / w), about 40% (w / w) to about 50% (w / w), about 50% (w / w) to about 80% (w / w), about 50% (w / w) to about 60% (w / w), about 70% (w / w) to about 80% (w / w), or about 80% (w / w) to about 90% (w / w) dextromethorphan.

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

[0337] In some embodiments, the amount of dextromethorphan is about 0.1 mg / kg to about 20 mg / kg, about 0.75 mg / kg to about 7.5 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 3 mg / kg, about 0.3 mg / kg to about 0.9 mg / kg, about 0.3 mg / kg to about 1 mg / kg, about 0.6 mg / kg to about 0.8 mg / kg, about 0.7 mg / kg about 0.8 mg / kg, about 0.75 mg / kg, about 0.4 mg / kg to about 1.5 mg / kg, about 1 mg / kg to about 2 mg / kg, about 10 mg / kg to about 20 mg / kg, about 12 mg / kg to about 17 mg / kg, about 15 mg / kg to about 20 mg / kg, about 1 mg / kg, about 1 mg / kg to about 10 mg / kg, or any value bounded by these ranges or any value therebetween.

[0338] The amount of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds in the therapeutic composition can vary. If an increase in the plasma concentration of dextromethorphan is desired, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds should be administered in an amount that will increase the plasma concentration of dextromethorphan. For example, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, can be administered in an amount that results in a plasma concentration of dextromethorphan in a human on the 8th, 9th, or 10th day that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, at least about 40 times, at least about 50 times, at least about 60 times, at least about 70 times, or at least about 80 times the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0339] In some embodiments, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, has a 12-hour area under the curve (AUC) from the time of administration that is at least about 2-fold, at least about 5-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 60-fold, at least about 70-fold, or at least about 80-fold greater than the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds on the 8th, 9th, or 10th day.0-12 ) or 12 hours after administration (C 平均 ) can be administered to a human in an amount of dextromethorphan that results in an average plasma concentration in humans of

[0340] In some embodiments, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, achieves a maximum plasma concentration in a human (C) on the 8th, 9th, or 10th day that is at least about 2-fold, at least about 5-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 30-fold, or at least about 40-fold the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds. 最大 Dextromethorphan can be administered to humans in an amount that results in a

[0341] Due to co-administration of bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, an increase in dextromethorphan plasma concentrations may occur on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered 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 dextromethorphan plasma concentration on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered can be at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, or at least about 10-fold the level that would be achieved by administering the same amount 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 the first day when the dextromethorphan plasma concentration is increased can be at least twice the AUC that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0343] In some embodiments, the dextromethorphan AUC on the first day that dextromethorphan plasma concentrations are increased, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 0-12 is at least about 15ng·hr / mL, at least about 17ng·hr / mL, at least about 19ng·hr / mL, at least about 20ng·hr / mL, at least about 22ng·hr / mL, at least about 23ng·hr / mL, at least about 24ng·hr / mL, at least about 25ng·hr / mL, at least about 26ng·hr / mL, at least about 27ng·hr / mL, at least about 28ng·hr / mL, at least about 29ng·hr / mL, at least about 30ng·hr / mL, at least about 31ng·hr / mL, at least about 32ng·hr / mL, at least about 33ng·hr / mL, at least about 34ng·hr / mL, at least about 35ng·hr / mL, at least about 36ng·hr / mL, at least about 37ng·hr / mL, at least about 38ng·hr The preferred range of ribonucleotides may be at least about 39 ng·hr / mL, at least about 40 ng·hr / mL, at least about 41 ng·hr / mL, at least about 42 ng·hr / mL, at least about 43 ng·hr / mL, at least about 44 ng·hr / mL, at least about 45 ng·hr / mL, at least about 46 ng·hr / mL, at least about 47 ng·hr / mL, at least about 48 ng·hr / mL, at least about 49 ng·hr / mL, at least about 50 ng·hr / mL, at least about 51 ng·hr / mL, at least about 52 ng·hr / mL, at least about 53 ng·hr / mL, at least about 54 ng·hr / mL, at least about 55 ng·hr / mL, at least about 56 ng·hr / mL, at least about 56.7 ng·hr / mL, and up to 10,000 ng·hr / mL.

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

[0345] In some embodiments, the dextromethorphan AUC on Day 8 is increased by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 0-24is at least about 50ng·hr / mL, at least about 75ng·hr / mL, at least about 100ng·hr / mL, at least about 200ng·hr / mL, at least about 300ng·hr / mL, at least about 400ng·hr / mL, at least about 500ng·hr / mL, at least about 600ng·hr / mL, at least about 700ng·hr / mL, at least about 800ng·hr / mL, at least about 900ng·hr / mL, at least about 1000ng·hr / mL, at least about 1100ng·hr / mL, at least about 1200ng·hr / mL, at least about 1300ng·hr / mL, at least about 1400ng·hr / mL, at least about 1500ng·hr / mL, at least about 1600ng·hr / mL, at least about 1700ng·hr / mL, ng·hr / mL, at least about 1800 ng·hr / mL, at least about 1900 ng·hr / mL, at least about 2000 ng·hr / mL, at least about 2100 ng·hr / mL, at least about 2200 ng·hr / mL, at least about 2300 ng·hr / mL, at least about 2400 ng·hr / mL, at least about 2500 ng·hr / mL, at least about 2600 ng·hr / mL, at least about 2700 ng·hr / mL, at least about 2800 ng·hr / mL, at least about 1850 ng·hr / mL, at least about 2900 ng·hr / mL, at least about 2950 ng·hr / mL, or at least about 2975.3 ng·hr / mL, and in some embodiments, up to about 100,000 ng·hr / mL.

