Compounds and combinations for treating neurological and psychiatric symptoms

Abstract

This disclosure relates to the administration of a combination of 1) bupropion hydrochloride in amounts of approximately 100-110 mg, approximately 104-106 mg, or approximately 105 mg or less, or an equivalent molar amount of bupropion in its free base form or other salt form, and 2) dextromethorphan hydrobromide in amounts of approximately 40-50 mg, approximately 44-46 mg, or approximately 45 mg or less, or an equivalent molar amount of dextromethorphan in its free base form or other salt form, in certain patient populations, including patients with moderate renal impairment, patients receiving potent CYP2D6 inhibitors, patients known to be in the CYP2D6 low metabolism group, patients requiring a non-dissociative NMDA antagonist, and patients at risk of QT prolongation.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority under U.S. Provisional Patent Application No. 63 / 578,941, filed on 25 August 2023, all of which are incorporated by reference. [Overview of the project] [Means for solving the problem]

[0002] This disclosure relates to the administration of a combination of 1) bupropion hydrochloride in an amount of approximately 100-110 mg, approximately 104-106 mg, or approximately 105 mg or less, or an equivalent molar amount of bupropion in its free base form or other salt form, and 2) dextromethorphan hydrobromide in an amount of approximately 40-50 mg, approximately 44-46 mg, or approximately 45 mg or less, or an equivalent molar amount of dextromethorphan in its free base form or other salt form, in a specific patient population.

[0003] Some embodiments include a method for treating major depressive disorder in a human patient, comprising administering to a human patient once daily a combination of i) about 100-110 mg of bupropion hydrochloride, or an equivalent molar amount of dextromethorphan in its free base form or other salt form, and ii) about 40-50 mg of dextromethorphan hydrobromide, or an equivalent molar amount of dextromethorphan in its free base form or other salt form, wherein the human patient has experienced major depressive disorder and has at least 13 scores on the Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR-16) scale, and the combination is administered in any dosage form.

[0004] Some embodiments include a method for reducing the risk of neurotoxicity to a human child, comprising: i) administering a combination of about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride to a human patient once or twice daily, wherein the human patient is a breastfeeding mother of a human child and has a major depressive disorder; and ii) advising the human patient not to breastfeed the human child while the combination is being administered to the human patient and for five days after the last dose of the combination.

[0005] Some embodiments include a method for treating major depressive disorder in a patient with moderate renal impairment, comprising administering a daily dose of (i) about 105 mg of bupropion hydrochloride and (ii) about 45 mg of dextromethorphan hydrobromide to a human patient having moderate renal impairment and experiencing major depressive disorder.

[0006] Some embodiments include a method for treating patients with neurological symptoms by administering a combination of dextromethorphan and bupropion, the method being A dosage form comprising 105 mg or less of bupropion hydrochloride, or an equivalent molar amount of bupropion free base or other salt form, and 45 mg or less of dextromethorphan hydrobromide, or an equivalent molar amount of dextromethorphan free base or other salt form, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide, and this dosage form is administered orally once daily to each patient. The patient was selected because 1) had neurological symptoms and 2) had moderate renal impairment, and the patient was determined to have moderate renal impairment by assay of a biological sample from the patient. The risk of drowsiness or dizziness in the aforementioned patients with moderate renal impairment is lower when the combination formulation is administered orally once daily to the patient than when the combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide is administered twice daily for the same number of days.

[0007] Some embodiments include a method of treating a patient with a combination of dextromethorphan and bupropion, wherein the patient is experiencing neurological symptoms, and the method is Obtaining biological samples from the aforementioned patients, or having obtained them previously, and To determine whether the patient has moderate renal impairment, perform an assay on the biological sample, or have done so previously. This includes the step of determining whether the patient has moderate renal impairment, If the patient has moderate renal impairment, a dosage form comprising 105 mg or less of bupropion hydrochloride, or an equivalent molar amount of bupropion free base or other salt form, and 45 mg or less of dextromethorphan hydrobromide, or an equivalent molar amount of dextromethorphan free base or other salt form, wherein the molar ratio of bupropion to dextromethorphan is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide, shall be orally administered to the patient once daily. If the patient does not have renal impairment, administer to the patient orally twice daily a dosage form comprising 105 mg of bupropion hydrochloride, or an equivalent molar amount of bupropion free base or other salt form, and 45 mg of dextromethorphan hydrobromide, or an equivalent molar amount of dextromethorphan free base or other salt form. The risk of drowsiness or dizziness in patients with moderate renal impairment is lower when a dosage form comprising the combination is orally administered to the patient once daily over the same number of days, than when the combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is administered to the patient twice daily over the same number of days.

[0008] Some embodiments provide a method of treating a patient experiencing a nervous system disorder, the method comprising: a) determining whether the patient is at risk of an adverse event associated with overexposure to dextromethorphan by: obtaining or having previously obtained a biological sample from the patient, and performing or having previously performed an assay on the biological sample to determine whether the patient has moderate renal impairment, wherein a result that the patient has moderate renal impairment indicates that the patient is at risk of an adverse event associated with overexposure to dextromethorphan; b) if the patient is at risk of an adverse event associated with overexposure to dextromethorphan, orally administering to the patient once daily a dosage form comprising a combination of 105 mg or less of bupropion hydrochloride, or a corresponding molar amount of bupropion free base or another salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or a corresponding molar amount of dextromethorphan free base or another salt form of dextromethorphan, wherein the molar ratio of bupropion to dextromethorphan is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; and c) if the patient is not at risk of an adverse event associated with overexposure to dextromethorphan, orally administering to the patient twice daily a dosage form comprising a combination of 105 mg of bupropion hydrochloride, or a corresponding molar amount of bupropion free base or another salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a corresponding molar amount of dextromethorphan free base or another salt form of dextromethorphan; comprising the steps of.

[0009] Some embodiments provide a method of treating a nervous system disorder with a combination of dextromethorphan and bupropion, the method comprising orally administering to the patient once per day a dosage form, wherein the dosage form comprises a combination of 105 mg or less of bupropion hydrochloride, or a corresponding molar amount of bupropion free base or another salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or a corresponding molar amount of dextromethorphan free base or another salt form of dextromethorphan, and the molar ratio of bupropion to dextromethorphan in the dosage form is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide, the patient is selected because 1) the patient has a nervous system disorder, and 2) the patient has moderate renal impairment, and the patient has been determined to have moderate renal impairment by an assay performed on a biological sample obtained from the patient, the risk of an adverse event occurring in said patient is reduced compared to the risk of an adverse event that would occur in said patient if said dosage form were administered to said patient twice per day.

[0010] Some embodiments comprise a method of treating a patient with a combination of dextromethorphan and bupropion, wherein the patient is experiencing a nervous system disorder, and the method comprises: obtaining, or having previously obtained, a biological sample from the patient; and performing, or having previously performed, an assay on said biological sample to determine whether said patient has moderate renal impairment, thereby comprising the step of determining whether said patient has moderate renal impairment, If the patient has moderate renal impairment, a dosage form comprising 105 mg or less of bupropion hydrochloride, or an equivalent molar amount of bupropion free base or other salt form, and 45 mg or less of dextromethorphan hydrobromide, or an equivalent molar amount of dextromethorphan free base or other salt form, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide, shall be orally administered to the patient once daily. If the patient does not have renal impairment, a dosage form comprising 105 mg of bupropion hydrochloride, or an equivalent molar amount of bupropion free base or other salt form, and 45 mg of dextromethorphan hydrobromide, or an equivalent molar amount of dextromethorphan free base or other salt form, shall be administered orally to the patient twice daily.

[0011] Some embodiments include a method for treating patients with neurological symptoms by administering a combination of dextromethorphan and bupropion, the method being The present invention provides a dosage form comprising 105 mg or less of bupropion hydrochloride, or an equivalent molar amount of bupropion free base or other salt form, and 45 mg or less of dextromethorphan hydrobromide, or an equivalent molar amount of dextromethorphan free base or other salt form, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide, and administers this dosage form orally once daily to the patient. The patient was selected because 1) had neurological symptoms and 2) had moderate renal impairment, and the patient was determined to have moderate renal impairment by assay of a biological sample from the patient. In patients with moderate renal impairment, the risk of drowsiness and dizziness is lower when the combination formulation is administered orally once daily to the patient than when the combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide is administered twice daily for the same number of days.

