Use of bupropion and dextromethorphan combination for the treatment of neurological conditions

Abstract

Provided herein are methods for treating major depressive disorder or agitation associated with Alzheimer's disease comprising administration of a combination therapy comprising bupropion and dextromethorphan. Specifically provided methods include administration of about 105 mg bupropion hydrochloride and about 45 mg dextromethorphan hydrobromide once a day or twice a day to a human subject about 41 years of age or older.

Description

[0001] This application is a divisional application of Chinese patent application No. 202180038675.3 (filed on March 29, 2021, invention title: Use of bupropion and dextromethorphan in combination for the treatment of neurological disorders).

[0002] Cross-reference of related applications

[0003] 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; and is also a partial continuation of U.S. Patent Application No. 16 / 894,713, filed June 5, 2020; all of these prior documents are incorporated herein by reference in their entirety. Summary of the Invention

[0004] Some implementations include a method for increasing dextromethorphan plasma levels in humans, the method comprising co-administering dextromethorphan with a metabolite or prodrug of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any of these compounds.

[0005] Some implementations include a method for increasing dextromethorphan plasma levels in a person, the method comprising co-administering erythromethone or its prodrug with dextromethorphan to the person, wherein the amount of dextromethorphan increases to an AUC of [missing value]. 0-12 Administer erythrobupropion or its prodrug at a dose of at least about 40 ng•hr / mL.

[0006] Some implementations include a method for increasing dextromethorphan plasma levels in a person, the method comprising co-administering erythromethone or a prodrug thereof with dextromethorphan to the person, wherein the amount of dextromethorphan increases to C60. 最大 Administer erythrobupropion or its prodrug at a dose of at least about 6 ng / mL.

[0007] Some implementations include a method for increasing dextromethorphan plasma levels in a person, the method comprising co-administering to the person erythromethasone or a prodrug thereof with dextromethorphan, wherein the C-level of dextromethorphan is increased during the period between two separate and consecutive administrations of dextromethorphan. avg Administer erythrobupropion or its prodrug at a dose of at least about 5 ng / mL.

[0008] Some implementations include methods for increasing the metabolic lifespan of dextromethorphan, including administering threo-hydroxybupropion or a prodrug thereof to a person who requires treatment with dextromethorphan, wherein the person is a rapid metabolizer of dextromethorphan, and wherein dextromethorphan and threo-hydroxybupropion are co-present in the person's body.

[0009] Some implementations include methods for reducing adverse events associated with dextromethorphan treatment, the methods comprising co-administering threobupropion or its prodrug with dextromethorphan to a human patient requiring dextromethorphan treatment, wherein the human patient is at risk of experiencing adverse events as a result of dextromethorphan treatment.

[0010] Some implementations include an oral sustained-release delivery system for dextromethorphan comprising a prodrug of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any of these compounds, dextromethorphan, and a water-soluble carrier.

[0011] Some implementations include a method of reducing the number of doses of dextromethorphan that can be administered without loss of efficacy, the method comprising orally administering an effective amount of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any of these compounds to a person requiring treatment with dextromethorphan.

[0012] Some implementations include methods for reducing dextrororphan plasma levels, comprising co-administering throsalbupropion or its prodrug and dextromethorphan to a person requiring dextromethorphan treatment, wherein throsalbupropion or its prodrug is administered on the first day of at least two days of dextromethorphan treatment, wherein a reduction in dextrororphan plasma levels occurs on the first day of co-administration of throsalbupropion or its prodrug with dextromethorphan compared to administration of the same amount of dextromethorphan without throsalbupropion or its prodrug.

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

[0014] Some implementations include methods for reducing dextromethorphan plasma levels, including co-administering bupropion and dextromethorphan to a person requiring treatment with dextromethorphan, wherein bupropion is administered on the first day of at least two days of dextromethorphan treatment, wherein a reduction in dextromethorphan plasma levels occurs on the first day of co-administration of bupropion and dextromethorphan compared to administration of the same amount of dextromethorphan without bupropion.

[0015] Some implementations include methods for reducing dextromethorphan plasma levels, comprising co-administering erythrobupropion or its prodrug and dextromethorphan to a person requiring dextromethorphan treatment, wherein erythrobupropion or its prodrug is administered on the first day of at least two days of dextromethorphan treatment, wherein a reduction in dextromethorphan plasma levels occurs on the first day of co-administration of erythrobupropion or its prodrug with dextromethorphan compared to administration of the same amount of dextromethorphan without erythrobupropion or its prodrug.

[0016] Some implementations include methods for reducing dextromethorphan plasma levels, comprising administering bupropion and dextromethorphan to a person requiring treatment with dextromethorphan for at least 8 consecutive days, wherein on the 8th day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained by administering the same amount of dextromethorphan for 8 consecutive days without bupropion.

[0017] Some implementations include methods for reducing dextromethorphan plasma levels, comprising administering hydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 8 consecutive days, wherein on the 8th day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained if the same amount of dextromethorphan were administered for 8 consecutive days without hydroxybupropion or its prodrug.

[0018] Some implementations include methods for reducing dextromethorphan plasma levels, comprising administering erythrobupropion or its prodrug and dextromethorphan to a person requiring dextromethorphan treatment for at least 8 consecutive days, wherein on the 8th day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained if the same amount of dextromethorphan were administered for 8 consecutive days without erythrobupropion or its prodrug.

[0019] Some implementations include methods for reducing dextromethorphan plasma levels, comprising co-administering threobupropion or its prodrug and dextromethorphan to a person requiring dextromethorphan treatment for at least 8 consecutive days, wherein, on the 8th day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained if the same amount of dextromethorphan were administered for 8 consecutive days without threobupropion or its prodrug.

[0020] Some implementations include a method for reducing dextromethorphan plasma levels, the method comprising administering bupropion and dextromethorphan to a person requiring treatment with dextromethorphan for at least 9 consecutive days, wherein on the 9th day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained by administering the same amount of dextromethorphan for 9 consecutive days without bupropion.

[0021] Some implementations include a method for reducing dextromethorphan plasma levels, the method comprising administering hydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 9 consecutive days, wherein, on the 9th day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained by administering the same amount of dextromethorphan for 9 consecutive days without hydroxybupropion or its prodrug.

[0022] Some implementations include a method for reducing dextromethorphan plasma levels, the method comprising administering erythrobupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 9 consecutive days, wherein, on the 9th day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained by administering the same amount of dextromethorphan for 9 consecutive days without erythrobupropion or its prodrug.

[0023] Some implementations include a method for reducing dextromethorphan plasma levels, the method comprising co-administering threobupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 9 consecutive days, wherein, on the 9th day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained by administering the same amount of dextromethorphan for 9 consecutive days without threobupropion or its prodrug.

[0024] Some implementations include a method for reducing dextromethorphan plasma levels, the method comprising administering bupropion and dextromethorphan to a person requiring treatment with dextromethorphan for at least 9 consecutive days, wherein on the 9th day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained by administering the same amount of dextromethorphan for 9 consecutive days without bupropion.

[0025] Some implementations include a method for reducing dextromethorphan plasma levels, the method comprising administering hydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 9 consecutive days, wherein, on the 9th day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained by administering the same amount of dextromethorphan for 9 consecutive days without hydroxybupropion or its prodrug.

[0026] Some implementations include a method for reducing dextromethorphan plasma levels, the method comprising administering erythrobupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 9 consecutive days, wherein, on the 9th day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained by administering the same amount of dextromethorphan for 9 consecutive days without erythrobupropion or its prodrug.

[0027] Some implementations include a method for reducing dextromethorphan plasma levels, the method comprising co-administering threobupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 9 consecutive days, wherein, on the 9th day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained by administering the same amount of dextromethorphan for 9 consecutive days without threobupropion or its prodrug.

[0028] Some implementations include a method for reducing dextromethorphan plasma levels, the method comprising administering bupropion and dextromethorphan to a person requiring treatment with dextromethorphan for at least 9 consecutive days, wherein on the 9th day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained by administering the same amount of dextromethorphan for 9 consecutive days without bupropion.

[0029] Some implementations include a method for reducing dextromethorphan plasma levels, the method comprising administering hydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 9 consecutive days, wherein, on the 9th day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained by administering the same amount of dextromethorphan for 9 consecutive days without hydroxybupropion or its prodrug.

[0030] Some implementations include a method for reducing dextromethorphan plasma levels, the method comprising administering erythrobupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 9 consecutive days, wherein, on the 9th day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained by administering the same amount of dextromethorphan for 9 consecutive days without erythrobupropion or its prodrug.

[0031] Some implementations include a method for reducing dextromethorphan plasma levels, the method comprising co-administering threobupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 9 consecutive days, wherein, on the 9th day, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained by administering the same amount of dextromethorphan for 9 consecutive days without threobupropion or its prodrug.

[0032] Some implementations include a method for reducing dextromethorphan plasma levels, the method comprising co-administering bupropion and dextromethorphan to a person requiring treatment with dextromethorphan for at least 10 consecutive days, wherein on day 10, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained by administering the same amount of dextromethorphan for 10 consecutive days without bupropion.

[0033] Some implementations include a method for reducing dextromethorphan plasma levels, the method comprising co-administering hydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 10 consecutive days, wherein on day 10, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained by administering the same amount of dextromethorphan for 10 consecutive days without hydroxybupropion or its prodrug.

[0034] Some implementations include a method for reducing dextromethorphan plasma levels, the method comprising co-administering erythrobupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 10 consecutive days, wherein on day 10, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained by administering the same amount of dextromethorphan for 10 consecutive days without erythrobupropion or its prodrug.

[0035] Some implementations include a method for reducing dextromethorphan plasma levels, the method comprising co-administering threobupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 10 consecutive days, wherein, on day 10, the dextromethorphan plasma level is lower than the dextromethorphan plasma level obtained by administering the same amount of dextromethorphan for 10 consecutive days without threobupropion or its prodrug.

[0036] 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 in the treatment of neurological disorders. Regardless of their stereochemistry, metabolites or prodrugs of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any of these compounds can effectively inhibit or reduce the metabolism of dextromethorphan in some individuals. This can be achieved by co-administering bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any of these compounds' metabolites or prodrugs with dextromethorphan.

[0037] Some implementations include methods for treating neurological disorders, the methods comprising administering to a person in need of: 1) dextromethorphan, or 2) a combination of an antidepressant compound and dextromethorphan, wherein the person is a rapid metabolizer of dextromethorphan.

[0038] Some implementations include methods for increasing dextromethorphan plasma levels in a person who needs to be treated with dextromethorphan, including co-administering bupropion with dextromethorphan to the person, wherein the person is a fast metabolizer of dextromethorphan.

[0039] Some implementations include methods for inhibiting the metabolism of dextromethorphan, including administering bupropion to a person who is a fast metabolizer of dextromethorphan, and wherein dextromethorphan and bupropion are co-present in the person.

[0040] Some implementations include methods for increasing the metabolic lifespan of dextromethorphan, including administering bupropion to a person who needs to be treated with dextromethorphan, wherein the person is a fast metabolizer of dextromethorphan, and wherein dextromethorphan and bupropion are co-present in the person's body.

[0041] Some implementations include methods to correct the rapid metabolism of dextromethorphan, including administering bupropion to the person in need.

[0042] Some implementations include methods to improve the antitussive properties of dextromethorphan, including administering bupropion to a person who needs treatment for a cough in conjunction with the administration of dextromethorphan.

[0043] Some implementations include a method for treating cough, which involves administering a combination of bupropion or another active compound with dextromethorphan to a person in need.

[0044] Some implementations include a method for treating neurological disorders, the method comprising administering 1) dextromethorphan or 2) bupropion and dextromethorphan to a person in need, wherein the administration of 1) dextromethorphan or 2) bupropion and dextromethorphan is performed at least once daily for at least 8 days, at least 9 days, or at least 10 days.

[0045] Some implementations include methods for treating neurological disorders, including administering bupropion at a dose of about 150 mg / day to about 300 mg / day and dextromethorphan at a dose of about 15 mg / day to about 60 mg / day to the person in need.

[0046] Some implementations include methods for increasing dextromethorphan plasma levels in a person requiring treatment with dextromethorphan, including co-administering hydroxybupropion or its prodrug with dextromethorphan to the person, wherein the person is a rapid metabolizer of dextromethorphan.

[0047] Some implementations include methods for increasing dextromethorphan plasma levels in individuals requiring treatment with dextromethorphan, including co-administering erythrobupropion or its prodrug with dextromethorphan to the individual, wherein the individual is a rapid metabolizer of dextromethorphan.

[0048] Some implementations include methods for increasing dextromethorphan plasma levels in individuals requiring treatment with dextromethorphan, including co-administering thiobupropion or its prodrug with dextromethorphan to the individual, wherein the individual is a rapid metabolizer of dextromethorphan.

[0049] Some implementations include methods for inhibiting the metabolism of dextromethorphan, including administering bupropion to a person who is a fast metabolizer of dextromethorphan, and wherein dextromethorphan and bupropion are co-present in the person.

[0050] Some implementations include methods for inhibiting the metabolism of dextromethorphan, including administering hydroxybupropion or a prodrug thereof to a person, wherein the person is a rapid metabolizer of dextromethorphan, and wherein dextromethorphan and hydroxybupropion are co-present in the person.

[0051] Some implementations include methods for inhibiting the metabolism of dextromethorphan, including administering erythromethanolide or a prodrug thereof to a person, wherein the person is a rapid metabolizer of dextromethorphan, and wherein dextromethorphan and erythromethanolide are co-present in the person.

[0052] Some implementations include methods for inhibiting the metabolism of dextromethorphan, including administering threo-hydroxybupropion or a prodrug thereof to a person, wherein the person is a rapid metabolizer of dextromethorphan, and wherein dextromethorphan and threo-hydroxybupropion are co-present in the person.

[0053] Some implementations include methods for increasing the metabolic lifespan of dextromethorphan, including administering hydroxybupropion or a prodrug thereof to a person who needs to be treated with dextromethorphan, wherein the person is a rapid metabolizer of dextromethorphan, and wherein dextromethorphan and hydroxybupropion are co-present in the person.

[0054] Some implementations include methods for increasing the metabolic lifespan of dextromethorphan, including administering erythromethanolide or a prodrug thereof to a person who requires treatment with dextromethorphan, wherein the person is a rapid metabolizer of dextromethorphan, and wherein dextromethorphan and erythromethanolide are co-present in the person.

[0055] Some implementations include a method for increasing dextromethorphan plasma levels, comprising co-administering bupropion and dextromethorphan to a person requiring treatment with dextromethorphan, wherein bupropion is administered on the first day of at least two days of co-administration of bupropion and dextromethorphan, wherein an increase in dextromethorphan plasma levels occurs on the first day of co-administration of bupropion and dextromethorphan compared to the same amount of dextromethorphan administered without bupropion.

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

[0057] Some implementations include a method for increasing dextromethorphan plasma levels, comprising co-administering erythrobupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan, wherein erythrobupropion or its prodrug is administered on the first day of at least two days of co-administration of erythrobupropion or its prodrug with dextromethorphan, wherein an increase in dextromethorphan plasma levels occurs on the first day of co-administration of erythrobupropion or its prodrug with dextromethorphan compared to the same amount of dextromethorphan administered without erythrobupropion or its prodrug.

[0058] Some implementations include a method for increasing dextromethorphan plasma levels, comprising co-administering thusophytophenone or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan, wherein the thusophytophenone or its prodrug is administered on the first day of at least two days of co-administration of thusophytophenone or its prodrug with dextromethorphan, wherein an increase in dextromethorphan plasma levels occurs on the first day of co-administration of thusophytophenone or its prodrug with dextromethorphan compared to the same amount of dextromethorphan used without thusophytophenone or its prodrug.

[0059] Some implementations include methods for increasing dextromethorphan plasma levels, comprising administering bupropion and dextromethorphan to a person requiring treatment with dextromethorphan for at least 5 consecutive days, wherein on day 5, the dextromethorphan plasma level is higher than the dextromethorphan plasma level obtained if the same amount of dextromethorphan were administered for 5 consecutive days without bupropion.

[0060] Some implementations include a method for increasing dextromethorphan plasma levels, comprising co-administering hydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 5 consecutive days, wherein on day 5, the dextromethorphan plasma level is higher than that obtained by administering the same amount of dextromethorphan for 5 consecutive days without hydroxybupropion or its prodrug.

[0061] Some implementations include a method for increasing dextromethorphan plasma levels, comprising administering erythromethone or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 5 consecutive days, wherein on day 5, the dextromethorphan plasma level is higher than that obtained by administering the same amount of dextromethorphan for 5 consecutive days without erythromethone or its prodrug.

[0062] Some implementations include a method for increasing dextromethorphan plasma levels, comprising co-administering thusophytophenone or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 5 consecutive days, wherein, on day 5, the dextromethorphan plasma level is higher than that obtained if the same amount of dextromethorphan were administered for 5 consecutive days without thusophytophenone or its prodrug.

[0063] Some implementations include a method for increasing dextromethorphan plasma levels, comprising administering bupropion and dextromethorphan to a person requiring treatment with dextromethorphan for at least 6 consecutive days, wherein on the 6th day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level obtained if the same amount of dextromethorphan were administered for 6 consecutive days without bupropion.

[0064] Some implementations include a method for increasing dextromethorphan plasma levels, comprising administering hydroxybupropion or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 6 consecutive days, wherein on the 6th day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level obtained if the same amount of dextromethorphan were administered for 6 consecutive days without hydroxybupropion or its prodrug.

[0065] Some implementations include a method for increasing dextromethorphan plasma levels, comprising administering erythromethone or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 6 consecutive days, wherein on the 6th day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level obtained if the same amount of dextromethorphan were administered for 6 consecutive days without erythromethone or its prodrug.

[0066] Some implementations include methods for increasing dextromethorphan plasma levels, comprising co-administering thusophytophenone or its prodrug and dextromethorphan to a person requiring treatment with dextromethorphan for at least 6 consecutive days, wherein, on the 6th day, the dextromethorphan plasma level is higher than that obtained if the same amount of dextromethorphan were administered for 6 consecutive days without thusophytophenone or its prodrug.

[0067] Some implementations include methods to reduce the trough effect of dextromethorphan, including co-administering bupropion and dextromethorphan to a human patient requiring treatment with dextromethorphan, wherein the plasma level of dextromethorphan 12 hours after co-administration of bupropion and dextromethorphan is at least twice the plasma level obtained if the same amount of dextromethorphan were administered in the absence of bupropion.

[0068] Some implementations include methods for reducing the dextromethorphan valence effect, including co-administering hydroxybupropion or its prodrug with dextromethorphan to a human patient requiring treatment with dextromethorphan, wherein the plasma level of dextromethorphan 12 hours after co-administration of hydroxybupropion or its prodrug with dextromethorphan is at least twice the plasma level obtained if the same amount of dextromethorphan were administered without hydroxybupropion or its prodrug.

[0069] Some implementations include methods for reducing the glutar effect of dextromethorphan, including co-administering erythrobupropion or its prodrug with dextromethorphan to a human patient requiring treatment with dextromethorphan, wherein the plasma level of dextromethorphan 12 hours after co-administration of erythrobupropion or its prodrug with dextromethorphan is at least twice the plasma level obtained if the same amount of dextromethorphan were administered without erythrobupropion or its prodrug.

[0070] Some implementations include methods for reducing the glutar effect of dextromethorphan, including co-administering throsylbupropion or its prodrug with dextromethorphan to a human patient requiring treatment with dextromethorphan, wherein the plasma level of dextromethorphan 12 hours after co-administration of throsylbupropion or its prodrug with dextromethorphan is at least twice the plasma level obtained if the same amount of dextromethorphan were administered without throsylbupropion or its prodrug.

[0071] Some implementations include methods for reducing adverse events associated with dextromethorphan treatment, the methods comprising co-administering bupropion and dextromethorphan to a human patient requiring dextromethorphan treatment, wherein the human patient is at risk of adverse events due to dextromethorphan treatment.

[0072] Some implementations include methods for reducing adverse events associated with dextromethorphan treatment, the methods comprising co-administering hydroxybupropion or its prodrug with dextromethorphan to a human patient requiring dextromethorphan treatment, wherein the human patient is at risk of experiencing adverse events as a result of dextromethorphan treatment.

[0073] Some implementations include methods for reducing adverse events associated with dextromethorphan treatment, the methods comprising co-administering erythrobupropion or its prodrug with dextromethorphan to a human patient requiring dextromethorphan treatment, wherein the human patient is at risk of experiencing adverse events as a result of dextromethorphan treatment.

[0074] Some implementations include methods for reducing adverse events associated with bupropion treatment, the methods comprising co-administering dextromethorphan and bupropion to a human patient requiring bupropion treatment who is at risk of adverse events due to bupropion treatment.

[0075] Some implementations include methods to correct the rapid metabolism of dextromethorphan, including administering hydroxybupropion or its prodrug to a person in need.

[0076] Some implementations include methods for correcting the rapid metabolism of dextromethorphan, including administering erythrobupropion or its prodrug to a person in need.

[0077] Some implementations include methods for correcting the rapid metabolism of dextromethorphan, including administering threo-hydroxybupropion or its prodrug to a person in need.

[0078] Some implementations include methods to improve the antitussive properties of dextromethorphan, including administering bupropion to a person in need of treatment for a cough in conjunction with the administration of dextromethorphan.

[0079] Some implementations include methods to improve the antitussive properties of dextromethorphan, including administering hydroxybupropion or its prodrug to a person in need of treating a cough in conjunction with the administration of dextromethorphan.

[0080] Some implementations include methods to improve the antitussive properties of dextromethorphan, including administering erythrohydroxybupropion or its prodrug to a person in need of treating a cough in conjunction with the administration of dextromethorphan.

[0081] Some implementations include methods to improve the antitussive properties of dextromethorphan, including administering throsylbupropion or its prodrug to a person in need of treating a cough in conjunction with the administration of dextromethorphan.

[0082] Some implementations include methods for treating cough, including administering a combination of hydroxybupropion or its prodrug and dextromethorphan to a person in need.

[0083] Some implementations include methods for treating cough, including administering a combination of erythrobupropion or its prodrug and dextromethorphan to a person in need.

[0084] Some implementations include methods for treating cough, including administering a combination of threobupropion or its prodrug and dextromethorphan to a person in need.

[0085] Some implementations include a method of treating neurological disorders, the method comprising administering bupropion and dextromethorphan to a person in need, wherein bupropion and dextromethorphan are administered at least once daily for at least 8 days, at least 9 days, or at least 10 days.

[0086] Some implementations include a method of treating neurological disorders, the method comprising administering hydroxybupropion or its prodrug and dextromethorphan to a person in need, wherein the bupropion and dextromethorphan are administered at least once daily for at least 8, 9, or 10 days.

[0087] Some implementations include a method of treating neurological disorders, the method comprising administering erythrobupropion or its prodrug and dextromethorphan to a person in need, wherein the erythrobupropion and dextromethorphan are administered at least once daily for at least 8 days, at least 9 days, or at least 10 days.

[0088] Some implementations include a method of treating neurological disorders, the method comprising administering thusophytobupropion or its prodrug and dextromethorphan to a person in need, wherein thusophytobupropion and dextromethorphan are administered at least once daily for at least 8 days, at least 9 days, or at least 10 days.

[0089] Some embodiments include pharmaceutical compositions, dosage forms, or drugs comprising a therapeutically effective amount of dextromethorphan, a therapeutically effective amount of an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds, and pharmaceutically acceptable excipients.

[0090] Some implementations include methods for reducing the risk of seizures associated with the use of bupropion to treat depression, the methods comprising oral administration of a combination of dextromethorphan and bupropion twice daily, wherein the methods: 1) at least effectively treat depression, and 2) reduce the risk of seizures in the person compared to the same number of days of oral administration of 150 mg of bupropion alone twice daily.

[0091] Some implementations include methods for improving the therapeutic effect of bupropion in treating depression, the methods comprising orally administering dextromethorphan and bupropion to a person suffering from depression twice daily, wherein such methods are more effective than treating the person’s depression by orally administering 150 mg of bupropion alone twice daily for 5 weeks.

[0092] In some implementations, the combination of dextromethorphan and bupropion is more effective than the independent oral administration of the same amount of dextromethorphan or bupropion alone.

[0093] Some implementations include methods for improving the efficacy of bupropion in treating depression, said methods comprising orally administering, once or twice daily, a combination of about 90 mg to about 125 mg of bupropion and about 0.3 mg / kg to about 1 mg / kg of dextromethorphan to a person suffering from depression for at least 23 days, wherein the combination of oral administration of bupropion and dextromethorphan is more effective in treating depression than oral administration of bupropion at the same dosage regimen without dextromethorphan.