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

[0347] In some embodiments, the dextromethorphan AUC on Day 9 is increased by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 0-12is at least about 40ng·hr / mL, at least about 50ng·hr / mL, at least about 60ng·hr / mL, at least about 70ng·hr / mL, at least about 80ng·hr / mL, at least about 90ng·hr / mL, at least about 100ng·hr / mL, at least about 150ng·hr / mL, at least about 200ng·hr / mL, at least about 250ng·hr / mL, at least about 300ng·hr / mL, at least about 350ng·hr / mL, at least About 400ng·hr / mL, at least about 450ng·hr / mL, at least about 500ng·hr / mL, at least about 550ng·hr / mL, about 500ng·hr / mL to about 600ng·hr / mL, about 500ng·hr / mL to about 550ng·hr / mL, about 500ng·hr / mL to about 525ng·hr / mL, about 525ng·hr / mL to about 600ng·hr / mL, at least about 600ng·hr / mL, at least about 650ng·hr / mL, at least about 700ng g·hr / mL, at least about 750ng·hr / mL, at least about 800ng·hr / mL, about 800ng·hr / mL to about 900ng·hr / mL, about 850ng·hr / mL to about 900ng·hr / mL, about 850ng·hr / mL to about 875ng·hr / mL, about 875ng·hr / mL to about 900ng·hr / mL, about 900ng·hr / mL to about 1,000ng·hr / mL, about 1,000ng·hr / mL to about 1,100ng·hr / mL, about 1,100ng·hr / 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 2,000ng·hr / mL, at least about 850ng·hr / mL, at least about 900ng·hr / mL, at least about 950ng·hr / mL, at least about 1000ng·hr / mL, at least about 1050ng·hr / mL, at least about 1100ng·hr / mL, at least about 1150ng·hr / mL, at least about 1200ng·hr / mL, at least about 1250ng·hr / mL, at least about 1300ng·hr / mL, at least about 1350ng·hr / mL , at least about 1400 ng·hr / mL, at least about 1450 ng·hr / mL, at least about 1500 ng·hr / mL, at least about 1550 ng·hr / mL, at least about 1600 ng·hr / mL, at least about 1625 ng·hr / mL, at least about 1650 ng·hr / mL, at least about 1675 ng·hr / mL, or at least about 1686.3 ng·hr / mL, and in some embodiments, up to about 50,000 ng·hr / mL.

[0348] In some embodiments, the dextromethorphan AUC on Day 9 is increased by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 0-24is at least about 50ng·hr / mL, at least about 75ng·hr / mL, at least about 100ng·hr / mL, at least about 200ng·hr / mL, at least about 300ng·hr / mL, at least about 400ng·hr / mL, at least about 500ng·hr / mL, at least about 600ng·hr / mL, at least about 700ng·hr / mL, at least about 800ng·hr / mL, at least about 900ng·hr / mL, at least about 1000ng·hr / mL, at least about 1100ng·hr / mL, at least about 1200ng·hr / mL, at least about 1300ng·hr / mL, at least about 1400ng·hr / mL, at least about 1500ng·hr / mL, at least about 1600ng·hr / mL, at least about 1700ng·hr / mL, ng·hr / mL, at least about 1800 ng·hr / mL, at least about 1900 ng·hr / mL, at least about 2000 ng·hr / mL, at least about 2100 ng·hr / mL, at least about 2200 ng·hr / mL, at least about 2300 ng·hr / mL, at least about 2400 ng·hr / mL, at least about 2500 ng·hr / mL, at least about 2600 ng·hr / mL, at least about 2700 ng·hr / mL, at least about 2800 ng·hr / mL, at least about 1850 ng·hr / mL, at least about 2900 ng·hr / mL, at least about 2950 ng·hr / mL, or at least about 2975.3 ng·hr / mL, and in some embodiments, up to about 100,000 ng·hr / mL.