[0012] Some embodiments include a method of treating a patient with a combination of dextromethorphan and bupropion, wherein the patient is experiencing neurological symptoms, and the method is Obtaining biological samples from the aforementioned patients, or having obtained them previously, and To determine whether the patient has moderate renal impairment, perform an assay on the biological sample, or have done so previously. This includes the step of determining whether the patient has moderate renal impairment, If the patient has moderate renal impairment, a dosage form comprising 105 mg or less of bupropion hydrochloride, or an equivalent molar amount of bupropion free base or other salt form, and 45 mg or less of dextromethorphan hydrobromide, or an equivalent molar amount of dextromethorphan free base or other salt form, wherein the molar ratio of bupropion to dextromethorphan is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide, shall be orally administered to the patient once daily. If the patient does not have renal impairment, a dosage form comprising 105 mg of bupropion hydrochloride, or an equivalent molar amount of bupropion free base or other salt form, and 45 mg of dextromethorphan hydrobromide, or an equivalent molar amount of dextromethorphan free base or other salt form, shall be orally administered to the patient twice daily. In patients with moderate renal impairment, the risk of drowsiness and dizziness is lower when the combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide is administered orally once daily to the patient than when the combination is administered twice daily for the same number of days.

[0013] Some embodiments include a method for treating major depressive disorder in human patients requiring combination therapy with a potent CYP2D6 inhibitor, comprising administering a combination of about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide once daily to a human patient, the human patient having experienced major depressive disorder and receiving combination therapy with a potent CYP2D6 inhibitor. In some embodiments, the potent CYP2D6 inhibitor is paroxetine.

[0014] Some embodiments include a method for treating major depressive disorder in a patient receiving potent CYP2D6 inhibitor combination therapy, comprising administering a daily dose of (i) about 105 mg of bupropion hydrochloride and (ii) about 45 mg of dextromethorphan hydrobromide to a human patient having major depressive disorder and receiving combination therapy with a CYP2D6 inhibitor.

[0015] Some embodiments include a method for treating major depressive disorder in a patient known to have a CYP2D6 dysmetabolism, comprising administering a daily dose of (i) about 105 mg of bupropion hydrochloride and (ii) about 45 mg of dextromethorphan hydrobromide to a human patient who has experienced major depressive disorder and is known to have a CYP2D6 dysmetabolism.

[0016] Some embodiments include a method for treating major depressive disorder using an N-methyl D-aspartate (NMDA) receptor antagonist, comprising administering a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide to human patients experiencing major depressive disorder at least twice daily, wherein dextromethorphan acts as a non-competitive antagonist of the NMDA receptor and a sigma-1 receptor agonist, and the human patients do not experience dissociation.

[0017] Some embodiments include a method for treating major depressive disorder in human patients at risk of QT prolongation, comprising administering a combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide at least twice daily to human patients who have experienced major depressive disorder and are at risk of QT prolongation and polymorphic ventricular tachycardia, in which the QT interval is not evaluated by electrocardiogram in the said human patients.

[0018] Some embodiments include a method for treating a patient with major depressive disorder, comprising administering a therapeutically effective dose of a combination of dextromethorphan and bupropion, wherein the patient has mild hepatic impairment as defined as Child-Pew A, or moderate hepatic impairment as defined as Child-Pew B, and the therapeutically effective dose is the same dose that would be administered to a patient with normal hepatic function.

[0019] Some embodiments involve determining whether a human patient has liver dysfunction, If the aforementioned human patient has mild hepatic impairment as defined as Child's Pugh A, or moderate hepatic impairment as defined as Child's Pugh B, the combination of 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride shall be administered to the aforementioned human patient twice daily. If the aforementioned human patient has severe hepatic impairment as defined as Child's Pugh C, the use of a combination of 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride should be avoided in the aforementioned human patient. This includes methods for treating major depressive disorder. [Brief explanation of the drawing]

[0020] [Figure 1] This study shows the effects of renal impairment, hepatic impairment, and CYP2D6 dysmetabolism on the pharmacokinetics of tablets containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride. [Figure 2] This study shows the weekly change from baseline in the MADRS total score for human patients who received tablets containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride twice daily. [Modes for carrying out the invention]

[0021] As stated above, this disclosure relates to the administration of combinations of 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride, or a corresponding molar amount of dextromethorphan in its free base form or other salt form; and 2) about 40-50 mg, about 44-46 mg, or about 45 mg of dextromethorphan hydrobromide, or a corresponding molar amount of dextromethorphan in its free base form or other salt form. For convenience, this combination is referred to herein as the "subject combination." In all examples in which the subject combination is referred herein, the combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is particularly intended.

[0022] In some embodiments, the subject combination is administered to patients who have experienced major depressive disorder and who have, or are selected for having, at least 13 scores on the Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR-16) prior to treatment.

[0023] The QIDS-SR-16, a 16-item patient assessment scale, is a shortened version of the 30-item Inventory of Depressive Symptomatology (IDS) and is designed to assess the severity of depressive symptoms. The QIDS-SR-16 assesses the criterion symptom domain for diagnosing major depressive disorder.

[0024] The Quick Response Depressive Symptom Scale (QIDS-SR-16) is a 16-item self-report scale that assesses depressive symptoms over the 7 days prior to the test. The questions cover nine symptom domains: sadness, concentration, self-criticism, suicidal ideation, interests, energy / fatigue, sleep disturbances, appetite / weight changes, and psychomotor agitation / inhibition. Each item is scored on a scale of 0 to 3 points. Four items (early insomnia, mid-stage insomnia, late-stage insomnia, hypersomnia) are used to assess the sleep domain. Two items (excitation and inhibition) are used to measure psychomotor activity. Four items (increased and decreased appetite, increased and decreased weight) are used to assess the appetite / weight domain. For each of these three domains (sleep, psychomotor activity, and appetite / weight), the highest score from any one item is used to score the domain. For the remaining six domains (sadness, concentration, energy, interests, guilt, and suicidal ideation), only one item is used to score them. The QIDS-SR-16 overall score is the sum of the scores across nine symptom areas, ranging from 0 to 27. A score of 5 or less indicates no depression, 6-10 indicates mild depression, 11-15 indicates moderate depression, 16-20 indicates severe depression, and a total score exceeding 21 indicates very severe depression.

[0025] Potent CYP2D6 inhibitors include, but are not limited to, fluoxetine, propafenone, quinidine, and paroxetine.

[0026] Dextromethorphan hydrobromide is a non-competitive NMDA receptor antagonist and sigma-1 receptor agonist.

[0027] The chemical name of dextromethorphan hydrobromide is morphinan,3-methoxy-17-methyl-,(9α,13α,14α),hydrobromide monohydrate. Dextromethorphan hydrobromide is empirically represented by formula C 18 H 25 It contains NO·HBr·H2O and has a molecular weight of 370.33. Its structural formula is: [ka] That is the case.

[0028] Dextromethorphan hydrobromide powder is a white or nearly white crystalline substance that is slightly soluble in water.

[0029] Bupropion hydrochloride is an aminoketone and a CYP450 2D6 inhibitor.

[0030] The chemical name of bupropion hydrochloride is (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propane hydrochloride. Bupropion hydrochloride is empirically formulated C 13 H 18 It contains ClNO·HCl and has a molecular weight of 276.2. Its structural formula is: [ka] That is the case.

[0031] Bupropion hydrochloride powder is white and dissolves well in water.

[0032] The subject combination may be included in oral dosage forms, including tablets such as sustained-release tablets. In some embodiments, the subject combination is included in dosage forms for oral administration and is available as round, two-layered tablets.

[0033] In some embodiments, each tablet containing the subject combination contains 45 mg of dextromethorphan hydrobromide in an immediate-release formulation. In some embodiments, each tablet containing the subject combination contains 105 mg of bupropion hydrochloride in an extended-release formulation. In some embodiments, each tablet containing the subject combination contains 45 mg of dextromethorphan hydrobromide in an immediate-release formulation and 105 mg of bupropion hydrochloride in an extended-release formulation.

[0034] In some embodiments, the tablet containing the subject combination contains l-cysteine ​​hydrochloride monohydrate. In some embodiments, the tablet containing the subject combination contains carbomer homopolymer. In some embodiments, the tablet containing the subject combination contains microcrystalline cellulose. In some embodiments, the tablet containing the subject combination contains colloidal silicon dioxide. In some embodiments, the tablet containing the subject combination contains crospovidone. In some embodiments, the tablet containing the subject combination contains stearic acid. In some embodiments, the tablet containing the subject combination contains magnesium stearate.

