Compounds and combinations thereof for treating depression in patients

Abstract

This disclosure relates to administration of a combination of: 1) about 100-110 mg, about 104-106 mg, or about 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion; and 2) about 40-50 mg, about 44-46 mg, or about 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of the free base form or another salt form of dextromethorphan.

Description

[0001]PCT Patent Application PCT of A3225.10038US01 COMPOUNDS AND COMBINATIONS THEREOF FOR TREATING DEPRESSION IN PATIENTS Inventor: Herriot Tabuteau CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Pat. App. Nos.63 / 605,337, filed December 1, 2023, and 63 / 605,408, filed December 1, 2023; which are expressly incorporated by reference herein in their entirety. SUMMARY Some embodiments include a method of improving interest-activity comprising administering a dosage form once daily or twice daily to a human patient in need thereof, wherein the dosage form comprises about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another form of bupropion, and about 105 mg of bupropion hydrochloride, or a molar equivalent amount of another form of bupropion, and wherein the human patient is experiencing major depressive disorder. Some embodiments include a method of treating major depressive disorder comprising administering a dosage form once daily or twice daily to a human patient in need thereof, wherein the dosage form comprises about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another form of dextromethorphan, and about 105 mg of bupropion hydrochloride, or a molar equivalent amount of another form of bupropion, and wherein the human patient is experiencing major depressive disorder, and has above average impairment in interest-activity as compared to other human patients experiencing major depressive disorder or has been treated with at least one prior treatment in the current major depressive episode. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 shows the interest-activity symptom score components.aThe QIDS-SR items (with scores from 0 to 3) were doubled for equal weight with the MADRS items (with scores from 0 to 6); higher interest-activity symptom score corresponds to more severe symptoms; MADRS represents Montgomery Åsberg Depression Rating Scale; QIDS-SR represents Quick Inventory of Depressive Symptomatology, Self-Report. PCT Patent Application PCT of A3225.10038US01 FIG.2A shows the interest-activity symptom scoreachange from baseline, and FIG.2B shows the interest-activity symptom scoreachange from response, wherein **P<0.01, ***P<0.001. Not adjusted for multiple comparisons.aThe interest-activity symptom score is the sum of 3 MADRS items (concentration, lassitude, and inability to feel) and 3 QIDS-SR items (concentration, interest, and energy). Higher interest-activity symptom score corresponds to more severe symptoms.bEstimates derived from MMRM with an unstructured covariance with fixed effects for baseline interest-activity symptom score, week, treatment group, and interaction terms for week and treatment group.con interest-activity symptom score from baseline. AXS-05 represents DM / BU. FIG.3 shows the average slopes of baseline interest-activity score with MADRS change from baseline across treatment weeks 1, 2, 3, 4, and 6. AXS-05 represents DM / BU. FIG.4A shows the changes in MADRS total score by baseline interest-activity symptom scoreawith control, and FIG.4B shows the changes in MADRS total score by baseline interest- activity symptom score with DM / BU.aThe interest-activity symptom score is the sum of 3 MADRS items (concentration, lassitude, and inability to feel) and 3 QIDS-SR items (concentration, interest, and energy). Higher interest-activity symptom score corresponds to more severe symptoms. High interest-activity is 1 SD above the mean in baseline interest- activity symptom score, average interest-activity score reflects mean baseline interest- activity symptom score, and low interest-activity score reflects 1 SD below the mean in interest-activity symptom score.bMarginal means for MADRS change from baseline scores. AXS-05 represents DM / BU. FIG. 5 shows the study design, wherein BID = twice daily; BL = baseline; DSM-5 = Diagnostic and statistical manual of mental disorders 5th edition; HAM-A = Hamilton Anxiety Rating Scale; MDD = major depressive disorder; MDE = major depressive episode; Q-LES-Q-SF = Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form. AXS-05 represents DM / BU. FIG.6A shows the Q-LES-Q-SF individual items, wherein 2 additional items (medication and overall life satisfaction) are not included in total score. PCT Patent Application PCT of A3225.10038US01 FIG.6B shows the Q-LES-Q-SF individual scoring, wherein the raw total score is the 14 items summed (14-70 total score) and then converted to percent score of maximum possible score. FIG.7 shows the MADRS total score response and remission. FIG. 8A shows the HAM-A score change from baseline. *P<0.001 for change from baseline calculated by 2-sided paired t-test.aLower score indicates improvement.bSample size at Week 1, n=141; Week 2, n=136; Week 6, n=124. AXS-05 represents DM / BU. FIG.8B shows the HAM-A score change from response. FIG. 9 shows the Q-LES-Q-SF percent and MADRS total score change from baseline. *P<0.001 for change from baseline calculated by 2-sided paired t-test for all timepoints.aHigher score indicates improvement.bLower score indicates improvement.cSample size at week 1, n=134; week 2, n=130; week 6, n=119. AXS-05 represents DM / BU. FIG. 10 shows the all individual Q-LES-Q-SF items and mean item scores which had consistent improvements from baseline except ability to get around physically, which had the highest baseline score (4.04, good).aQ-LES-Q-SF item not included in percent score. DETAILED DESCRIPTION As mentioned above, this disclosure relates to administration of a combination of: 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion; and 2) about 40-50 mg, about 44-46 mg, or about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base form or another salt form of dextromethorphan. This combination is referred to for convenience herein as the “subject combination.” In every instance where the subject combination is referred to herein, the combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is specifically contemplated. Dextromethorphan hydrobromide is an uncompetitive NMDA receptor antagonist and a sigma-1 receptor agonist. The chemical name of dextromethorphan hydrobromide is morphinan, 3-methoxy-17- methyl- PCT Patent Application PCT of A3225.10038US01 the empirical formula C18H25NO•HBr•H2O and a molecular weight of 370.33. The structural formula is: Dextromethorphan hydrobromide powder is white or almost white, crystalline, and sparingly soluble in water. Bupropion hydrochloride is an aminoketone and CYP4502D6 inhibitor. The chemical name of bupropion hydrochloride is: (±)-1-(3-chlorophenyl)-2-[(1,1- dimethylethyl)amino]-1-propanone hydrochloride. Bupropion hydrochloride has the empirical formula C13H18ClNO•HCl and a molecular weight of 276.2. The structural formula is: Bupropion hydrochloride powder is white and highly soluble in water. Other forms of dextromethorphan and bupropion may be used, such as other salt forms or the free base forms. The subject combination may be contained in an oral dosage form, including a tablet, such as an extended-release tablet. In some embodiments, the subject combination is contained in a dosage form for oral administration and is available as round bilayer tablets. 