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

[0350] In some embodiments, the dextromethorphan AUC on Day 10 is increased by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 0-12is at least about 40ng·hr / mL, at least about 50ng·hr / mL, at least about 60ng·hr / mL, at least about 70ng·hr / mL, at least about 80ng·hr / mL, at least about 90ng·hr / mL, at least about 100ng·hr / mL, at least about 150ng·hr / mL, at least about 200ng·hr / mL, at least about 250ng·hr / mL, at least about 300ng·hr / mL, at least about 350ng·hr / mL, at least about About 400ng·hr / mL, at least about 450ng·hr / mL, at least about 500ng·hr / mL, at least about 550ng·hr / mL, about 500ng·hr / mL to about 600ng·hr / mL, about 500ng·hr / mL to about 550ng·hr / mL, about 500ng·hr / mL to about 525ng·hr / mL, about 525ng·hr / mL to about 600ng·hr / mL, at least about 600ng·hr / mL, at least about 650ng·hr / mL, at least about 700ng g·hr / mL, at least about 750ng·hr / mL, at least about 800ng·hr / mL, about 800ng·hr / mL to about 900ng·hr / mL, about 850ng·hr / mL to about 900ng·hr / mL, about 850ng·hr / mL to about 875ng·hr / mL, about 875ng·hr / mL to about 900ng·hr / mL, about 900ng·hr / mL to about 1,000ng·hr / mL, about 1,000ng·hr / mL to about 1,100ng·hr / mL, about 1,100ng·hr / 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 2,000ng·hr / mL, at least about 850ng·hr / mL, at least about 900ng·hr / mL, at least about 950ng·hr / mL, at least about 1000ng·hr / mL, at least about 1050ng·hr / mL, at least about 1100ng·hr / mL, at least about 1150ng·hr / mL, at least about 1200ng·hr / mL, at least about 1250ng·hr / mL, at least about 1300ng·hr / mL, at least about 1350ng·hr / mL, at least about 1400ng·hr / mL, at least about 1450ng·hr / mL, at least about 1500ng·hr / mL, at least about 1550ng·hr / mL, at least about 1600ng·hr / mL, at least about 1625ng·hr / mL, at least about 1650ng·hr / mL, at least about 1675 ng·hr / mL, or at least about 1686.3 ng·hr / mL, and in some embodiments, up to about 50,000 ng·hr / mL.

[0351] In some embodiments, the dextromethorphan AUC on Day 10 is increased by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 0-24is at least about 50ng·hr / mL, at least about 75ng·hr / mL, at least about 100ng·hr / mL, at least about 200ng·hr / mL, at least about 300ng·hr / mL, at least about 400ng·hr / mL, at least about 500ng·hr / mL, at least about 600ng·hr / mL, at least about 700ng·hr / mL, at least about 800ng·hr / mL, at least about 900ng·hr / mL, at least about 1000ng·hr / mL, at least about 1100ng·hr / mL, at least about 1200ng·hr / mL, at least about 1300ng·hr / mL, at least about 1400ng·hr / mL, at least about 1500ng·hr / mL, at least about 1600ng·hr / mL, at least about 1700ng·hr / mL, ng·hr / mL, at least about 1800 ng·hr / mL, at least about 1900 ng·hr / mL, at least about 2000 ng·hr / mL, at least about 2100 ng·hr / mL, at least about 2200 ng·hr / mL, at least about 2300 ng·hr / mL, at least about 2400 ng·hr / mL, at least about 2500 ng·hr / mL, at least about 2600 ng·hr / mL, at least about 2700 ng·hr / mL, at least about 2800 ng·hr / mL, at least about 1850 ng·hr / mL, at least about 2900 ng·hr / mL, at least about 2950 ng·hr / mL, or at least about 2975.3 ng·hr / mL, and in some embodiments, up to about 100,000 ng·hr / mL.

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

[0353] In some embodiments, the dextromethorphan C on Day 1 is increased by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 最大 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. 最大 may be at least twice as large.

[0354] In some embodiments, the dextromethorphan plasma concentration is increased by, for example, co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 最大is at least about 1.0 ng / mL, at least about 1.5 ng / mL, at least about 2.0 ng / mL, at least about 2.5 ng / mL, at least about 3.0 ng / mL, at least about 3.1 ng / mL, at least about 3.2 ng / mL, at least about 3.3 ng / mL, at least about 3.4 ng / mL, at least about 3.5 ng / mL, at least about 3.6 ng / mL, at least about 3.7 ng / mL, at least about 3.8 ng / mL, at least about 3.9 ng / mL, at least about 4.0 ng / mL, at least about 4.1 ng / mL, at least about about 4.2ng / mL, at least about 4.3ng / mL, at least about 4.4ng / mL, at least about 4.5ng / mL, at least about 4.6ng / mL, at least about 4.7ng / mL, at least about 4.8ng / mL, at least about 4.9ng / mL, at least about 5.0ng / mL, at least about 5.1ng / mL, at least about 5.2ng / mL, at least about 5.3ng / mL, at least about 5.4ng / mL, at least about 5.5ng / mL, at least about 5.6ng / mL, at least about 5.7ng / mL, at least about 5.7ng / mL 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, may be at least about 7.4 ng / mL, at least about 7.5 ng / mL, at least about 7.6 ng / mL, at least about 7.7 ng / mL, at least about 7.8 ng / mL, at least about 7.9 ng / mL, at least about 8.0 ng / mL, at least about 8.1 ng / mL, at least about 8.2 ng / mL, at least about 8.3 ng / mL, at least about 8.4 ng / mL, at least about 8.5 ng / mL, at least about 8.6 ng / mL, or at least about 8.7 ng / mL, and in some embodiments, up to about 1000 ng·hr / mL.