[0094] Some implementations include a method for treating treatment-resistant depression, the method comprising: selecting a person suffering from depression who has previously failed to be successfully treated with at least one antidepressant; and administering oral dextromethorphan-bupropion combination therapy to the person once or twice daily for at least about five weeks; wherein the dextromethorphan-bupropion combination therapy comprises about 40 mg to about 70 mg of dextromethorphan and about 100 mg to about 140 mg of bupropion.

[0095] Some implementations include methods for rapidly relieving symptoms of depression, the methods comprising administering a combination of bupropion and dextromethorphan to a person in need once or twice daily, wherein the person experiences a therapeutic effect within two weeks of the first day of administration of the combination of bupropion and dextromethorphan.

[0096] Some implementations include methods for treating depression, which involve administering a combination of bupropion and dextromethorphan to a person in need once or twice daily, wherein the person is of Asian descent.

[0097] Some implementations include methods for treating smoking-related nicotine addiction, the methods comprising administering a combination of bupropion and dextromethorphan to a person with nicotine addiction for at least 21 consecutive days daily, wherein the person is an unrestricted (ad-lib) smoker, wherein the person is administered a total of 200 mg to 250 mg of bupropion and 80 mg to 140 mg of dextromethorphan daily, and wherein the method is more effective than administering the same amount of bupropion alone.

[0098] In some implementations involving the treatment of nicotine addiction, such as those measured by a reduction in the average number of cigarettes smoked per day, administration of a combination of bupropion and dextromethorphan resulted in a reduction of nicotine intensity by at least 20% compared to bupropion alone.

[0099] In some implementations involving the treatment of nicotine addiction, administration of a combination of bupropion and dextromethorphan resulted in a reduction of exhaled carbon monoxide levels by at least 10% compared to bupropion alone.

[0100] In some embodiments involving the treatment of nicotine addiction, administration of the combination of bupropion and dextromethorphan twice daily in two equal fractions results in a greater reduction in nicotine self-administration intensity at specific time points (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, or another time point described herein) compared to the effect of administering one of the two fractions for the same duration or by not administering the combination. Attached Figure Description

[0101] Figure 1 The graph shows the change in mean plasma concentration of dextromethorphan over time after administration on day 8 to subjects who received dextromethorphan alone or in combination with bupropion.

[0102] Figure 2 This describes the mean dextromethorphan AUC in subjects who received dextromethorphan alone or in combination with bupropion on day 8. 0-12 .

[0103] Figure 3 This describes the mean dextromethorphan AUC in subjects who received dextromethorphan alone or in combination with bupropion on day 8. 0-24 .

[0104] Figure 4 This describes the mean dextromethorphan AUC in subjects who received dextromethorphan alone or in combination with bupropion on day 8. 0-inf .

[0105] Figure 5 The change in dextromethorphan AUC in subjects who received dextromethorphan alone on day 8 was described compared with that of dextromethorphan and bupropion.

[0106] Figure 6 The mean dextromethorphan AUC was described for subjects who received dextromethorphan alone or in combination with bupropion on days 1 and 8. 0-12 .

[0107] Figure 7 The mean dextromethorphan plasma concentration was described in subjects who were given dextromethorphan alone or with bupropion.

[0108] Figure 8 The mean maximum plasma concentration of dextromethorphan was described for subjects who were given dextromethorphan alone or in combination with bupropion on days 1 and 8.

[0109] Figure 9 The graph shows the change in mean plasma concentration of dextromethorphan over time after administration of dextromethorphan alone or dextromethorphan and bupropion on day 8.

[0110] Figure 10 The mean maximum plasma concentrations of dextromethorphan were described for subjects who received dextromethorphan alone or dextromethorphan and bupropion on days 1 and 8.

[0111] Figure 11 The mean dextromethorphan AUC was described for subjects who received dextromethorphan alone or in combination with bupropion on days 1 and 8. 0-12 .

[0112] Figure 12 The efficacy of various antidepressant compounds in inhibiting the metabolism of dextromethorphan in human liver microsomes was described.

[0113] Figure 13 This is a graph showing the change in the mean total MADRS score relative to baseline over time during the 6-week dosing period for subjects who received bupropion alone or a combination of dextromethorphan and bupropion.

[0114] Figure 14 This describes the percentage of subjects who achieved remission (MADRS ≤ 10) over time during the 6-week dosing period, whether they were given bupropion alone or a combination of dextromethorphan and bupropion.

[0115] Figure 15 This is a graph showing the decrease in the total MADRS score of the subjects described in Example 6 over time.

[0116] Figure 16 This is a graph showing the percentage of responders over time among the subjects described in Example 6.

[0117] Figure 17 This is a graph showing the percentage of subjects who responded to treatment over time, as described in Example 6.

[0118] Figure 18 This is a graph showing the change in the total MADRS score of the subjects described in Example 7 over time relative to baseline.

[0119] Figure 19 This is a graph showing the change in the QIDS-SR-16 total score of the subjects described in Example 7 over time relative to baseline.

[0120] Figure 20 This is a graph showing the percentage of subjects (QIDS-SR-16 score ≤ 5) who achieved remission over time as described in Example 7.

[0121] Figure 21 This is a graph showing the change in cognitive items of the subjects’ MGH-CPFQ over time relative to baseline, as described in Example 7.

[0122] Figure 22 This is a graph showing the change in the total CMAI score of the subjects described in Example 8 over time relative to baseline.

[0123] Figure 23 This is a graph showing the percentage decrease in the subject's CMAI over time relative to baseline, as described in Example 8.

[0124] Figure 24 This is a graph showing the percentage of respondents with a CMAI reduction of ≥ 30% over time, as described in Example 8.

[0125] Figure 25 It describes the relationship with Murrough (Journal of Affective Disorders 218 (2017) 277-283), Figure 3 Compared to the combination of dextromethorphan and quinidine (DM / Q) reported in Example A), the MADRS score of the DM / BU clinical trial in Example 10 was reduced relative to baseline. Detailed Implementation

[0126] Some implementations include methods for treating neurological disorders, including administering a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds to a person in need.

[0127] Some implementations include methods to enhance the therapeutic properties of dextromethorphan in the treatment of neurological disorders, including co-administering dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds.

[0128] Some implementations include methods for increasing dextromethorphan plasma levels in individuals who are rapid metabolizers of dextromethorphan, including co-administering an antidepressant compound such as bupropion with dextromethorphan to the individual.

[0129] Some implementations include methods for inhibiting the metabolism of dextromethorphan, including administering an antidepressant compound such as bupropion to a person who is a rapid metabolizer of dextromethorphan, and wherein dextromethorphan and the antidepressant are co-present in the person's body.

[0130] Some implementations include methods for increasing the metabolic lifespan of dextromethorphan, including increasing the elimination half-life (T0) of dextromethorphan. 1 / 2 This includes administering an antidepressant compound such as bupropion to a person who is a rapid metabolizer of dextromethorphan, and in which dextromethorphan and the antidepressant compound coexist in the person's body.

[0131] Some implementations include methods to correct the rapid metabolism of dextromethorphan, including administering antidepressant compounds such as bupropion to people in need, such as those needing pain treatment.

[0132] Some implementations include methods for improving the therapeutic properties of dextromethorphan in the treatment of neurological disorders, including administering an antidepressant compound such as bupropion to a person in need of treatment for a neurological disorder in conjunction with the administration of dextromethorphan.

[0133] Some implementations include methods for treating neurological disorders, including administering a combination of an antidepressant compound such as bupropion and dextromethorphan to a person in need.

[0134] The co-administration of an antidepressant compound (such as bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a prodrug of an antidepressant compound) with dextromethorphan may occur once or multiple times on a single day, or for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, or more days. In some embodiments, co-administration is performed at least daily for at least two consecutive days.

[0135] In some implementations, the co-administration of an antidepressant compound (such as bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a prodrug of an antidepressant compound) with dextromethorphan can occur once a day for 1, 2, 3, 4, 5, 6, or 7 days, and then be administered twice daily.

[0136] Dextromethorphan has the structure shown below.

[0137]

[0138] Dextromethorphan is used as a cough suppressant. According to the FDA labeling requirements for dextromethorphan products under OTC Monograph [21 CFR 341.74], dextromethorphan should be administered six times daily (every 4 hours), four times daily (every 6 hours), or three times daily (every 8 hours). OTC Monograph [21 CFR 341.74] also states that "this dosage is equivalent to an oral dose of dextromethorphan hydrobromide… of 10 to 20 mg every 4 hours or 30 mg every 6 to 8 hours, not exceeding 120 mg in 24 hours, or as directed by a physician."

[0139] Dextromethorphan is rapidly metabolized in the human liver. This rapid hepatic metabolism may limit systemic drug exposure in individuals who are rapid metabolizers. Humans can be: 1) rapid metabolizers of dextromethorphan—they metabolize dextromethorphan rapidly; 2) weak metabolizers of dextromethorphan—they only weakly metabolize dextromethorphan; or 3) intermediate metabolizers of dextromethorphan—they metabolize dextromethorphan somewhere between rapid and weak metabolizers. Rapid metabolizers can also be ultra-rapid metabolizers. Rapid metabolizers of dextromethorphan constitute a significant portion of the human population. Dextromethorphan can be metabolized, for example, to dextromethorphanone.

[0140] When the same oral dose of dextromethorphan is administered, plasma levels of dextromethorphan are significantly higher in poorly metabolized or intermediately metabolized individuals compared to those with extensive metabolites. Low plasma concentrations of dextromethorphan limit its clinical utility as a monotherapy in rapid metabolizers and potentially intermediate metabolizers. Some therapeutically active compounds, including antidepressants such as bupropion, inhibit the metabolism of dextromethorphan and increase its plasma concentrations, thereby improving its therapeutic efficacy. Similarly, antidepressants allow for less frequent administration of dextromethorphan without sacrificing therapeutic efficacy, 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.

[0141] Co-administration of antidepressants (such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds) with dextromethorphan or dextrophene can enhance the mechanism of action or pharmacological properties of dextromethorphan and dextrophene. The mechanisms of action of dextromethorphan and dextrophene may include σ-1 agonist and NMDA antagonist properties, calcium channel blockade, muscarinic binding, serotonin transporter (5HTT) inhibition, and μ-receptor enhancement.

[0142] Some implementations include co-administering an antidepressant (such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds) with dextromethorphan or dextrophene to agonize, antagonize, or modulate σ-1 receptors or NMDA receptors; block calcium channels; bind to muscarinic receptors; inhibit serotonin transporters (5HTT); or enhance μ receptors.

[0143] The pharmacological properties of dextromethorphan and dextrophene may include antagonism of NMDA high-affinity sites NMDR-2A and functional NMDR-2B receptors; σ-1 stimulation; putative mTOR activation (via σ-1 stimulation, μ enhancement, β-adrenergic receptor stimulation, and 5HTT inhibition); putative AMPA receptor transport (via mTOR activation, PCP antagonism, σ-1 stimulation, β stimulation, μ enhancement, and 5HTT inhibition); and dendritogenesis, spinogenesis, synaptogenesis, and neuronal survival achieved through NMDA antagonism and σ-1 and mTOR signaling. Some implementations include co-administering an antidepressant (e.g., bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds) with dextromethorphan or dextrophene to bind, agonize, antagonize, stimulate, activate, inhibit, influence the transport of or regulate the following substances: NMDA high-affinity sites, NMDR-2A, functional NMDR-2B receptors, σ-1 receptors, putative mTOR receptors (e.g., by stimulating σ-1, enhancing μ receptors, stimulating β-adrenergic receptors, or inhibiting 5HTT), or putative AMPA receptors (e.g., by activating mTOR, antagonizing PCP activity, stimulating σ-1 receptors, stimulating β-adrenergic receptors, enhancing μ receptors, or inhibiting 5HTT). Some implementations involve co-administering an antidepressant (e.g., bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds) with dextromethorphan or dextrophene to induce, increase, decrease, or otherwise modulate dendritic generation, dendritic spine formation, or synapse formation. Some implementations involve co-administering an antidepressant (e.g., bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds) with dextromethorphan or dextrophene to induce, increase, decrease, or otherwise modulate neuronal survival achieved through NMDA antagonism and / or σ-1 and / or mTOR signaling.

[0144] The pharmacological properties of dextromethorphan and dextrophene may include inhibition of 5-HTT and norepinephrine transporters, σ-1 stimulation, NMDA and PCP antagonism, and possible stimulation of serotonin 5HT1b / d receptors. Some implementations involve co-administering an antidepressant (e.g., bupropion, hydroxybupropion, erythrobupropion, threobupropion, or a metabolite or prodrug of any of these compounds) with dextromethorphan or dextrophene to bind, agonize, antagonize, stimulate, activate, inhibit, influence the transport of or modulate 5-HTT and / or norepinephrine transporters, σ-1 receptors, NMDA and / or PCP receptors, and / or stimulate serotonin 5HT1b / d receptors.

[0145] Other properties of dextromethorphan and dextrophene include possible presynaptic α-2 adrenergic receptor antagonism or postsynaptic α-2 stimulation, β stimulation, and possible muscarinic and μ antagonism. Some implementations involve co-administering an antidepressant (e.g., bupropion, hydroxybupropion, erythrobupropion, threobupropion, or a metabolite or prodrug of any of these compounds) with dextromethorphan or dextrophene to bind, agonize, antagonize, stimulate, activate, inhibit, influence the transport of, or regulate presynaptic α-2 adrenergic receptors, postsynaptic α-2 receptors, β-adrenergic receptors, muscarinic receptors, or μ receptors. Dextromethorphan and dextrophene can be glial cell regulators. Some implementations involve co-administering an antidepressant (such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds) with dextromethorphan or dextrophene to modulate glial cells.

[0146] Pain or other neurological disorders can be treated by increasing dextromethorphan plasma levels or increasing dextromethorphan bioavailability, for example by administering a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant compound (such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds) to the person in need.

[0147] Examples of neurological disorders that can be treated or can be treated with increased efficacy by increasing dextromethorphan levels (e.g., those that can be achieved through a combination of dextromethorphan and an antidepressant (e.g., bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds) include, but are not limited to: mood disorders, mental disorders, brain dysfunction, movement disorders, dementia, motor neuron disease, neurodegenerative diseases, seizure disorders, and headaches.

[0148] Mood disorders that can be treated by increasing dextromethorphan levels or by combining dextromethorphan with antidepressants (such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds) include, but are not limited to, depression, major depressive disorder, treatment-resistant depression and treatment-resistant bipolar disorder, bipolar disorder (including cyclothymia), seasonal affective disorder, mood disorders, chronic depression (mild depression), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, and attention deficit disorder. Disorders, ADD, attention deficit hyperactivity disorder (ADDH) and attention deficit / hyperactivity disorder (AD / HD), bipolar and manic disorders, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychosexual dysfunction, pseudobulbar effect and mood instability.

[0149] Depression can manifest as depressive symptoms. These symptoms may include psychological changes such as mood swings, intense sadness, hopelessness, mental slowing, poor concentration, pessimistic worry, agitation, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal thoughts or attempts, and / or self-deprecation. Physical symptoms of depression may include insomnia, anorexia, loss of appetite, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, aches, pains, headaches, cramps, digestive problems, and / or circadian rhythm abnormalities.

[0150] Some patients may remain inadequately or unresponsive to treatment, even after treatment with medications such as antidepressants. Treatment-resistant depression (TRD), or treatment-resistant depression, is a condition typically associated with patients who have failed treatment with at least two antidepressants. A partial diagnosis of TRD is for patients who, after appropriate doses and durations of treatment, such as during a current depressive episode, have an inadequate response to antidepressant therapy. TRD can be more difficult to treat due to comorbidities of other medical or psychological conditions, such as substance / alcohol abuse or eating disorders, or misdiagnosis of TRD. Some patients with TRD have an inadequate response to one, two, three, or more adequate antidepressant treatment trials, or have been unresponsive or inadequately responsive to one, two, three, or more prior antidepressant treatments. In some implementations, patients undergoing treatment for treatment-resistant depression have failed with at least one, two, three, four, five, six, seven, eight, nine, ten, or more antidepressant therapies.

[0151] Measures of improved therapeutic effects, which can be achieved through treatment with increased dextromethorphan bioavailability or plasma levels, or through treatment with a combination of dextromethorphan and antidepressants (e.g., bupropion, hydroxybupropion, erythrobupropion, threobupropion, or metabolites or prodrugs of any of these compounds), include, but are not limited to: the Montgomery-Asberg Depression Rating Scale (MADRS), the Well-being and Quality of Life Questionnaire-Short Form, the Impairment Measurement Tool, the Sheehan Disability Scale, the Patient Rated Inventory of Side Effects (PRISE), the Columbia-Suicide Severity Rating Scale (C-SSRS), the Quick Inventory of Depressive Symptomatology (Self-Report, QIDS-SR), and the Clinical Global Assessment Scale. The following questionnaires were used to assess the severity of depression in children: Cognitive and Physical Functioning Questionnaire (CPFQ) from Massachusetts General Hospital, 17-item Hamilton Rating Scale for Depression (HAM-D17), Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ), 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16), Sheehan Disability Scale (SDS), Clinical Global Impression of Severity of Illness (CGI-S), and Clinical Global Impression of Change.CGI-C, EuroQOL 5 Dimension 5 Level (EQ-5D-5L), Patient Global Impression of Change (PGIC), 7-item Generalized Anxiety Disorder (GAD-7), Clinical Global Impressions-Improvement (CGI-1), Sheehan's Disability Scale (SDS), 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16), Hamilton Anxiety Scale (HAM-A), Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), CPFQ-Cognitive Subscale (items 4-7), Brief Psychiatric Rating Scale. Scale, BPRS, etc.; Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Task (RAVLT), Trail Making Test (TMT), Stroop Colour Naming Test (STROOP), Simple Reaction Time (SRT), Choice Reaction Time (CRT), etc. In some embodiments, treatment of a person with a combination of dextromethorphan and bupropion can improve (e.g., reduce) their score on one of the above-mentioned assessments compared to baseline or placebo 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%. In some embodiments, this improvement is compared to baseline. In some embodiments,This improvement is compared to a placebo.

[0152] The combination of bupropion and dextromethorphan can result in a rapid therapeutic effect, such as within approximately 1 week, 2 weeks, 3 weeks, or 4 weeks of initiation of treatment. For example, improvement in any of the assessments described herein can be observed within these timeframes, including but not limited to MADRS, Well-being and Quality of Life Satisfaction Questionnaire-Short Form, Impairment Measurement Tool, PRISE, C-SSRS, QIDS-SR, CGI, CPFQ, HAM-D17, MGH ATRQ, CGI-S, CGI-C, EQ-5D-5L, PGIC, GAD-7, CGI-1, SDS, QIDS-SR16, HAM-A, CPFQ, CPFQ Cognitive Subscale (items 4-7), BPRS, DSST, RAVLT, TMT, STROOP, SRT, CRT, etc.

[0153] In some embodiments, the enhanced bioavailability of dextromethorphan or a combination of dextromethorphan with an antidepressant (such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds) can be achieved 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.

[0154] Patients who may benefit from the treatment described in this article include pediatric patients, such as those under approximately 18 years of age, approximately 0–5 years of age, approximately 5–10 years of age, approximately 10–12 years of age, or approximately 12–18 years of age; adult patients, such as those aged approximately 18–70 years of age, approximately 18–65 years of age, approximately 18–30 years of age, approximately 10–20 years of age, approximately 20–30 years of age, approximately 30–40 years of age, approximately 40–50 years of age, approximately 50–60 years of age, approximately 60–70 years of age, approximately 70–80 years of age, approximately 80–90 years of age, approximately 30–50 years of age, or approximately 50–65 years of age; elderly patients, such as those over 65 years of age, approximately 65–75 years of age, or approximately 75–90 years of age; or those over 90 years of age and approximately 41 years of age or older.

[0155] In some implementations, (e.g., for a type of depression) the person treated with the combination of dextromethorphan and bupropion is Asian, or selected as Asian. In some implementations, (e.g., for a type of depression) the person treated with the combination of dextromethorphan and bupropion is Japanese, or selected as Japanese. In some implementations, (e.g., for a type of depression) the person treated with the combination of dextromethorphan and bupropion is Korean, or selected as Korean. In some implementations, (e.g., for a type of depression) the person treated with the combination of dextromethorphan and bupropion is Chinese, or selected as Chinese. Assignment of individuals to be Asian, Chinese, Japanese, or Korean may be based on self-reporting by that individual. Among these Asian individuals, the combination of dextromethorphan and bupropion is effective in treating depression that cannot be treated with bupropion alone. This can be particularly important because Asian patients may suffer from more severe depression compared to people from other racial or cultural groups.

[0156] In some implementations, the person does not suffer from or is selected not to suffer from a depressive episode characterized by psychosis or catatonic psychosis.

[0157] In some implementations, the person does not have or is selected not to have mania, hypomania, or mixed episodes, which include bipolar disorder (type 1 or type 2) and substance-induced (e.g., antidepressant-induced) mania, or hypomania / mixed episodes.

[0158] In some implementations, the person does not have or is selected not to have schizophrenia, affective schizophrenia, or another psychotic disorder.

[0159] In some implementations, the person does not suffer from or is selected not to suffer from panic disorder, which may or may not be accompanied by agoraphobia.

[0160] In some implementations, the person does not have or is selected not to have obsessive-compulsive disorder.

[0161] In some implementations, the person does not have or is selected not to have bulimia or anorexia nervosa.

[0162] In some implementations, the person does not have or is selected not to have persistent neurocognitive impairment.

[0163] In some implementations, the person is either not suffering from or is selected not to suffer from any anxiety disorder in the six months prior to treatment.

[0164] In some implementations, a person treated with a combination of dextromethorphan and bupropion (e.g., for a type of depression) according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Textual Revision (DSM-IV-TR), and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Clinical Trials Version SCID-5-CT, has or is selected to have a diagnosis of major depressive disorder. In some implementations, based on SCID-5-CT, the person currently meets the DSM-5 criteria for MDD without psychotic features.

[0165] In some implementations, (e.g. for a type of depression) a person treated with the combination of dextromethorphan and bupropion has or is selected to have a major depressive episode lasting between about 8 weeks and about 24 months, about 1-6 months, about 6-12 months, about 1-2 years, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 6 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 18 months, at least about 2 years, about 1-12 weeks, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 2-4 years, about 4-6 years, about 6-10 years, about 10-20 years or longer.

[0166] In some implementations, (e.g. for a type of depression) a person treated with a combination of dextromethorphan and bupropion has or is selected to have about 1 to 100 or more lifetime depressive episodes, such as major depressive episodes, including at least 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 10, at least about 15, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, about 1-5, about 5-10, about 10-20, about 20-30, about 30-40, about 40-50, about 50-60, about 60-70, about 70-80, about 80-90, about 90-100, or about 4-7 lifetime depressive episodes.

[0167] In some implementations, (e.g. for a type of depression) a person treated with a combination of dextromethorphan and bupropion has or is selected to have a 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., current major depressive episode).

[0168] In some implementations, (e.g., for a type of depression) a person treated with the combination of dextromethorphan and bupropion has been using or has been selected to have been using background antidepressant therapy, which uses, for example, a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), or bupropion at a stable dose for at least 4 weeks prior to entering a double-blind treatment period. In some implementations, the antidepressant therapy continues in conjunction with treatment using the combination of bupropion and dextromethorphan.

[0169] In some implementations, (e.g., for a type of depression) the person treated with the combination of dextromethorphan and bupropion is male, or is selected to be male. In some implementations, (e.g., for a type of depression) the person treated with the combination of dextromethorphan and bupropion is female, or is selected to be female.

[0170] In some implementations (e.g., for a type of depression), the person treated with the combination of dextromethorphan and bupropion has or is selected to have approximately 18-40 kg / m 2 Approximately 18.5 kg / m 2 Less than 18.5 kg / m 2 Approximately 19 kg / m 2 Approximately 19-24.9 kg / m 2 Approximately 25 kg / m 2 Approximately 25-29 kg / m 2 Approximately 29 kg / m 2 More than 29 kg / m 2 Approximately 18-22 kg / m 2 Approximately 22-24 kg / m 2 Approximately 24-26 kg / m 2 Approximately 26-28 kg / m 2 Approximately 28-30 kg / m 2 Approximately 30-32 kg / m 2 Approximately 32-34 kg / m 2 Approximately 34-36 kg / m 2Approximately 36-38 kg / m 2 Approximately 38-40 kg / m 2 Approximately 18-26 kg / m 2 Approximately 26-34 kg / m 2 or approximately 34-40 kg / m 2 Body Mass Index (BMI).

[0171] The MADRS is a clinician-assessed scale. It is used to assess depressive symptoms during the preceding week. Participants are rated on 10 items to assess feelings of guilt, sadness, fatigue, pessimism, inner tension, suicidal ideation, decreased sleep or appetite, agitation, anxiety, weight loss, somatic symptoms, difficulty concentrating, and lack of interest. Each item is rated on a 7-point scale. A score of 0 indicates no symptoms, and a score of 6 indicates the most severe symptoms.