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 of the subject combination contains 105 mg of bupropion hydrochloride in an extended-release formulation. In some embodiments, each tablet of the subject combination contains 45 mg of dextromethorphan hydrobromide in an immediate- PCT Patent Application PCT of A3225.10038US01 release formulation and 105 mg of bupropion hydrochloride in an extended-release formulation. In some embodiments, a tablet containing the subject combination contains L- cysteine hydrochloride monohydrate. In some embodiments, a tablet containing the subject combination contains carbomer homopolymer. In some embodiments, a tablet containing the subject combination contains microcrystalline cellulose. In some embodiments, a tablet containing the subject combination contains colloidal silicon dioxide. In some embodiments, a tablet containing the subject combination contains crospovidone. In some embodiments, a tablet containing the subject combination contains stearic acid. In some embodiments, a tablet containing the subject combination contains magnesium stearate. In some embodiments, a tablet containing the subject combination contains the following inactive ingredients: L-cysteine hydrochloride monohydrate, carbomer homopolymer, microcrystalline cellulose, colloidal silicon dioxide, crospovidone, stearic acid, and magnesium stearate. In some embodiments, the starting dosage of the subject combination is 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride in one tablet that is administered once daily in the morning. In some embodiments, after 3 days, the dosage is increased to one tablet (or one dosage form containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) twice daily, e.g., given at least 8 hours apart. In some embodiments, no more than two doses containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride are administered in the same day. The subject combination may be administered orally with or without food. In some embodiments, the tablets are swallowed whole, and not crushed, divided, or chewed. In some embodiments, the subject combination is administered to the human patient twice daily until the human patient experiences a reduction from baseline of at least about 7, at least about 11, at least about 13, or at least about 15.9 in the human patient’s total MADRS score. In some embodiments, the human patient experiences a reduction from baseline in total MADRS score in the human patient for administering the subject combination that is PCT Patent Application PCT of A3225.10038US01 more than the patient would experience if a placebo were administered. The human patient taking the subject combination may experience the greater reduction in MADRS score than taking a placebo at, for example, after 1 week of administration, after 2 weeks of administration, after 3 weeks of administration, after 4 weeks of administration, after 5 weeks of administration, after 6 weeks of administration, or at other times. In some embodiments, the human patient is selected for having an interest-activity score of at least about 30, such as about 30-33, about 33-36, about 33-34, about 34-35, about 35-36, about 33, about 34, about 35, or about 36. The interest-activity score is based upon the following questions from the MADRS: Concentration difficulties, Lassitude, and Inability to Feel, and the following questions from the QIDS-SR: Concentration / decision making, General Interest, and Energy level. These questions are presented in the Table below. The QIDS-SR scores are doubled, and the sum of the MADRS scores and the doubled QIDS-SR scores is the interest-activity score. Interest-Activity Score Components PCT Patent Application PCT of A3225.10038US01 PCT Patent Application PCT of A3225.10038US01 Treatment may result in the interest-activity score of the human patient being reduced by: at leastbaseline as compared to what would result fromadministering a placebo. These results may be achieved, for example, at 1 week, at 2 weeks, at 3 weeks, at 4 weeks, at 6 weeks, etc. Treatment with the subject combination comprising dextromethorphan and bupropion may be a particularly effective treatment option in individuals with MDD who have substantially impaired interest and activity. In people with MDD, prominent interest-activity symptoms (low interest, reduced activity, indecisiveness, and lack of enjoyment) at baseline may be associated with poor treatment response to serotonergic antidepressants. In some embodiments, the treatment may significantly improve interest-activity symptom scores compared with control. In some embodiments, the treatment may exhibit comparable reductions in depressive symptoms regardless of severity of baseline interest-activity symptoms. PCT Patent Application PCT of A3225.10038US01 Treatment with the subject combination comprising dextromethorphan and bupropion for up to 1 year may rapidly and durably improve quality of life in people with MDD who failed 1 prior antidepressant in the current major depressive episode (MDE). Improvements may occur across the broad range of items associated with quality of life including overall life satisfaction, sense of wellbeing, and ability to function in daily life. The treatment may rapidly and durably improve depression and anxiety symptoms. The treatment may have long-term efficacy and safety in this patient population. In the subject combination, bupropion inhibits the metabolism of dextromethorphan via CYP2D6. Dextromethorphan, when co-administered with bupropion, displays nonlinear pharmacokinetics at steady state, with greater than dose-proportional changes in AUC and Cmax for varying doses of dextromethorphan (30 to 60 mg) and less than dose-proportional changes for varying doses of bupropion (75 to 150 mg). Steady state plasma concentrations of dextromethorphan and bupropion when given as the subject combination are achieved within 8 days. The accumulation ratios for dextromethorphan at steady state are about 20 and about 32, respectively based on Cmaxand AUC0-12. The accumulation ratios for bupropion at steady state are 1.1 and 1.5, respectively based on Cmaxand AUC0-12. After administration of the subject combination, the