[0355] In some embodiments, the dextromethorphan C on Day 8 is increased by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 最大is about 50ng / mL to about 60ng / 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 to 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 115ng / mL, about 115ng / mL to about 120ng / mL, about 120ng / mL to about 1 30ng / mL, about 130ng / mL to about 135ng / mL, about 135ng / mL to about 140ng / mL, about 140ng / mL to about 145ng / mL, about 145ng / mL to about 150ng / mL, about 150ng / mL to about 155ng / mL, about 155ng / mL to about 160ng / mL, about 160ng / mL to about 170ng / mL, about 170ng / mL to about 200ng / mL, at least about 6.0ng / mL, at least about 7.0ng / mL, at least about 8.0ng / mL, at least about 9.0ng / mL, at least about 10ng / 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 in some embodiments may be up to about 10,000 ng / mL.

[0356] In some embodiments, the dextromethorphan C on Day 9 is increased by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 最大is about 50ng / mL to about 60ng / 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 to 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 115ng / mL, about 115ng / mL to about 120ng / mL, about 120ng / mL to about 130ng / mL, about 130ng / mL to about 135ng / mL, about 135ng / mL to about 140ng / mL, about 140ng / mL to about 145ng / mL, about 145ng / mL to about 150ng / mL, about 150ng / mL to about 155ng / mL, about 155ng / mL to about 160ng / mL, about 160ng / mL to about 170ng / mL, about 170ng / mL to about 200ng / mL, at least about 6.0ng / mL, at least about 7.0ng / mL, at least about 8.0ng / mL 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 may 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 up to about 10,000 ng / mL.

[0357] In some embodiments, the dextromethorphan C C on Day 10 is increased by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 最大is about 50ng / mL to about 60ng / 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 to 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 115ng / mL, about 115ng / mL to about 120ng / mL, about 120ng / mL to about 1 30ng / mL, about 130ng / mL to about 135ng / mL, about 135ng / mL to about 140ng / mL, about 140ng / mL to about 145ng / mL, about 145ng / mL to about 150ng / mL, about 150ng / mL to about 155ng / mL, about 155ng / mL to about 160ng / mL, about 160ng / mL to about 170ng / mL, about 170ng / mL to about 200ng / mL, at least about 6.0ng / mL, at least about 7.0ng / mL, at least about 8.0ng / mL, at least about 9.0ng / mL, at least about 10ng / 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 in some embodiments may be up to about 10,000 ng / mL.

[0358] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, over the period between two separate and consecutive administrations of dextromethorphan, provides a 200 ng / mL or 300 ng / mL or 400 ng / mL or 500 ng / mL or 600 ng / mL or 700 ng / mL or 800 ng / mL or 900 ng / mL or 1000 ng / mL or 1100 ng / mL or 1200 ng / mL or 1300 ng / mL or 1400 ng / mL or 1500 ng / mL or 1600 ng / mL or 1700 ng / mL or 1800 ng / mL or 1900 ng / mL or 2000 ng / mL or 2100 ng / mL or 2200 ng / mL or 2300 ng / mL or 2400 ng / mL or 2500 ng / mL or 2600 ng / mL or 2700 ng / mL or 2800 ng / mL or 3000 ng / mL or 3100 ng / mL or 3200 ng / mL or 3300 ng / mL or 3400 ng / mL or 3500 ng / mL or 4000 ng / mL or 4100 ng / mL or 4200 ng / mL or 4300 ng / mL or 4400 ng / mL or 4500 ng / mL or 5100 ng / mL or 5200 ng / mL or 5300 ng / mL or 5400 ng / mL or 5500 ng / mL or 6500 ng / mL or 40ng / mL, at least about 45ng / mL, at least about 50ng / mL, at least about 55ng / mL, at least about 60ng / mL, at least about 65ng / mL, at least about 70ng / mL, at least about 75ng / mL, at least about 80ng / mL, at least about 85ng / mL, at least about 90ng / mL, at least about 95ng / mL, at least about 100ng / mL, at least about 105ng / mL, at least about 110ng / mL, at least about 115ng / mL, at least about 120ng / mL, at least about 125ng / mL, at least about 130ng / mL, at least about 135ng / mL, at least about 140ng / 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, Dextromethorphan C may be from about 115 ng / mL to about 120 ng / mL, from about 120 ng / mL to about 130 ng / mL, from about 130 ng / mL to about 135 ng / mL, from about 135 ng / mL to about 140 ng / mL, from about 140 ng / mL to about 145 ng / mL, from about 145 ng / mL to about 150 ng / mL, from about 150 ng / mL to about 155 ng / mL, from about 155 ng / mL to about 160 ng / mL, from about 160 ng / mL to about 170 ng / mL, from about 170 ng / mL to about 200 ng / mL, and in some embodiments, up to about 10,000 ng / mL. 平均 For example, if dextromethorphan is administered at 8:00 AM and 8:00 PM on Day 1, and dextromethorphan is not administered after 8:00 AM and before 8:00 PM on Day 1, the period between the two separate but consecutive administrations of dextromethorphan is from just after 8:00 AM to just before 8:00 PM on Day 1.