[0172] In some implementations, (e.g. for a type of depression) a person treated with a combination of dextromethorphan and bupropion has or is selected to have an 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.

[0173] In some embodiments, treatment with the combination of dextromethorphan and bupropion results in a reduction in a person's MADRS score 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, this reduction is compared to baseline. In some embodiments, this reduction is compared to placebo.

[0174] In some implementations, treatment with a combination of dextromethorphan and bupropion resulted in MADRS scores of less than 34, approximately 20-34, approximately 7-19, approximately 0-6, approximately 30 or less, approximately 26 or less, approximately 25 or less, approximately 20 or less, approximately 17 or less, approximately 14 or less, approximately 12 or less, approximately 10 or less, approximately 8 or less, approximately 6 or less, approximately 5 or less, approximately 4 or less, approximately 3 or less, approximately 2 or less, approximately 1 or less, approximately 0, approximately 0.1-6, and approximately 0. 1-1, about 1-2, 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.

[0175] The MADRS-6 subscale is the sum of responses to 6 out of 10 MADRS items, which are considered to represent the core symptoms of depression: reported sadness, significant sadness, inner tension, fatigue, inability to feel, and pessimistic thoughts. MADRS items not included in the MADRS-6 score include 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 total score ranges from 0 to 60. The questionnaire includes questions about the following symptoms: 1. significant 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; 10. suicidal ideation. Typical cutoffs are: a) 0 to 6 – normal / asymptomatic; b) 7 to 19 – mild depression; c) 20 to 34 – moderate depression; and d) >34 – severe depression.

[0176] In some implementations, (e.g. for a type of depression) a person 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 before the start of treatment.

[0177] In some embodiments, treatment with the combination of dextromethorphan and bupropion results in a reduction in a person's MADRS-6 score 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, this reduction is compared to baseline. In some embodiments, this reduction is compared to placebo.

[0178] In some implementations, treatment with a combination of dextromethorphan and bupropion resulted in a MADRS-6 score of 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 0.1-6, about 0.1-1, about 1-2, about 2-3, about 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-12, about 12-15, about 0.1-3, about 3-6, about 6-8, about 6-9, or about 9-15.

[0179] In some implementations, (e.g. for a type of depression) a person treated with a combination of dextromethorphan and bupropion has or is selected to have a MADRS score of 2, 4 or 6 on item 1 (significant grief) prior to the start of treatment.

[0180] In some embodiments, treatment with the combination of dextromethorphan and bupropion results in a reduction of at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% in the person's MADRS score on item 1 compared to baseline or placebo. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0181] In some implementations, treatment with a combination of dextromethorphan and bupropion resulted in a score of approximately 2 or lower on MADRS item 1.

[0182] Treatment efficacy can be assessed at any suitable time, such as, for example, weeks 1-2, 1-3, 1-4, 1-6, 4-6, 6-8, 8-12, 12-16, at the 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 at any other time. In some implementations, MADRS is used to assess treatment efficacy weekly.

[0183] The CGI-S scale is a clinician-rated scale used to assess the severity of a subject's current mental illness state compared to a group of subjects with MDD. Subjects are rated on a scale of 1 to 7, where 1 represents "normal" and 7 represents "most severely ill subject." The CGI-S can be performed by personnel with extensive professional training and experience in assessing mental illness. Possible ratings are: 1) Normal, no illness at all; 2) Borderline psychosis; 3) Mild illness; 4) Moderate illness; 5) Obvious illness; 6) Severe illness; and 7) Most severely ill patient.

[0184] In some implementations, (e.g. for a type of depression) a person treated with a combination of dextromethorphan and bupropion has or is selected to have a Clinical Global Impression-Severity Scale (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.

[0185] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction in a person's 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, this reduction is compared to baseline. In some embodiments, this reduction is compared to placebo.

[0186] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction in a person's 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 0.1–6, about 0.1–1, about 1–2, about 2–3, about 3–4, about 4–5, about 5–6, about 0.1–3, or about 3–6. In some embodiments, this reduction is compared to baseline. In some embodiments, this reduction is compared to placebo.

[0187] The therapeutic effect can be assessed at any appropriate time, such as, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-6, weeks 2-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, 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 at any other time.

[0188] The QIDS-SR-16, a 16-item scale used for patient rating, is a simplified version of the 30-item Depression Symptom Scale (IDS) and is designed to assess the severity of depressive symptoms. The QIDS-SR-16 rating criteria symptom domain is used to diagnose major depressive episodes.

[0189] The QIDS-SR can be used to assess a subject's depressive symptoms over the past 7 days. Subjects report symptom severity on 10 items: sleep, feelings of sadness, appetite, weight change, attention, self-esteem, suicidal ideation, overall interest level, energy level, psychomotor retardation, and irritability. Each item can be rated on a 4-point scale, where a score of 0 reflects no symptoms and a score of 3 reflects the most severe symptom.

[0190] The total QIDS score ranges from 0 to 27, where a score of 5 or lower indicates no depression, a score of 6 to 10 indicates mild depression, 11 to 15 indicates moderate depression, 16 to 20 indicates severe depression, and a total score greater than 21 indicates very severe depression.

[0191] In some implementations, (e.g. for a type of depression) a person treated with a combination of dextromethorphan and bupropion has or is selected to have a QIDS-SR-16 score of at least about 16, at least about 18, at least about 21, at least about 24, at least about 27, at least about 30, at least about 33, about 16-18, about 16-19, about 16-20, about 18-21, about 21-24, about 24-27, about 15-21, or about 21-27 before starting treatment.

[0192] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction in a person's QIDS-SR-16 score by 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, this reduction is compared to baseline. In some embodiments, this reduction is compared to placebo.

[0193] In some implementations, treatment with a combination of dextromethorphan and bupropion resulted in a QIDS-SR-16 score of about 6 or lower, about 5 or lower, about 4 or lower, about 3 or lower, about 2 or lower, about 1 or lower, about 0.1-6, about 0.1-5, about 0.1-1, about 1-2, about 2-3, about 3-4, about 4-5, about 5-6, about 0.1-3, or about 3-6. The therapeutic effect can be assessed at any appropriate time, such as, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, 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 at any other time.

[0194] The CGI-I scale is a clinician-rated scale used to assess overall improvement or deterioration in mental illness, regardless of whether the investigator considers the improvement or deterioration to be a result of medication. Subjects are rated on a scale of 1 to 7, where 1 indicates significant improvement and 7 indicates very poor condition. The CGI-I can be administered by personnel with extensive professional training and experience in assessing mental illness.

[0195] In some implementations, treatment with a combination of dextromethorphan and bupropion resulted in a CGI-1 score of about 3 or less, about 2 or less, about 1, about 1-2, or about 2-3 in the person.

[0196] The therapeutic effect can be assessed at any appropriate time, such as, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, 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 at any other time.

[0197] The VAMS (Patient-Rated Mood Scale) consists of a 100mm line with graphs, diagrams, or graphic representations of extreme emotions at each end, such as happiness and sadness (e.g., a sad face at one end and a happy face at the other). Each end of the line can be further anchored by word statements describing the extreme emotion. Participants are asked to rate their emotions on the markers on the line. The distance on the line is measured and calculated as a numerical score from 0 to 100. Participants may be asked to complete the VAMS daily.

[0198] In some implementations, (e.g. for a type of depression) a person 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.

[0199] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction in a person's VAMS 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, this reduction is compared to baseline. In some embodiments, this reduction is compared to placebo.

[0200] In some implementations, treatment with a combination of dextromethorphan and bupropion resulted in 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, about 0-10 mm, about 10-20 mm, about 20-30 mm, about 30-40 mm, about 40-50 mm, about 0-25 mm, or about 25-50 mm.

[0201] The therapeutic effect can be assessed at any appropriate time, such as, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, 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 at any other time.

[0202] The Columbia Suicide Severity Scale (C-SSRS) is a clinician-rated tool that reports the severity of both suicidal ideation and behavior. Suicidal ideation is categorized using a five-item scale: 1 (Desire to die); 2 (Unspecific suicidal thoughts); 3 (Intention to commit suicide by any means [unplanned], but without the intent to act); 4 (Intentional suicidal ideation with some intent to act but without a specific plan); and 5 (Intentional suicidal ideation with a specific plan and intent). The C-SSRS also captures information about the intensity of the ideation, particularly the frequency, duration, controllability, determinants, and causes of the most severe types. Suicidal behavior is categorized using a five-item scale: 0 (No suicidal behavior), 1 (Preparation for action or behavior), 2 (Abandonment of attempt), 3 (Interruption of attempt), and 4 (Actual attempt). If suicidal behavior represents different episodic symptoms, more than one category may be selected. For actual attempts only, actual or potentially fatal attempts are categorized as initial, most fatal, and most recent.

[0203] C-SSRS can be performed each time the person being treated sees a health professional. C-SSRS can be tailored to the subject's lifelong medical history of suicidal ideation and behavior, as well as their most recent period of recollection.

[0204] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction of a person's Columbia Suicide Severity Scale (C-SSRS) score by 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, this reduction is compared to baseline. In some embodiments, this reduction is compared to placebo.

[0205] The therapeutic effect can be assessed at any appropriate time, such as, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, 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 at any other time.

[0206] The Sheehan Disability Scale (SDS) is a self-rated tool used to measure the impact of a patient's symptoms on three areas: work / school, social life, and family responsibilities. For each of these three areas, scores range from 0 to 10. Along this line, numbers best representing the extent of impairment in each area are marked from 0 (absolutely none) to 10 (extreme). To assess overall functional impairment, these three areas are summarized by adding the scores for each of the three areas together, resulting in a total SDS score ranging from 0 (no impairment) to 30 (highly impaired).

[0207] In some implementations, (e.g. for a type of depression) a person treated with a combination of dextromethorphan and bupropion has or is selected to have the following Sheehan Disability Scale (SDS) scores: 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 total SDS score.

[0208] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction in a person's SDS 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, this reduction is compared to baseline. In some embodiments, this reduction is compared to placebo.

[0209] The therapeutic effect can be assessed at any appropriate time, such as, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, 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 at any other time.

[0210] The Hamilton Depression Rating Scale (HAM-D, HRSD, HDRS, or HAMD-17) is a 17-item scale used by clinicians to rate a subject's depressive state based on the degree of depression, guilt, suicidal ideation, anxiety, agitation, insight level, insomnia pattern, loss of interest in work and other activities, weight loss, hypochondriasis, and psychomotor retardation. It can also be used to identify genital and somatic symptoms. Items are rated on a scale of 0 to 2 or 0 to 4. Higher scores indicate greater severity. For example, a HAM-D depression score of 10 to 13 is considered mild; 14 to 17 is considered mild to moderate; and >17 is considered moderate to severe.

[0211] In some implementations, (e.g. for a type of depression) a person treated with a combination of dextromethorphan and bupropion 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 before the start of treatment.

[0212] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction in a person's HAM-D 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, this reduction is compared to baseline. In some embodiments, this reduction is compared to placebo.

[0213] Treatment efficacy can be assessed at any suitable time, such as, for example, weeks 1-2, 1-3, 1-4, 1-5, 1-6, 4-6, 6-8, 8-12, 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 at any other time. In some implementations, HAM-D is used to assess treatment efficacy weekly.

[0214] The following table can be used to convert from MADRS scores to HAM-D scores and vice versa.

[0215]

[0216]

[0217]

[0218]

[0219]

[0220] The Hamilton Anxiety Rating Scale (HAM-A) is a clinician-administered scale consisting of 14 items, each rated on a five-point scale ranging from 0 (absent) to 4 (very severe). The highest possible total score is 56, representing the most severe form of anxiety; the lowest possible score is 0, representing no anxiety.

[0221] In some implementations, (e.g. for a type of depression) a person treated with a combination of dextromethorphan and bupropion has or is selected to have a Hamilton Anxiety Rating 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.

[0222] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction in a person's HAM-A 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, this reduction is compared to baseline. In some embodiments, this reduction is compared to placebo.

[0223] The therapeutic effect can be assessed at any appropriate time, such as, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, 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 at any other time.

[0224] 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 occur or persist during long-term treatment of depression. Participants rate the perceived quality of their physical and cognitive function. The rating scale is from 1 to 6, with increasing severity, and individually assesses seven different items: motivation / enthusiasm, wakefulness / alertness, energy, focus / attention, recall, word-finding ability, and sharpness / mental acuity. The physical dimensions of the CPFQ assess somnolence and fatigue, while the cognitive dimensions assess apathy, poor attention, forgetfulness, word-finding difficulty, and mental dullness. Higher scores indicate greater impairment.

[0225] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction in a person's CPFQ score by 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, this reduction is compared to baseline. In some embodiments, this reduction is compared to placebo.

[0226] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction of at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% in a person's CPFQ cognitive subscale (items 4-7) score compared to baseline or placebo. In some embodiments, this reduction is compared to baseline. In some embodiments, this reduction is compared to placebo.

[0227] The therapeutic effect can be assessed at any appropriate time, such as, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, 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 at any other time.

[0228] The Brief Psychiatric Rating Scale (BPRS) is a clinician-administered scale developed to measure psychotic symptoms such as depression, anxiety, hallucinations, and aberrant behavior. Each symptom is rated from 1 (absent) to 7 (very severe). If an item is not rated, zero is entered, and that item is excluded from the analysis. This scale should be administered by a clinician with extensive knowledge of psychotic disorders and capable of interpreting the constructs used in the ratings. Factor 1 (Reality Distortion) items are suspiciousness, hallucinatory behavior, and abnormal thought content.

[0229] In some implementations, (e.g. for a type of depression) a person treated with a combination of dextromethorphan and bupropion has or is selected to have a Brief Psychiatric Rating Scale (BPRS) score with the following starting scores: 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.

[0230] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction in a person's BPRS factor 1 score by at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, about 0.1–6, about 0.1–1, about 1–2, about 2–3, about 3–4, about 4–5, about 5–6, about 0.1–3, or about 3–6 compared to baseline or placebo. In some embodiments, this reduction is compared to baseline. In some embodiments, this reduction is compared to placebo.

[0231] The therapeutic effect can be assessed at any appropriate time, such as, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, 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 at any other time.

[0232] In some implementations, (e.g. for a type of depression) a person treated with a combination of dextromethorphan and bupropion has or is selected to have a Beck Depression Scale (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.

[0233] The Beck Depression Inventory (BDI, BDI-1A, BDI-II) is a 21-question multiple-choice self-report scale asking how a subject felt in the previous week. Each question has four possible responses with varying intensities. When scoring the test, each answer is assigned a value from 0 to 3, and the total score is then compared to a key to determine the severity of depression. A higher total score indicates more severe depressive symptoms. The standard cutoff scores are as follows: 0-9: minimal depression; 10-18: mild depression; 19-29: moderate depression; and 30-63: severe depression.

[0234] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a reduction in a person's BDI 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, this reduction is compared to baseline. In some embodiments, this reduction is compared to placebo.

[0235] The therapeutic effect can be assessed at any appropriate time, such as, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, 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 at any other time.

[0236] In some implementations (e.g. for a type of depression), a person treated with a combination of dextromethorphan and bupropion has or is selected to have a C-reactive protein (CRP) level of at least 0.5 mg / L, at least 1 mg / L, at least 2 mg / L, or higher.

[0237] In some embodiments, administration of the combination of dextromethorphan and bupropion results in a human CRP level that is at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% improved compared to baseline or placebo. In some embodiments, the reduction is compared to baseline. In some embodiments, the reduction is compared to placebo.

[0238] The therapeutic effect can be assessed at any appropriate time, such as, for example, weeks 1-2, weeks 1-3, weeks 1-4, weeks 1-5, weeks 1-6, weeks 4-6, weeks 6-8, weeks 8-12, weeks 12-16, 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 at any other time.

[0239] The following table can be used to convert between some of the scores in the above assessment.

[0240]

[0241] 1 Severity of depression. 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe, 4 = Very Severe.

[0242]

[0243] 1 Severity of depression. 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe, 4 = Very Severe.

[0244]

[0245]

[0246]

[0247] In some embodiments, the combination of dextromethorphan and bupropion is a novel, orally administered NMDA receptor antagonist with multimodal activity for the treatment of central nervous system (CNS) disorders. Dextromethorphan is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, also known as a glutamate receptor modulator, with a novel mechanism of action that differs from currently available therapies for depression.

[0248] Dextromethorphan is also a σ-1 receptor agonist, a nicotinic acetylcholine receptor antagonist, and an inhibitor of serotonin and norepinephrine transporters. Bupropion increases the bioavailability of dextromethorphan and is an inhibitor of norepinephrine and dopamine reuptake, as well as a nicotinic acetylcholine receptor antagonist. Both dextromethorphan and bupropion are nicotinic acetylcholine receptor antagonists, representing a mechanism associated with nicotine dependence. Therefore, the combination of dextromethorphan and bupropion offers a potential new mechanism of action for smoking cessation therapy.

[0249] In some embodiments, the combination of dextromethorphan and bupropion can be used to treat nicotine addiction. In some embodiments, the combination of dextromethorphan and bupropion can be administered to a person once or twice daily. In some embodiments, the combination of dextromethorphan and bupropion can be administered to a person twice daily. In some embodiments, the combination of dextromethorphan and bupropion can be administered to a person 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 can be administered to a person twice daily for at least 1 week, at least 2 weeks, at least 3 weeks, or longer.

[0250] In some embodiments, the smoker may be, or may be selected to be, an unrestricted smoker. In some embodiments, the smoker may be, or may be selected to have smoked an average of 10 or more cigarettes per day before administration of the combination of dextromethorphan and bupropion, such as about 10, about 10-15, about 10-17, about 10-20, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 20-25, about 25-30, about 30-40, about 40-50 or more cigarettes.

[0251] In some embodiments, the combination of dextromethorphan and bupropion can be used to treat nicotine addiction, and the combination contains about 30-100 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 35 mg, about 35 mg, about 55 mg, about 65 mg, about 75 mg, about 85 mg, or about 95 mg of dextromethorphan in its free base or salt form. In some embodiments, dextromethorphan is in the HBr salt form.

[0252] In some embodiments, the combination of dextromethorphan and bupropion can be used to treat nicotine addiction, wherein the combination contains 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 150-160 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 its free base or salt form. In some implementations, bupropion is in the form of an HCl salt.

[0253] In some implementations, administration of a combination of dextromethorphan and bupropion to a person results in a reduction in smoking intensity, as measured using the number of cigarettes smoked per day as assessed by a daily smoking diary.

[0254] Treatment of individuals with a combination of dextromethorphan and bupropion resulted in a reduction of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, approximately 5-10%, approximately 10-15%, approximately 15-20%, approximately 20-25%, approximately 25-30%, 10-20%, approximately 20-30%, approximately 30-40%, approximately 40-50%, approximately 50-60%, approximately 60-80%, approximately 80-100%, approximately 20%, approximately 25%, or more, compared to bupropion alone, over a certain period of time (e.g., 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).

[0255] Treatment with a combination of dextromethorphan and bupropion resulted 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, approximately 8-9, approximately 8-10, approximately 10-15, approximately 15-20, approximately 25 or more cigarettes per day.

[0256] Compared to smokers treated with bupropion alone, patients treated with a combination of dextromethorphan and bupropion experienced a greater proportion of smokers, for example, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, approximately 35%, approximately 50%, approximately 60%, approximately 60-80%, approximately 80-90%, and approximately 90-100%, experiencing a reduction of more than 50% in exhaled carbon monoxide levels, which is a biochemical indicator of smoking intensity.

[0257] Compared to those who missed one or two doses of the combination of dextromethorphan and bupropion, those treated with the combination of dextromethorphan and bupropion resulted 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 second day.

[0258] Smoking cessation treatment with the combination of dextromethorphan and bupropion resulted in improvements relative to bupropion alone that were similar to those reported relative to placebo in studies using a similar design for the approved smoking cessation treatment varenicline.

[0259] In some embodiments, enhanced bioavailability of dextromethorphan, or a combination of dextromethorphan with an antidepressant (e.g., bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds), can be used as adjunctive therapy for any of the conditions described herein, including TRD. For example, adjunctive therapy may be used in combination with other antidepressants, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, clomipramine, doxepin, fluoxetine, mianzalequin, imipramine, 2-chloroimipramine, amitriptyline, amoxapine, norimipramine, protriptyline, trimethimipramine, nortriptyline, maprotiline, phenelzine, isozolidinedion, transphenylcyclopropionamide, paroxetine, trazodone, citalopram, sertraline, aryloxyaminoindane, benatizine, etc. Escitalopram, fluvoxamine, venlafaxine, norvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, mirtazapine, tersofencin, butofencin, moclobemide, rasagiline, nipramine, isoniazid, isoprochloraz, toloxacin, butiline, duthiramine, dibenzapine, iproindole, lofepramine, opipipexole, norfluoxetine, dapoxetine, ketamine, etc., or any metabolites or prodrugs of these compounds, or any pharmaceutically acceptable salts of these compounds.

[0260] In some embodiments, TRD can be treated by enhanced bioavailability or plasma levels of dextromethorphan, or by combination of dextromethorphan with an antidepressant (e.g., bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds), and can result in a reduction of depressive symptoms of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100%, or any other reduction within the range defined by any of these values.

[0261] Mental disorders that can be treated by increasing plasma levels of dextromethorphan, such as those treated by combining dextromethorphan with antidepressants (e.g., bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs 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, bipolar disorder, hypomania, unipolar depression, depression, stress disorder, somatic symptom disorder, personality disorder, psychosis, schizophrenia, delusional disorder, schizophrenic disorder, schizophrenia syndrome, aggressive behavior, Alzheimer's disease aggressive behavior, agitation, and Alzheimer's disease agitation.

[0262] As the disease progresses, agitation, characteristic of Alzheimer's disease, can occur. Agitation can manifest as inappropriate verbal, emotional, and / or physical behaviors. Inappropriate behaviors may include, but are not limited to: incoherent rambling, inappropriate emotional responses, demands for attention, threats, irritability, frustration, screaming, repetitive questioning, mood swings, swearing, abusive language, physical outbursts, emotional distress, restlessness, shredding, sleep disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive limb movements, hoarding, shadowing, hitting, scratching, biting, aggression, hyperactivity, and / or kicking.

[0263] In some embodiments, agitation in Alzheimer's disease can be treated by increasing plasma levels of dextromethorphan or by combining dextromethorphan with an antidepressant (such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds), and can result in a reduction of agitation-related symptoms of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100%, or any other reduction within the range defined by any of these values.

[0264] 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 approximately 6 million people in the United States, a number projected to increase to approximately 14 million by 2050. Up to 70% of AD patients have been reported to experience agitation, manifesting as emotional distress, aggressive behavior, disruptive irritability, and disinhibition. Managing agitation is a top priority for AD patients. Agitation in AD patients is associated with increased caregiver burden, functional decline, accelerated cognitive decline, earlier nursing home placement, and increased mortality. Currently, there are no FDA-approved treatments for agitation in AD patients.

[0265] Measures to improve the therapeutic effect by enhancing the bioavailability or plasma level of dextromethorphan, or by combining dextromethorphan with antidepressants (such as bupropion, hydroxybupropion, erythrobupropion, threobupropion, or metabolites or prodrugs of any of these compounds), include, but are not limited to, the Neuropsychiatric Inventory-Clinician rating scale, overall and all domains; the Neuropsychiatric Inventory-Clinician rating scale agitationdomain; the Cohen-Mansfield Agitation Inventory (CMAI); and the Cornell Scale for Depression in... Dementia (CSDD); Neuropsychiatric questionnaire (NPI agitation / aggressive behavior domain); Concomitant medication (frequent use of concomitant medication); Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL);The Neuropsychiatric Inventory (NPI) includes various domains and a total NPI score (range 0-144), including the NPI-C Apathy domain, NPI Aggression / Aggression Caregiver Distress, Modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Agitation (mADCS-CGIC), Patient Global Impression of Change (PGIC) (as assessed by caregivers), Dementia Quality of Life (DEMQOL), Quality of Life-Alzheimer's Disease Measure (QoL-AD), Zarit Burden Scale, Resource Utilization in Dementia (RUD), and Alzheimer's Disease Assessment Scale-Cognitive Subscale. Subscale (ADAS-Cog), Mini-Mental State Examination (MMSE), Caregiver Strain Index (CSI), Individual Domain of the Neuropsychiatric Inventory (NPI), Total Neuropsychiatric Inventory (NPI) score, Neuropsychiatric questionnaire (NPI agitation / aggression domain), Neuropsychiatric questionnaire (NPI domain of negative caregiver stress (NPIDomains)), etc.