median Tmaxof dextromethorphan is about 3 hours and the median Tmax of bupropion is about 2 hours. The Cmaxof hydroxybupropion metabolite occurs approximately 3 hours post-dose and is approximately 14 times the peak level of bupropion. The AUC0-12 hydroxybupropion is about 19 times that of bupropion. The Cmaxof the erythrohydroxybupropion and threohydroxybupropion metabolites occurs approximately 4 hours post-dose and is approximately equal to and about 5 times that of bupropion, respectively. The AUC0-12values of erythrohydroxybupropion and threohydroxybupropion are about 1.2 and about 7 times that of bupropion, respectively. The subject combination can be taken with or without food. Dextromethorphan Cmaxand AUC0-12 maxand AUC0-12the subject combination was administered with food. PCT Patent Application PCT of A3225.10038US01 The plasma protein binding of dextromethorphan is approximately 60- similar to that for bupropion; whereas the extent of protein binding of the threohydroxybupropion metabolite is about half that seen with bupropion. Following 8 days of administration of the subject combination in extensive metabolizers, the mean elimination half-life of dextromethorphan was increased approximately 3-fold to about 22 hours, as compared to dextromethorphan given without bupropion. The mean elimination half-life of dextromethorphan and bupropion was 22 hours and 15 hours, respectively. The apparent elimination half-life of hydroxybupropion, erythrohydroxybupropion and threohydroxybupropion metabolites were approximately 35, 44 and 33 hours, respectively. Unlike the combination of quinidine and dextromethorphan, at a dose of a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide given twice a day, the subject combination does not prolong the QT interval to any clinically relevant extent. Thus, for a human patient who is experiencing major depressive disorder and is at risk of QT prolongation and torsades de pointes, electrocardiographic evaluation of QT interval is not typically conducted on the human patient. The subject combination may be used for adjunctive treatment of major depressive disorder or depression. In addition to major depressive disorder, the subject combination may be used to treat other diseases in conditions in the patient populations or circumstances described herein. For example, the subject combination may be used to treat pain or a neurological disorder. Examples of neurological disorders that may be treated with the subject combination include, but are not limited to: affective disorders, psychiatric disorders, cerebral function disorders, movement disorders, dementias, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches. Affective disorders that may be treated by the subject combination include, but are not limited to, depression, major depression, treatment resistant depression, treatment resistant bipolar depression, bipolar disorders including cyclothymia, seasonal affective PCT Patent Application PCT of A3225.10038US01 disorder, mood disorders, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit disorder with hyperactivity (ADDH), and attention deficit / hyperactivity disorder (AD / HD), bipolar and manic conditions, obsessive-compulsive disorder, bulimia, obesity or weight-gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psycho-sexual dysfunction, pseudobulbar affect, and emotional lability. Depression may be manifested by depressive symptoms. These symptoms may include psychological changes such as changes in mood, feelings of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal thoughts, or attempts, and / or self-deprecation. Physical symptoms of depression may include insomnia, anorexia, appetite loss, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, aches, pains, headaches, cramps, digestive issues, and / or abnormal hormonal circadian rhythms. Psychiatric disorders that may be treated by the subject combination, include, but are not limited to, anxiety disorders, including but not limited to, phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD); mania, manic depressive illness, hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizotypy, aggression, aggression in Alzheimer’s disease, agitation, and agitation in Alzheimer’s disease. Alzheimer’s disease may also be referred to as dementia of the Alzheimer’s type. Other neurobehavioral symptoms of Alzheimer’s disease that may be treated include disinhibition and apathy. Agitation in Alzheimer’s disease occurs as the disease progresses. Agitation may present itself as inappropriate verbal, emotional, and / or physical behaviors. Inappropriate behaviors may include, but are not limited to, incoherent babbling, inappropriate emotional response, demands for attention, threats, irritability, frustration, screaming, repetitive questions, mood swings, cursing, abusive language, physical outbursts, emotional distress, restlessness, shredding, sleeping disturbances, delusions, hallucinations, pacing, wandering, PCT Patent Application PCT of A3225.10038US01 searching, rummaging, repetitive body motions, hoarding, shadowing, hitting, scratching, biting, combativeness, hyperactivity, and / or kicking. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, and behavioral and psychological symptoms including agitation. AD is the most common form of dementia and afflicts an estimated 6 million individuals in the United States, a number that is anticipated to increase to approximately 14 million by 2050. Agitation aggressive behaviors, disruptive irritability, and disinhibition. Managing agitation is a priority in AD. Agitation in patients with AD has been associated with increased caregiver burden, decreased functioning, accelerated cognitive decline, earlier nursing home placement, and increased mortality. There are currently no therapies approved by the FDA for the treatment of agitation in patients with AD. Neurobehavioral symptoms have been known to appear during dementia and may be treated by the combination. Caregivers or families may feel more overwhelmed by patients' behavioral / psychological symptoms than by their cognitive impairment. Common forms of the syndrome are Alzheimer's disease, vascular dementia, dementia with Lewy bodies (abnormal aggregates of protein that develop inside nerve cells), and a group of diseases that contribute to frontotemporal dementia (degeneration of the frontal lobe of the brain). The symptoms that dementia patients have are similar to those of psychiatric disorders, but some are slightly different from each other. Neurobehavioral symptoms associated with dementia include depression, apathy, agitation, disinhibition, hallucinations, delusions, psychosis, impulsiveness, aggressiveness, compulsion, excessive sex drive, and personality disorders. Neurobehavioral symptoms such as disinhibition may also be found in other conditions such as traumatic brain