[0359] In some embodiments, the dextromethorphan C on Day 8 is increased by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 平均is at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL 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 The concentration may 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, about 170 ng / mL to about 200 ng / mL, and in some embodiments, up to about 10,000 ng / mL. 平均The value is the period between two separate but consecutive doses of dextromethorphan, or if dextromethorphan is administered only once on day 8, C 平均 may be for 12 hours after the first dose of dextromethorphan.

[0360] In some embodiments, the dextromethorphan C on Day 9 is increased by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 平均is at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, at least about 115 ng / mL, at least about 120 ng / mL, at least about 125 ng / mL, at least about 130 ng / mL, at least about 135 ng / mL, at least about 140 ng / mL, or at least about 145 ng / mL 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 ng / mL, about 115ng / mL to about 120ng / mL, about 120ng / mL to about 130ng / mL, about 130ng / mL to about 135ng / mL, about 135ng / mL to about 140ng / mL, about 140ng / mL to about 145ng / mL, about 145ng / mL to about 150ng / mL, about 150ng / mL to about 155ng / mL, about 155ng / mL to about 160ng / mL, about 160ng / mL to about 170ng / mL, about 170ng / mL to about 200ng / mL, and in some embodiments, up to about 10,000ng / mL. 平均The value is the period between two separate but consecutive administrations of dextromethorphan, or C if dextromethorphan is administered only once on day 9. 平均 may be for 12 hours after the first dose of dextromethorphan.

[0361] In some embodiments, the dextromethorphan C C on Day 10 is increased by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 平均is at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL 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 The concentration may 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, about 170 ng / mL to about 200 ng / mL, and in some embodiments, up to about 10,000 ng / mL. 平均The value is the period between two separate but consecutive administrations of dextromethorphan, or C if dextromethorphan is administered only once on day 10. 平均 may be for 12 hours after the first dose of dextromethorphan.

[0362] The fluctuation index value FI (%) of dextromethorphan can be calculated using the formula:

number

[0363] In some embodiments, the dextromethorphan FI (%) on day 8 when the plasma concentration of dextromethorphan is elevated, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is reduced by at least 1.5-fold or at least 2-fold compared to 8 days of dextromethorphan administration without elevated plasma concentrations, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0364] In some embodiments, the dextromethorphan FI (%) on day 9 when the plasma concentration of dextromethorphan is elevated, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is reduced by at least 1.5-fold or at least 2-fold compared to 9 days of dextromethorphan administration without elevated plasma concentrations, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0365] In some embodiments, the dextromethorphan FI (%) on day 10 when the plasma concentration of dextromethorphan is elevated, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is reduced by at least 1.5-fold or at least 2-fold compared to 10 days of dextromethorphan administration without elevated plasma concentrations, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0366] In some embodiments, the dextromethorphan FI (%) on day 8, when the plasma concentration of dextromethorphan is increased, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, 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 a range bounded by any of these values.

[0367] In some embodiments, the dextromethorphan FI (%) on day 9, when the plasma concentration of dextromethorphan is increased, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, 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 a range bounded by any of these values.

[0368] In some embodiments, the dextromethorphan FI (%) on day 10, when the plasma concentration of dextromethorphan is enhanced, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, 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 a range bounded by any of these values.

[0369] In some embodiments, the dextromethorphan FI (%) on day 8 when the plasma concentration of dextromethorphan is elevated, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is reduced by at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 6-fold compared to 8 days of dextromethorphan administration without elevated plasma concentrations, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0370] In some embodiments, the dextromethorphan FI (%) on day 9 when the plasma concentration of dextromethorphan is elevated, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is reduced by at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 6-fold compared to 9 days of dextromethorphan administration without elevated plasma concentrations, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0371] In some embodiments, the dextromethorphan FI (%) on day 10 when the plasma concentration of dextromethorphan is elevated, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is reduced by at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 6-fold compared to 10 days of dextromethorphan administration without elevated plasma concentrations, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0372] In some embodiments, the dextromethorphan FI(%) on day 8, when the plasma concentration of dextromethorphan is increased, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is 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 a range bounded by any of these values.

[0373] In some embodiments, the dextromethorphan FI(%) on day 9, when the plasma concentration of dextromethorphan is enhanced, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is 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 a range bounded by any of these values.

[0374] In some embodiments, the dextromethorphan FI(%) on day 9, when the plasma concentration of dextromethorphan is enhanced, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is 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 a range bounded by any of these values.

[0375] In some embodiments, the dextromethorphan trough concentration (e.g., the plasma concentration 12 hours after administration; also referred to as "Cmin") on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered will be at least twice the trough level that would be achieved with the administration of the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0376] 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 Cmin on the first day that the dextromethorphan plasma concentration is increased is at least about 0.8 ng / mL, at least about 0.9 ng / mL, at least about 1.0 ng / mL, at least about 1.1 ng / mL, at least about 1.2 ng / mL, / mL, at least about 1.3 ng / mL, at least about 1.4 ng / mL, at least about 1.5 ng / mL, at least about 1.6 ng / mL, at least about 1.7 ng / mL, at least about 1.8 ng / mL, at least about 1.9 ng / mL, at least about 2.0 ng / mL, at least about 2.1 ng / mL, at least about 2.2 ng / mL, at least about 2.3 ng / mL, at least about 2.4 ng / mL, at least about 2.5 ng / mL, or at least about 2.5 ng / mL, and can be up to about 100 ng / mL.