[0266] Substance addiction that can be treated by enhancing the bioavailability or plasma levels of dextromethorphan or by combining dextromethorphan with antidepressants (such as bupropion, hydroxybupropion, erythrobupropion, threobupropion, or metabolites or prodrugs of any of these compounds) includes, but is not limited to, drug dependence, addiction to cocaine, psychostimulants (e.g., crack cocaine, cocaine pills, methamphetamine), nicotine, alcohol, opioids, sedatives and hypnotics, cannabis (cannabis or 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, and addiction to chewing tobacco.

[0267] Brain dysfunction that can be treated by enhancing the bioavailability or plasma levels of dextromethorphan or by combining dextromethorphan with antidepressants (such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds) includes, but is not limited to, conditions involving intellectual impairment, such as Alzheimer's disease, Alzheimer's disease, memory loss, amnesia / amnesia syndrome, epilepsy, altered consciousness, coma, decreased attention, speech disorders, vocal dysarthria, Parkinson's disease, Lennox-Gastaut syndrome, autism, ADHD, and schizophrenia. Brain dysfunction also includes conditions caused by cerebrovascular diseases, including but not limited to stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, and head injury, where symptoms include altered consciousness, Alzheimer's disease, coma, decreased attention, and speech disorders.

[0268] Movement disorders that can be treated by enhancing the bioavailability or plasma levels of dextromethorphan or by combining dextromethorphan with antidepressants (such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds) include, but are not limited to, akathisia, dyskinesia, synkinesis, choreoathetosis, ataxia, tetany, unilateral tetany, bradykinesia, cerebral palsy, chorea, Huntington's disease, rheumatic chorea, Siddenham's chorea, movement disorders, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, Tourette syndrome, and Wilson's disease.

[0269] Dementia that can be treated by enhancing the bioavailability or plasma level of dextromethorphan or by combining dextromethorphan with antidepressants (such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds) includes, but is not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, Lewy body dementia, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normobaric hydrocephalus, Huntington's disease, Wernicke-Korsakov syndrome, and Pick's disease.

[0270] Motor neuron diseases that can be treated by enhancing the bioavailability or plasma levels of dextromethorphan or by combining dextromethorphan with antidepressants (such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds) include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-poliomyelitis syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophies, Dixacks disease, Sandhof's disease, and hereditary spastic paraplegia.

[0271] Neurodegenerative diseases that can be treated by enhancing the bioavailability or plasma levels of dextromethorphan or by combining dextromethorphan with antidepressants (such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds) include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, and muscular atrophy. Lateral sclerosis (ALS or Glenk disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, autosomal dominant cerebral arteriosclerosis with subcortical infarction and leukoencephalopathy (CADASIL), muscular dystrophy, Chuck-Mally-Duss disease (CMT), familial spastic paraplegia, neurofibroma, olivopontocerebellar atrophy or degeneration, striatum substantia nigra degeneration, Chuck-Mally-Duss disease, and spastic paraplegia.

[0272] Paroxysmal disorders that can be treated by enhancing the bioavailability or plasma levels of dextromethorphan or 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, epileptic seizures, non-epileptic seizures, epilepsy, and febrile seizures; partial seizures, including but not limited to simple partial seizures, Jacksonian seizures, complex partial seizures, and continuous partial epilepsy; generalized seizures, including but not limited to generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

[0273] Headache types that can be treated by enhancing the bioavailability or plasma level of dextromethorphan or by combining dextromethorphan with antidepressants (such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds) include, but are not limited to, migraine, tension headache, and cluster headache.

[0274] Other neurological disorders that can be treated by enhancing the bioavailability or plasma levels of dextromethorphan or by combining dextromethorphan with antidepressants (such as bupropion, hydroxybupropion, erythrobupropion, threobupropion, or metabolites or prodrugs of any of these compounds) include: Ritter syndrome, autism, tinnitus, disorders of consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy; voice disorders due to uncontrolled laryngeal spasms, including but not limited to abducens spasm, adductor spasm, tonic voice, and voice tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity such as methotrexate neurotoxicity; urinary incontinence, including but not limited to stress incontinence, urge incontinence, and fecal incontinence; and erectile dysfunction.

[0275] In some implementations, dextromethorphan in combination with 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, pseudobulbar effect, depression (including anti-treatment depression), symptoms related to memory and cognition, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Ritter syndrome, paroxysmal symptoms, cough (including chronic cough), and so on.

[0276] In some embodiments, dextromethorphan can be used in combination with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds to treat treatment-resistant depression.

[0277] In some embodiments, dextromethorphan can be used in combination with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds to treat abnormal pain.

[0278] In some embodiments, dextromethorphan in combination with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds can be used to treat refractory hyperalgesia.

[0279] In some embodiments, dextromethorphan can be used in combination with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds to treat dermatitis.

[0280] The analgesic properties of dextromethorphan can be enhanced by means of co-administering dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds together with dextromethorphan.

[0281] The analgesic properties of bupropion can be enhanced by methods that include co-administering dextromethorphan with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolites or prodrugs of these compounds.

[0282] In some embodiments, ketamine or another NMDA receptor antagonist may be administered together with an antidepressant (such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds).

[0283] 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).

[0284] These methods can be used to treat or relieve any type of pain, including but not limited to musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, sensory nociceptive pain, inflammatory pain, arthritis pain, and complex regional pain syndromes.

[0285] In some embodiments, co-administration of dextromethorphan with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds may be used to treat or reduce inflammation or inflammatory conditions, such as Crohn's disease, including inflammation-related pain.

[0286] In some embodiments, dextromethorphan may be co-administered with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds for the treatment of psoriasis, cancer, viral infections, or as adjunctive therapy for multiple myeloma.

[0287] Examples of musculoskeletal pain include lower back pain (i.e., lumbosacral pain), primary dysmenorrhea, and arthritis-related pain (such as pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, axial spondyloarthritis (including ankylosing spondylitis), pain associated with vertebral compression fractures, fibrous dysplasia, osteogenesis imperfecta, Paget's disease, transient osteoporosis, and transient osteoporosis of the hip.

[0288] In some implementations, a combination of dextromethorphan and an antidepressant (such as bupropion) can be administered orally to relieve musculoskeletal pain, including low back pain, and pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatoid diseases, periarticular disorders, axial spondyloarthritis including ankylosing spondylitis, Paget's disease, fibrous dysplasia, SAPHO syndrome, transient osteoporosis of the hip, vertebral compression fractures, osteoporosis, etc.

[0289] In some implementations, a combination of dextromethorphan and an antidepressant (such as bupropion) can be administered to relieve inflammatory pain, including musculoskeletal pain, arthritis pain, and complex regional pain syndromes.

[0290] Arthritis refers to inflammatory joint diseases that may be associated with pain. Examples of arthritis pain include pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatoid) arthritis, non-articular rheumatoid diseases, periarticular disorders, neuropathic arthropathy including Charcot's foot, axial spondyloarthritis including ankylosing spondylitis, and pain associated with SAPHO syndrome.

[0291] In some implementations, dextromethorphan is used in combination with an antidepressant such as bupropion to treat chronic musculoskeletal pain.

[0292] In some implementations, dextromethorphan can be administered in combination with an antidepressant (such as bupropion) to relieve complex regional pain syndromes, such as complex regional pain syndrome type I (CRPS-1), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or another type of CRPS. CRPS is an inflammatory pain. CRPS may also have a neurological component. Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain in the limbs, which may be accompanied by edema and autonomic, motor, and sensory changes.

[0293] In some implementations, a combination of dextromethorphan and an antidepressant (such as bupropion) can be administered orally to relieve neuropathic pain.

[0294] Examples of neuropathic pain include diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathy, phantom limb pain, and central pain. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy, and neuropathy associated with radiation therapy and chemotherapy, among others.

[0295] In some implementations, a combination of dextromethorphan and an antidepressant (such as bupropion) can be administered to relieve fibromyalgia.

[0296] The term “treatment” includes any activity that diagnoses, cures, alleviates, treats, or prevents disease in a person or other animal, or otherwise affects the structure or any function of the body of a person or other animal.

[0297] Any antidepressant can be used in combination with dextromethorphan to improve the therapeutic properties of dextromethorphan. Dextromethorphan and antidepressant compounds can be administered in separate compositions or dosage forms, or in a single composition or dosage form containing both.

[0298] Quinidine can be co-administered with dextromethorphan to provide enhanced dextromethorphan plasma levels. For combinations of quinidine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the daily dose is approximately 1-1000 mg, 1-10 mg, 10 mg, approximately 5 mg, approximately 4.5 mg, approximately 1-3 mg, approximately 2-4 mg, approximately 3-5 mg, approximately 4-6 mg, approximately 5-7 mg, approximately 6-8 mg, approximately 7-9 mg, approximately 8-10 mg, approximately 9-11 mg, approximately 10-12 mg, approximately 4.5-5 mg, 20 mg, 30 mg, 30-100 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 10-30 mg, approximately 30-50 mg, approximately 50-70 mg, approximately 10-90 mg of quinidine, or any dose within the range defined by any of these values.

[0299] Antidepressant compounds that can be co-administered with dextromethorphan include, but are not limited to, bupropion, hydroxybupropion, erythrobupropion, threobupropion, clomipramine, doxepin, fluoxetine, miansheline, imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimethamipramine, desitriptyline, maprotiline, phenelzine, isozolidine, transphenylcyclopropionamide, paroxetine, trazodone, citalopram, sertraline, aryloxyaminoindane, benatizine, and escitalopram. Phthalopram, fluvoxamine, venlafaxine, norvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, mirtazapine, tersofencin, butofencin, moclobemide, rasagiline, nipramine, isoniazid, isopronil, toloxacin, butiline, duthiramine, dibenzapine, iproindole, lofepramine, opipipexole, norfluoxetine, dapoxetine, ketamine, etc., or any metabolites or prodrugs of these compounds, or any pharmaceutically acceptable salts of these compounds.

[0300] For the combination of ketamine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.01-0.2 mg, approximately 0.2-0.4 mg, approximately 0.4-0.6 mg, approximately 0.6-0.8 mg, approximately 0.8-1 mg, approximately 1-1.2 mg, approximately 1.2-1.4 mg, approximately 1.4-1.6 mg, approximately 1.6-1.8 mg, approximately 1.8-2 mg, approximately 2-2.2 mg, approximately 2.2-2.4 mg, approximately 2.4-2.6 mg, approximately 2.6-2.8 mg, approximately 2.8-3 mg, approximately 3-3.2 mg, approximately 3.2-3.4 mg, approximately 3.4-3.6 mg, approximately 3.6-3.8 mg, approximately 3.8-4 mg. mg, approximately 3.9-4.1 mg, approximately 4-4.2 mg, approximately 0.2-0.4 mg, approximately 0.2-0.6 mg, approximately 0.2-0.8 mg, approximately 0.2-1 mg, approximately 0.2-1.2 mg, approximately 0.2-1.4 mg, approximately 0.2-1.6 mg, approximately 0.2-1.8 mg, approximately 0.2-2.0 mg, 0.2-2.5 mg, approximately 0.2-3.0 mg, approximately 0.2-3.5 mg, approximately 0.2-4 mg.0 mg, approximately 5-10 mg, approximately 10-15 mg, approximately 15-20 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-150 mg, approximately 150-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 10-500 mg, approximately 50-400 mg, approximately 50-300 mg, approximately 100-250 mg, approximately 1-10 mg, approximately 10-200 mg, approximately 10-150 mg mg, approximately 10-100 mg, approximately 10-180 mg, approximately 10-160 mg, approximately 10-140 mg, approximately 10-120 mg, approximately 10-100 mg, approximately 10-20 mg, approximately 20-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-350 mg ketamine at doses of approximately 350-400 mg, approximately 25 mg, approximately 50 mg, approximately 100 mg, or approximately 250 mg, or any dose within the range defined by any of these values.

[0301] For the combination of tersofencin and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.1–0.2 mg, approximately 0.1–0.3 mg, approximately 0.1–0.4 mg, approximately 0.1–0.5 mg, approximately 0.1–0.6 mg, approximately 0.1–0.7 mg, approximately 0.1–0.8 mg, approximately 0.1–0.9 mg, approximately 0.1–0.1 mg, approximately 0.1–0.12 mg, approximately 0.01–0.2 mg, approximately 0.1–0.3 mg, approximately 0.2–0.4 mg, approximately 0.3–0.5 mg, approximately 0.4–0.6 mg, approximately 0.5–0.7 mg, approximately 0.6–0.8 mg, approximately 0.7–0.9 mg. tersofenoxine, approximately 0.8–1 mg, approximately 0.9–1.1 mg, or any dose within the range defined by any of these values.

[0302] For the combination of butofenoxam and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.01-0.2 mg, approximately 0.2-0.4 mg, approximately 0.4-0.6 mg, approximately 0.6-0.8 mg, approximately 0.8-1 mg, approximately 1-1.2 mg, approximately 1.2-1.4 mg, approximately 1.4-1.6 mg, approximately 1.6-1.8 mg, approximately 1.8-2 mg, approximately 2-2.2 mg, approximately 2.2-2.4 mg, approximately 2.4-2.6 mg, approximately 2.6-2.8 mg, approximately 2.8-3 mg, approximately 3-3.2 mg, approximately 3.2-3.4 mg, approximately 3.4-3.6 mg, approximately 3.6-3.8 mg, approximately 3.8-4 mg. Sofosbuvir, or any dose within the range defined by any of these values, may be taken in doses of 3.9–4.1 mg, 4–4.2 mg, 0.2–0.4 mg, 0.2–0.6 mg, 0.2–0.8 mg, 0.2–1 mg, 0.2–1.2 mg, 0.2–1.4 mg, 0.2–1.6 mg, 0.2–1.8 mg, 0.2–2.0 mg, 0.2–2.5 mg, 0.2–3.0 mg, 0.2–3.5 mg, or 0.2–4.0 mg.

[0303] For the combination of clomipramine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 10-500 mg, approximately 50-400 mg, approximately 50-300 mg, approximately 100-250 mg, approximately 1-10 mg, approximately 10-200 mg, approximately 10-150 mg, approximately 10-100 mg, approximately 10-180 mg, approximately 10-160 mg, approximately 10-140 mg, approximately 10-120 mg, approximately 10-100 mg, approximately 10-20 mg, approximately 20-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg. Clomipramine, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-350 mg, approximately 350-400 mg, approximately 25 mg, approximately 50 mg, approximately 100 mg, approximately 250 mg, or any dose within the range defined by any of these values.

[0304] For the combination of doxepin and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-500 mg, approximately 1-10 mg, approximately 1-40 mg, approximately 1-30 mg, approximately 1-20 mg, approximately 1-18 mg, approximately 1-16 mg, approximately 1-14 mg, approximately 1-12 mg, approximately 1-10 mg, approximately 10-150 mg, approximately 10-125 mg, approximately 10-100 mg, approximately 10-75 mg, approximately 10-70 mg, approximately 10-60 mg, approximately 10-50 mg, approximately 10-40 mg, approximately 10-30 mg, approximately 10-20 mg, approximately 20-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg. Doxepin at approximately 70-80 mg, 80-90 mg, 90-100 mg, 100-120 mg, 120-140 mg, 140-160 mg, 160-180 mg, 180-200 mg, 200-220 mg, 220-240 mg, 240-250 mg, 250-260 mg, 260-280 mg, 280-300 mg, 300-320 mg, 320-350 mg, 350-400 mg, 400-500 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 250 mg, or 300 mg, or any dose within the range defined by any of these values.

[0305] For the combination of fluoxetine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), it may be administered at the following daily doses: 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 of fluoxetine, or any dose within the range defined by any of these values.

[0306] For the combination of mirtazapine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-300 mg, approximately 1-90 mg, approximately 1-60 mg, approximately 1-30 mg, approximately 1-25 mg, approximately 1-20 mg, approximately 1-15 mg, approximately 1-10 mg, approximately 10-20 mg, approximately 20-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 30 mg, approximately 60 mg, approximately 9 ... 1 mg, about 120 mg, about 150 mg of mirtracerin, or any dose within the range defined by any of these values.

[0307] For the combination of imipramine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-10 mg, approximately 5-150 mg, approximately 5-125 mg, approximately 5-100 mg, approximately 5-75 mg, approximately 5-60 mg, approximately 5-50 mg, approximately 5-40 mg, approximately 5-30 mg, approximately 5-25 mg, approximately 5-20 mg, approximately 5-15 mg, approximately 10-20 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg. Imipramine at a dose of approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-500 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, or approximately 300 mg, or any dose within the range defined by any of these values.

[0308] For the combination of 2-chloroimidamine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.1–0.25 mg, approximately 0.25–0.5 mg, approximately 0.5–0.75 mg, approximately 0.75–1 mg, approximately 1–5 mg, approximately 5–10 mg, approximately 10–15 mg, approximately 15–20 mg, approximately 20–25 mg, approximately 25–30 mg, approximately 30–40 mg, approximately 40–50 mg, approximately 50–60 mg, approximately 60–70 mg, approximately 70–80 mg, approximately 80–90 mg, approximately 90–100 mg, approximately 100–120 mg, approximately 120–140 mg, approximately 140–150 mg, approximately 150–160 mg. mg, approximately 160-180 mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg mg, approximately 600 mg of 2-chloroimidamine, or any dose within the range defined by any of these values.

[0309] For the combination of amitriptyline and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-10 mg, approximately 5-100 mg, approximately 5-70 mg, approximately 5-60 mg, approximately 5-50 mg, approximately 5-40 mg, approximately 5-35 mg, approximately 5-30 mg, approximately 5-25 mg, approximately 5-20 mg, approximately 10-20 mg, approximately 20-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg. Amitriptyline at approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-500 mg, approximately 10 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, or any dose within the range defined by any of these values.

[0310] For the combination of amoxapine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-10 mg, approximately 10-20 mg, approximately 10-300 mg, approximately 10-250 mg, approximately 10-200 mg, approximately 10-150 mg, approximately 10-120 mg, approximately 10-100 mg, approximately 10-80 mg, approximately 10-60 mg, approximately 10-40 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg. Amoxapine at approximately 140-160 mg, 160-180 mg, 180-200 mg, 200-220 mg, 220-240 mg, 240-250 mg, 250-260 mg, 260-280 mg, 280-300 mg, 300-320 mg, 320-350 mg, 350-400 mg, 400-500 mg, 500-600 mg, 600-700 mg, 700-800 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 250 mg, 300 mg, or 400 mg, or any dose within the range defined by any of these values.

[0311] For the combination of desipramine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-10 mg, approximately 1-15 mg, approximately 10-20 mg, approximately 10-25 mg, approximately 10-30 mg, approximately 10-40 mg, approximately 10-50 mg, approximately 10-60 mg, approximately 10-70 mg, approximately 10-80 mg, approximately 10-90 mg, approximately 10-100 mg, approximately 10-120 mg, approximately 10-140 mg, approximately 10-150 mg, approximately 10-180 mg, approximately 10-200 mg, approximately 20-30 mg, approximately 20-40 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 40-60 mg, approximately 50-60 mg. mg, approximately 60-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 90-110 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 180-220 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 280-320 mg, approximately 300-350 mg, approximately 350-400 mg, approximately 100-200 mg, approximately 25-100 mg, approximately 25 mg, approximately 50 mg, approximately 100 mg, approximately 200 mg, approximately 250 mg mg of desipramine, or any dose within the range defined by any of these values.

[0312] For the combination of protriptyline and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 5-100 mg, approximately 2-5 mg, approximately 2-6 mg, approximately 2-7 mg, approximately 2-8 mg, approximately 2-9 mg, approximately 2-10 mg, approximately 2-11 mg, approximately 2-12 mg, approximately 2-13 mg, approximately 2-14 mg, approximately 2-15 mg, approximately 2-20 mg, approximately 2-21 mg, approximately 2-22 mg, approximately 2-23 mg, approximately 2-24 mg, approximately 2-25 mg, approximately 2-26 mg, approximately 2-27 mg, approximately 2-28 mg, approximately 2-29 mg, approximately 2-30 mg, approximately 2-35 mg, approximately 2-40 mg, approximately 15-60 mg, approximately 1-5 mg, approximately 5-10 mg. Protiline at approximately 10-15 mg, approximately 15-20 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-35 mg, approximately 35-40 mg, approximately 40-45 mg, approximately 45-50 mg, approximately 50-55 mg, approximately 55-60 mg, approximately 60-65 mg, approximately 65-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 60 mg, approximately 100 mg, approximately 150 mg, or any dose within the range defined by any of these values.

[0313] For the combination of trimethoprim and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 20-300 mg, approximately 1-10 mg, approximately 5-20 mg, approximately 5-25 mg, approximately 5-30 mg, approximately 5-35 mg, approximately 5-40 mg, approximately 5-45 mg, approximately 5-50 mg, approximately 5-55 mg, approximately 5-60 mg, approximately 5-65 mg, approximately 5-70 mg, approximately 5-75 mg, approximately 5-100 mg, approximately 5-125 mg, approximately 5-150 mg, approximately 10-20 mg, approximately 20-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg, approximately 70-80 mg. mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 100-200 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 180-220 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-500 mg, approximately 10 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg mg of trimethoprim, or any dose within the range defined by any of these values.

[0314] For the combination of nortriptyline and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-5 mg, approximately 5-10 mg, approximately 5-20 mg, approximately 5-25 mg, approximately 5-30 mg, approximately 5-35 mg, approximately 5-40 mg, approximately 5-45 mg, approximately 5-50 mg, approximately 5-55 mg, approximately 5-60 mg, approximately 5-65 mg, approximately 5-70 mg, approximately 5-75 mg, approximately 5-100 mg, approximately 5-125 mg, approximately 5-150 mg, approximately 10-15 mg, approximately 15-20 mg, approximately 20-25 mg, approximately 20-30 mg, approximately 25-30 mg, approximately 30-35 mg, approximately 30-50 mg, approximately 35-40 mg, approximately 40-45 mg. Nortriptyline at approximately 45-50 mg, approximately 50-150 mg, approximately 50-55 mg, approximately 55-60 mg, approximately 60-65 mg, approximately 65-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 80-120 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 60 mg, approximately 100 mg, approximately 150 mg, or any dose within the range defined by any of these values.

[0315] For the combination of maprotiline and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-5 mg, approximately 5-10 mg, approximately 5-20 mg, approximately 5-25 mg, approximately 5-30 mg, approximately 5-35 mg, approximately 5-40 mg, approximately 5-45 mg, approximately 5-50 mg, approximately 5-55 mg, approximately 5-60 mg, approximately 5-65 mg, approximately 5-70 mg, approximately 5-75 mg, approximately 5-100 mg, approximately 5-125 mg, approximately 5-150 mg, approximately 10-15 mg, approximately 10-250 mg, approximately 10-75 mg, approximately 10-50 mg, approximately 15-20 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-35 mg, approximately 35-40 mg. mg, approximately 40-45 mg, approximately 45-50 mg, approximately 50-55 mg, approximately 55-60 mg, approximately 60-65 mg, approximately 60-90 mg, approximately 65-70 mg, approximately 70-75 mg, approximately 75-80 mg, approximately 80-85 mg, approximately 80-120 mg, approximately 85-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 100-150 mg, approximately 120-125 mg, approximately 125-140 mg, approximately 140-150 mg, approximately 150-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 200-225 mg, approximately 210-240 mg, approximately 200-250 mg, approximately 10 mg, approximately 25 mg, approximately 30 mg, approximately 50 mg, approximately 75 Maprotiline at mg, approximately 100 mg, approximately 150 mg, approximately 225 mg, or any dose within the range defined by any of these values.

[0316] For the combination of phenelzine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-5 mg, approximately 5-10 mg, approximately 5-20 mg, approximately 5-25 mg, approximately 5-30 mg, approximately 5-35 mg, approximately 5-40 mg, approximately 5-45 mg, approximately 5-50 mg, approximately 5-55 mg, approximately 5-60 mg, approximately 5-65 mg, approximately 5-70 mg, approximately 5-75 mg, approximately 5-90 mg, approximately 10-15 mg, approximately 15-20 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-35 mg, approximately 35-40 mg, approximately 40-45 mg, approximately 40-50 mg, approximately 45-50 mg, approximately 50-55 mg, approximately 50-70 ...10-15 mg, approximately Phenylezine, or any dose within the range defined by any of these values, in the following amounts: approximately 50-200 mg, approximately 55-60 mg, approximately 60-65 mg, approximately 60-90 mg, approximately 65-70 mg, approximately 70-80 mg, approximately 80-90 mg, 80-120 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 100-150 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 10 mg, approximately 15 mg, approximately 30 mg, approximately 60 mg, approximately 100 mg, approximately 150 mg, or any dose within the range defined by any of these values.