injury. Agitation in patients with Alzheimer’s disease may be assessed using the Cohen Mansfield Agitation Inventory or CMAI. The CMAI assesses various behaviors including, Hitting (including self), Kicking , Grabbing onto people, Pushing, Throwing things, Biting , Scratching, Spitting, Hurting self or others, Tearing things or destroying property, Making physical sexual advances, Pacing, aimless wandering, Inappropriate dress or disrobing, Trying to get to a different place, Intentional falling, Eating / drinking inappropriate substances, Handling things inappropriately, Hiding things, Hoarding things, Performing repetitive PCT Patent Application PCT of A3225.10038US01 mannerisms, General restlessness, Screaming , Making verbal sexual advances, Cursing or verbal aggression, Repetitive sentences or questions, Strange noises (weird laughter or crying), Complaining, Negativism, Constant unwarranted request for attention or help. Schizophrenia may be treated by the combination including positive symptoms and / or negative symptoms of schizophrenia, or residual symptoms of schizophrenia. Other conditions that may treated include intermittent explosive disorder. Cerebral function disorders that may be treated by the subject combination include, but are not limited to, disorders involving intellectual deficits such as senile dementia, Alzheimer’s type dementia, memory loss, amnesia / amnestic syndrome, epilepsy, disturbances of consciousness, coma, lowering of attention, speech disorders, voice spasms, Parkinson’s disease, Lennox-Gastaut syndrome, autism, hyperkinetic syndrome, and schizophrenia. Cerebral function disorders also include disorders caused by cerebrovascular diseases including, but not limited to, stroke, cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis, head injuries, and the like where symptoms include disturbance of consciousness, senile dementia, coma, lowering of attention, and speech disorders. Substance addiction abuse that may be treated by the subject combination includes, but is not limited to, drug dependence, addiction to cocaine, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, anxiolytic and hypnotic drugs, cannabis(marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatilenitrites. Nicotine addiction includes nicotine addiction of all known forms, such as smoking cigarettes, cigars and / or pipes, e-cigarettes or vaping, and addiction to chewing tobacco. Movement disorders that may be treated by the subject combination include, but are not limited to, akathisia, akinesia, associated movements, athetosis, ataxia, ballismus, hemiballismus, 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 legs syndrome (RLS), tremor, essential tremor, and Tourette’s syndrome, and Wilson’s disease. PCT Patent Application PCT of A3225.10038US01 Dementias that may be treated by the subject combination include, but are not limited to, Alzheimer’s disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, fronto-temporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington’s disease, Wernicke-Korsakoff Syndrome, and Pick’s disease. Motor neuron diseases that may be treated by the subject combination include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophies, Tay-Sach’s disease, Sandhoff disease, and hereditary spastic paraplegia. Neurodegenerative diseases that may be treated the subject combination include, but are not limited to, Alzheimer’s disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich’s ataxia, Huntington’s disease, Lewy body disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson’s disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophies, Charcot-Marie-Tooth disease (CMT), familial spastic paraparesis, neurofibromatosis, olivopontine cerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplesia. Seizure disorders that may be treated by the subject combination include, but are not limited to, epileptic seizures, nonepileptic seizures, epilepsy, febrile seizures; partial seizures including, but not limited to, simple partial seizures, Jacksonian seizures, complex partial seizures, and epilepsia partialis continua; generalized seizures including, but not limited to, generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus. Types of headaches that may be treated by the subject combination include, but are not limited to, migraine, tension, and cluster headaches. Other neurological disorders that may be treated by the subject combination include, Rett Syndrome, autism, tinnitus, disturbances of consciousness disorders, sexual dysfunction, PCT Patent Application PCT of A3225.10038US01 intractable coughing, narcolepsy, cataplexy; voice disorders due to uncontrolled laryngeal muscle spasms, including, but not limited to, abductor spasmodic dysphonia, adductor spasmodic dysphonia, muscular tension dysphonia, and vocal tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity, such as methotrexate neurotoxicity; incontinence including, but not limited, stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction. In some embodiments, the subject combination may be used to treat pain, joint pain, pain associated with sickle cell disease, pseudobulbar affect, depression (including treatment resistant depression), disorders related to memory and cognition, schizophrenia, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Rhett’s syndrome, seizures, cough (including chronic cough), etc. In some embodiments, the subject combination may be administered orally to relievemusculoskeletal pain including low back pain, and pain associated with rheumatoid arthritis,juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, sero-negative (non- rheumatoid) arthropathies, non-articular rheumatism, peri-articular disorders, axial spondyloarthritis including ankylosing spondylitis, Paget’s disease, fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip, vertebral crush fractures, osteoporosis, etc. In some embodiments, the subject combination may be administered to relieve inflammatory pain including musculoskeletal pain, arthritis pain, and complex regional pain syndrome. Arthritis refers to inflammatory joint diseases that can be associated with pain. Examples of arthritis pain include pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, peri-articular disorders, neuropathic arthropathies including Charcot’s foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome. In some embodiments, the subject combination is used to treat chronic musculoskeletal pain. In some embodiments, the subject composition may be administered to relieve complex regional pain syndrome, such as complex regional pain syndrome type I (CRPS-I), PCT Patent Application PCT of A3225.10038US01 complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or another type of CRPS. CRPS is a type of inflammatory pain. CRPS can also have a neuropathic component. Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain in a limb that can be accompanied by edema, and autonomic, motor, and sensory changes. In some embodiments, the subject composition may be administered orally to relieve neuropathic pain. Examples of neuropathic pain include pain due to diabetic peripheral neuropathy or diabetic peripheral neuropathic pain, post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, central pain, pain due to multiple sclerosis, etc. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV- associated neuropathy, and radio- or chemo-therapy associated neuropathy, etc. In some embodiments, the subject composition may be administered to relieve fibromyalgia. The term “treating” or “treatment” includes the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals, or any activity that otherwise affects the structure or any function of the body of man or other animals. The following are examples of embodiments that are specifically contemplated by the inventor: Embodiment 1. A method of improving interest-activity comprising administering a dosage form once daily or twice daily to a human patient in need thereof, wherein dosage form comprises about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another form of bupropion, and about 105 mg of bupropion hydrochloride, or a molar equivalent amount of another form of bupropion, and wherein the human patient is experiencing major depressive disorder. Embodiment 2. A method of treating major depressive disorder comprising administering a dosage form once daily or twice daily to a human patient in need thereof, wherein dosage form comprises about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another form of bupropion, and about 105 mg of bupropion hydrochloride, or a molar equivalent amount of another form of bupropion, and wherein the PCT Patent Application PCT of A3225.10038US01 human patient is experiencing major depressive disorder and has above average impairment in interest-activity as compared to other human patients experiencing major depressive disorder. Embodiment 3. The method of embodiment 1 or 2, wherein the human patient has an interest-activity score of 33, 34, 35, or 36. Embodiment 4. The method of any preceding embodiment, wherein the combination of about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride is administered to the human patient once daily for about 6 weeks. Embodiment 5. The method of any preceding embodiment, wherein the combination of about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride is administered to the human patient twice daily for at least 6 weeks. Embodiment 6. The method of any preceding embodiment, wherein the dosage form is a solid dosage form. Embodiment 7. The method of any preceding embodiment, wherein the dosage form further contains a carbomer homopolymer. Embodiment 8. The method of any preceding embodiment, wherein the dosage form further contains colloidal silicon dioxide. Embodiment 9. The method of any preceding embodiment, wherein the dosage form further contains crospovidone. Embodiment 10. The method of any preceding embodiment, wherein the dosage form further contains glyceryl monocaprylocaprate. Embodiment 11. The method of any preceding embodiment, wherein the dosage form further contains L-cysteine hydrochloride monohydrate. Embodiment 12. The method of any preceding embodiment, wherein the dosage form further contains magnesium stearate. Embodiment 13. The method of any preceding embodiment, wherein the dosage form further contains microcrystalline cellulose. PCT Patent Application PCT of A3225.10038US01 Embodiment 14. The method of any preceding embodiment, wherein the dosage form further contains polyvinyl alcohol. Embodiment 15. The method of any preceding embodiment, wherein the dosage form further contains red iron oxide. Embodiment 16. The method of any preceding embodiment, wherein the dosage form further contains sodium lauryl sulfate. Embodiment 17. The method of any preceding embodiment, wherein the dosage form further contains stearic acid. Embodiment 18. The method of any preceding embodiment, wherein the dosage form further contains talc. Embodiment 19. The method of any preceding embodiment, wherein the dosage form further contains titanium dioxide. Embodiment 20. The method of any preceding embodiment, wherein the dosage form further contains yellow iron oxide. Embodiment 21. The method of any preceding embodiment, wherein the dosage form is a tablet. Embodiment 22. The method of embodiment 21, wherein the tablet is a bilayer tablet. Embodiment 23. The method of any preceding embodiment, wherein the dosage form is orally administered. Embodiment 24. The method of embodiment 23, wherein the solid dosage form is orally administered in the morning. Embodiment 25. The method of any preceding embodiment, wherein the dextromethorphan is in an immediate-release formulation. Embodiment 26. The method of any preceding embodiment, wherein the bupropion is in an extended-release formulation. Embodiment 27. A method of treating major depressive disorder comprising administering a dosage form once daily or twice daily to a human patient in need thereof, wherein dosage form comprises about 45 mg of dextromethorphan hydrobromide, or a molar PCT Patent Application PCT of A3225.10038US01 equivalent amount of another form of dextromethorphan, and about 105 mg of bupropion hydrochloride, or a molar equivalent amount of another form of bupropion, and wherein the human patient is experiencing major depressive disorder and has been treated with at least one prior treatment in the current major depressive episode. Embodiment 28. The method of embodiment 27, wherein the human patient has a MADRS total score of at least 30. Embodiment 29. The method of embodiment 27, wherein the human patient has a CGI- S total score of at least 4. Embodiment 30. The method of embodiment 27, wherein the human patient has a HAM-A score of at least 15. Embodiment 31. The method of embodiment 27, wherein the human patient has a Q- LES-Q-SF percent score that is less than 42. Embodiment 32. The method of any preceding embodiment, wherein the combination of about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride is administered to the human patient once daily for about 6 weeks. Embodiment 33. The method of any preceding embodiment, wherein the combination of about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride is administered to the human patient twice daily for at least 6 weeks. Embodiment 34. The method of any preceding embodiment, wherein the dosage form is a solid dosage form. Embodiment 35. The method of any preceding embodiment, wherein the dosage form further contains a carbomer homopolymer. Embodiment 36. The method of any preceding embodiment, wherein the dosage form further contains colloidal silicon dioxide. Embodiment 37. The method of any preceding embodiment, wherein the