[0377] In some embodiments, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, the dextromethorphan plasma concentration is increased to a dextromethorphan Cmin on day 5 of 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 10.0 ng / mL, at least about 11.0 ng / mL, at least about 12.0 ng / mL, at least about 13.0 ng / mL, at least about 14.0 ng / mL, at least about 15.0 ng / mL, at least about 16.0 ng / mL, at least about 17.0 ng / mL, at least about 18.0 ng / mL, at least about 19.0 ng / mL, at least about 20.0 ng / mL, at least about 21.0 ng / mL, at least about 22.0 ng / mL, at least about 23.0 ng / mL, at least about 24.0 ng / mL, at least about 25.0 ng / mL, at least about 26.0 ng / mL, at least about 27.0 ng / mL, at least about 28.0 ng / mL, at least about 29.0 ng / mL, at least about 30.0 ng / mL, at least about 31.0 ng / mL, at least about 32.0 ng / mL, at least about 33.0 ng / mL may be at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, or at least about 80.9 ng / mL, and may be up to about 10,000 ng / mL.

[0378] In some embodiments, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, the dextromethorphan plasma concentration is increased such that the dextromethorphan Cmin 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, at least about 10.0 ng / mL, at least about 11.0 ng / mL, at least about 12.0 ng / mL, at least about 13.0 ng / mL, at least about 14.0 ng / mL, at least about 15.0 ng / mL, at least about 16.0 ng / mL, at least about 17.0 ng / mL, at least about 18.0 ng / mL, at least about 19.0 ng / mL, at least about 20.0 ng / mL, at least about 21.0 ng / mL, at least about 22.0 ng / mL, at least about 23.0 ng / mL, at least about 24.0 ng / mL, at least about 25.0 ng / mL, at least about 26.0 ng / mL, at least about 27.0 ng / mL, at least about 28.0 ng / mL, at least about 29.0 ng / mL, at least about 30.0 ng / mL, at least about 31.0 ng / mL, at least about 32.0 ng / mL, at least about 33.0 ng / It can be about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, or at least about 102.2 ng / mL, and can be up to about 10,000 ng / mL.

[0379] In some embodiments, e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, the dextromethorphan plasma concentration is increased to a dextromethorphan C min on day 7 of 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, the dextromethorphan C on Day 8 is increased by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 最小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 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 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, 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 may 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, or about 170 ng / mL to about 200 ng / mL, and may be up to about 10,000 ng / mL.

[0381] In some embodiments, the dextromethorphan C on Day 9 is increased by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 最小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 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL , at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, at least about 115 ng / mL, 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 may be 15ng / mL, about 115ng / mL to about 120ng / mL, about 120ng / mL to about 130ng / mL, about 130ng / mL to about 135ng / mL, about 135ng / mL to about 140ng / mL, about 140ng / mL to about 145ng / mL, about 145ng / mL to about 150ng / mL, about 150ng / mL to about 155ng / mL, about 155ng / mL to about 160ng / mL, about 160ng / mL to about 170ng / mL, or about 170ng / mL to about 200ng / mL, and may be up to about 10,000ng / mL.

[0382] In some embodiments, the dextromethorphan C on day 10 is increased by co-administering dextromethorphan with, for example, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 最小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 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL , at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, at least about 115 ng / mL, 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 may be 15ng / mL, about 115ng / mL to about 120ng / mL, about 120ng / mL to about 130ng / mL, about 130ng / mL to about 135ng / mL, about 135ng / mL to about 140ng / mL, about 140ng / mL to about 145ng / mL, about 145ng / mL to about 150ng / mL, about 150ng / mL to about 155ng / mL, about 155ng / mL to about 160ng / mL, about 160ng / mL to about 170ng / mL, or about 170ng / mL to about 200ng / mL, and may be up to about 10,000ng / mL.