[0035] In some embodiments, the tablets comprising the subject combination include the following inactive components: l-cysteine ​​hydrochloride monohydrate, carbomer homopolymer, microcrystalline cellulose, colloidal silicon dioxide, crospovidone, stearic acid, and magnesium stearate.

[0036] In some embodiments, the starting dose of the subject combination is 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride in one tablet administered once daily in the morning. In some embodiments, after 3 days, the dose is increased to one tablet (or one dosage form containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) twice daily, administered, for example, with an interval of at least 8 hours between doses. In some embodiments, more than two doses containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride are not administered on the same day.

[0037] In patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, dose adjustment is not recommended compared to the dose recommended for patients with normal hepatic function.

[0038] The pharmacokinetics of the combination of 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride have not been evaluated in patients with severe hepatic impairment (Child-Pugh C). The use of the combination of 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride is not recommended or should be avoided in patients with severe hepatic impairment.

[0039] The subject combination can be administered orally with or without a meal. In some embodiments, the tablets are swallowed whole and not crushed, split, or chewed.

[0040] Patients with renal impairment may require special treatment.

[0041] In some embodiments, the state of renal impairment in a subject can be determined by measuring the individual “estimated glomerular filtration rate” or “eGFR”. eGFR in mL / min / 1.73m 2 This is calculated using the Modified Dietary Therapy for Renal Disease [MDRD] formula: (eGFR in mL / min) / 1.73m 2=175×(serum creatinine in mg / dL) -1.154 ×age -0.203 ×0.742 (for females)×1.212 (for Black individuals)

[0042] For details regarding the calculation of eGFR, reference can be made to, for example, Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, Van Lente F: Chronic Kidney Disease Epidemiology Collaboration. Expressing the Modification of Diet in Renal Disease Study Equation for Estimating Glomerular Filtration Rate with Standardized Serum Creatinine Values. Ann Intern Med. 2009;150(9):604-12.

[0043] The status of renal impairment based on guidance from the Food and Drug Administration (FDA) is as follows. ·Normal: eGFR≧90 mL / min / 1.73 m 2 ·Mild: eGFR 60 to 89 mL / min / 1.73 m 2 (i.e., ≧60 to <90) ·Moderate: eGFR 30 to 59 mL / min / 1.73 m 2 (i.e., ≧30 to <60) ·Severe: eGFR 15 to 29 mL / min / 1.73 m 2 (i.e., ≧15 to <30) ·End-stage renal disease (ESRD): eGFR<15 mL / min / 1.73 m 2 , wherein the subject is not undergoing hemodialysis, or is undergoing hemodialysis.

[0044] See Industry Guidance on Pharmacokinetics in Patients with Renal Impairment—Impacts on Study Design, Data Analysis, and Dosage and Labelling. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), February 2010. As used herein, “individuals with hepatic impairment” means individuals who have mild, moderate, or severe hepatic impairment, or who may have ESRD.

[0045] In some embodiments, moderate renal impairment (30-59 mL / min / 1.73 m) 2 For patients with an estimated glomerular filtration rate (eGFR) or glomerular filtration rate (GFR), the recommended daily dose of the subject combination is 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride, or an equivalent molar amount of other forms of dextromethorphan and / or bupropion, for example, one tablet (or one dosage form containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) once daily, for example, one tablet or one oral dosage form every morning, or a combination of 52.5 mg of bupropion and approximately 22.5 mg of dextromethorphan hydrobromide orally twice daily. In some embodiments, the patient is monitored for any adverse reactions that may be attributable to dextromethorphan, such as drowsiness and dizziness.

[0046] Moderate renal impairment can be determined by assays, such as assayers that determine creatinine levels in biological samples from patients, such as blood samples. Plasma creatinine levels from blood samples can be used to estimate glomerular filtration rate (GFR).

[0047] Patients using the subject combination in combination with a potent CYP2D6 inhibitor may require special administration. The use of the subject combination in combination with a potent CYP2D6 inhibitor increases plasma concentrations of dextromethorphan. In some embodiments, the recommended dose of the subject combination when administered concurrently with a potent CYP2D6 inhibitor is one tablet per day (or a dosage form containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride), such as one tablet or other oral dosage form, taken daily in the morning. In some embodiments, patients are monitored for possible side effects attributable to dextromethorphan, such as drowsiness and dizziness.

[0048] Patients known to be CYP2D6 dysmetabolists (PM) may require special administration. In some embodiments, the recommended dose for patients known to be CYP2D6 dysmetabolists is one tablet per day (or a dosage form containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride), such as one tablet or other oral dosage form, taken daily in the morning.

[0049] Special precautions may be necessary when switching a patient to a monoamine oxidase inhibitor (MAOI) antidepressant, or from a monoamine oxidase inhibitor (MAOI) antidepressant to the subject combination. In some embodiments, at least 14 days must elapse between the discontinuation of an MAOI for the treatment of depression and the initiation of treatment with the subject combination. Conversely, in some embodiments, at least 14 days must elapse after discontinuation of the subject combination before initiating an MAOI antidepressant.

[0050] There is data reporting the presence of bupropion and its metabolites in human breast milk. There is no data on the effects of bupropion or its metabolites on breast milk production. Limited data on bupropion use in breastfeeding patients have not revealed a clear association with adverse reactions in breastfed infants.

[0051] Neurotoxic findings have been observed in young rats 7 days postnatally (PND) treated with the dextromethorphan / quinidine combination, which corresponds to the third trimester of pregnancy to the first few months of life, and may extend to 3 years of age in humans. It is unknown whether dextromethorphan is present in human breast milk. There is no data on the effects of dextromethorphan on breastfed infants or on breast milk production. Due to the potential for neurotoxicity, in some embodiments, patients should be advised that breastfeeding is not recommended during the duration of treatment with the dextromethorphan and bupropion combination and for 5 days after the last dose.

[0052] In some embodiments, human children receiving the subject combination are at risk of seizures. In some embodiments, the human children are about 3 years of age or younger. In some embodiments, human children receiving the subject combination are at risk of neurotoxicity.

[0053] For breastfeeding human mothers, a combination of approximately 45 mg of dextromethorphan hydrobromide and approximately 105 mg of bupropion hydrochloride may be taken for approximately 1 to 6 weeks, approximately 6 weeks, or at least approximately 6 weeks, after which treatment may be discontinued at least 5 days before breastfeeding begins.

[0054] In some embodiments, human patients produce breast milk that is substantially free of dextromethorphan five days after the last dose of the combination.

[0055] In some embodiments, human patients produce breast milk that is substantially free of bupropion five days after the last dose of the combination.

[0056] In some embodiments, human children of patients receiving the subject combination are not exposed to detectable amounts of dextromethorphan while breastfeeding.

[0057] In some embodiments, human children of patients receiving the subject combination are not exposed to detectable amounts of bupropion while breastfeeding.

[0058] In some embodiments, the subject combination is administered until the human patient's total MADRS score decreases by at least about 7, at least about 11, at least about 13, or at least about 15.9. Once the desired decrease in the MADRS score is reached, the human patient may discontinue treatment, wait at least 5 days, and then begin breastfeeding her child.

[0059] In some embodiments, the human child is a breastfed infant.

[0060] In some embodiments, human patients who receive the subject combination experience a greater reduction from baseline in their total MADRS score than they would experience if they received a placebo. Human patients taking the subject combination may experience a greater reduction in their MADRS score than those taking a placebo at 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or longer after administration.

[0061] In this subject combination, bupropion inhibits the metabolism of dextromethorphan via CYP2D6. When dextromethorphan is co-administered with bupropion, it exhibits nonlinear pharmacokinetics at steady state, and AUC and C12 are different when the dose of dextromethorphan (30-60 mg) is varied. max The change was greater than the dose-proportional change, but when the bupropion dose (75-150 mg) was changed, the change was less than the dose-proportional change.

[0062] When the subject combination is administered, steady-state plasma concentrations of dextromethorphan and bupropion are achieved within 8 days. The steady-state accumulation rate of dextromethorphan is C max and AUC 0-12Based on this, the values ​​are approximately 20 and approximately 32, respectively. The accumulation rate of bupropion in the steady state is C max and AUC 0-12 Based on this, the values ​​are approximately 1.1 and 1.5, respectively.