dosage form further contains crospovidone. Embodiment 38. The method of any preceding embodiment, wherein the dosage form further contains glyceryl monocaprylocaprate. PCT Patent Application PCT of A3225.10038US01 Embodiment 39. The method of any preceding embodiment, wherein the dosage form further contains L-cysteine hydrochloride monohydrate. Embodiment 40. The method of any preceding embodiment, wherein the dosage form further contains magnesium stearate. Embodiment 41. The method of any preceding embodiment, wherein the dosage form further contains microcrystalline cellulose. Embodiment 42. The method of any preceding embodiment, wherein the dosage form further contains polyvinyl alcohol. Embodiment 43. The method of any preceding embodiment, wherein the dosage form further contains red iron oxide. Embodiment 44. The method of any preceding embodiment, wherein the dosage form further contains sodium lauryl sulfate. Embodiment 45. The method of any preceding embodiment, wherein the dosage form further contains stearic acid. Embodiment 46. The method of any preceding embodiment, wherein the dosage form further contains talc. Embodiment 47. The method of any preceding embodiment, wherein the dosage form further contains titanium dioxide. Embodiment 48. The method of any preceding embodiment, wherein the dosage form further contains yellow iron oxide. Embodiment 49. The method of any preceding embodiment, wherein the dosage form is a tablet. Embodiment 50. The method of embodiment 49, wherein the tablet is a bilayer tablet. Embodiment 51. The method of any preceding embodiment, wherein the dosage form is orally administered. Embodiment 52. The method of embodiment 51, wherein the solid dosage form is orally administered in the morning. PCT Patent Application PCT of A3225.10038US01 Embodiment 53. The method of any preceding embodiment, wherein the dextromethorphan is in an immediate-release formulation. Embodiment 54. The method of any preceding embodiment, wherein the bupropion is in an extended-release formulation. EXAMPLES Example 1 Evaluation of DM / BU (dextromethorphan-bupropion) in Major Depressive Disorder Using the Interest-Activity Domain Key Questions Does DM / BU improve interest-activity symptoms in people with MDD? Does severity of interest-activity symptoms at baseline impact depression outcomes with DM / BU treatment? Conclusions In people with MDD, prominent interest-activity symptoms (low interest, reduced activity, indecisiveness, and lack of enjoyment) at baseline are associated with poor treatment response to serotonergic antidepressants. This post hoc analysis evaluated the interest-activity symptom score, a newer measure derived from the MADRS and QIDS-SR. DM / BU, an oral NMDA receptor antagonist and sigma-1 receptor agonist, significantly improved interest-activity symptom scores compared with control. DM / BU exhibited comparable reductions in depressive symptoms regardless of severity of baseline interest-activity symptoms. These results suggest that DM / BU may be a particularly effective treatment option in individuals with MDD who have substantially impaired interest and activity. Introduction Major depressive disorder (MDD) is a highly prevalent, chronic, disabling disorder and a leading cause of suicide. In people who respond to monoaminergic antidepressants, it often takes weeks to observe clinically meaningful improvements in depression symptoms. PCT Patent Application PCT of A3225.10038US01 Serotonergic antidepressants have demonstrated reduced effectiveness in people with depression who have prominent symptoms of impaired interest and activity (low interest, reduced activity, indecisiveness, and lack of enjoyment), a finding that has been replicated in multiple studies, including: 1) Genome-based Therapeutic Drugs for Depression (GENDEP; N=811);2) Sequenced Treatment Alternatives to Relieve Depression (STAR*D; a subgroup ofN=3637); and 3) Canadian Biomarker Integration Network in Depression trial 1 (CAN-BIND-1;N=211). Therefore, alternative, mechanistically novel antidepressants are needed for individuals with MDD who have impairments in interest and activity. DM / BU: A Novel, Oral NMDA Receptor Antagonist DM / BU (dextromethorphan-bupropion [Auvelity® extended-release tablet]) is a novel, oral, N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist approved by the US Food and Drug Administration for the treatment of MDD in adults. Dextromethorphan is an antagonist of the NMDA receptor and a sigma-1 receptor agonist. Bupropion is an aminoketone and cytochrome P4502D6 inhibitor that increases the bioavailability of dextromethorphan. Methods & Study Design This post hoc analysis pooled data from 2 double-blind, randomized, controlled, 6- week trials of DM / BU in individuals with moderate to severe MDD: 1) The GEMINI trial (NCT04019704) was placebo controlled (DM / BU, n=156; placebo,n=162); and 2) The ASCEND trial (NCT03595579) used bupropion as an active control (DM / BU,n=43; bupropion, n=37). Both studies met their primary endpoint, with DM / BU demonstrating statistically significant improvement on the Montgomery Åsberg Depression Rating Scale (MADRS) compared with control. PCT Patent Application PCT of A3225.10038US01 This analysis investigated the interest-activity symptom score, which has been used previously and is defined by the sum of 3 MADRS items (concentration, lassitude, and inability to feel) and 3 Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR) items (concentration, interest, and energy) (FIG.1). This post hoc pooled analysis evaluated 2 hypotheses (Table 1) Note: MADRS = Montgomery Åsberg Depression Rating Scale; MMRM = mixed model for repeated measures. Key Findings Patient Population Baseline demographics and clinical characteristics were similar between groups (Table 2) PCT Patent Application PCT of A3225.10038US01 a bIncludes American Indian or Alaska Native, Native Hawaiian or Pacific Islander, multiple races, other, or not reported.cIndividuals with treatment- treatments in the current MDE) were excluded from ASCEND and GEMINI. MADRS = Montgomery Åsberg Depression Rating Scale; MDE = major depressive episode. Hypothesis 1. DM / BU would produce greater improvement in interest-activity compared with control DM / BU treatment significantly improved change from baseline (reduced score) in interest-activity symptom score compared with placebo at every time point (FIG.2A). A significantly greater percentage of people achieved interest-activity symptom score response with DM / BU compared with placebo at every time point (FIG.2B). Hypothesis 2. Efficacy of DM / BU would be maintained regardless of individuals’ baseline severity of interest-activity score In the control group, higher baseline interest-activity impairment was associated with P<0.05) (FIG.3) PCT Patent Application PCT of A3225.10038US01 There was no significant association