[0383] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds 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 when bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan are co-administered 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 dextromethorphan plasma concentration on the first day may be reduced by at least 5% compared to the dextromethorphan plasma concentration that would 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 for at least five consecutive days to a human being in need of dextromethorphan treatment, wherein the dextromethorphan plasma concentration on the fifth day is greater than the dextromethorphan plasma concentration that would be achieved by administering the same amount without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds for five consecutive days. For example, the dextromethorphan plasma concentration on day 5 (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) can be at least 5 times, at least 10 times, at least 20 times, at least 40 times, at least 50 times, at least 60 times, at least 65 times, or up to about 500 times the level that would be achieved by administering the same amount of dextromethorphan administered for 5 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a 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 human being in need of treatment with dextromethorphan for at least six consecutive days, wherein the dextromethorphan plasma concentration on the sixth day is greater than the dextromethorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds for six consecutive days. For example, the dextromethorphan plasma concentration on day 6 (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) can be at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 75 times, or up to about 500 times the level that would be achieved by administering the same amount of dextromethorphan administered for 6 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a 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 human being in need of treatment with dextromethorphan for at least seven consecutive days, wherein the dextromethorphan plasma concentration on the seventh day is greater than the dextromethorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds for seven consecutive days. For example, the dextromethorphan plasma concentration on day 7 (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) can be at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 70 times, at least 80 times, at least 90 times, or up to about 500 times the level that would be achieved by administering the same amount of dextromethorphan administered for 7 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a 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 the 8th day, dextromethorphan has a plasma concentration, e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after co-administration, that is at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or up to about 1000 times the plasma concentration that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds for 8 consecutive days.

[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 human being in need of dextromethorphan treatment for at least eight consecutive days, wherein the dextromethorphan plasma concentration on the eighth day is lower than the dextromethorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds for eight consecutive days. For example, the dextrorphan plasma concentration on day 8 (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to the dextrorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan administered for 8 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a 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 the 9th day, dextromethorphan has a plasma concentration, e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after co-administration, that is at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or up to about 1000 times the plasma concentration that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds for 9 consecutive days.

[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 human being in need of treatment with dextromethorphan for at least 9 consecutive days, wherein the dextromethorphan plasma concentration on the 9th day is lower than the dextromethorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds for 9 consecutive days. For example, the dextrorphan plasma concentration on day 9 (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to the dextrorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan administered for 9 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a 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 the 10th day, dextromethorphan has a plasma concentration, e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after co-administration, that is at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or up to about 1000 times the plasma concentration that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds for 10 consecutive days.

[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 human being in need of treatment with dextromethorphan for at least 10 consecutive days, wherein the dextromethorphan plasma concentration on the 10th day is lower than the dextromethorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds for 10 consecutive days. For example, the dextrorphan plasma concentration on the 10th day (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to the dextrorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan administered for 10 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0393] In some embodiments, bupropion has an AUC of bupropion in humans on day 8 that is at least about 100 ng·hr / mL, at least about 200 ng·hr / mL, at least about 500 ng·hr / mL, at least about 600 ng·hr / mL, at least about 700 ng·hr / mL, at least about 800 ng·hr / mL, at least about 900 ng·hr / mL, at least about 1,000 ng·hr / mL, at least about 1,200 ng·hr / mL, at least 1,600 ng·hr / mL, or up to about 15,000 ng·hr / mL. 0-12 can be administered to a human in an amount that results in

[0394] In some embodiments, bupropion has a C of bupropion in humans on day 8 that is 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. 平均 can be administered to a human in an amount that results in

[0395] In some embodiments, bupropion has a C of bupropion in humans on day 8 that is 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. 最大 can be administered to a human in an amount that results in

[0396] Some liquid compositions have a % w / v content of about 0.0001% (w / v) to about 50% (w / v), about 0.01% (w / v) to about 20% (w / v), about 0.01% to about 10% (w / v), about 1% (w / v) to about 3% (w / v), about 3% (w / v) to about 5% (w / v), about 5% (w / v) to about 7% (w / v), about 5% (w / v) to about 15% (w / v), about 7% (w / v) to about 10% (w / v), about 10% (w / v) to about 15% (w / v), about 15% (w / v) to about 20% (w / v), about 20% (w / v) to about 30% (w / v), about 30% (w / v) to about 40% (w / v), or about 40% (w / v) to about 50% (w / v) bupropion, or any amount of bupropion in a range bounded by, or between, any of these values.

[0397] Some liquid dosage forms may contain about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 40 mg to about 90 mg, about 200 mg to about 300 mg, about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 100 mg to about 105 mg, about 105 mg to about 200 mg, about 110 mg to about 140 mg, about 180 mg to about 220 mg, about 280 mg to about 320 mg, about 105 mg, about 200 mg, about 150 mg, or about 300 mg of bupropion, e.g., bupropion chloride, or any amount of bupropion in a range bounded by, or between, any of these values.

[0398] Some solid compositions have a mass fraction of at least about 5% (w / w), at least about 10% (w / w), at least about 20% (w / w), at least about 50% (w / w), at least about 70% (w / w), at least about 80%, about 10% (w / w) to about 30% (w / w), about 10% (w / w) to about 20% (w / w), about 20% (w / w) to about 30% (w / w), about 30% (w / w) to about 50% (w / w), about 30% (w / w) to about The composition may contain 40% (w / w), about 40% (w / w) to about 50% (w / w), about 50% (w / w) to about 80% (w / w), about 50% (w / w) to about 60% (w / w), about 70% (w / w) to about 80% (w / w), or about 80% (w / w) to about 90% (w / w) bupropion, or any amount of bupropion in a range bounded by, or between, any of these values.