[0317] For the combination of isocarboxazid and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-5 mg, approximately 2-5 mg, approximately 2-6 mg, approximately 2-7 mg, approximately 2-8 mg, approximately 2-9 mg, approximately 2-10 mg, approximately 2-11 mg, approximately 2-12 mg, approximately 2-13 mg, approximately 2-14 mg, approximately 2-15 mg, approximately 2-16 mg, approximately 2-17 mg, approximately 2-18 mg, approximately 2-19 mg, approximately 2-20 mg, approximately 2-21 mg, approximately 2-22 mg, approximately 2-23 mg, approximately 2-24 mg, approximately 2-25 mg, approximately 2-26 mg, approximately 2-27 mg, approximately 2-28 mg, approximately 2-29 mg, approximately 2-30 mg, approximately 2-35 mg, etc. mg, approximately 2-40 mg, approximately 2-45 mg, approximately 2-50 mg, approximately 2-55 mg, approximately 2-60 mg, approximately 5-10 mg, approximately 5-15 mg, approximately 10-15 mg, approximately 10-60 mg, approximately 15-20 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-35 mg, approximately 30-50 mg, approximately 35-40 mg, approximately 40-45 mg, approximately 45-50 mg, approximately 50-55 mg, approximately 50-70 mg, approximately 55-60 mg, approximately 60-65 mg, approximately 65-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg Isocarbohydrazine at a dose of approximately 10 mg, 15 mg, 30 mg, 60 mg, 100 mg, or 150 mg, or any dose within the range defined by any of these values.

[0318] For the combination of tranylcypromine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-5 mg, approximately 1-30 mg, approximately 1-25 mg, approximately 1-20 mg, approximately 2-5 mg, approximately 2-6 mg, approximately 2-7 mg, approximately 2-8 mg, approximately 2-9 mg, approximately 2-10 mg, approximately 2-11 mg, approximately 2-12 mg, approximately 2-13 mg, approximately 2-14 mg, approximately 2-15 mg, approximately 2-16 mg, approximately 2-17 mg, approximately 2-18 mg, approximately 2-19 mg, approximately 2-20 mg, approximately 2-21 mg, approximately 2-22 mg, approximately 2-23 mg, approximately 2-24 mg, approximately 2-25 mg, approximately 2-26 mg, approximately 2-27 mg, approximately 2-28 mg, approximately 2-28 mg, approximately 2-28 mg, approximately 2-25 mg, approximately 2-26 mg, approximately 2-27 mg, approximately 2-28 mg, approximately 2-28 mg, approximately 2-20 mg, approximately 2-21 mg, approximately 2-22 mg, approximately 2-23 mg, approximately 2-24 mg, approximately 2-25 mg, approximately 2-26 mg, approximately 2-27 mg, approximately 2-28 mg, approximately 2-28 mg, approximately 2-20 mg, approximately 2-20 mg, approximately 2-21 mg, approximately 2-22 mg, approximately 2-23 mg, approximately 2-24 mg, approximately 2-25 mg, approximately 2-26 mg, approximately 2-27 mg, approximately 2-28 mg, approximately 2-28 mg, approximately mg, approximately 2-29 mg, approximately 2-30 mg, approximately 2-35 mg, approximately 2-40 mg, approximately 2-45 mg, approximately 2-50 mg, approximately 2-55 mg, approximately 2-60 mg, approximately 5-10 mg, approximately 10-15 mg, approximately 15-20 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-35 mg, approximately 35-40 mg, approximately 40-45 mg, approximately 45-50 mg, approximately 50-55 mg, approximately 55-60 mg, approximately 60-65 mg, approximately 65-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 10 mg, approximately 15 100 mg, about 30 mg, about 60 mg, about 100 mg, about 150 mg of tranylcyclopropane, or any dose within the range defined by any of these values.

[0319] For the combination of paroxetine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-5 mg, approximately 1-50 mg, approximately 1-20 mg, approximately 1-15 mg, approximately 1-10 mg, approximately 2-5 mg, approximately 2-6 mg, approximately 2-7 mg, approximately 2-8 mg, approximately 2-9 mg, approximately 2-10 mg, approximately 2-11 mg, approximately 2-12 mg, approximately 2-13 mg, approximately 2-14 mg, approximately 2-15 mg, approximately 2-16 mg, approximately 2-17 mg, approximately 2-18 mg, approximately 2-19 mg, approximately 2-20 mg, approximately 2-30 mg, approximately 2-40 mg, approximately 2-50 mg, approximately 5-10 mg, approximately 10-15 mg, approximately 15-20 mg, approximately 20-25 mg, approximately 20-25 mg. Paroxetine at approximately 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 45-50 mg, 50-55 mg, 55-60 mg, 60-65 mg, 65-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-120 mg, 120-140 mg, 140-160 mg, 160-180 mg, 180-200 mg, 10 mg, 15 mg, 20 mg, 30 mg, 60 mg, 100 mg, or 150 mg, or any dose within the range defined by any of these values.

[0320] For the combination of trazodone and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-10 mg, approximately 10-20 mg, approximately 10-30 mg, approximately 10-40 mg, approximately 10-50 mg, approximately 10-60 mg, approximately 10-70 mg, approximately 10-80 mg, approximately 10-90 mg, approximately 10-100 mg, approximately 10-120 mg, approximately 10-140 mg, approximately 10-150 mg, approximately 10-180 mg, approximately 10-200 mg, approximately 10-250 mg, approximately 10-300 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg. mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-150 mg, approximately 150-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 25 mg, approximately 50 Trazodone at a dose of approximately 75 mg, 100 mg, 150 mg, 250 mg, 300 mg, 400 mg, or 600 mg, or any dose within the range defined by any of these values.

[0321] For the combination of citalopram and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-5 mg, approximately 1-20 mg, approximately 1-15 mg, approximately 1-10 mg, approximately 2-5 mg, approximately 2-6 mg, approximately 2-7 mg, approximately 2-8 mg, approximately 2-9 mg, approximately 2-10 mg, approximately 2-11 mg, approximately 2-12 mg, approximately 2-13 mg, approximately 2-14 mg, approximately 2-15 mg, approximately 2-20 mg, approximately 2-25 mg, approximately 2-30 mg, approximately 2-35 mg, approximately 2-40 mg, approximately 5-10 mg, approximately 10-15 mg, approximately 15-20 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-35 mg, approximately 35-40 mg. Citalopram at approximately 40-45 mg, 45-50 mg, 50-55 mg, 55-60 mg, 60-65 mg, 65-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-120 mg, 120-140 mg, 140-160 mg, 160-180 mg, 180-200 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, 100 mg, or 150 mg, or any dose within the range defined by any of these values.

[0322] For the combination of sertraline and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-5 mg, approximately 1-50 mg, approximately 1-45 mg, approximately 1-40 mg, approximately 1-30 mg, approximately 1-20 mg, approximately 2-5 mg, approximately 2-6 mg, approximately 2-7 mg, approximately 2-8 mg, approximately 2-9 mg, approximately 2-10 mg, approximately 2-11 mg, approximately 2-12 mg, approximately 2-13 mg, approximately 2-14 mg, approximately 2-15 mg, approximately 2-16 mg, approximately 2-17 mg, approximately 2-18 mg, approximately 2-19 mg, approximately 2-20 mg, approximately 2-21 mg, approximately 2-22 mg, approximately 2-23 mg, approximately 2-24 mg, approximately 2-25 mg, approximately 2-26 mg, approximately 2-26 mg, approximately 2-24 mg, approximately 2-25 mg, approximately 2-26 ... mg, approximately 2-27 mg, approximately 2-28 mg, approximately 2-29 mg, approximately 2-30 mg, approximately 2-35 mg, approximately 2-40 mg, approximately 2-45 mg, approximately 2-50 mg, approximately 5-10 mg, approximately 10-15 mg, approximately 15-20 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-35 mg, approximately 35-40 mg, approximately 40-45 mg, approximately 45-50 mg, approximately 50-55 mg, approximately 55-60 mg, approximately 60-65 mg, approximately 65-70 mg, approximately 70-75 mg, approximately 75-80 mg, approximately 80-85 mg, approximately 85-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-125 mg, approximately 125-140 mg, approximately 140-150 mg Sertraline at approximately 150-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 200-300 mg, approximately 10 mg, approximately 25 mg, approximately 30 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 225 mg, or any dose within the range defined by any of these values.

[0323] For the combination of aryloxyaminoindaminozide and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.1–0.25 mg, approximately 0.25–0.5 mg, approximately 0.5–0.75 mg, approximately 0.75–1 mg, approximately 1–5 mg, approximately 5–10 mg, approximately 10–15 mg, approximately 15–20 mg, approximately 20–25 mg, approximately 25–30 mg, approximately 30–40 mg, approximately 40–50 mg, approximately 50–60 mg, approximately 60–70 mg, approximately 70–80 mg, approximately 80–90 mg, approximately 90–100 mg, approximately 100–120 mg, approximately 120–140 mg, approximately 140–150 mg, approximately 150–160 mg. mg, approximately 160-180 mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg mg of aryloxyaminoindene, or any dose within the range defined by any of these values.

[0324] For the combination of benzimidazole and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.1-0.25 mg, approximately 0.25-0.5 mg, approximately 0.5-0.75 mg, approximately 0.75-1 mg, approximately 1-5 mg, approximately 5-10 mg, approximately 10-15 mg, approximately 15-20 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-150 mg, approximately 150-160 mg, approximately 160-180 mg. mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg mg, approximately 600 mg of benzylphenidate, or any dose within the range defined by any of these values.

[0325] For the combination of escitalopram and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-5 mg, approximately 2-5 mg, approximately 2-6 mg, approximately 2-7 mg, approximately 2-8 mg, approximately 2-9 mg, approximately 2-10 mg, approximately 2-12 mg, approximately 2-14 mg, approximately 2-15 mg, approximately 2-20 mg, approximately 5-10 mg, approximately 5-15 mg, approximately 10-15 mg, approximately 10-30 mg, approximately 15-20 mg, approximately 15-30 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-35 mg, approximately 35-40 mg, approximately 40-45 mg, approximately 45-50 mg, approximately 50-55 mg, approximately 55-60 mg, approximately 60-65 mg. Escitalopram at a dose of approximately 65-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-200 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, or approximately 50 mg, or any dose within the range defined by any of these values.

[0326] For the combination of fluvoxamine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 50-300 mg, 1-10 mg, approximately 10-20 mg, approximately 10-30 mg, approximately 10-40 mg, approximately 10-50 mg, approximately 10-60 mg, approximately 10-70 mg, approximately 10-80 mg, approximately 10-90 mg, approximately 10-100 mg, approximately 10-120 mg, approximately 10-140 mg, approximately 10-150 mg, approximately 10-180 mg, approximately 10-200 mg, approximately 10-250 mg, approximately 10-300 mg, approximately 20-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg. mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 90-110 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 180-220 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 240-260 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 280-320 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-500 mg, approximately 10 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg Fluvoxamine of 100 mg, approximately 250 mg, approximately 300 mg, or any dose within the range defined by any of these values.

[0327] For the combination of venlafaxine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-10 mg, approximately 5-20 mg, approximately 5-25 mg, approximately 5-30 mg, approximately 5-35 mg, approximately 5-40 mg, approximately 5-45 mg, approximately 5-50 mg, approximately 5-55 mg, approximately 5-60 mg, approximately 5-65 mg, approximately 5-70 mg, approximately 5-75 mg, approximately 5-100 mg, approximately 5-125 mg, approximately 5-150 mg, approximately 10-20 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg, approximately 70-80 mg. mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-150 mg, approximately 120-180 mg, approximately 150-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg Venlafaxine at a dose of approximately 225 mg, approximately 250 mg, approximately 375 mg, approximately 400 mg, or approximately 600 mg, or any dose within the range defined by any of these values.

[0328] For the combination of desvenlafaxine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 2-5 mg, approximately 2-6 mg, approximately 2-7 mg, approximately 2-8 mg, approximately 2-9 mg, approximately 2-10 mg, approximately 2-11 mg, approximately 2-12 mg, approximately 2-13 mg, approximately 2-14 mg, approximately 2-15 mg, approximately 2-20 mg, approximately 2-21 mg, approximately 2-22 mg, approximately 2-23 mg, approximately 2-24 mg, approximately 2-25 mg, approximately 2-30 mg, approximately 2-35 mg, approximately 2-40 mg, approximately 2-45 mg, approximately 2-50 mg, approximately 2-75 mg, approximately 2-100 mg, approximately 1-5 mg, approximately 5-10 mg, approximately 10-15 mg, approximately 15-20 mg. Desvenlafaxine, approximately 20-25 mg, approximately 20-30 mg, approximately 25-30 mg, approximately 30-35 mg, approximately 35-40 mg, approximately 40-45 mg, approximately 40-60 mg, approximately 45-50 mg, approximately 50-55 mg, approximately 55-60 mg, approximately 60-65 mg, approximately 65-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 80-120 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 60 mg, approximately 100 mg, approximately 150 mg, or any dose within the range defined by any of these values.

[0329] For the combination of duloxetine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-5 mg, approximately 2-5 mg, approximately 2-6 mg, approximately 2-7 mg, approximately 2-8 mg, approximately 2-9 mg, approximately 2-10 mg, approximately 2-11 mg, approximately 2-12 mg, approximately 2-13 mg, approximately 2-14 mg, approximately 2-15 mg, approximately 2-20 mg, approximately 2-21 mg, approximately 2-22 mg, approximately 2-23 mg, approximately 2-24 mg, approximately 2-25 mg, approximately 2-26 mg, approximately 2-27 mg, approximately 2-28 mg, approximately 2-29 mg, approximately 2-30 mg, approximately 2-35 mg, approximately 2-40 mg, approximately 2-45 mg, approximately 2-60 mg, approximately 2-90 mg. mg, approximately 2-120 mg, approximately 5-10 mg, approximately 10-15 mg, approximately 15-20 mg, approximately 20-25 mg, approximately 20-40 mg, approximately 25-30 mg, approximately 30-35 mg, approximately 30-50 mg, approximately 35-40 mg, approximately 40-45 mg, approximately 45-50 mg, approximately 50-55 mg, approximately 50-70 mg, approximately 55-60 mg, approximately 60-65 mg, approximately 65-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 60 mg, approximately 100 mg mg, approximately 120 mg of duloxetine, or any dose within the range defined by any of these values.

[0330] For the combination of mirtazapine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 2-5 mg, approximately 2-6 mg, approximately 2-7 mg, approximately 2-8 mg, approximately 2-9 mg, approximately 2-10 mg, approximately 2-11 mg, approximately 2-12 mg, approximately 2-13 mg, approximately 2-14 mg, approximately 2-15 mg, approximately 2-20 mg, approximately 2-25 mg, approximately 2-30 mg, approximately 2-35 mg, approximately 2-40 mg, approximately 2-45 mg, approximately 1-5 mg, approximately 5-10 mg, approximately 5-100 mg, approximately 10-15 mg, approximately 10-50 mg, approximately 15-20 mg, approximately 15-45 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-35 mg. Mirtazapine at doses of approximately 35-40 mg, 40-45 mg, 45-50 mg, 50-55 mg, 55-60 mg, 60-65 mg, 65-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-120 mg, 120-140 mg, 140-160 mg, 160-180 mg, 180-200 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 60 mg, or 75 mg, or any dose within the range defined by any of these values.

[0331] For the combination of nefazodone and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-10 mg, approximately 10-20 mg, approximately 20-40 mg, approximately 20-50 mg, approximately 20-60 mg, approximately 20-70 mg, approximately 20-80 mg, approximately 20-90 mg, approximately 20-100 mg, approximately 20-120 mg, approximately 20-140 mg, approximately 20-160 mg, approximately 20-180 mg, approximately 20-200 mg, approximately 20-250 mg, approximately 20-300 mg, approximately 20-450 mg, approximately 20-600 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg. mg, approximately 60-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 80-120 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-150 mg, approximately 150-160 mg, approximately 160-180 mg, approximately 160-240 mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg Nefazodone at a dose of approximately 600-650 mg, approximately 650-700 mg, approximately 700-1000 mg, approximately 1000-1500 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, or approximately 600 mg, or any dose within the range defined by any of these values.

[0332] For the combination of selegiline and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), it can be administered in the following daily doses: about 0.5-2 mg, about 2-5 mg, about 1-10 mg, about 1-9 mg, about 1-8 mg, about 1-7 mg, about 1-6 mg, about 1-5 mg, about 1-3 mg, about 3-5 mg, about 5-10 mg, about 5-15 mg, about 10-15 mg, about 15-25 mg, about 25-30 mg, about 30-35 mg, about 35-40 mg, about 40-45 mg, about 45-50 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg of selegiline, or any dose within the range defined by any of these values.

[0333] For the combination of sibutramine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-5 mg, approximately 1-15 mg, approximately 1-10 mg, approximately 1-8 mg, approximately 5-10 mg, approximately 10-15 mg, approximately 15-20 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-35 mg, approximately 35-40 mg, approximately 40-45 mg, approximately 45-50 mg, approximately 50-55 mg, approximately 55-60 mg, approximately 60-65 mg, approximately 65-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 ... Sibutramine at doses of approximately 30 mg, 40 mg, 60 mg, 100 mg, or 120 mg, or any dose within the range defined by any of these values.

[0334] For the combination of rasagiline and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), it can be administered at the following daily doses: 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, about 2 mg of rasagiline, or any dose within the range defined by any of these values.

[0335] For the combination of mirtazapine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-7.5 mg, approximately 7.5-12.5 mg, approximately 5-20 mg, approximately 5-100 mg, approximately 5-90 mg, approximately 5-80 mg, approximately 5-70 mg, approximately 5-60 mg, approximately 5-50 mg, approximately 5-40 mg, approximately 12.5-15 mg, approximately 15-20 mg, approximately 20-30 mg, approximately 20-25 mg, approximately 25-30 mg, approximately 30-35 mg, approximately 35-40 mg, approximately 40-45 mg, approximately 45-50 mg, approximately 50-55 mg, approximately 40-60 mg, approximately 55-60 mg, approximately 60-65 mg, approximately 65-70 mg. Milnacipran at approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 80-120 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 180-220 mg, approximately 200-300 mg, approximately 300-400 mg, approximately 7.5 mg, approximately 12.5 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 60 mg, approximately 100 mg, approximately 200 mg, or any dose within the range defined by any of these values.

[0336] For the combination of moclobemide and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 1-10 mg, approximately 10-20 mg, approximately 20-25 mg, approximately 20-450 mg, approximately 20-300 mg, approximately 20-250 mg, approximately 20-200 mg, approximately 20-150 mg, approximately 20-100 mg, approximately 25-30 mg, approximately 30-40 mg, approximately 40-50 mg, approximately 50-60 mg, approximately 60-70 mg, approximately 70-80 mg, approximately 80-90 mg, approximately 90-100 mg, approximately 100-120 mg, approximately 120-140 mg, approximately 140-150 mg, approximately 150-160 mg, approximately 160-180 mg. mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-320 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 430-470 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg mg, approximately 600 mg of moclobemide, or any dose within the range defined by any of these values.

[0337] For the combination of niacinamide and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.1–0.25 mg, approximately 0.25–0.5 mg, approximately 0.5–0.75 mg, approximately 0.75–1 mg, approximately 1–5 mg, approximately 5–10 mg, approximately 10–15 mg, approximately 15–20 mg, approximately 20–25 mg, approximately 25–30 mg, approximately 30–40 mg, approximately 40–50 mg, approximately 50–60 mg, approximately 60–70 mg, approximately 70–80 mg, approximately 80–90 mg, approximately 90–100 mg, approximately 100–120 mg, approximately 120–140 mg, approximately 140–150 mg, approximately 150–160 mg, approximately 160–180 mg. mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg mg of niacinamide, or any dose within the range defined by any of these values.

[0338] For the combination of isoniazid and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.1–0.25 mg, approximately 0.25–0.5 mg, approximately 0.5–0.75 mg, approximately 0.75–1 mg, approximately 1–5 mg, approximately 5–10 mg, approximately 10–15 mg, approximately 15–20 mg, approximately 20–25 mg, approximately 25–30 mg, approximately 30–40 mg, approximately 40–50 mg, approximately 50–60 mg, approximately 60–70 mg, approximately 70–80 mg, approximately 80–90 mg, approximately 90–100 mg, approximately 100–120 mg, approximately 120–140 mg, approximately 140–150 mg, approximately 150–160 mg, approximately 160–180 mg. mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg mg of isoniazid, or any dose within the range defined by any of these values.

[0339] For the combination of iproclozide and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.1–0.25 mg, approximately 0.25–0.5 mg, approximately 0.5–0.75 mg, approximately 0.75–1 mg, approximately 1–5 mg, approximately 5–10 mg, approximately 10–15 mg, approximately 15–20 mg, approximately 20–25 mg, approximately 25–30 mg, approximately 30–40 mg, approximately 40–50 mg, approximately 50–60 mg, approximately 60–70 mg, approximately 70–80 mg, approximately 80–90 mg, approximately 90–100 mg, approximately 100–120 mg, approximately 120–140 mg, approximately 140–150 mg. mg, approximately 150-160 mg, approximately 160-180 mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg mg, approximately 600 mg of isopropylchlorohydrazine, or any dose within the range defined by any of these values.

[0340] For the combination of toloxacin and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.1–0.25 mg, approximately 0.25–0.5 mg, approximately 0.5–0.75 mg, approximately 0.75–1 mg, approximately 1–5 mg, approximately 5–10 mg, approximately 10–15 mg, approximately 15–20 mg, approximately 20–25 mg, approximately 25–30 mg, approximately 30–40 mg, approximately 40–50 mg, approximately 50–60 mg, approximately 60–70 mg, approximately 70–80 mg, approximately 80–90 mg, approximately 90–100 mg, approximately 100–120 mg, approximately 120–140 mg, approximately 140–150 mg, approximately 150–160 mg, approximately 160–180 mg. mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg mg of toloxacin, or any dose within the range defined by any of these values.

[0341] For the combination of buteline and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.1–0.25 mg, approximately 0.25–0.5 mg, approximately 0.5–0.75 mg, approximately 0.75–1 mg, approximately 1–5 mg, approximately 5–10 mg, approximately 10–15 mg, approximately 15–20 mg, approximately 20–25 mg, approximately 25–30 mg, approximately 30–40 mg, approximately 40–50 mg, approximately 50–60 mg, approximately 60–70 mg, approximately 70–80 mg, approximately 80–90 mg, approximately 90–100 mg, approximately 100–120 mg, approximately 120–140 mg, approximately 140–150 mg, approximately 150–160 mg, approximately 160–180 mg. mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg mg of butiline, or any dose within the range defined by any of these values.

[0342] For the combination of duthiram and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.1–0.25 mg, approximately 0.25–0.5 mg, approximately 0.5–0.75 mg, approximately 0.75–1 mg, approximately 1–5 mg, approximately 5–10 mg, approximately 10–15 mg, approximately 15–20 mg, approximately 20–25 mg, approximately 25–30 mg, approximately 30–40 mg, approximately 40–50 mg, approximately 50–60 mg, approximately 60–70 mg, approximately 70–80 mg, approximately 80–90 mg, approximately 90–100 mg, approximately 100–120 mg, approximately 120–140 mg, approximately 140–150 mg, approximately 150–160 mg, approximately 160–180 mg. mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg mg of duthiram, or any dose within the range defined by any of these values.

[0343] For the combination of dibenzapekine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.1–0.25 mg, approximately 0.25–0.5 mg, approximately 0.5–0.75 mg, approximately 0.75–1 mg, approximately 1–5 mg, approximately 5–10 mg, approximately 10–15 mg, approximately 15–20 mg, approximately 20–25 mg, approximately 25–30 mg, approximately 30–40 mg, approximately 40–50 mg, approximately 50–60 mg, approximately 60–70 mg, approximately 70–80 mg, approximately 80–90 mg, approximately 90–100 mg, approximately 100–120 mg, approximately 120–140 mg, approximately 140–150 mg, approximately 150–160 mg, approximately 160–180 mg. mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg mg of dibenzapine, or any dose within the range defined by any of these values.

[0344] For the combination of iproindole and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.1–0.25 mg, approximately 0.25–0.5 mg, approximately 0.5–0.75 mg, approximately 0.75–1 mg, approximately 1–5 mg, approximately 5–10 mg, approximately 10–15 mg, approximately 15–20 mg, approximately 20–25 mg, approximately 25–30 mg, approximately 30–40 mg, approximately 40–50 mg, approximately 50–60 mg, approximately 60–70 mg, approximately 70–80 mg, approximately 80–90 mg, approximately 90–100 mg, approximately 100–120 mg, approximately 120–140 mg, approximately 140–150 mg, approximately 150–160 mg, approximately 160–180 mg. mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg mg of iproindole, or any dose within the range defined by any of these values.