between baseline interest-activity symptom score with MADRS total score in the DM / BU P=0.787). There was no association between baseline interest-activity symptom score and MADRS change from baseline in the DM / BU group at any treatment week (all P values >0.05). Changes from baseline in MADRS total score were similar among participants with low, average, and high baseline interest-activity symptom scores throughout the trial in the DM / BU treatment group, but differed in the control treatment group (FIG.4A and FIG.4B). In the control group, high baseline interest-activity symptom scores were associated with less improvement in depression symptoms. Safety with DM / BU were dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis. Example 2 Impact of DM / BU (dextromethorphan-bupropion) on Depressive Symptoms, Anxiety, and Quality of Life in Patients with One Prior Treatment Failure: Results from the EVOLVE Long- Term, Open-Label Study Key Question How does long-term DM / BU treatment impact depression symptoms, anxiety, and quality of life in people with depression treated with at least 1 prior treatment in their current major depressive episode (MDE)? Conclusions Treatment with DM / BU for up to 1 year rapidly and durably improved quality of life in people with MDD who failed 1 prior antidepressant in the current MDE. Improvements occurred across the broad range of items associated with quality of life including overall life satisfaction, sense of wellbeing, and ability to function in daily life. In a naturalistic setting, treatment with DM / BU also rapidly and durably improved depression and anxiety symptoms. PCT Patent Application PCT of A3225.10038US01 Long-term treatment with DM / BU was generally well tolerated. These data support the long-term efficacy and safety of DM / BU in this patient population. Introduction People with major depressive disorder (MDD) have significantly impaired quality of life, with lower quality of life than other chronic diseases. -line SSRI treatment and --linetreatment. In people who respond to monoaminergic antidepressants, it often takes weeks to observe clinically meaningful improvements in depression and improvements in quality of life generally lag behind symptomatic improvements. Quality of life does not return to normal with antidepressant treatment for most people, even in those with remission of depression. Mechanistically novel, fast, and effective approaches to depression treatment which also improve quality of life are needed AXS-05: A Novel, Oral NMDA Receptor Antagonist AXS-05 (dextromethorphan-bupropion [Auvelity® extended-release tablet]) is a novel, oral, N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist approved by the US Food and Drug Administration for the treatment of MDD in adults. Dextromethorphan is an antagonist of the NMDA receptor and a sigma-1 receptor agonist. Bupropion is an aminoketone and cytochrome P4502D6 inhibitor that increases the bioavailability of dextromethorphan. Methods & Study Design EVOLVE (Evaluation of NMDA Modulation for Depressive Episodes, NCT04634669)was an open-label, phase 2, US trial, investigating DM / BU in people with MDD treated with at least 1 prior treatment in their current MDE (FIG.5) PCT Patent Application PCT of A3225.10038US01 This analysis presents efficacy endpoints in the de novo participants who were directly enrolled (n=146 safety population, n=145 modified intent-to-treat population), with an emphasis on quality of life as measured by the Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form (Q-LES-Q-SF; FIG.6A) and scoring (FIG.6B). Key Findings Patient Population At baseline, participants had moderate-to-severe depression, mild-to-moderate anxiety, and severely impaired quality of life (Table 3). a Q-LES- ,CGI-S: Clinical Global Impressions Scale – Severity; HAM-A: Hamilton Anxiety Rating Scale; MADRS: Montgomery Åsberg Depression Rating Scale; mITT: modified intent-to-treat population; Q-LES-Q-SF: Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form. Depression and Anxiety Symptoms DM / BU treatment significantly improved depression symptoms as early as Week 1, with durable improvement for the 12-month open-label treatment period. PCT Patent Application PCT of A3225.10038US01 Montgomery Åsberg Depression Rating Scale (MADRS) response and remission rates generally increased over the study (FIG.7). There were significant reductions from baseline in anxiety symptoms at every visit, which were durable through Month 12 (FIG.8A). Hamilton Anxiety Rating Scale (HAM-A) response and remission increased for the duration of the study (FIG.8B). Quality of Life DM / BU treatment also rapidly improved quality of life, with significant Q-LES-Q-SF percent score improvement from baseline at every visit, which mirrored improvements in depression symptoms (FIG.9) All individual Q-LES-Q-SF items had consistent improvements from baseline except ability to get around physically, which had the highest baseline score (4.04, good) (FIG.10) Safety Long-term DM / BU treatment was well tolerated Treatment- -related TEAE. . - . Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as amounts, percentage, and so forth used in the specification and claims are to be understood in all instances as indicating both the exact values as shown and as being modified by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. PCT Patent Application PCT of A3225.10038US01 Use of the term “comprising” or “comprises” herein also contemplates that use of “consisting essentially of,” “consists essentially of,” “consisting of,” or “consists of” in its place. Affirmative recitation of an element anywhere herein should be understood to contemplate both including and excluding that element. The terms “a,” “an,” “the” and similar referents used in the context of describing the embodiments (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the claims. Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from a group, for reasons of convenience and / or to expedite prosecution. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups if used in the appended claims. Certain embodiments are described herein, including the best mode known to the inventors for carrying out the claimed embodiments. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the claimed embodiments to be practiced otherwise than specifically described herein. Accordingly, the claims include all modifications andequivalents of the subject matter recited in the claims as permitted by applicablelaw. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context. PCT Patent Application PCT of A3225.10038US01 In closing, it is to be understood that the embodiments disclosed herein are illustrativeof the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, but not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to embodiments precisely as shown and described.