[0399] Some solid dosage forms include about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 40 mg to about 90 mg, about 200 mg to about 300 mg, about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 100 mg to about 120 mg, about 105 mg to about 200 mg, about 90 mg to about 120 mg, about 100 mg to about 110 The dosage form may comprise about 100 mg, about 110 mg to about 140 mg, about 50 mg to about 150 mg, about 180 mg to about 220 mg, about 280 mg to about 320 mg, about 105 mg, about 200 mg, about 150 mg, or about 300 mg of bupropion, e.g., bupropion chloride, or any amount of bupropion in a range bounded by, or between, any of these values.

[0400] In some embodiments, bupropion is administered at a dose that results in a bupropion plasma concentration of about 0.1 μM to about 10 μM, about 0.1 μM to about 5 μM, about 0.2 μM to about 3 μM, about 0.1 μM to about 1 μM, about 0.2 μM to about 2 μM, about 1 μM to about 10 μM, about 1 μM to about 5 μM, about 2 μM to about 3 μM, or about 2.8 μM to about 3 μM, about 1.5 μM to about 2 μM, about 4.5 μM to about 5 μM, about 2.5 μM to about 3 μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, or any plasma concentration in a range bounded by, or between, any of these values.

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

[0402] In some embodiments, the bupropion, hydroxybupropion, or prodrug of hydroxybupropion has an AUC of hydroxybupropion in humans on day 8 that is at least about 3,000 ng·hr / mL, at least about 7,000 ng·hr / mL, at least about 10,000 ng·hr / mL, at least about 15,000 ng·hr / mL, at least about 20,000 ng·hr / mL, at least about 30,000 ng·hr / mL, with an upper limit of about 50,000 ng·hr / mL, with an upper limit of about 150,000 ng·hr / mL, or any AUC in a range bounded by, or between, any of these values. 0-12 can be administered to a human in an amount that results in

[0403] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion has a C 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, with an upper limit of about 10,000 ng / mL, with an upper limit of about 50,000 ng / mL, or any C in a range bounded by any of these values, on day 8. 最大 , or any C between these values最大 The C of hydroxybupropion in humans is 最大 can be administered to a human in an amount that results in

[0404] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion has a C 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, with an upper limit of about 10,000 ng / mL, with an upper limit of about 50,000 ng / mL, or any C in a range bounded by any of these values, on day 8. 平均 , or any C between these values 平均 The C of hydroxybupropion in humans is 平均 can be administered to a human in an amount that results in

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

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

[0407] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion has a C 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, up to about 2,000 ng / mL, up to about 10,000 ng / mL, or any C in a range bounded by any of these values, on day 8. 最大 , or any C between these values 最大 The C of threohydroxybupropion in humans is 最大 can be administered to a human in an amount that results in

[0408] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion has a C 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, up to about 2,000 ng / mL, up to about 10,000 ng / mL, or any C in a range bounded by any of these values, on day 8. 平均 , or any C between these values 平均 The C of threohydroxybupropion in humans is 平均can be administered to a human in an amount that results in

[0409] In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion is administered at a dose that results in an erythrohydroxybupropion plasma concentration of about 0.1 μM to about 10 μM, about 0.1 μM to about 5 μM, about 0.2 μM to about 3 μM, about 0.1 μM to about 1 μM, about 0.2 μM to about 2 μM, about 1 μM to about 10 μM, about 1 μM to about 5 μM, about 2 μM to about 3 μM, or about 2.8 μM to about 3 μM, about 1.5 μM to about 2 μM, about 4.5 μM to about 5 μM, about 2.5 μM to about 3 μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, or any plasma concentration in a range bounded by, or between, any of these values.

[0410] In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion, on day 8, has an AUC of erythrohydroxybupropion in humans that is at least about 200 ng·hr / mL, at least about 400 ng·hr / mL, at least about 700 ng·hr / mL, at least about 1,000 ng·hr / mL, at least about 1,500 ng·hr / mL, at least about 3,000 ng·hr / mL, with an upper limit of about 5,000 ng·hr / mL, with an upper limit of about 30,000 ng·hr / mL, or any AUC in a range bounded by, or between, any of these values. 0-12 can be administered to a human in an amount that results in

[0411] In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion has a C of at least about 30 ng / mL, at least about 60 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, at least about 150 ng / mL, at least about 200 ng / mL, at least about 300 ng / mL, an upper limit of about 1,000 ng / mL, or any C in a range bounded by any of these values, on day 8. 最大 , or any C between these values 最大 C of erythrohydroxybupropion in humans, 最大 can be administered to a human in an amount that results in

[0412] In some embodiments, bupropion, erythrohydroxybupr...

Claims

[Claim 1] administering a combination of drugs once or twice daily to a human in need of such treatment, said human being being about 41 years of age or older, said combination of drugs comprising: about 105 mg of bupropion hydrochloride, or the molar equivalent of bupropion in the free base or another salt form; about 45 mg of dextromethorphan hydrobromide, or the molar equivalent of dextromethorphan in free base or other salt form; 13. A method for treating agitation associated with major depressive disorder or Alzheimer's disease, comprising administering to said patient a therapeutically effective amount of a medicament for treating agitation associated with major depressive disorder or Alzheimer's disease.

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