[0345] For the combination of lofepramine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.1–0.25 mg, approximately 0.25–0.5 mg, approximately 0.5–0.75 mg, approximately 0.75–1 mg, approximately 1–5 mg, approximately 5–10 mg, approximately 10–15 mg, approximately 15–20 mg, approximately 20–25 mg, approximately 25–30 mg, approximately 30–40 mg, approximately 40–50 mg, approximately 50–60 mg, approximately 60–70 mg, approximately 70–80 mg, approximately 80–90 mg, approximately 90–100 mg, approximately 100–120 mg, approximately 120–140 mg, approximately 140–150 mg, approximately 150–160 mg, approximately 160–180 mg. mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg mg of lofepramine, or any dose within the range defined by any of these values.

[0346] For the combination of opipexole and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.1–0.25 mg, approximately 0.25–0.5 mg, approximately 0.5–0.75 mg, approximately 0.75–1 mg, approximately 1–5 mg, approximately 5–10 mg, approximately 10–15 mg, approximately 15–20 mg, approximately 20–25 mg, approximately 25–30 mg, approximately 30–40 mg, approximately 40–50 mg, approximately 50–60 mg, approximately 60–70 mg, approximately 70–80 mg, approximately 80–90 mg, approximately 90–100 mg, approximately 100–120 mg, approximately 120–140 mg, approximately 140–150 mg, approximately 150–160 mg, approximately 160–180 mg. mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg mg of ocipipridol, or any dose within the range defined by any of these values.

[0347] For the combination of norfluoxetine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.1–0.25 mg, approximately 0.25–0.5 mg, approximately 0.5–0.75 mg, approximately 0.75–1 mg, approximately 1–5 mg, approximately 5–10 mg, approximately 10–15 mg, approximately 15–20 mg, approximately 20–25 mg, approximately 25–30 mg, approximately 30–40 mg, approximately 40–50 mg, approximately 50–60 mg, approximately 60–70 mg, approximately 70–80 mg, approximately 80–90 mg, approximately 90–100 mg, approximately 100–120 mg, approximately 120–140 mg, approximately 140–150 mg, approximately 150–160 mg, approximately 160–180 mg. mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg mg of norfluoxetine, or any dose within the range defined by any of these values.

[0348] For the combination of dapoxetine and dextromethorphan (including deuterated dextromethorphan, such as d6-dextromethorphan, and non-deuterated dextromethorphan), the following daily doses can be administered: approximately 0.1–0.25 mg, approximately 0.25–0.5 mg, approximately 0.5–0.75 mg, approximately 0.75–1 mg, approximately 1–5 mg, approximately 5–10 mg, approximately 10–15 mg, approximately 15–20 mg, approximately 20–25 mg, approximately 25–30 mg, approximately 30–40 mg, approximately 40–50 mg, approximately 50–60 mg, approximately 60–70 mg, approximately 70–80 mg, approximately 80–90 mg, approximately 90–100 mg, approximately 100–120 mg, approximately 120–140 mg, approximately 140–150 mg, approximately 150–160 mg, approximately 160–180 mg. mg, approximately 180-200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-320 mg, approximately 320-350 mg, approximately 350-400 mg, approximately 400-450 mg, approximately 450-500 mg, approximately 500-550 mg, approximately 550-600 mg, approximately 600-650 mg, approximately 650-700 mg, approximately 700-800 mg, approximately 800-1000 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 600 mg mg of dapoxetine, or any dose within the range defined by any of these values.

[0349] Bupropion has the structure shown below (shown is bupropion hydrochloride).

[0350]

[0351] The combination of bupropion and dextromethorphan can provide greater efficacy, such as better pain relief, than either component alone. In rapid metabolizers, dextromethorphan is rapidly and fully metabolized, even at high doses, resulting in low systemic exposure. In addition to its antidepressant and analgesic properties, bupropion is an inhibitor of dextromethorphan metabolism. Bupropion is an inhibitor of dopamine and norepinephrine reuptake. It is also a nicotinic acetylcholine receptor antagonist and can modulate cytokines associated with inflammatory diseases. Bupropion can affect the levels of tumor necrosis factor-α and interferon-γ. The metabolites of bupropion are also inhibitors of dextromethorphan metabolism; these include hydroxybupropion, threohydroxybupropion (also known as threohydrobupropion or threodihydrobupropion), and erythrohydroxybupropion (also known as erythrohydrobupropion or erythodihydrobupropion). Therefore, bupropion, including bupropion forms that are rapidly converted in vivo (e.g., salts, hydrates, solvates, polymorphs, etc.), are prodrugs for hydroxybupropion, threonylbupropion, and erythrohydroxybupropion. Prodrugs for bupropion may include N-methylbupropion and N-benzylbupropion.

[0352] As mentioned above, this inhibitory effect can increase dextromethorphan plasma levels, producing additive or synergistic effects, such as relief of neurological symptoms including pain, depression, and smoking cessation. Therefore, although inhibiting dextromethorphan metabolism is only one of the many potential benefits of this combination, co-administration of dextromethorphan and bupropion may enhance the efficacy of bupropion in many individuals. For many individuals, co-administration of dextromethorphan and bupropion can enhance the analgesic properties of bupropion. For many individuals, co-administration of dextromethorphan and bupropion can also enhance the antidepressant properties of bupropion, including a faster onset of action.

[0353] Another potential benefit of co-administering dextromethorphan with bupropion is that it can be used to reduce the likelihood of adverse events associated with dextromethorphan treatment, such as drowsiness. This could be useful, for example, in human patients at risk of adverse events due to dextromethorphan treatment.

[0354] Another potential benefit of co-administering dextromethorphan with bupropion is that it can be used to reduce the likelihood of adverse events, such as episodic symptoms, associated with treatment with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds. For example, this could be used in human patients at risk of experiencing adverse events resulting from treatment with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds.

[0355] Co-administration of dextromethorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds may reduce central nervous system adverse events, gastrointestinal events, or other types of adverse events associated with any of these compounds. Central nervous system (CNS) adverse events include, but are not limited to, nervousness, dizziness, insomnia, light-headedness, tremors, hallucinations, convulsions, CNS depression, fear, anxiety, headache, increased irritability or excitability, tinnitus, drowsiness, stupor, sedation, somnolence, confusion, disorientation, fatigue, incoordination, euphoria, nervousness, insomnia, sleep disorders, seizures, excitement, catatonic-like state, hysteria, hallucinations, fantasies, delusions, headache and / or migraine, and extrapyramidal symptoms such as oculogyric crisis, torticollis, hyperexcitability, increased muscle tension, ataxia and / or tongue protrusion.

[0356] Gastrointestinal adverse events include, but are not limited to, nausea, vomiting, abdominal pain, dysphagia, indigestion, diarrhea, bloating, flatulence, gastric ulcer with bleeding, loose stools, constipation, abdominal pain, heartburn, belching, loss of appetite, feeling of fullness, indigestion, flatulence, hyperacidity, dry mouth, gastrointestinal disturbances, and stomach pain.

[0357] 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 require that the two compounds be administered in the same dosage form. For example, the two compounds may be administered in a single dosage form, or they may be administered in two separate dosage forms. Furthermore, the two compounds may be administered simultaneously, but this is not required. These compounds may be given at different times, provided that they are both present in the body for at least a portion of the time during which treatment is administered via co-administration.

[0358] Side effects of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, and / or dextromethorphan can be reduced by administering bupropion, hydroxybupropion, erythrohydroxybupropion, or threohydroxybupropion together with dextromethorphan. Examples of reduced side effects include abnormal sensations of spinning and movement, agitation, weakness in the arms, bloating, blurred vision, burning sensation in the eyes, tinnitus, changes in vital signs (including but not limited to heart rate, respiratory rate, body temperature, and blood pressure), coldness, constipation, difficulty concentrating, difficulty sleeping, difficulty falling asleep, difficulty urinating, difficulty defecating, ear discomfort, eye discomfort, stomach upset, dizziness, dry lips, dry mouth, dry throat, dysmenorrhea, fatigue, feeling feverish, feeling dizzy, feeling more agitated than usual, feeling more tired than usual, feeling tired, tremors, weakness in the hands, headache, heartburn, etc. Hot flashes, elevated blood pressure, increased skin sensitivity, increased skin sensitivity on the head and face, involuntary muscle contractions, involuntary muscle contractions throughout the body, knee pain, leg weakness, dizziness, loose stools, loss of appetite, back pain, menstrual irregularities, metallic taste, increased salivation, dry mucous membranes, nasal congestion, nausea, runny nose, mild pressure sensation in the eyes, tremors when stretching or yawning, skin sensitivity, skin sensitivity on the arms, face and / or head, difficulty sleeping, loose stools, stomach pain, stomach upset, sweaty hands and / or feet, throat irritation, sore throat, tinnitus, tremors and / or weakness. Any of these side effects, or any of them, may be referred to or grouped according to the corresponding, equivalent, or other relevant terms in the Medical Dictionary for Regulatory Activities (MedRA).

[0359] In some embodiments, co-administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds with dextromethorphan results in both the metabolite or prodrug of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any of these compounds, and dextromethorphan contributing to the pain-relieving properties of the combination. For example, the combination may have improved pain-relieving performance, including potentially faster onset of action, compared to bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds alone, or compared to dextromethorphan alone.

[0360] In some embodiments, the combination has improved pain-relieving properties compared to bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolites or prodrugs of these compounds alone, with the improvement being at least about 0.5%, at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least 100%, up to about 500%, or up to about 1000%, about 0.5% to about 1000%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, or about 40% to about 50%. About 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100% to about 110%, about 110% to about 120%, about 120% to about 130%, about 130% to about 140%, about 140% to about 150%, about 150% to about 160%, about 160% to about 170%, about 170% to about 180%, about 180% to about 190%, about 190% to about 200%, or any amount of pain relief defined by any of these values ​​or within the range therebetween.

[0361] In some embodiments, the combination has improved pain relief performance compared to dextromethorphan alone, with the improvement being at least about 0.5%, at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least 100%, up to about 500%, or up to about 1000%, about 0.5% to about 1000%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, and about 70% to 80%, about 80% to 90%, about 90% to 100%, about 100% to 110%, about 110% to 120%, about 120% to 130%, about 130% to 140%, about 140% to 150%, about 150% to 160%, about 160% to 170%, about 170% to 180%, about 180% to 190%, about 190% to 200%, or any amount of pain relief within or defined by any of these values.

[0362] Unless otherwise stated, any reference to the compounds described herein, such as dextromethorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any other means, includes pharmaceutically acceptable salts; alternative solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; deuterated compounds, such as deuterated dextromethorphan; or any chemical substance that can be rapidly converted into the compounds described herein under the conditions used as described herein.

[0363] In some embodiments, an excess of a stereoisomer of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds may be administered. In other embodiments, an excess of an 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) or an excess of an 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) of a metabolite or prodrug of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any of these compounds may be administered.

[0364] Examples of deuterium-rich bupropion and / or enantiomeric deuterium-rich bupropion include, but are not limited to, those shown below.

[0365]

[0366]

[0367] In some embodiments, dextromethorphan is formulated as an immediate-release formulation with a metabolite or prodrug of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any of these compounds; and in other embodiments, a metabolite or prodrug of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any of these compounds is formulated as a sustained-release formulation.

[0368] Examples of deuterium-modified dextromethorphan include, but are not limited to, those shown below.

[0369]

[0370]

[0371] d6-dextromethorphan

[0372] Dosage forms or compositions can be blends or mixtures of dextromethorphan and compounds that inhibit the metabolism of dextromethorphan, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolites or prodrugs of these compounds, either individually or within a carrier. For example, dextromethorphan and bupropion can be dispersed within each other or together within a carrier. The dispersion may comprise a mixture of solid materials in which the individual particles are essentially one compound, but the particles are dispersed within each other; this may occur, for example, if two powders of two different drugs are blended with a solid carrier material and the blending is carried out in solid form. In some embodiments, dextromethorphan and bupropion can be dispersed substantially uniformly within the composition or dosage form. Alternatively, dextromethorphan and bupropion can be in separate domains or separate phases within the composition or dosage form. For example, one drug may be in a coating, while another drug may be in a core within the coating. For example, one drug may be configured for sustained release, while another drug may be configured for immediate release.

[0373] Some implementations involve tablet administration, the tablet containing bupropion in a sustained-release form and dextromethorphan in an immediate-release form. While there are many ways to achieve sustained release of bupropion, in some implementations, bupropion is combined with hydroxypropyl methylcellulose. For example, bupropion hydrochloride particles can be blended with microcrystalline cellulose and hydroxypropyl methylcellulose (e.g., METHOCEL®) to form a blended powder. This can then be combined with the immediately-released dextromethorphan in a single tablet.

[0374] Dextromethorphan and / or antidepressants (e.g., bupropion, hydroxybupropion, threo-hydroxybupropion, and erythro-hydroxybupropion), or non-bupropion antidepressants (for convenience, they are collectively referred to herein as "therapeutic compounds") may be combined with a drug carrier selected based on the chosen route of administration and, for example, standard pharmaceutical procedures as described in Remington's Pharmaceutical Sciences, 2005. The relative proportions of the active ingredient and the carrier may be determined, for example, by the solubility and chemical properties of the compound, the chosen route of administration, and standard pharmaceutical procedures.

[0375] Therapeutic compounds can be administered by any means that allows one or more active agents to come into contact with one or more desired sites of action in the patient's body. The compounds can be administered as a single therapeutic agent or in combination with other therapeutic agents by any conventional means that can be used in conjunction with a drug. For example, they can be administered as the sole active ingredient in a pharmaceutical composition, or they can be used in combination with other therapeutically active ingredients.

[0376] Therapeutic compounds can be administered to human patients in a variety of forms suitable for a chosen route of administration (e.g., oral or parenteral). In this regard, parenteral administration includes administration via intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial (including transdermal), ocular, sublingual, and buccal routes; and local administration, including ocular, dermal, eye, rectal, and via inhalation, aerosol, nasal inhalation, and the rectal system.

[0377] The ratio of dextromethorphan to bupropion can vary. In some embodiments, the weight ratio of dextromethorphan to bupropion can be from about 0.1 to about 10, from about 0.1 to about 2, from about 0.2 to about 1, from about 0.1 to about 0.5, from about 0.1 to about 0.3, from about 0.2 to about 0.4, from about 0.3 to about 0.5, from about 0.5 to about 0.7, from about 0.8 to about 1, from about 0.2, from about 0.3, from about 0.4, from about 0.45, from about 0.6, from about 0.9, or any ratio within or between any of these values. A ratio of 0.1 indicates that the weight of dextromethorphan is 1 / 10 of the weight of bupropion. A ratio of 10 indicates that the weight of dextromethorphan is 10 times that of bupropion.

[0378] The amount of dextromethorphan in a therapeutic composition can vary. For example, some liquid compositions may contain about 0.0001% (w / v) to about 50% (w / v), about 0.01% (w / v) to about 20% (w / v), about 0.01% to about 10% (w / v), about 0.001% (w / v) to about 1% (w / v), about 0.1% (w / v) to about 0.5% (w / v), about 1% (w / v) to about 3% (w / v), 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) dextromethorphan.

[0379] Some liquid dosage forms may contain about 10 mg to about 500 mg, about 30 mg to about 350 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 55 mg, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 80 mg to about 100 mg, about 110 mg to about 130 mg, about 170 mg to about 190 mg, about 45 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of dextromethorphan, or any amount of dextromethorphan defined by any of these values ​​or within the range thereof.

[0380] Some solid compositions may contain at least about 5% (w / w), at least about 10% (w / w), at least about 20% (w / w), at least about 50% (w / w), at least about 70% (w / w), at least about 80%, about 10% (w / w) to about 30% (w / w), about 10% (w / w) to about 20% (w / w), about 20% (w / w) to about 30% (w / w), about 30% (w / w) to about 50% (w / w), 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.

[0381] Some solid dosage forms may contain about 10 mg to about 500 mg, about 30 mg to about 350 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 80 mg to about 100 mg, about 110 mg to about 130 mg, about 170 mg to about 190 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of dextromethorphan, or any amount of dextromethorphan defined by any of these values ​​or within the range thereof.

[0382] In some implementations, the amount of dextromethorphan may be in the range of about 0.1 mg / kg to about 20 mg / kg, about 0.75 mg / kg to about 7.5 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 3 mg / kg, about 0.3 mg / kg to about 0.9 mg / kg, about 0.3 mg / kg to about 1 mg / kg, about 0.6 mg / kg to about 0.8 mg / kg, about 0.7 mg / kg to about 0.8 mg / kg, about 0.75 mg / kg, about 0.4 mg / kg to about 1.5 mg / kg, about 1 mg / kg to about 2 mg / kg, about 10 mg / kg to about 20 mg / kg, about 12 mg / kg to about 17 mg / kg, about 15 mg / kg to about 20 mg / kg, about 1 mg / kg, about 1 mg / kg to about 10 mg / kg, or any value defined by or between these ranges, based on the patient's weight.

[0383] The amounts of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds in the therapeutic composition may vary. If increasing plasma levels of dextromethorphan is desired, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites or prodrugs of any of these compounds should be administered in an amount that increases plasma levels of dextromethorphan. For example, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds may be administered in an amount that results in a plasma concentration of dextromethorphan in the human body at day 8, day 9, or day 10 equal to the plasma concentration of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any of these compounds' metabolites or prodrugs, at least about 2, at least about 5, at least about 10, at least about 15, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, or at least about 80 times that of bupropion.

[0384] In some embodiments, a metabolite or prodrug of bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any of these compounds may be used to result in the area under the curve (AUC) at day 8, day 9, or day 10 from the time of administration of dextromethorphan. 0-12 Or the mean plasma concentration (C) of people 12 hours after administration of dextromethorphan. avgThe drug is administered to a human in an amount that is at least about 2, at least about 5, at least about 10, at least about 15, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, or at least about 80 times the plasma concentration of the same amount of dextromethorphan without bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolite or prodrug of these compounds.

[0385] In some embodiments, a metabolite or prodrug of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any of these compounds can be used to achieve the maximum plasma concentration (C) of dextromethorphan in the human body at day 8, day 9, or day 10. max Or C 最大 The drug is administered to a human in an amount that is at least about 2, at least about 5, at least about 10, at least about 15, at least about 20, at least about 30, or at least about 40 times the plasma concentration of the same amount of dextromethorphan without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds.

[0386] With co-administration of bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or any metabolite or prodrug of these compounds, compared to administration of the same amount of dextromethorphan without any metabolite or prodrug of bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or any metabolite or prodrug of these compounds, an increase in dextromethorphan plasma concentration may occur on the first day of administration of bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or any metabolite or prodrug of these compounds. For example, on the first day of administration of bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or any metabolite or prodrug of these compounds, the plasma level of dextromethorphan may be at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 4 times, at least about 5 times, at least about 6 times, at least about 7 times, at least about 8 times, at least about 9 times, or at least about 10 times.

[0387] In some embodiments, on the first day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan AUC can be at least twice the AUC obtained if the same amount of dextromethorphan were administered without bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds).

[0388] In some embodiments, on the first day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds), the AUC of dextromethorphan is... 0-12 It can be at least about 15 ng•hr / mL, at least about 17 ng•hr / mL, at least about 19 ng•hr / mL, at least about 20 ng•hr / mL, at least about 22 ng•hr / mL, at least about 23 ng•hr / mL, at least about 24 ng•hr / mL, at least about 25 ng•hr / mL, at least about 26 ng•hr / mL, at least about 27 ng•hr / mL, at least about 28 ng•hr / mL, at least about 29 ng•hr / mL, at least about 30 ng•hr / mL, at least about 31 ng•hr / mL, at least about 32 ng•hr / mL, at least about 33 ng•hr / mL, at least about 34 ng•hr / mL, at least about 35 ng•hr / mL, at least about 36 ng•hr / mL, at least about 37 ng•hr / mL, at least about 38 ng•hr / mL, at least about 39 ng•hr / mL. 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, or at least about 56.7 ng•hr / mL, and may be up to 10,000 ng•hr / mL.

[0389] In some embodiments, on the eighth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan AUC is... 0-12It can be at least about 40 ng•hr / mL, at least about 50 ng•hr / mL, at least about 60 ng•hr / mL, at least about 70 ng•hr / mL, at least about 80 ng•hr / mL, at least about 90 ng•hr / mL, at least about 100 ng•hr / mL, at least about 150 ng•hr / mL, at least about 200 ng•hr / mL, at least about 250 ng•hr / mL, at least about 300 ng•hr / mL, at least about 350 ng•hr / mL, at least about 400 ng•hr / mL, at least about 450 ng•hr / mL, at least about 500 ng•hr / mL, at least about 550 ng•hr / mL, about 500 ng•hr / mL to about 600 ng•hr / mL, about 500 ng•hr / mL to about 550 ng•hr / mL, about 500 ng•hr / mL to about 525 ng•hr / mL. ng•hr / mL, about 525 ng•hr / mL to about 600 ng•hr / mL, at least about 600 ng•hr / mL, at least about 650 ng•hr / mL, at least about 700 ng•hr / mL, at least about 750 ng•hr / mL, at least about 800 ng•hr / mL, about 800 ng•hr / mL to about 900 ng•hr / mL, about 850 ng•hr / mL to about 900 ng•hr / mL, about 850 ng•hr / mL to about 875 ng•hr / mL, about 875 ng•hr / mL to about 900 ng•hr / mL, about 900 ng•hr / mL to about 1000 ng•hr / mL, about 1000 ng•hr / mL to about 1100 ng•hr / mL, about 1100 ng•hr / mL to about 1200 ng•hr / mL, about 1200 ng•hr / mL to about 1300 ng•hr / mL, about 1300 ng•hr / mL to about 1400 ng•hr / mL, about 1400 ng•hr / mL to about 1500 ng•hr / mL, about 1500 ng•hr / mL to about 1600 ng•hr / mL, about 1600 ng•hr / mL to about 1700 ng•hr / mL, about 1700 ng•hr / mL to about 1800 ng•hr / mL, about 1800 ng•hr / mL to about 2000 ng•hr / mL, at least about 850 ng•hr / mL, at least about 900 ng•hr / mL, at least about 950 ng•hr / mL, at least about 1000 ng•hr / mL, at least about 1050 ng•hr / mL, at least about 1100 ng•hr / mL, at least about 1150 ng•hr / mL ng•hr / mL, at least about 1200 ng•hr / mL, at least about 1250The concentrations are approximately 1300 ng·hr / mL, 1350 ng·hr / mL, 1400 ng·hr / mL, 1450 ng·hr / mL, 1500 ng·hr / mL, 1550 ng·hr / mL, 1600 ng·hr / mL, 1625 ng·hr / mL, 1650 ng·hr / mL, 1675 ng·hr / mL, or 1686.3 ng·hr / mL, and in some embodiments may be up to approximately 50,000 ng·hr / mL.

[0390] In some embodiments, on the eighth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan AUC is... 0-24 It can be at least about 50 ng•hr / mL, at least about 75 ng•hr / mL, at least about 100 ng•hr / mL, at least about 200 ng•hr / mL, at least about 300 ng•hr / mL, at least about 400 ng•hr / mL, at least about 500 ng•hr / mL, at least about 600 ng•hr / mL, at least about 700 ng•hr / mL, at least about 800 ng•hr / mL, at least about 900 ng•hr / mL, at least about 1000 ng•hr / mL, at least about 1100 ng•hr / mL, at least about 1200 ng•hr / mL, at least about 1300 ng•hr / mL, at least about 1400 ng•hr / mL, at least about 1500 ng•hr / mL, at least about 1600 ng•hr / mL, at least about 1700 ng•hr / mL, at least about 1800 ng•hr / mL. The concentrations are approximately 1900 ng·hr / mL, at least about 2000 ng·hr / mL, at least about 2100 ng·hr / mL, at least about 2200 ng·hr / mL, at least about 2300 ng·hr / mL, at least about 2400 ng·hr / mL, at least about 2500 ng·hr / mL, at least about 2600 ng·hr / mL, at least about 2700 ng·hr / mL, at least about 2800 ng·hr / mL, at least about 1850 ng·hr / mL, at least about 2900 ng·hr / mL, at least about 2950 ng·hr / mL, or at least about 2975.3 ng·hr / mL, and in some embodiments may be up to about 100,000 ng·hr / mL.