[0063] After administration of the subject combination, dextromethorphan T max The median time for bupropion T is approximately 3 hours. max The median time is approximately 2 hours. C of hydroxybupropion metabolites max This occurs approximately 3 hours after administration and is at a peak level approximately 14 times higher than that of bupropion. (AUC of hydroxybupropion) 0-12 It is approximately 19 times that of bupropion. C of erythrohydroxybupropion and threohydro metabolites max These events occur approximately 10 hours after administration and are roughly equivalent to and about 5 times that of bupropion, respectively. AUC of erythrohydroxybupropion and threohydroxybupropion. 0-12 These values ​​are approximately 1.2 times and 7 times that of bupropion, respectively.

[0064] The subject combination can be taken with or without food. When the subject combination is administered with food, dextromethorphan C max and AUC 0-12 These showed no change and a 14% decrease, respectively, and bupropion C max and AUC 0-12 These will increase by 3% and 6%, respectively.

[0065] Dextromethorphan has a plasma protein binding rate of approximately 60-70%, while bupropion has a rate of 84%. The degree of protein binding of hydroxybupropion metabolites is similar to that of bupropion, while the degree of protein binding of threohydroxybupropion metabolites is about half that of bupropion.

[0066] After administering the subject combination to the high-metabolism group for 8 days, the mean elimination half-life of dextromethorphan increased to approximately 22 hours, roughly three times longer, compared to dextromethorphan administered without bupropion.

[0067] The mean elimination half-lives of dextromethorphan and bupropion were 22 hours and 15 hours, respectively. The apparent elimination half-lives of hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion metabolites were approximately 35, 44, and 33 hours, respectively.

[0068] Esketamine is a non-competitive NMDA receptor antagonist and, in combination with oral antidepressants, is indicated for the treatment of treatment-resistant depression in adults. Treatment of treatment-resistant depression carries a risk of dissociation. The label on esketamine states that, due to the risk of sedation and dissociation, patients should be monitored for at least two hours after each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the medical setting.

[0069] Dissociation includes delusional perception, depersonalization / derealization disorder, derealization, diplopia, dissociation, paresthesia, coldness, heat sensation, sensation of changes in body temperature, hallucinations, auditory hallucinations, visual hallucinations, hyperacusis, illusions, eye discomfort, oral paresthesia, numbness, oral numbness, pharyngeal numbness, photophobia, altered time perception, tinnitus, blurred vision, and visual impairment.

[0070] The subject combination is a combination of dextromethorphan, a non-competitive N-methyl-D-aspartate (NDMA) receptor antagonist and sigma-1 receptor agonist, and bupropion, an aminoketone and CYP450 2D6 inhibitor indicated for the treatment of major depressive disorder (MDD) in adults. Unlike esketamine, the subject combination can be administered without dissociation or dissociative events. In some embodiments, patients are not monitored for dissociation after administration of the subject combination.

[0071] The following information includes the types of dissociation and other effects that can be avoided with the combination of dextromethorphan and bupropion.

[0072] In clinical trials, based on the modified Observer Alertness / Sedation Scale (MOAA / S), 48%–61% of patients treated with esketamine became sedated, and 0.3%–0.4% of patients treated with esketamine experienced loss of consciousness (MOAA / S score 0). The combination of dextromethorphan and bupropion may achieve NMDA receptor antagonism without a significant risk of sedation.

[0073] Because sedation may be delayed or prolonged, patients receiving esketamine must be monitored by a healthcare professional for at least two hours during each treatment session, after which an assessment is conducted to determine when the patient is considered clinically stable and ready to leave the medical setting. Such monitoring is not required in treatment with the combination of dextromethorphan and bupropion.

[0074] Patients being treated with esketamine must be carefully monitored for sedation when esketamine is used in combination with CNS depressants. Such monitoring is not required in the treatment of the subject combination of dextromethorphan and bupropion.

[0075] Esketamine is only available through limited programs under a Risk Assessment and Mitigation Strategy (REMS). Such limitations are not required for the subject combination of dextromethorphan and bupropion.

[0076] The most common psychological effects of esketamine are dissociative and / or perceptual alterations (including distortions of time, space, and illusions), derealization, and depersonalization (61%–84% of patients treated with esketamine developed dissociative or perceptual alterations based on the Clinical Diagnostic Dissociative Scale). Due to the potential to induce dissociative effects, patients with psychosis must be carefully evaluated before being administered esketamine. Such evaluation is not required in the treatment of the combination of dextromethorphan and bupropion. Treatment with esketamine should only be initiated if the benefits outweigh the risks. Such limitations are not required in the treatment of the combination of dextromethorphan and bupropion.

[0077] Due to the risk of dissociation, patients receiving esketamine must be monitored by a healthcare professional for at least two hours during each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting. Such monitoring, assessment, or limitation is not required in the treatment of the subject combination of dextromethorphan and bupropion.

[0078] Dissociation includes paranoid perception, depersonalization / derealization disorder, derealization, diplopia, dissociation, paresthesia, coldness, heat sensation, sensation of temperature changes, hallucinations, auditory hallucinations, visual hallucinations, mixed hallucinations, hyperacusis, illusions, ocular discomfort, oral paresthesia, paresthesia, oral paresthesia, pharyngeal paresthesia, photophobia, altered time perception, tinnitus, blurred vision, and visual disturbances.

[0079] Esketamine is a Schedule III controlled substance (CIII) and can be abused or diverted. The subject combination of dextromethorphan and bupropion is not a controlled substance. The risk of abuse or misuse for each patient must be assessed before prescription, and all patients receiving esketamine must be monitored during treatment for the occurrence of these behaviors or conditions, including drug-seeking behavior. Such monitoring or assessment is not required in the treatment of the subject combination of dextromethorphan and bupropion.

[0080] Esketamine is only available through a limited program under a Risk Assessment and Mitigation Strategy (REMS), known as Esketamine REMS, due to the risk of reported adverse outcomes from sedation, dissociation, abuse, and misuse. Such limitations are not required for the subject combination of dextromethorphan and bupropion.

[0081] Key requirements for esketamine REMS include the following: • Medical facilities must be certified for the program, and esketamine, - Dispensing and administering only in medical settings. - Patients receiving treatment on an outpatient basis (for example, at clinics and medical offices) must register for this program. - The drug is administered by the patient under the direct supervision of a healthcare professional, and the patient is monitored by a healthcare professional for at least two hours after administration of esketamine. We guarantee that it is so.

[0082] None of these requirements apply to the subject combination of dextromethorphan and bupropion.

[0083] Esketamine was evaluated for safety in 262 adults in two Phase 3 trials (Trial 3 and Trial 4) and one Phase 2 trial to treat depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior.

[0084] Sedation was assessed by adverse event reporting and the Modified Observer Alertness / Sedation Scale (MOAA / S). On the MOAA / S, a score of 5 meant "responds immediately to being called by name in a normal voice," a score of 0 meant "unresponsive to painful trapezius compression," a score of 4 meant "responds slowly to being called by name in a normal voice," a score of 3 meant "responds only to being called by name loudly and / or repeatedly," a score of 2 meant "responds only to mild stimulation or shaking," and a score of 1 meant "unresponsive to mild stimulation or shaking." A decrease in the MOAA / S score from baseline was considered to indicate the presence of sedation, and such decreases occurred in more patients receiving esketamine than placebo in short-term treatment-resistant depression (TRD) trials. An increased incidence of dose-related sedation (MOAA / S score < 5) was observed in fixed-dose trials of TRD. Table 1 shows the incidence of sedation (MOAA / S score < 5) in fixed-dose studies in adult patients under 65 years of age with TRD, and in flexible-dose studies in patients 65 years of age and older with TRD.

[0085] [Table 1]

[0086] In trials for treating depressive symptoms in adults with major depressive disorder (MDD) accompanied by acute suicidal ideation or behavior, similar to the results for treatment-resistant depression shown in Table 1, the incidence of sedation (MOAA / S score < 5) was higher in patients treated with esketamine and oral antidepressants compared to patients treated with placebo and oral antidepressants (AD).