Claims

PCT Patent Application PCT of A3225.10038US01 CLAIMS1. A method of improving interest-activity comprising administering a dosage form oncedaily or twice daily to a human patient in need thereof, wherein dosage form comprises about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another form of bupropion, and about 105 mg of bupropion hydrochloride, or a molar equivalent amount of another form of bupropion, and wherein the human patient is experiencing major depressive disorder.

2. A method of treating major depressive disorder comprising administering a dosageform once daily or twice daily to a human patient in need thereof, wherein dosage form comprises about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another form of dextromethorphan, and about 105 mg of bupropion hydrochloride, or a molar equivalent amount of another form of bupropion, and wherein the human patient is experiencing major depressive disorder and has above average impairment in interest-activity as compared to other human patients experiencing major depressive disorder.

3. A method of treating major depressive disorder comprising administering a dosageform once daily or twice daily to a human patient in need thereof, wherein dosage form comprises about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another form of dextromethorphan, and about 105 mg of bupropion hydrochloride, or a molar equivalent amount of another form of bupropion, and wherein the human patient is experiencing major depressive disorder and has been treated with at least one prior treatment in the current major depressive episode.

4. The method of claim 1, 2 or 3, wherein the human patient has an interest-activityscore of 33, 34, 35, or 36.

5. The method of claim 3, wherein the human patient has a MADRS total score of at least30.

6. The method of claim 3, wherein the human patient has a CGI-S total score of at least4.

7. The method of claim 3, wherein the human patient has a HAM-A score of at least 15.PCT Patent Application PCT of A3225.10038US018. The method of claim 3, wherein the human patient has a Q-LES-Q-SF percent scorethat is less than 42.

9. The method of any preceding claim, wherein the combination of about 45 mg ofdextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride is administered to the human patient once daily for about 6 weeks.

10. The method of any preceding claim, wherein the combination of about 45 mg ofdextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride is administered to the human patient twice daily for at least 6 weeks.

11. The method of any preceding claim, wherein the dosage form is a solid dosage form.

12. The method of any preceding claim, wherein the dosage form further contains acarbomer homopolymer.

13. The method of any preceding claim, wherein the dosage form further containscolloidal silicon dioxide.

14. The method of any preceding claim, wherein the dosage form further containscrospovidone.

15. The method of any preceding claim, wherein the dosage form further contains glycerylmonocaprylocaprate.

16. The method of any preceding claim, wherein the dosage form further contains L-cysteine hydrochloride monohydrate.

17. The method of any preceding claim, wherein the dosage form further containsmagnesium stearate.

18. The method of any preceding claim, wherein the dosage form further containsmicrocrystalline cellulose.

19. The method of any preceding claim, wherein the dosage form further containspolyvinyl alcohol.

20. The method of any preceding claim, wherein the dosage form further contains rediron oxide.PCT Patent Application PCT of A3225.10038US0121. The method of any preceding claim, wherein the dosage form further contains sodiumlauryl sulfate.

22. The method of any preceding claim, wherein the dosage form further contains stearicacid.

23. The method of any preceding claim, wherein the dosage form further contains talc.

24. The method of any preceding claim, wherein the dosage form further containstitanium dioxide.

25. The method of any preceding claim, wherein the dosage form further contains yellowiron oxide.

26. The method of any preceding claim, wherein the dosage form is a tablet.

27. The method of claim 26, wherein the tablet is a bilayer tablet.

28. The method of any preceding claim, wherein the dosage form is orally administered.

29. The method of claim 28, wherein the solid dosage form is orally administered in themorning.

30. The method of any preceding claim, wherein the dextromethorphan is in animmediate-release formulation.

31. The method of any preceding claim, wherein the bupropion is in an extended-releaseformulation.

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