[0391] In some embodiments, on the eighth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan AUC is... 0-infIt can be at least about 75 ng•hr / mL, at least about 100 ng•hr / mL, at least about 200 ng•hr / mL, at least about 300 ng•hr / mL, at least about 400 ng•hr / mL, at least about 500 ng•hr / mL, at least about 600 ng•hr / mL, at least about 700 ng•hr / mL, at least about 800 ng•hr / mL, at least about 900 ng•hr / mL, at least about 1000 ng•hr / mL, at least about 1100 ng•hr / mL, at least about 1200 ng•hr / mL, at least about 1300 ng•hr / mL, at least about 1400 ng•hr / mL, at least about 1500 ng•hr / mL, at least about 1600 ng•hr / mL, at least about 1700 ng•hr / mL, at least about 1800 ng•hr / mL, at least about 1900 ng•hr / mL. ng•hr / mL, at least about 2000 ng•hr / mL, at least about 2100 ng•hr / mL, at least about 2200 ng•hr / mL, at least about 2300 ng•hr / mL, at least about 2400 ng•hr / mL, at least about 2500 ng•hr / mL, at least about 2600 ng•hr / mL, at least about 2700 ng•hr / mL, at least about 2800 ng•hr / mL, at least about 2900 ng•hr / mL, at least about 3000 ng•hr / mL, at least about 3100 ng•hr / mL, at least about 3200 ng•hr / mL, at least about 3300 ng•hr / mL, at least about 3400 ng•hr / mL, at least about 3500 ng•hr / mL, at least about 3600 ng•hr / mL, at least about 3700 ng•hr / mL, at least about 3800 ng•hr / mL ng•hr / mL, at least about 3900 ng•hr / mL, at least about 4000 ng•hr / mL, at least about 4100 ng•hr / mL, at least about 4200 ng•hr / mL, at least about 4300 ng•hr / mL, at least about 4400 ng•hr / mL, at least about 4500 ng•hr / mL, at least about 4600 ng•hr / mL, at least about 4700 ng•hr / mL, at least about 4800 ng•hr / mL, at least about 4900 ng•hr / mL, at least about 5000 ng•hr / mL, at least about 5100 ng•hr / mL, at least about 5200 ng•hr / mL, at least about 5300 ng•hr / mL, at least about 5400 ng•hr / mL, at least about 5500 ng•hr / mL, at least about 5600 ng•hr / mL, at least about 5700 ng•hr / mL ng•hr / mL, at least about 5800 ng•hr / mL, at least about 5900The concentrations are approximately 6000 ng·hr / mL, at least about 6100 ng·hr / mL, at least about 6200 ng·hr / mL, at least about 6300 ng·hr / mL, at least about 6400 ng·hr / mL, at least about 6500 ng·hr / mL, at least about 6600 ng·hr / mL, at least about 6700 ng·hr / mL, at least about 6800 ng·hr / mL, at least about 6900 ng·hr / mL, at least about 7000 ng·hr / mL, at least about 7100 ng·hr / mL, at least about 7150 ng·hr / mL, at least about 7200 ng·hr / mL, or at least about 7237.3 ng·hr / mL, and in some embodiments may be up to about 100000 ng·hr / mL.

[0392] In some embodiments, on the ninth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan AUC is... 0-12It can be at least about 40 ng•hr / mL, at least about 50 ng•hr / mL, at least about 60 ng•hr / mL, at least about 70 ng•hr / mL, at least about 80 ng•hr / mL, at least about 90 ng•hr / mL, at least about 100 ng•hr / mL, at least about 150 ng•hr / mL, at least about 200 ng•hr / mL, at least about 250 ng•hr / mL, at least about 300 ng•hr / mL, at least about 350 ng•hr / mL, at least about 400 ng•hr / mL, at least about 450 ng•hr / mL, at least about 500 ng•hr / mL, at least about 550 ng•hr / mL, about 500 ng•hr / mL to about 600 ng•hr / mL, about 500 ng•hr / mL to about 550 ng•hr / mL, about 500 ng•hr / mL to about 525 ng•hr / mL. ng•hr / mL, about 525 ng•hr / mL to about 600 ng•hr / mL, at least about 600 ng•hr / mL, at least about 650 ng•hr / mL, at least about 700 ng•hr / mL, at least about 750 ng•hr / mL, at least about 800 ng•hr / mL, about 800 ng•hr / mL to about 900 ng•hr / mL, about 850 ng•hr / mL to about 900 ng•hr / mL, about 850 ng•hr / mL to about 875 ng•hr / mL, about 875 ng•hr / mL to about 900 ng•hr / mL, about 900 ng•hr / mL to about 1000 ng•hr / mL, about 1000 ng•hr / mL to about 1100 ng•hr / mL, about 1100 ng•hr / mL to about 1200 ng•hr / mL, about 1200 ng•hr / mL to about 1300 ng•hr / mL, about 1300 ng•hr / mL to about 1400 ng•hr / mL, about 1400 ng•hr / mL to about 1500 ng•hr / mL, about 1500 ng•hr / mL to about 1600 ng•hr / mL, about 1600 ng•hr / mL to about 1700 ng•hr / mL, about 1700 ng•hr / mL to about 1800 ng•hr / mL, about 1800 ng•hr / mL to about 2000 ng•hr / mL, at least about 850 ng•hr / mL, at least about 900 ng•hr / mL, at least about 950 ng•hr / mL, at least about 1000 ng•hr / mL, at least about 1050 ng•hr / mL, at least about 1100 ng•hr / mL, at least about 1150 ng•hr / mL ng•hr / mL, at least about 1200 ng•hr / mL, at least about 1250The concentrations are approximately 1300 ng·hr / mL, 1350 ng·hr / mL, 1400 ng·hr / mL, 1450 ng·hr / mL, 1500 ng·hr / mL, 1550 ng·hr / mL, 1600 ng·hr / mL, 1625 ng·hr / mL, 1650 ng·hr / mL, 1675 ng·hr / mL, or 1686.3 ng·hr / mL, and in some embodiments may be up to approximately 50,000 ng·hr / mL.

[0393] In some embodiments, on the ninth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan AUC is... 0-24 It can be at least about 50 ng•hr / mL, at least about 75 ng•hr / mL, at least about 100 ng•hr / mL, at least about 200 ng•hr / mL, at least about 300 ng•hr / mL, at least about 400 ng•hr / mL, at least about 500 ng•hr / mL, at least about 600 ng•hr / mL, at least about 700 ng•hr / mL, at least about 800 ng•hr / mL, at least about 900 ng•hr / mL, at least about 1000 ng•hr / mL, at least about 1100 ng•hr / mL, at least about 1200 ng•hr / mL, at least about 1300 ng•hr / mL, at least about 1400 ng•hr / mL, at least about 1500 ng•hr / mL, at least about 1600 ng•hr / mL, at least about 1700 ng•hr / mL, at least about 1800 ng•hr / mL. The concentrations are approximately 1900 ng·hr / mL, at least about 2000 ng·hr / mL, at least about 2100 ng·hr / mL, at least about 2200 ng·hr / mL, at least about 2300 ng·hr / mL, at least about 2400 ng·hr / mL, at least about 2500 ng·hr / mL, at least about 2600 ng·hr / mL, at least about 2700 ng·hr / mL, at least about 2800 ng·hr / mL, at least about 1850 ng·hr / mL, at least about 2900 ng·hr / mL, at least about 2950 ng·hr / mL, or at least about 2975.3 ng·hr / mL, and in some embodiments may be up to about 100,000 ng·hr / mL.

[0394] In some embodiments, on the ninth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan AUC is... 0-infIt can be at least about 75 ng•hr / mL, at least about 100 ng•hr / mL, at least about 200 ng•hr / mL, at least about 300 ng•hr / mL, at least about 400 ng•hr / mL, at least about 500 ng•hr / mL, at least about 600 ng•hr / mL, at least about 700 ng•hr / mL, at least about 800 ng•hr / mL, at least about 900 ng•hr / mL, at least about 1000 ng•hr / mL, at least about 1100 ng•hr / mL, at least about 1200 ng•hr / mL, at least about 1300 ng•hr / mL, at least about 1400 ng•hr / mL, at least about 1500 ng•hr / mL, at least about 1600 ng•hr / mL, at least about 1700 ng•hr / mL, at least about 1800 ng•hr / mL, at least about 1900 ng•hr / mL. ng•hr / mL, at least about 2000 ng•hr / mL, at least about 2100 ng•hr / mL, at least about 2200 ng•hr / mL, at least about 2300 ng•hr / mL, at least about 2400 ng•hr / mL, at least about 2500 ng•hr / mL, at least about 2600 ng•hr / mL, at least about 2700 ng•hr / mL, at least about 2800 ng•hr / mL, at least about 2900 ng•hr / mL, at least about 3000 ng•hr / mL, at least about 3100 ng•hr / mL, at least about 3200 ng•hr / mL, at least about 3300 ng•hr / mL, at least about 3400 ng•hr / mL, at least about 3500 ng•hr / mL, at least about 3600 ng•hr / mL, at least about 3700 ng•hr / mL, at least about 3800 ng•hr / mL ng•hr / mL, at least about 3900 ng•hr / mL, at least about 4000 ng•hr / mL, at least about 4100 ng•hr / mL, at least about 4200 ng•hr / mL, at least about 4300 ng•hr / mL, at least about 4400 ng•hr / mL, at least about 4500 ng•hr / mL, at least about 4600 ng•hr / mL, at least about 4700 ng•hr / mL, at least about 4800 ng•hr / mL, at least about 4900 ng•hr / mL, at least about 5000 ng•hr / mL, at least about 5100 ng•hr / mL, at least about 5200 ng•hr / mL, at least about 5300 ng•hr / mL, at least about 5400 ng•hr / mL, at least about 5500 ng•hr / mL, at least about 5600 ng•hr / mL, at least about 5700 ng•hr / mL ng•hr / mL, at least about 5800 ng•hr / mL, at least about 5900The concentrations are approximately 6000 ng·hr / mL, at least about 6100 ng·hr / mL, at least about 6200 ng·hr / mL, at least about 6300 ng·hr / mL, at least about 6400 ng·hr / mL, at least about 6500 ng·hr / mL, at least about 6600 ng·hr / mL, at least about 6700 ng·hr / mL, at least about 6800 ng·hr / mL, at least about 6900 ng·hr / mL, at least about 7000 ng·hr / mL, at least about 7100 ng·hr / mL, at least about 7150 ng·hr / mL, at least about 7200 ng·hr / mL, or at least about 7237.3 ng·hr / mL, and in some embodiments may be up to about 100000 ng·hr / mL.

[0395] In some embodiments, on the tenth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan AUC is... 0-12It can be at least about 40 ng•hr / mL, at least about 50 ng•hr / mL, at least about 60 ng•hr / mL, at least about 70 ng•hr / mL, at least about 80 ng•hr / mL, at least about 90 ng•hr / mL, at least about 100 ng•hr / mL, at least about 150 ng•hr / mL, at least about 200 ng•hr / mL, at least about 250 ng•hr / mL, at least about 300 ng•hr / mL, at least about 350 ng•hr / mL, at least about 400 ng•hr / mL, at least about 450 ng•hr / mL, at least about 500 ng•hr / mL, at least about 550 ng•hr / mL, about 500 ng•hr / mL to about 600 ng•hr / mL, about 500 ng•hr / mL to about 550 ng•hr / mL, about 500 ng•hr / mL to about 525 ng•hr / mL. ng•hr / mL, about 525 ng•hr / mL to about 600 ng•hr / mL, at least about 600 ng•hr / mL, at least about 650 ng•hr / mL, at least about 700 ng•hr / mL, at least about 750 ng•hr / mL, at least about 800 ng•hr / mL, about 800 ng•hr / mL to about 900 ng•hr / mL, about 850 ng•hr / mL to about 900 ng•hr / mL, about 850 ng•hr / mL to about 875 ng•hr / mL, about 875 ng•hr / mL to about 900 ng•hr / mL, about 900 ng•hr / mL to about 1,000 ng•hr / mL, about 1,000 ng•hr / mL to about 1,100 ng•hr / mL, about 1,100 ng•hr / mL to about 1,200 ng•hr / mL ng•hr / mL, about 1,200 ng•hr / mL to about 1,300 ng•hr / mL, about 1,300 ng•hr / mL to about 1,400 ng•hr / mL, about 1,400 ng•hr / mL to about 1,500 ng•hr / mL, about 1,500 ng•hr / mL to about 1,600 ng•hr / mL, about 1,600 ng•hr / mL to about 1,700 ng•hr / mL, about 1,700 ng•hr / mL to about 1,800 ng•hr / mL, about 1,800 ng•hr / mL to about 2,000 ng•hr / mL, at least about 850 ng•hr / mL, at least about 900 ng•hr / mL, at least about 950 ng•hr / mL, at least about 1000 ng•hr / mL, at least about 1050 ng•hr / mL, at least about 1100 ng•hr / mL, at least about 1150 ng•hr / mL, at least about 1200 ng•hr / mL, at least about 1250 ng•hr / mL, at least about 1300 ng•hr / mL, at least about 1350 ng•hr / mL, at least about 1400 ng•hr / mL, at least about 1450 ng•hr / mL, at least about 1500 ng•hr / mL, at least about 1550 ng•hr / mL, at least about 1600 ng•hr / mL, at least about 1625 ng•hr / mL, at least about 1650 The concentration is ng•hr / mL, at least about 1675 ng•hr / mL, or at least about 1686.3 ng•hr / mL, and in some embodiments may be up to about 50,000 ng•hr / mL.

[0396] In some embodiments, on the tenth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan AUC is... 0-24It can be at least about 50 ng•hr / mL, at least about 75 ng•hr / mL, at least about 100 ng•hr / mL, at least about 200 ng•hr / mL, at least about 300 ng•hr / mL, at least about 400 ng•hr / mL, at least about 500 ng•hr / mL, at least about 600 ng•hr / mL, at least about 700 ng•hr / mL, at least about 800 ng•hr / mL, at least about 900 ng•hr / mL, at least about 1000 ng•hr / mL, at least about 1100 ng•hr / mL, at least about 1200 ng•hr / mL, at least about 1300 ng•hr / mL, at least about 1400 ng•hr / mL, at least about 1500 ng•hr / mL, at least about 1600 ng•hr / mL, at least about 1700 ng•hr / mL, at least about 1800 ng•hr / mL. The concentrations are approximately 1900 ng·hr / mL, at least about 2000 ng·hr / mL, at least about 2100 ng·hr / mL, at least about 2200 ng·hr / mL, at least about 2300 ng·hr / mL, at least about 2400 ng·hr / mL, at least about 2500 ng·hr / mL, at least about 2600 ng·hr / mL, at least about 2700 ng·hr / mL, at least about 2800 ng·hr / mL, at least about 1850 ng·hr / mL, at least about 2900 ng·hr / mL, at least about 2950 ng·hr / mL, or at least about 2975.3 ng·hr / mL, and in some embodiments may be up to about 100,000 ng·hr / mL.

[0397] In some embodiments, on the tenth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan AUC is... 0-infIt can be at least about 75 ng•hr / mL, at least about 100 ng•hr / mL, at least about 200 ng•hr / mL, at least about 300 ng•hr / mL, at least about 400 ng•hr / mL, at least about 500 ng•hr / mL, at least about 600 ng•hr / mL, at least about 700 ng•hr / mL, at least about 800 ng•hr / mL, at least about 900 ng•hr / mL, at least about 1000 ng•hr / mL, at least about 1100 ng•hr / mL, at least about 1200 ng•hr / mL, at least about 1300 ng•hr / mL, at least about 1400 ng•hr / mL, at least about 1500 ng•hr / mL, at least about 1600 ng•hr / mL, at least about 1700 ng•hr / mL, at least about 1800 ng•hr / mL, at least about 1900 ng•hr / mL. ng•hr / mL, at least about 2000 ng•hr / mL, at least about 2100 ng•hr / mL, at least about 2200 ng•hr / mL, at least about 2300 ng•hr / mL, at least about 2400 ng•hr / mL, at least about 2500 ng•hr / mL, at least about 2600 ng•hr / mL, at least about 2700 ng•hr / mL, at least about 2800 ng•hr / mL, at least about 2900 ng•hr / mL, at least about 3000 ng•hr / mL, at least about 3100 ng•hr / mL, at least about 3200 ng•hr / mL, at least about 3300 ng•hr / mL, at least about 3400 ng•hr / mL, at least about 3500 ng•hr / mL, at least about 3600 ng•hr / mL, at least about 3700 ng•hr / mL, at least about 3800 ng•hr / mL ng•hr / mL, at least about 3900 ng•hr / mL, at least about 4000 ng•hr / mL, at least about 4100 ng•hr / mL, at least about 4200 ng•hr / mL, at least about 4300 ng•hr / mL, at least about 4400 ng•hr / mL, at least about 4500 ng•hr / mL, at least about 4600 ng•hr / mL, at least about 4700 ng•hr / mL, at least about 4800 ng•hr / mL, at least about 4900 ng•hr / mL, at least about 5000 ng•hr / mL, at least about 5100 ng•hr / mL, at least about 5200 ng•hr / mL, at least about 5300 ng•hr / mL, at least about 5400 ng•hr / mL, at least about 5500 ng•hr / mL, at least about 5600 ng•hr / mL, at least about 5700 ng•hr / mL ng•hr / mL, at least about 5800 ng•hr / mL, at least about 5900The concentrations are approximately 6000 ng·hr / mL, at least about 6100 ng·hr / mL, at least about 6200 ng·hr / mL, at least about 6300 ng·hr / mL, at least about 6400 ng·hr / mL, at least about 6500 ng·hr / mL, at least about 6600 ng·hr / mL, at least about 6700 ng·hr / mL, at least about 6800 ng·hr / mL, at least about 6900 ng·hr / mL, at least about 7000 ng·hr / mL, at least about 7100 ng·hr / mL, at least about 7150 ng·hr / mL, at least about 7200 ng·hr / mL, or at least about 7237.3 ng·hr / mL, and in some embodiments may be up to about 100000 ng·hr / mL.

[0398] In some embodiments, on the first day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds), dextromethorphan C max C can be obtained by administering the same amount of dextromethorphan without the presence of bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or any metabolites or prodrugs of these compounds. max At least twice as much.

[0399] In some embodiments, on the first day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds), dextromethorphan C maxIt can be at least about 1.0 ng / mL, at least about 1.5 ng / mL, at least about 2.0 ng / mL, at least about 2.5 ng / mL, at least about 3.0 ng / mL, at least about 3.1 ng / mL, at least about 3.2 ng / mL, at least about 3.3 ng / mL, at least about 3.4 ng / mL, at least about 3.5 ng / mL, at least about 3.6 ng / mL, at least about 3.7 ng / mL, at least about 3.8 ng / mL, at least about 3.9 ng / mL, at least about 4.0 ng / mL, at least about 4.1 ng / mL, at least about 4.2 ng / mL, at least about 4.3 ng / mL, at least about 4.4 ng / mL, at least about 4.5 ng / mL, at least about 4.6 ng / mL, at least about 4.7 ng / mL, at least about 4.8 ng / mL, at least about 4.9 ng / mL. ng / mL, at least about 5.0 ng / mL, at least about 5.1 ng / mL, at least about 5.2 ng / mL, at least about 5.3 ng / mL, at least about 5.4 ng / mL, at least about 5.5 ng / mL, at least about 5.6 ng / mL, at least about 5.7 ng / mL, at least about 5.8 ng / mL, at least about 5.9 ng / mL, at least about 6.0 ng / mL, at least about 6.1 ng / mL, at least about 6.2 ng / mL, at least about 6.3 ng / mL, at least about 6.4 ng / mL, at least about 6.5 ng / mL, at least about 6.6 ng / mL, at least about 6.7 ng / mL, at least about 6.8 ng / mL, at least about 6.9 ng / mL, at least about 7.0 ng / mL, at least about 7.1 ng / mL, at least about 7.2 ng / mL, at least about 7.3 ng / mL The concentration 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 may be up to about 1000 ng•hr / mL.

[0400] In some embodiments, on the eighth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan AUC is... 0-12It can be approximately 50 ng / mL to approximately 60 ng / mL, approximately 50 ng / mL to approximately 55 ng / mL, approximately 55 ng / mL to approximately 60 ng / mL, approximately 80 ng / mL to approximately 90 ng / mL, approximately 80 ng / mL to approximately 85 ng / mL, approximately 85 ng / mL to approximately 90 ng / mL, approximately 90 ng / mL to approximately 95 ng / mL, approximately 95 ng / mL to approximately 100 ng / mL, approximately 100 ng / mL to approximately 105 ng / mL, approximately 105 ng / mL to approximately 110 ng / mL, approximately 110 ng / mL to approximately 115 ng / mL, approximately 115 ng / mL to approximately 120 ng / mL, approximately 120 ng / mL to approximately 130 ng / mL, approximately 130 ng / mL to approximately 135 ng / mL, approximately 135 ng / mL to approximately 140 ng / mL, approximately 140 ng / mL to about 145 ng / mL, about 145 ng / mL to about 150 ng / mL, about 150 ng / mL to about 155 ng / mL, about 155 ng / mL to about 160 ng / mL, about 160 ng / mL to about 170 ng / mL, about 170 ng / mL to about 200 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 The concentrations are approximately 100 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, at least about 115 ng / mL, at least about 120 ng / mL, at least about 125 ng / mL, at least about 130 ng / mL, at least about 135 ng / mL, at least about 140 ng / mL, at least about 145 ng / mL, at least about 150 ng / mL, at least about 155 ng / mL, or at least about 158.1 ng / mL, and in some embodiments may be up to about 10,000 ng / mL.

[0401] In some embodiments, on the ninth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan AUC is... 0-12It can be approximately 50 ng / mL to approximately 60 ng / mL, approximately 50 ng / mL to approximately 55 ng / mL, approximately 55 ng / mL to approximately 60 ng / mL, approximately 80 ng / mL to approximately 90 ng / mL, approximately 80 ng / mL to approximately 85 ng / mL, approximately 85 ng / mL to approximately 90 ng / mL, approximately 90 ng / mL to approximately 95 ng / mL, approximately 95 ng / mL to approximately 100 ng / mL, approximately 100 ng / mL to approximately 105 ng / mL, approximately 105 ng / mL to approximately 110 ng / mL, approximately 110 ng / mL to approximately 115 ng / mL, approximately 115 ng / mL to approximately 120 ng / mL, approximately 120 ng / mL to approximately 130 ng / mL, approximately 130 ng / mL to approximately 135 ng / mL, approximately 135 ng / mL to approximately 140 ng / mL, approximately 140 ng / mL to about 145 ng / mL, about 145 ng / mL to about 150 ng / mL, about 150 ng / mL to about 155 ng / mL, about 155 ng / mL to about 160 ng / mL, about 160 ng / mL to about 170 ng / mL, about 170 ng / mL to about 200 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 The concentrations are approximately 100 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, at least about 115 ng / mL, at least about 120 ng / mL, at least about 125 ng / mL, at least about 130 ng / mL, at least about 135 ng / mL, at least about 140 ng / mL, at least about 145 ng / mL, at least about 150 ng / mL, at least about 155 ng / mL, or at least about 158.1 ng / mL, and in some embodiments may be up to about 10,000 ng / mL.

[0402] In some embodiments, on the tenth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan AUC is... 0-12It can be approximately 50 ng / mL to approximately 60 ng / mL, approximately 50 ng / mL to approximately 55 ng / mL, approximately 55 ng / mL to approximately 60 ng / mL, approximately 80 ng / mL to approximately 90 ng / mL, approximately 80 ng / mL to approximately 85 ng / mL, approximately 85 ng / mL to approximately 90 ng / mL, approximately 90 ng / mL to approximately 95 ng / mL, approximately 95 ng / mL to approximately 100 ng / mL, approximately 100 ng / mL to approximately 105 ng / mL, approximately 105 ng / mL to approximately 110 ng / mL, approximately 110 ng / mL to approximately 115 ng / mL, approximately 115 ng / mL to approximately 120 ng / mL, approximately 120 ng / mL to approximately 130 ng / mL, approximately 130 ng / mL to approximately 135 ng / mL, approximately 135 ng / mL to approximately 140 ng / mL, approximately 140 ng / mL to about 145 ng / mL, about 145 ng / mL to about 150 ng / mL, about 150 ng / mL to about 155 ng / mL, about 155 ng / mL to about 160 ng / mL, about 160 ng / mL to about 170 ng / mL, about 170 ng / mL to about 200 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 The concentrations are approximately 100 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, at least about 115 ng / mL, at least about 120 ng / mL, at least about 125 ng / mL, at least about 130 ng / mL, at least about 135 ng / mL, at least about 140 ng / mL, at least about 145 ng / mL, at least about 150 ng / mL, at least about 155 ng / mL, or at least about 158.1 ng / mL, and in some embodiments may be up to about 10,000 ng / mL.