[0087] (Dissociation / Perceptual changes) Esketamine induces dissociative symptoms (including derealization and depersonalization) and near-disturbances (time and space distortions, as well as illusions). In clinical trials, dissociation was transient and occurred on the day of administration. Dissociation was assessed by adverse event reporting and the Diagnostic Dissociative Sensitivity Scale (CADSS). A CADSS total score greater than 4 indicates the presence of dissociative symptoms, and such increases to 4 or higher occurred in a large number of patients with esketamine compared to placebo in short-term treatment-resistant depression trials. A dose-related increase in the incidence of dissociative symptoms (CADSS total score > 4 and change > 0) was observed in fixed-dose trials for treatment-resistant depression. Table 2 shows the incidence of dissociation (CADSS total score > 4 and change > 0) in fixed-dose trials in adult patients under 65 years of age with treatment-resistant depression, and in flexible-dose trials in patients 65 years of age and older with treatment-resistant depression.

[0088] [Table 2]

[0089] In a trial to treat depressive symptoms in adults with acute suicidal ideation or behavior (MDD), patients treated with esketamine and oral AD also had a higher proportion of patients exhibiting dissociation (CADSS total score > 4 and change > 0) (84%) compared to patients treated with placebo and oral AD (16%).

[0090] Because the subject combination can be administered without dissociation or dissociative events, the risk of abuse is reduced compared to esketamine. Abuse is defined as the intentional, non-treatment use of a drug, even once, for a desired psychological or physiological effect. In clinical trials of the subject combination of dextromethorphan and bupropion, drug-seeking behavior was not evident, but these observations were not systematic. Therefore, patients with a history of drug abuse should be carefully monitored for signs of misuse or abuse of the subject combination of dextromethorphan and bupropion (e.g., development of tolerance, increased dosage, drug-seeking behavior).

[0091] Unlike the quinidine and dextromethorphan combination, the combination dose of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide, administered twice daily, does not prolong the QT interval to a clinically relevant degree. Therefore, in human patients with a history of major depressive disorder and at risk of QT prolongation and polymorphic ventricular tachycardia, electrocardiographic assessment of the QT interval is not typically performed in human patients.

[0092] The combination of themes may be used for the adjunctive treatment of major depressive disorder or depression.

[0093] In addition to major depressive disorder, the subject combination may be used to treat other conditions present in the patient population or circumstances described herein. For example, the subject combination may be used to treat pain or neurological disorders. Examples of neurological disorders that may be treated with the subject combination include, but are not limited to, mood disorders, psychiatric disorders, cerebral dysfunction, motor disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[0094] Affective disorders that can be treated by combinations of themes include, but are not limited to, depression, major depressive disorder, treatment-resistant depression, treatment-resistant bipolar depression, bipolar disorder including cyclothymic disorder, seasonal affective disorder, mood disorders, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADDH), attention deficit / hyperactivity disorder (ADHD), bipolar disorder and manic episodes, obsessive-compulsive disorder, bulimia nervosa, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, drug addiction or abuse, nicotine addiction, psychogenic dysfunction, emotional dysregulation, and emotional instability.

[0095] Depression may be manifested by depressive symptoms. These symptoms may include changes in mood, intense sadness, despair, mental numbness, difficulty concentrating, pessimistic worry, restlessness, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal thoughts or attempts, and / or self-deprecation. Physical symptoms of depression may include insomnia, anorexia, loss of appetite, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, pain, headaches, seizures, digestive problems, and / or circadian rhythm disturbances of hormones.

[0096] Mental disorders that can be treated by combinations of themes include, but are not limited to, anxiety disorders including phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD); mania, manic-depressive illness, hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizophrenia, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease. Alzheimer's disease may also be called Alzheimer's dementia. Other neurobehavioral symptoms of Alzheimer's disease that can be treated include disinhibition and apathy.

[0097] Excitation in Alzheimer's disease occurs as the disease progresses. Excitation can itself manifest as inappropriate verbal, emotional, and / or physical behaviors. Inappropriate behaviors may include, but are not limited to, incoherent babbling, inappropriate emotional responses, attention-seeking, threats, irritability, frustration, shouting, repetitive questioning, mood swings, swearing, abusive language, physical outbursts, emotional distress, restlessness, shredding, sleep disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body movements, hoarding, stalking, hitting, scratching, biting, aggressiveness, hyperactivity, and / or kicking.

[0098] Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral and psychological symptoms, including agitation. AD is the most common form of dementia, affecting an estimated 6 million people in the United States, a number projected to increase to approximately 14 million by 2050. Agitation is reported to be present in up to 70% of patients with AD and is characterized by emotional distress, aggressive behavior, disruptive hypersensitivity, and a lack of inhibition. Managing agitation is a priority in AD. Agitation in patients with AD is associated with increased caregiver burden, decreased function, accelerated cognitive decline, earlier admission to nursing homes, and increased mortality. Currently, there are no FDA-approved treatments for agitation in patients with AD.

[0099] Neurobehavioral symptoms are known to appear during dementia and can be treated in combination. Caregivers or family members may feel more burdened by the patient's behavioral / psychological symptoms than by the cognitive impairment. Common forms of symptoms include Alzheimer's disease, vascular dementia, Lewy body dementia (abnormal protein aggregates that occur in nerve cells), and the group of disorders that contribute to frontotemporal dementia (degeneration of the frontal lobe of the brain). The symptoms experienced by patients with dementia are similar to those of other mental disorders, but some differ slightly from each other. Neurobehavioral symptoms associated with dementia include depression, apathy, agitation, disinhibition, hallucinations, delusions, psychosis, impulsivity, aggression, obsessive-compulsive disorder, hypersexuality, and personality disorders. Neurobehavioral symptoms such as disinhibition can also be seen in other conditions such as traumatic brain injury.

[0100] Agitation in patients with Alzheimer's disease can be assessed using the Cohen-Mansfield Agitation Scale, or CMAI. The CMAI assesses a range of behaviors, including hitting (including oneself), kicking, grabbing, pushing, throwing, biting, scratching, spitting, harming oneself or others, tearing or ripping things, physical sexual seduction, pacing, aimless wandering, inappropriate dressing or undressing, trying to go somewhere else, deliberately falling, ingesting inappropriate substances, improper handling of objects, hiding things, hoarding things, repetitively performing distinctive habits, general restlessness, shouting, verbal sexual seduction, insults or verbal aggression, repeating sentences or questions, strange noises (strange laughter or crying), complaining, negativity, and constantly demanding unduly attention or help.

[0101] Schizophrenia can be treated with a combination of positive and / or negative symptoms of schizophrenia, or residual symptoms of schizophrenia. Other treatable conditions include intermittent explosive disorder.

[0102] Brain dysfunctions that can be treated by combinations of the themes include, but are not limited to, senile dementia, Alzheimer's disease, memory loss, amnesia / amnesia syndrome, epilepsy, impaired consciousness, coma, decreased attention, speech disorders, voice spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperactivity syndrome, and intellectual disabilities such as schizophrenia. Brain dysfunction also includes, but is not limited to, disorders caused by cerebrovascular diseases such as stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, and head trauma, the symptoms of which include impaired consciousness, senile dementia, coma, decreased attention, and speech disorders.

[0103] Drug addictions that can be treated by combinations of subjects include, but are not limited to, addiction to cocaine, psychostimulants (crack, cocaine, speed, methamphetamine, etc.), nicotine, alcohol, opioids, anxiolytics and hypnotics, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as smoking tobacco, cigars and / or pipes, e-cigarettes or vapes, and chewing tobacco.

[0104] Motor disorders that can be treated by combinations of themes include, but are not limited to, akathisia, bradykinesia, congenital dyskin, athetosis, ataxia, ballism, unilateral ballism, bradykinesia, cerebral palsy, chorea, Huntington's disease, Huntington's disease chorea, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless leg syndrome (RLS), tremor, essential tremor, Tourette's syndrome, and Wilson's disease.

[0105] Dementia that can be treated by combinations of themes include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, Lewy body dementia, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff syndrome, and Pick's disease.

[0106] Motor neuron diseases that can be treated by combinations of the subjects include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophy, Tay-Sachs disease, Sandoff disease, and hereditary spastic paraplegia.

[0107] Neurodegenerative diseases that can be treated by combinations of subjects include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar spinal muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, autosomal dominant cerebral arteriovenous disease with subcortical infarction and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth disease (CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0108] Seizure disorders that can be treated by combinations of the themes include, but are not limited to, epileptic seizures, non-epileptic seizures, epilepsy, and febrile convulsions; but are not limited to, partial seizures including simple partial seizures, Jacksonian seizures, complex partial seizures, and persistent partial epilepsy; but are not limited to, generalized seizures including generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

[0109] The types of headaches that can be treated by combinations of themes include, but are not limited to, migraines, tension headaches, and cluster headaches.