[0403] In some implementations, the C of dextromethorphan is such that during the period between two separate and consecutive administrations of dextromethorphan, the C... avgAdminister bupropion, hydroxybupropion, threobupropion, erythrobupropion, or any metabolite or prodrug of these compounds in the following amounts: 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. ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, at least about 115 ng / mL, at least about 120 ng / mL, at least about 125 ng / mL, at least about 130 ng / mL, at least about 135 ng / mL, at least about 140 ng / mL, or at least about 140.5 ng / mL, about 20 ng / mL to about 30 ng / mL, about 30 ng / mL to about 40 ng / mL, about 40 ng / mL to about 50 ng / mL, about 50 ng / mL to about 55 ng / mL, about 55 ng / mL to about 60 ng / mL, about 80 ng / mL to about 90 ng / mL, about 80 ng / mL to about 85 ng / mL, about 85 ng / mL to about 90 ng / mL ng / mL, about 90 ng / mL to about 95 ng / mL, about 95 ng / mL to about 100 ng / mL, about 100 ng / mL to about 105 ng / mL, about 105 ng / mL to about 110 ng / mL, about 110 ng / mL to about 115 ng / mL, about 115 ng / mL to about 120 ng / mL, about 120 ng / mL to about 130 ng / mL, about 130 ng / mL to about 135 ng / mL, about 135 ng / mL to about 140 ng / mL, about 140 ng / mL to about 145 ng / mL, about 145 ng / mL to about 150 ng / mL, about 150 ng / mL to about 155 ng / mL, about 155 ng / mL to about 160 ng / mL, about 160 ng / mL to about 170 ng / mL, about 170 The concentration can be from about 200 ng / mL to about 200 ng / mL, and in some embodiments, it can be up to about 10,000 ng / mL.For example, if dextromethorphan is administered at 8 a.m. and 8 p.m. on day 1, and not administered after 8 a.m. and before 8 p.m. on day 1, then the time interval between the two separate and consecutive administrations of dextromethorphan is from immediately after 8 a.m. to immediately before 8 p.m. on day 1.

[0404] In some embodiments, on day eight (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds) to enhance dextromethorphan plasma levels, dextromethorphan C avgIt can be at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, at least about 115 ng / mL, at least about 120 ng / mL, at least about 125 ng / mL, at least about 130 ng / mL, at least about 135 ng / mL, at least about 140 ng / mL, or at least about 140.5 ng / mL, about 20 ng / mL to about 30 ng / mL, about 30 ng / mL to about 40 ng / mL, about 40 ng / mL to about 50 ng / mL, about 50 ng / mL to about 55 ng / mL, about 55 ng / mL to about 60 ng / mL, about 80 ng / mL to about 90 ng / mL, about 80 ng / mL to about 85 ng / mL, about 85 ng / mL to about 90 ng / mL, about 90 ng / mL to about 95 ng / mL, about 95 ng / mL to about 100 ng / mL, about 100 The concentrations are approximately 105 ng / mL to 105 ng / mL, approximately 105 ng / mL to 110 ng / mL, approximately 110 ng / mL to 115 ng / mL, approximately 115 ng / mL to 120 ng / mL, approximately 120 ng / mL to 130 ng / mL, approximately 130 ng / mL to 135 ng / mL, approximately 135 ng / mL to 140 ng / mL, approximately 140 ng / mL to 145 ng / mL, approximately 145 ng / mL to 150 ng / mL, approximately 150 ng / mL to 155 ng / mL, approximately 155 ng / mL to 160 ng / mL, approximately 160 ng / mL to 170 ng / mL, approximately 170 ng / mL to 200 ng / mL, and in some embodiments, up to approximately 10,000 ng / mL. The C given above... avgThe value can be for the period between two separate and consecutive administrations of dextromethorphan, or if dextromethorphan is administered only once on day 8, then C avg It can be administered 12 hours after the first dose of dextromethorphan.

[0405] In some embodiments, on the ninth day (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds) to enhance dextromethorphan plasma levels, dextromethorphan C avgIt can be at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, at least about 115 ng / mL, at least about 120 ng / mL, at least about 125 ng / mL, at least about 130 ng / mL, at least about 135 ng / mL, at least about 140 ng / mL, or at least about 140.5 ng / mL, about 20 ng / mL to about 30 ng / mL, about 30 ng / mL to about 40 ng / mL, about 40 ng / mL to about 50 ng / mL, about 50 ng / mL to about 55 ng / mL, about 55 ng / mL to about 60 ng / mL, about 80 ng / mL to about 90 ng / mL, about 80 ng / mL to about 85 ng / mL, about 85 ng / mL to about 90 ng / mL, about 90 ng / mL to about 95 ng / mL, about 95 ng / mL to about 100 ng / mL, about 100 The concentrations are approximately 105 ng / mL to 105 ng / mL, approximately 105 ng / mL to 110 ng / mL, approximately 110 ng / mL to 115 ng / mL, approximately 115 ng / mL to 120 ng / mL, approximately 120 ng / mL to 130 ng / mL, approximately 130 ng / mL to 135 ng / mL, approximately 135 ng / mL to 140 ng / mL, approximately 140 ng / mL to 145 ng / mL, approximately 145 ng / mL to 150 ng / mL, approximately 150 ng / mL to 155 ng / mL, approximately 155 ng / mL to 160 ng / mL, approximately 160 ng / mL to 170 ng / mL, approximately 170 ng / mL to 200 ng / mL, and in some embodiments, up to approximately 10,000 ng / mL. The C given above... avgThe value can be for the period between two separate and consecutive administrations of dextromethorphan, or if dextromethorphan is administered only once on day 9, then C avg It can be administered 12 hours after the first dose of dextromethorphan.

[0406] In some embodiments, on the tenth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds), dextromethorphan C avgIt can be at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, at least about 115 ng / mL, at least about 120 ng / mL, at least about 125 ng / mL, at least about 130 ng / mL, at least about 135 ng / mL, at least about 140 ng / mL, or at least about 140.5 ng / mL, about 20 ng / mL to about 30 ng / mL, about 30 ng / mL to about 40 ng / mL, about 40 ng / mL to about 50 ng / mL, about 50 ng / mL to about 55 ng / mL, about 55 ng / mL to about 60 ng / mL, about 80 ng / mL to about 90 ng / mL, about 80 ng / mL to about 85 ng / mL, about 85 ng / mL to about 90 ng / mL, about 90 ng / mL to about 95 ng / mL, about 95 ng / mL to about 100 ng / mL, about 100 The concentrations are approximately 105 ng / mL to 105 ng / mL, approximately 105 ng / mL to 110 ng / mL, approximately 110 ng / mL to 115 ng / mL, approximately 115 ng / mL to 120 ng / mL, approximately 120 ng / mL to 130 ng / mL, approximately 130 ng / mL to 135 ng / mL, approximately 135 ng / mL to 140 ng / mL, approximately 140 ng / mL to 145 ng / mL, approximately 145 ng / mL to 150 ng / mL, approximately 150 ng / mL to 155 ng / mL, approximately 155 ng / mL to 160 ng / mL, approximately 160 ng / mL to 170 ng / mL, approximately 170 ng / mL to 200 ng / mL, and in some embodiments, up to approximately 10,000 ng / mL. The C given above... avgThe value can be for the period between two separate and consecutive administrations of dextromethorphan, or if dextromethorphan is administered only once on day 10, then C avg It can be administered 12 hours after the first dose of dextromethorphan.

[0407] The dextromethorphan volatility index value FI (%) can be determined by the following equation:

[0408] .

[0409] In some embodiments, on the eighth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or any metabolite or prodrug of these compounds), the dextromethorphan FI (%) may be at least 1.5 times or at least 2 times less than the enhancement of plasma levels obtained by administering dextromethorphan for eight days without, for example, by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or any metabolite or prodrug of these compounds.

[0410] In some embodiments, on the ninth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan FI (%) may be at least 1.5 times or at least 2 times less than the enhancement of plasma levels obtained by administering dextromethorphan for nine days without, for example, by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0411] In some embodiments, on the tenth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or any metabolite or prodrug of these compounds), the dextromethorphan FI (%) may be at least 1.5 times or at least 2 times less than the enhancement of plasma levels obtained by administering dextromethorphan for ten days without, for example, by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or any metabolite or prodrug of these compounds.

[0412] In some embodiments, on the eighth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan FI (%) can be less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any FI (%) value within the range defined by any of these values.

[0413] In some embodiments, on the ninth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan FI (%) can be less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any FI (%) value within the range defined by any of these values.

[0414] In some embodiments, on the ninth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan FI (%) can be less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any FI (%) value within the range defined by any of these values.

[0415] In some embodiments, on the eighth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan FI (%) can be at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, or at least 6 times less than the enhancement of plasma levels obtained by administering dextromethorphan for eight days without, for example, by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0416] In some embodiments, on the ninth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan FI (%) can be at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, or at least 6 times less than the enhancement of plasma levels obtained by administering dextromethorphan for nine days without, for example, by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0417] In some embodiments, on the tenth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or any metabolite or prodrug of these compounds), the dextromethorphan FI (%) may be at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, or at least 6 times less than the enhancement of plasma levels obtained by administering dextromethorphan for ten days without, for example, by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or any metabolite or prodrug of these compounds.

[0418] In some embodiments, on the eighth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan FI (%) can be 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 the range defined by any of these values.

[0419] In some embodiments, on the ninth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan FI (%) can be 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 the range defined by any of these values.

[0420] In some embodiments, on the ninth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds), the dextromethorphan FI (%) can be 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 the range defined by any of these values.

[0421] In some embodiments, on the first day after administration of bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds, the dextromethorphan glutamate level (e.g., plasma level 12 hours after administration, also referred to herein as "C") is measured. min "" can be at least twice the trough level obtained if the same amount of dextromethorphan is administered without bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or any metabolites or prodrugs of these compounds.

[0422] In some embodiments, on the first day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds), dextromethorphan C min It may be at least about 0.8 ng / mL, at least about 0.9 ng / mL, at least about 1.0 ng / mL, at least about 1.1 ng / mL, at least about 1.2 ng / mL, at least about 1.3 ng / mL, at least about 1.4 ng / mL, at least about 1.5 ng / mL, at least about 1.6 ng / mL, at least about 1.7 ng / mL, at least about 1.8 ng / mL, at least about 1.9 ng / mL, at least about 2.0 ng / mL, at least about 2.1 ng / mL, at least about 2.2 ng / mL, at least about 2.3 ng / mL, at least about 2.4 ng / mL, at least about 2.5 ng / mL, or at least about 2.5 ng / mL, and may be up to about 100 ng / mL.

[0423] In some embodiments, on the fifth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds), dextromethorphan C minIt may be at least about 1.5 ng / mL, at least about 2.0 ng / mL, at least about 3.0 ng / mL, at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, or at least about 80.9 ng / mL. The concentration can be ng / mL, and can be up to about 10,000 ng / mL.

[0424] In some embodiments, on the sixth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds), dextromethorphan C min It can be at least about 1.5 ng / mL, at least about 2.0 ng / mL, at least about 3.0 ng / mL, at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL. The concentration may be ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, or at least about 102.2 ng / mL, and may be up to about 10,000 ng / mL.

[0425] In some embodiments, on the seventh day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds), dextromethorphan C minIt can be at least about 1.5 ng / mL, at least about 2.0 ng / mL, at least about 3.0 ng / mL, at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL. The concentration may be ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, or at least about 110.6 ng / mL, and may be up to about 10,000 ng / mL.

[0426] In some embodiments, on day eight (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds) to enhance dextromethorphan plasma levels, dextromethorphan C minIt can be at least about 1.5 ng / mL, at least about 2.0 ng / mL, at least about 3.0 ng / mL, at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL. ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, at least about 115 ng / mL, at least about 119.3 ng / mL, about 20 ng / mL to about 30 ng / mL, about 30 ng / mL to about 40 ng / mL, about 40 ng / mL to about 50 ng / mL, about 50 ng / mL to about 55 ng / mL, about 55 ng / mL to about 60 ng / mL, about 80 ng / mL to about 90 ng / mL, about 80 ng / mL to about 85 ng / mL, about 85 ng / mL to about 90 ng / mL, about 90 ng / mL to about 95 ng / mL, about 95 ng / mL to about 100 ng / mL, about 100 ng / mL to about 105 ng / mL, about 105 ng / mL to about 110 ng / mL The concentrations are approximately 110 ng / mL to approximately 115 ng / mL, approximately 115 ng / mL to approximately 120 ng / mL, approximately 120 ng / mL to approximately 130 ng / mL, approximately 130 ng / mL to approximately 135 ng / mL, approximately 135 ng / mL to approximately 140 ng / mL, approximately 140 ng / mL to approximately 145 ng / mL, approximately 145 ng / mL to approximately 150 ng / mL, approximately 150 ng / mL to approximately 155 ng / mL, approximately 155 ng / mL to approximately 160 ng / mL, approximately 160 ng / mL to approximately 170 ng / mL, or approximately 170 ng / mL to approximately 200 ng / mL, and in some embodiments may be up to approximately 10,000 ng / mL.

[0427] In some embodiments, on the ninth day (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds) to enhance dextromethorphan plasma levels, dextromethorphan C minIt can be at least about 1.5 ng / mL, at least about 2.0 ng / mL, at least about 3.0 ng / mL, at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL. ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, at least about 115 ng / mL, at least about 119.3 ng / mL, about 20 ng / mL to about 30 ng / mL, about 30 ng / mL to about 40 ng / mL, about 40 ng / mL to about 50 ng / mL, about 50 ng / mL to about 55 ng / mL, about 55 ng / mL to about 60 ng / mL, about 80 ng / mL to about 90 ng / mL, about 80 ng / mL to about 85 ng / mL, about 85 ng / mL to about 90 ng / mL, about 90 ng / mL to about 95 ng / mL, about 95 ng / mL to about 100 ng / mL, about 100 ng / mL to about 105 ng / mL, about 105 ng / mL to about 110 ng / mL The concentrations are approximately 110 ng / mL to approximately 115 ng / mL, approximately 115 ng / mL to approximately 120 ng / mL, approximately 120 ng / mL to approximately 130 ng / mL, approximately 130 ng / mL to approximately 135 ng / mL, approximately 135 ng / mL to approximately 140 ng / mL, approximately 140 ng / mL to approximately 145 ng / mL, approximately 145 ng / mL to approximately 150 ng / mL, approximately 150 ng / mL to approximately 155 ng / mL, approximately 155 ng / mL to approximately 160 ng / mL, approximately 160 ng / mL to approximately 170 ng / mL, or approximately 170 ng / mL to approximately 200 ng / mL, and in some embodiments may be up to approximately 10,000 ng / mL.

[0428] In some embodiments, on the tenth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with bupropion, hydroxybupropion, threobupropion, erythrobupropion, or a metabolite or prodrug of any of these compounds), dextromethorphan C minIt can be at least about 1.5 ng / mL, at least about 2.0 ng / mL, at least about 3.0 ng / mL, at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL. ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, at least about 115 ng / mL, at least about 119.3 ng / mL, about 20 ng / mL to about 30 ng / mL, about 30 ng / mL to about 40 ng / mL, about 40 ng / mL to about 50 ng / mL, about 50 ng / mL to about 55 ng / mL, about 55 ng / mL to about 60 ng / mL, about 80 ng / mL to about 90 ng / mL, about 80 ng / mL to about 85 ng / mL, about 85 ng / mL to about 90 ng / mL, about 90 ng / mL to about 95 ng / mL, about 95 ng / mL to about 100 ng / mL, about 100 ng / mL to about 105 ng / mL, about 105 ng / mL to about 110 ng / mL The concentrations are approximately 110 ng / mL to approximately 115 ng / mL, approximately 115 ng / mL to approximately 120 ng / mL, approximately 120 ng / mL to approximately 130 ng / mL, approximately 130 ng / mL to approximately 135 ng / mL, approximately 135 ng / mL to approximately 140 ng / mL, approximately 140 ng / mL to approximately 145 ng / mL, approximately 145 ng / mL to approximately 150 ng / mL, approximately 150 ng / mL to approximately 155 ng / mL, approximately 155 ng / mL to approximately 160 ng / mL, approximately 160 ng / mL to approximately 170 ng / mL, or approximately 170 ng / mL to approximately 200 ng / mL, and in some embodiments may be up to approximately 10,000 ng / mL.

[0429] In some embodiments, bupropion, hydroxybupropion, threobupropion, erythrobupropion, 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, wherein a decrease in dextromethorphan plasma levels occurs on the first day when a metabolite or prodrug of bupropion, hydroxybupropion, threobupropion, erythrobupropion, or any of these compounds is co-administered with dextromethorphan on the same day as when the same amount of dextromethorphan is administered without the use of a metabolite or prodrug of bupropion, hydroxybupropion, threobupropion, erythrobupropion, or any of these compounds is co-administered with dextromethorphan. For example, the dextromethorphan plasma level on the first day may be at least 5% lower than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion.

[0430] In some embodiments, bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds is co-administered with dextromethorphan to a person requiring dextromethorphan treatment for at least 5 consecutive days, wherein on day 5, the plasma level of dextromethorphan is higher than that achieved by administering the same amount of dextromethorphan for 5 consecutive days without bupropion, hydroxybupropion, threo-hydroxybupropion, erythro-hydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the plasma level of dextromethorphan on day 5 (e.g., at 0, 1, 3, 6, or 12 hours after administration) can be at least 5, at least 10, at least 20, at least 40, at least 50, at least 60, at least 65, or as much as about 500 times the level obtained if dextromethorphan were administered in the same amount for 5 consecutive days without bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolites or prodrugs of these compounds.

[0431] In some embodiments, bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolite or prodrug of these compounds, and dextromethorphan are co-administered to a person requiring treatment with dextromethorphan for at least 6 consecutive days, wherein on day 6, the plasma level of dextromethorphan is higher than that obtained by administering the same amount of dextromethorphan for 6 consecutive days without bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolite or prodrug of these compounds. For example, the plasma level of dextromethorphan on day 6 (e.g., at 0, 1, 3, 6, or 12 hours after administration) can be at least 5, at least 10, at least 20, at least 30, at least 50, at least 60, at least 70, at least 75, or as much as about 500 times the level obtained if dextromethorphan were administered in the same amount for 6 consecutive days without bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolites or prodrugs of these compounds.

[0432] In some embodiments, bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolite or prodrug of these compounds, and dextromethorphan are co-administered to a person requiring treatment with dextromethorphan for at least 7 consecutive days, wherein on day 7, the plasma level of dextromethorphan is higher than that obtained by administering the same amount of dextromethorphan for 7 consecutive days without bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolite or prodrug of these compounds. For example, the plasma level of dextromethorphan on day 7 (e.g., at 0, 1, 3, 6, or 12 hours after administration) can be at least 5, at least 10, at least 20, at least 30, at least 50, at least 70, at least 80, at least 90, or as much as about 500 times the level obtained if dextromethorphan were administered in the same amount for 7 consecutive days without bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolites or prodrugs of these compounds.

[0433] In some embodiments, bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolite or prodrug of these compounds, is co-administered with dextromethorphan for at least 8 consecutive days, wherein on day 8, for example at 0, 1, 3, 6, or 12 hours after co-administration of bupropion and dextromethorphan, the plasma level of dextromethorphan is at least 5, at least 10, at least 20, at least 30, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, or as much as about 1000 times the plasma level obtained by administering the same amount of dextromethorphan for 8 consecutive days without bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolite or prodrug of these compounds.

[0434] In some embodiments, bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolite or prodrug of these compounds, and dextromethorphan are co-administered to a person requiring dextromethorphan treatment for at least 8 consecutive days, wherein on day 8, the dextromethorphan plasma level is lower than that obtained by administering the same amount of dextromethorphan for 8 consecutive days without bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolite or prodrug of these compounds. For example, the plasma level of dextromethorphan on day 8 (e.g., at 0, 1, 3, 6, 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 plasma level of dextromethorphan obtained by administering the same amount of dextromethorphan for 8 consecutive days without bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolites or prodrugs of these compounds.

[0435] In some embodiments, bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolite or prodrug of these compounds, is co-administered with dextromethorphan for at least nine consecutive days, wherein on the ninth day, for example at 0, 1, 3, 6, or 12 hours after co-administration of bupropion and dextromethorphan, the plasma level of dextromethorphan is at least 5, at least 10, at least 20, at least 30, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, or as much as about 1000 times the plasma level obtained by administering the same amount of dextromethorphan for nine consecutive days without bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolite or prodrug of these compounds.

[0436] In some embodiments, bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolite or prodrug of these compounds, and dextromethorphan are administered to a person requiring treatment with dextromethorphan for at least nine consecutive days, wherein on the ninth day, the dextromethorphan plasma level is lower than that obtained by administering the same amount of dextromethorphan for nine consecutive days without bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolite or prodrug of these compounds. For example, the plasma level of dextromethorphan on day nine (e.g., at 0, 1, 3, 6, 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 plasma level of dextromethorphan obtained by administering the same amount of dextromethorphan for nine consecutive days without bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolites or prodrugs of these compounds.

[0437] In some embodiments, bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolite or prodrug of these compounds, is co-administered with dextromethorphan for at least ten consecutive days, wherein on the tenth day, for example at 0, 1, 3, 6, or 12 hours after co-administration of bupropion and dextromethorphan, the plasma level of dextromethorphan is at least 5, at least 10, at least 20, at least 30, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, or as much as about 1000 times the plasma level obtained by administering the same amount of dextromethorphan for ten consecutive days without bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolite or prodrug of these compounds.

[0438] In some embodiments, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds, and dextromethorphan are co-administered to a person requiring treatment with dextromethorphan for at least ten consecutive days, wherein on the tenth day, the dextromethorphan plasma level is lower than that obtained by administering the same amount of dextromethorphan for ten consecutive days without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds. For example, the plasma level of dextromethorphan on day 10 (e.g., at 0, 1, 3, 6, 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 plasma level of dextromethorphan obtained by administering the same amount of dextromethorphan for ten consecutive days without bupropion, hydroxybupropion, erythrobupropion, threobupropion, or any metabolites or prodrugs of these compounds.

[0439] In some implementations, bupropion can achieve an AUC of bupropion in the human body on day 8. 0-12 Administered to humans in amounts of 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 1000 ng•hr / mL, at least about 1200 ng•hr / mL, at least 1600 ng•hr / mL, or up to about 15000 ng•hr / mL.

[0440] In some implementations, bupropion can result in a C10 concentration in the body on day 8. avg Administered to humans in amounts of at least about 10 ng / mL, at least about 20 ng / mL, at least about 40 ng / mL, at least about 50 ng / mL, at least about 60 ng / mL, at least about 70 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, at least 120 ng / mL, or up to 1500 ng / mL.

[0441] In some implementations, bupropion can result in a C10 concentration in the body on day 8. max Administered to humans in amounts of at least about 10 ng / mL, at least about 20 ng / mL, at least about 50 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, at least about 110 ng / mL, at least about 120 ng / mL, at least about 130 ng / mL, at least about 140 ng / mL, at least 200 ng / mL, or up to 1500 ng / mL.

[0442] Some liquid compositions may contain about 0.0001% (w / v) to about 50% (w / v), about 0.01% (w / v) to about 20% (w / v), about 0.01% to about 10% (w / v), about 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 defined by these values ​​or within the range thereof.

[0443] 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 110 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 within or between any of these values.

[0444] Some solid compositions may contain at least about 5% (w / w), at least about 10% (w / w), at least about 20% (w / w), at least about 50% (w / w), at least about 70% (w / w), at least about 80%, about 10% (w / w) to about 30% (w / w), about 10% (w / w) to about 20% (w / w), about 20% (w / w) to about 30% (w / w), about 30% (w / w) to about 50% (w / w), 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) amount of bupropion, or any amount of bupropion defined by any of these values ​​or within a range thereof.

[0445] Some solid 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 120 mg, about 105 mg to about 200 mg, about 90 mg to about 120 mg, about 100 mg to about 110 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 within or between any of these values.

[0446] In some embodiments, bupropion is administered at a dose that results in plasma levels 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 level within or between any of these values.

[0447] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion is administered at a dose that results in plasma levels of hydroxybupropion of about 0.1 μM to about 10 μM, about 0.1 μM to about 5 μM, about...

Claims

1. A method for treating major depressive disorder or agitation associated with Alzheimer's disease, comprising administering a combination of medications once or twice daily to a person in need, wherein the person is approximately 41 years of age or older, wherein the combination of medications comprises: Approximately 105 mg of bupropion hydrochloride or a molar equivalent of free base or another salt form of bupropion; and Approximately 45 mg of dextromethorphan hydrobromide, or molar equivalents of dextromethorphan in the form of a free base or another salt.

2. The method of claim 1, wherein the person suffers from agitation associated with Alzheimer's disease.

3. The method according to claim 2, wherein about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide are administered to the person twice daily.

4. The method according to claim 2, wherein the person is administered about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide twice daily for at least 8 consecutive days.

5. The method according to claim 2, wherein the person is administered about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide twice daily for at least 14 consecutive days.

6. The method according to claim 2, wherein the person is administered about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide twice daily for at least 30 consecutive days.

7. The method of claim 1, wherein the person suffers from major depressive disorder.

8. The method according to claim 7, wherein the person is administered about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide twice daily for at least 8 consecutive days.

9. The method according to claim 7, wherein the person is administered about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide twice daily for at least 14 consecutive days.

10. The method of claim 7, wherein the person is administered about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide twice daily for at least 30 consecutive days.

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