[0110] Other neurological disorders that can be treated by combinations of the themes include, but are not limited to, Rett syndrome, autism, tinnitus, impaired consciousness, sexual dysfunction, intractable cough, narcolepsy, and cataplexy; but are not limited to, voice disorders due to uncontrolled laryngeal muscle spasms, including abductor spasmodic dysphonia, adductor spasmodic dysphonia, myotonic dysphonia, and vocal cord tremor; diabetic neuropathy and chemotherapy-induced neurotoxicity such as methotrexate neurotoxicity; but are not limited to, incontinence such as stress-induced urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.

[0111] In some embodiments, combinations of subjects may be used to treat pain, arthralgia, pain associated with sickle cell disease, emotional dysregulation, depression (including treatment-resistant depression), memory and cognitive impairments, motor disorders, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, seizures, cough (including chronic cough), etc.

[0112] In some embodiments, the subject combination may be administered to relieve low back pain and musculoskeletal pain, including pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatic) arthritis, non-rheumatoid arthritis, periarthritis, axial spondyloarthritis including ankylosing spondylitis, Paget's disease, fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip, vertebral comminuted fractures, osteoporosis, etc.

[0113] In some embodiments, the subject combination may be administered to relieve musculoskeletal pain, arthritis pain, and inflammatory pain, including complex regional pain syndrome.

[0114] Arthritis refers to inflammatory joint diseases that may be associated with pain. Examples of arthritis include pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatic) arthritis, non-rheumatic arthritis, periarthritis, neuropathic arthritis including Charcot foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome.

[0115] In some embodiments, the subject combination is used to treat chronic musculoskeletal pain.

[0116] In some embodiments, the subject composition may be administered to alleviate complex regional pain syndromes such as complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or other types of CRPS. CRPS is a type of inflammatory pain. CRPS also has 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, autonomic, motor, and sensory changes.

[0117] In some embodiments, the subject composition is administered to relieve neuropathic pain.

[0118] Examples of neuropathic pain include pain due to diabetic peripheral neuropathy or diabetic peripheral neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, central pain, and pain due to multiple sclerosis. 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 radiotherapy or chemotherapy.

[0119] In some embodiments, the subject composition may be administered to alleviate fibromyalgia.

[0120] In some embodiments, the subject composition may be co-administered with one or more potent CYP2D6 inhibitors. It has been shown that the combination of the subject with one or more CYP2D6 inhibitors increases plasma concentrations of dextromethorphan. Therefore, it is recommended to monitor patients for possible side effects or adverse reactions attributable to dextromethorphan, such as drowsiness and dizziness.

[0121] When the subject composition is co-administered with one or more potent CYP2D6 inhibitors, dose adjustments may be necessary. Adjustments to lower doses of bupropion and / or dextromethorphan in the subject combination, or adjustments to reduce the frequency of administration of the subject combination, may reduce side effects or adverse reactions such as drowsiness, dizziness, or combinations thereof in patients, but are not limited to these. For example, the recommended dose of the subject combination when co-administered with one or more potent CYP2D6 inhibitors is a tablet containing 45 mg or less of dextromethorphan hydrobromide and 105 mg or less of bupropion hydrochloride, administered once daily, such as once daily in the morning.

[0122] Administering the subject combination once daily to patients receiving potent CYP2D6 inhibitors may reduce side effects such as drowsiness, dizziness, or combinations thereof, compared to administering the subject combination twice daily for the same number of days. In some embodiments, drowsiness may be reduced by reducing the dose or frequency of administration of the subject combination. In some embodiments, dizziness may be reduced by reducing the dose or frequency of administration. Since dizziness can lead to falls, adjusting the amount or frequency of administration of the subject combination may reduce the risk of falls in patients taking the subject combination. For example, once-daily administration of the subject combination may reduce the risk of falls in patients compared to twice-daily administration of the subject combination for the same number of days. This may be important, for example, in elderly patients or patients suffering from dementia, such as those with Alzheimer's disease.

[0123] In some embodiments, the subject composition may be administered to patients with moderate renal impairment. As described herein, administration of the subject composition to patients with low CYP2D6 metabolism has been shown to increase plasma dextromethorphan concentrations compared to patients without low CYP2D6 metabolism. Therefore, it is recommended to monitor patients for possible side effects or adverse reactions attributable to dextromethorphan, such as drowsiness and dizziness.

[0124] If the patient has moderate renal impairment, dose adjustments may be necessary. Adjustments to lower doses of bupropion and / or dextromethorphan in the subject combination, or adjustments to reduce the frequency of administration of the subject combination, may reduce the risk of adverse reactions or side effects, such as drowsiness, dizziness, or combinations thereof, in the patient. For example, the recommended dose of the subject combination when administered to a patient with moderate renal impairment is a tablet containing 45 mg or less of dextromethorphan hydrobromide and 105 mg or less of bupropion hydrochloride, once daily, such as once daily in the morning.

[0125] Administering the subject combination once daily to patients with moderate renal impairment may reduce the risk of side effects, or a combination thereof, including, but not limited to, drowsiness, dizziness, or a combination thereof, compared to administering the subject combination twice daily for the same number of days. In some embodiments, drowsiness may be reduced by reducing the dose or frequency of administration of the subject combination. In some embodiments, dizziness may be reduced by reducing the dose or frequency of administration. Since dizziness can lead to falls, adjusting the amount of the subject combination administered to a lower dose or to a lower frequency of administration may reduce the risk of falls in patients taking the subject combination. For example, taking the subject combination once daily may reduce the risk of falls in patients compared to taking the subject combination twice daily for the same number of days. This may be important, for example, in elderly patients or patients suffering from dementia, such as those with Alzheimer's disease.

[0126] The terms “to treat” or “treatment” include any activity that diagnoses, treats, alleviates, manages or prevents disease in humans or other animals, or otherwise affects the structure or function of the body of a human or other animal.

[0127] The subject matter combinations are the following U.S. Patents: 8,569,328, 9,168,234, 9,189,905, 9,205,083, 9,238,032, 9,278,095, 9,314,462, 9,370,513, 9,375,429, 9,408,815, 9,421,176, 9,457,023, 9,457,025, 9,474,731, 9,486,450, and 9,700,528. , No. 9,700,553, No. 9,707,191, No. 9,763,932, No. 9,861,595, No. 9,867,819, No. 9,968,568, No. 10,058,518, No. 10,064,857, No. 10,0 80,727, 10,092,560, 10,092,561, 10,105,327, 10,105,361, 10,251,879, 10,463,634, 10,512,643, 10,54 8,857, 10,596,167, 10,772,850, 10,780,064, 10,780,066, 10,786,469, 10,786,496, 10,799,497, 10,80 6,710, 10,864,209, 10,874,663, 10,874,664, 10,874,665, 10,881,624, 10,881,657, 10,894,046, 10,894 In any of ,047, 10,898,453, the combination of bupropion and dextromethorphan may be used to treat any disease or condition identified as treatable by such combination, all of which are incorporated herein by reference in their entirety for their disclosure of diseases treatable by such combination, including specific embodiments and combinations described therein.

[0128] Furthermore, the following U.S. provisional applications—No. 63 / 359,143 filed on 7 July 2022, No. 63 / 370,592 filed on 5 August 2022, No. 63 / 396,182 filed on 8 August 2022, No. 63 / 373,040 filed on 19 August 2022, and No. 63 / 401,541 filed on 26 August 2022—are also incorporated herein by reference in their entirety.

[0129] (Example 1) In a subject combination study involving seven subjects with moderate renal impairment (GFR 30-60 mL / min) compared to six condition-matched controls with normal renal function (sex, age, and weight range matched to subjects with impairment), exposure to both dextromethorphan and bupropion increased approximately twofold, and clearance decreased by 50%.

[0130] (Example 2) Approximately 7% to 10% of Caucasians and 3% to 8% of African Americans lack the ability to metabolize CYP2D6 substrates and are classified as low-metabolism groups. In three individuals in the low-metabolism group, the pharmacokinetics of the subject combination were as follows: dextromethorphan C max and AUC 0-12 Compared to the high-metabolism group, the levels increased by approximately 3 times and 3.4 times, respectively. In the efficacy trial, steady-state pharmacokinetic data from 12 patients in the low-metabolism group treated with the subject combination showed generally higher plasma concentrations of dextromethorphan than those in the non-low-metabolism group.

[0131] (Example 3) In 29 healthy volunteers, co-administration of the SSRI paroxetine with the subject combination containing dextromethorphan and bupropion was tested. Paroxetine increased systemic exposure to dextromethorphan 2.5 times, while bupropion had no effect. When co-administered with the subject combination, systemic exposure to paroxetine increased 1.2 times. Based on these results, when the subject combination is prescribed with a CYP2D6 inhibitor, the subject combination should be administered once daily. Caution should be exercised when administering the subject combination in combination with drugs that are rapidly metabolized via CYP2D6.

[0132] (Example 4) The tablets are prepared for oral administration. They are round, two-layer tablets. Each tablet contains 45 mg of dextromethorphan hydrobromide (equivalent to 32.98 mg of dextromethorphan free base) in an immediate-release formulation and 105 mg of bupropion hydrochloride (equivalent to 91.14 mg of bupropion free base) in a sustained-release formulation. Each tablet contains the following inactive ingredients: carbomer homopolymer, colloidal silicon dioxide, crospovidone, glyceryl monocaprylocate, L-cysteine ​​hydrochloride monohydrate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, red iron oxide, sodium lauryl sulfate, stearic acid, talc, titanium dioxide, and / or yellow iron oxide.

[0133] (Example 5) The properties of the tablets in Example 4, which included a combination of dextromethorphan hydrobromide, a non-competitive NMDA receptor antagonist and sigma-1 receptor agonist, and bupropion hydrochloride, an aminoketone and CYP450 2D6 inhibitor, were tested.

[0134] Figure 1 summarizes the effects of renal impairment, hepatic impairment, and the status of the CYP2D6 dysmetabolism group on exposure to the tablets in Example 4.

[0135] The results shown in Figure 1 are based on plasma concentrations in human patients after administration of tablets containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride twice daily for 8 days. Data are GMR and 90% CI. The references used were healthy subjects matched for renal and hepatic impairment studies, representing the hypermetabolism or hyperfast metabolism groups, respectively, for CYP2D6 metabolism. AUC represents the area under the plasma concentration-time curve from 0 to 12 hours, BUP represents bupropion, CI is the confidence interval, and C max is the maximum plasma concentration, DM represents dextromethorphan, GMR represents the geometric mean ratio, and PK represents pharmacokinetics.

[0136] In Figure 1, the results for patients with moderate renal impairment are designated as "Group 1," the results for patients with moderate hepatic impairment are designated as "Group 2," and the results for patients with CYP2D6 dysmetabolism are designated as "Group 3." The results are summarized in Table 3 below.

[0137] [Table 3]

[0138] For example, in patients with moderate hepatic impairment (Group 2), the AUC of dextromethorphan and bupropion 0-12 and C max There was no significant difference compared to that of healthy patients.

[0139] In patients with moderate hepatic impairment, the AUC of dextromethorphan 0-12 The mean ratio compared to healthy patients was 1.17, with a 90% confidence interval of 0.85–1.61.

[0140] In patients with moderate hepatic impairment, dextromethorphan C max The mean ratio compared to healthy patients was 1.21, with a 90% confidence interval of 0.90–1.62.

[0141] In patients with moderate hepatic impairment, the AUC of bupropion 0-12 The mean ratio compared to healthy patients was 1.36, with a 90% confidence interval of 0.86–2.15.

[0142] In patients with moderate hepatic impairment, bupropion C max The mean ratio compared to healthy patients was 1.44, with a 90% confidence interval of 0.90–2.30.

[0143] Based on these results, it is recommended not to adjust the dose in patients known to have mild or moderate hepatic impairment.

[0144] In patients with moderate renal impairment, the AUC of dextromethorphan 0-12 A 2.21-fold increase in dextromethorphan C max A 2.10-fold increase in bupropion's AUC 0-12 Then, a 1.80-fold increase, bupropion C max A 1.87-fold increase was observed.

[0145] Based on these results, dose adjustment is recommended in patients known to have moderate renal impairment, as they will have higher concentrations of dextromethorphan and bupropion than patients with healthy renal function. The recommended total daily dose for patients known to have moderate renal impairment is approximately 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride (for example, one tablet containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride once daily, for example, in the morning), or equivalent amounts of other forms of dextromethorphan and / or bupropion.

[0146] (Example 6) The effect of co-administration of 20 mg of paroxetine on dextromethorphan exposure was measured in patients taking the Example 4 tablet containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride twice daily. The AUC of dextromethorphan was compared to patients taking the tablet twice daily without paroxetine. 0-12 It increased 2.69 times, and the C of dextromethorphan max It increased 2.38 times.

[0147] (Example 7) In a placebo-controlled clinical trial (Trial 1), the efficacy of the Example 4 tablets for the treatment of major depressive disorder in adults was demonstrated. In this trial, adult patients (ages 18–85 years) meeting the criteria of the Diagnostic and Statistical Manual of Mental Disorders for MDD (DSM-5) were randomly assigned to receive either the Example 1 tablets ("DM / BU," 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) twice daily for 6 weeks (N=156) or a placebo twice daily (N=162). The median age of patients in Trial 1 was 41 years, 67% were female, 55% were Caucasian, 35% were Black, and 5% were Asian. Here, "N" represents the number of adult patients.

[0148] The primary outcome measure was the change in the total Montgomery-Asberg Depression Rating Scale (MADRS) score from baseline to week 6. The MADRS is a clinician rating scale used to assess the severity of depressive symptoms. Patients rate feelings of sadness, inner tension, decreased sleep or appetite, difficulty concentrating, fatigue, lack of interest, pessimism, and suicidal ideation on a 10-item scale. MADRS scores range from 0 to 60, with higher scores indicating more severe depression. DM / BU was statistically significantly superior to placebo in improvement of depressive symptoms, as measured by the decrease in the total MADRS score at week 6 (see Table 4 and Figure 2).

[0149] Table 4. Primary efficacy results for the change from baseline in the total MADRS score at 6 weeks in adults with MDD. [Table 4]

[0150] Figure 1 shows the weekly change from baseline in the total MADRS score. The change in total MADRS score from baseline to week 1, and the change in total MADRS score from baseline to week 2, were pre-specified secondary efficacy endpoints. The difference between DM / BU and placebo in the change from baseline in total MADRS score was statistically significant at weeks 1 and 2.

[0151] No differences in response were suggested in studies of demographic subgroups based on age, sex, and race.

[0152] Unless otherwise specified, all numerical values ​​representing quantities such as component amounts, quantities, and percentages used in the specification and claims should be understood in all cases to represent both the exact value as indicated and a value modified by the terms "approximately," "about," or "nearly." Therefore, unless otherwise indicated, the numerical parameters shown herein and in the appended claims are approximations that may vary depending on the desired properties to be obtained. At the very least, without attempting to limit the application as equivalents to the claims, each numerical parameter should be interpreted, at least in light of the number of significant figures reported, by applying ordinary rounding methods.

[0153] The use of the terms “comprising” or “comprises” in this specification is also intended to be replaced by “consisting essentially of,” “consists essentially of,” “consisting of,” or “consists of.”

[0154] Any positive description of an element in this specification should be understood as intended to both include and exclude that element.

[0155] The terms “a,” “an,” “the,” and similar references used in the context of describing embodiments (particularly in the context of the following claims) should be construed to cover both singular and plural forms unless otherwise stated or unless the context clearly contradicts this. All embodiments or use of exemplary language (e.g., “like”) provided herein are intended to better illustrate the embodiments and not to limit the scope of any claim. Nothing described herein should be construed as indicating non-claim elements essential to the implementation of a claim.

[0156] The grouping of alternative elements or embodiments disclosed herein should not be construed as limitation. Each group's components may be referenced and claimed individually or in any combination with other components of the group or other elements found herein. For convenience and / or expediency of procedure, it is anticipated that one or more components of a group may be included in or removed from the group. If such inclusion or removal occurs, this specification shall be deemed to include the modified group and, when used in the appended claims, shall satisfy all descriptions of the Markush group.

[0157] This specification describes several embodiments, including the best mode for carrying out the claimed embodiments as known to the inventor. Of course, variations of these described embodiments will be obvious to those skilled in the art by reading the preceding description. The inventor expects that those skilled in the art will appropriately use such variations, and the inventor intends to carry out the claimed embodiments in ways other than those specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter described herein, as permitted by applicable law. Furthermore, any combination of the above elements with any conceivable variations is conceivable unless otherwise stated herein or unless it is clearly inconsistent with the context.

[0158] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be adopted are within the scope of the claims. Therefore, alternative embodiments can be utilized in accordance with the teachings herein, not as examples but as examples. Accordingly, the claims are not limited to the embodiments shown and described.

[0159] (Note) (Note 1) A method for treating major depressive disorder in human patients, comprising administering once daily to human patients who have experienced major depressive disorder and have a score of at least 13 on the Quick IdS-SR-16 (QIDS-SR-16), the combination comprising: (i) approximately 100 mg to approximately 110 mg of bupropion hydrochloride, or an equivalent molar amount of dextromethorphan in its free base form or other salt form; and (ii) approximately 40 mg to approximately 50 mg of dextromethorphan hydrobromide, or an equivalent molar amount of dextromethorphan in its free base form or other salt form, wherein the combination is administered in any dosage form.

[0160] (Note 2) The method according to Appendix 1, wherein bupropion and dextromethorphan are contained in a single tablet, and the tablet containing approximately 105 mg of bupropion hydrochloride and approximately 45 mg of dextromethorphan hydrobromide is administered orally twice daily.

[0161] (Note 3) Dextromethorphan T max The method described in Appendix 1 takes approximately 3 hours.

[0162] (Note 4) Steady-state plasma concentrations of dextromethorphan and bupropion were achieved within 8 days, and the steady-state accumulation rate of dextromethorphan was C max The method described in Appendix 1, which is approximately 20.

[0163] (Note 5) Steady-state plasma concentrations of dextromethorphan and bupropion were achieved within 8 days, and the steady-state accumulation rate of dextromethorphan was measured at AUC. 0-12 The method described in Appendix 1, which is approximately 32.

[0164] (Note 6) The method according to Appendix 1, wherein the combination of approximately 45 mg of dextromethorphan hydrobromide and approximately 105 mg of bupropion hydrochloride is administered to the human patient twice daily until the human patient experiences a reduction of at least approximately 7 from baseline in the human patient's total MADRS score.

[0165] (Note 7) The method according to Appendix 1, wherein the combination of approximately 45 mg of dextromethorphan hydrobromide and approximately 105 mg of bupropion hydrochloride is administered to the human patient twice daily until the human patient experiences a reduction of at least approximately 11 from baseline in the human patient's total MADRS score.

[0166] (Note 8) The method according to Appendix 1, wherein the combination of approximately 45 mg of dextromethorphan hydrobromide and approximately 105 mg of bupropion hydrochloride is administered to the human patient twice daily until the human patient experiences a reduction of at least approximately 13 from baseline in the human patient's total MADRS score.

[0167] (Note 9) The method according to Appendix 1, wherein the combination of approximately 45 mg of dextromethorphan hydrobromide and approximately 105 mg of bupropion hydrochloride is administered to the human patient twice daily until the human patient experiences a reduction of at least approximately 15.9 from baseline in the human patient's total MADRS score.

[0168] (Note 10) The method described in Appendix 1, wherein the reduction from baseline in the total MADRS score of the human patient when administered the combination is greater than the reduction when administered with placebo.

[0169] (Note 11) The method according to Appendix 1, wherein, after one week of administration, the reduction from baseline in the total MADRS score of the human patient administered the combination is greater than the reduction when a placebo is administered.

[0170] (Note 12) The method according to Appendix 1, wherein, after two weeks of administration, the reduction from baseline in the total MADRS score of the human patient administered the combination is greater than the reduction when a placebo is administered.

[0171] (Note 13) The method according to Appendix 1, wherein, after 3 weeks of administration, the reduction from baseline in the total MADRS score of the human patient administered the combination is greater than the reduction when a placebo is administered.

[0172] (Note 14) The method according to Appendix 1, wherein, after 4 weeks of administration, the reduction from baseline in the total MADRS score of the human patient administered the combination is greater than the reduction when administered placebo.

[0173] (Note 15) The method according to Appendix 1, wherein, after 5 weeks of administration, the reduction from baseline in the total MADRS score of the human patient administered the combination is greater than the reduction when administered with placebo.

[0174] (Note 16) The method according to Appendix 1, wherein, after 6 weeks of administration, the reduction from baseline in the total MADRS score of the human patient administered the combination is greater than the reduction when administered placebo.

[0175] (Note 17) The method according to Appendix 1, wherein the dosage form is a solid dosage form.

[0176] (Note 18) The dosage form is administered orally, as described in Appendix 1.

[0177] (Note 19) The aforementioned dosage form is the method described in Appendix 1, which releases dextromethorphan immediately.

[0178] (Note 20) The dosage form is the method described in Appendix 1, which releases bupropion over a sustained period.

Claims

1. A method for treating major depressive disorder in a human patient, comprising administering once daily to a human patient who has experienced major depressive disorder and has a score of at least 13 on the Quick IdS-SR-16 (QIDS-SR-16), the combination comprising: (i) approximately 100 mg to approximately 110 mg of bupropion hydrochloride, or an equivalent molar amount of dextromethorphan in its free base form or other salt form; and (ii) approximately 40 mg to approximately 50 mg of dextromethorphan hydrobromide, or an equivalent molar amount of dextromethorphan in its free base form or other salt form, wherein the combination is administered in any dosage form.

2. The method according to claim 1, wherein bupropion and dextromethorphan are contained in a single tablet, and the tablet containing about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide is administered orally twice daily.

3. Dextromethorphan T ｍａｘ The method according to claim 1, which takes approximately 3 hours.

4. Steady-state plasma concentrations of dextromethorphan and bupropion were achieved within 8 days, and the steady-state accumulation rate of dextromethorphan was C ｍａｘ The method according to claim 1, wherein the value is approximately 20.

5. Steady-state plasma concentrations of dextromethorphan and bupropion were achieved within 8 days, and the steady-state accumulation rate of dextromethorphan was AUC. ０－１２ The method according to claim 1, wherein the value is approximately 32.

6. The method according to claim 1, wherein the combination of approximately 45 mg of dextromethorphan hydrobromide and approximately 105 mg of bupropion hydrochloride is administered to the human patient twice daily until the human patient experiences a reduction of at least approximately 7 from baseline in the human patient's total MADRS score.

7. The method according to claim 1, wherein the combination of approximately 45 mg of dextromethorphan hydrobromide and approximately 105 mg of bupropion hydrochloride is administered to the human patient twice daily until the human patient experiences a reduction of at least approximately 11 from baseline in the human patient's total MADRS score.

8. The method according to claim 1, wherein the combination of approximately 45 mg of dextromethorphan hydrobromide and approximately 105 mg of bupropion hydrochloride is administered to the human patient twice daily until the human patient experiences a reduction of at least approximately 13 from baseline in the human patient's total MADRS score.

9. The method according to claim 1, wherein the combination of approximately 45 mg of dextromethorphan hydrobromide and approximately 105 mg of bupropion hydrochloride is administered to the human patient twice daily until the human patient experiences a reduction of at least approximately 15.9 from baseline in the human patient's total MADRS score.

10. The method according to claim 1, wherein the reduction from baseline in the total MADRS score of the human patient when administered the combination is greater than the reduction when administered a placebo.

11. The method according to claim 1, wherein, after one week of administration, the reduction from baseline in the total MADRS score of the human patient administered the combination is greater than the reduction when a placebo is administered.

12. The method according to claim 1, wherein, after two weeks of administration, the reduction from baseline in the total MADRS score of the human patient administered the combination is greater than the reduction when a placebo is administered.

13. The method according to claim 1, wherein, after three weeks of administration, the reduction from baseline in the total MADRS score of the human patient administered the combination is greater than the reduction when a placebo is administered.

14. The method according to claim 1, wherein, after four weeks of administration, the reduction from baseline in the total MADRS score of the human patient administered the combination is greater than the reduction when a placebo is administered.

15. The method according to claim 1, wherein, after 5 weeks of administration, the reduction from baseline in the total MADRS score of the human patient administered the combination is greater than the reduction when a placebo is administered.

16. The method according to claim 1, wherein, after 6 weeks of administration, the reduction from baseline in the total MADRS score of the human patient administered the combination is greater than the reduction when administered a placebo.

17. The method according to claim 1, wherein the dosage form is a solid dosage form.

18. The method according to claim 1, wherein the dosage form is administered orally.

19. The method according to claim 1, wherein the dosage form immediately releases dextromethorphan.

20. The method according to claim 1, wherein the dosage form releases bupropion over a sustained period.

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