Compounds and combinations thereof for treating depression in a patient

Abstract

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

Description

[0001] Inventor: Heriot Tabtio

[0002] Cross-reference to related applications

[0003] This application claims priority to U.S. Provisional Patent Application No. 63 / 605,337, filed December 1, 2023, and U.S. Provisional Patent Application No. 63 / 605,408, filed December 1, 2023, which are expressly incorporated herein by reference in their entirety. Summary of the Invention

[0004] Some implementations include a method for improving interest-activity, the method comprising administering a dosage form once or twice daily to a human patient in need, wherein the dosage form comprises approximately 45 mg of dextromethorphan hydrobromide or a molar equivalent of another form of bupropion, and approximately 105 mg of bupropion hydrochloride or a molar equivalent of another form of bupropion, and wherein the human patient is experiencing major depressive disorder.

[0005] Some implementations include a method of treating major depressive disorder, the method comprising administering a dosage form once or twice daily to a human patient in need, wherein the dosage form comprises about 45 mg of dextromethorphan hydrobromide or a molar equivalent of another form of dextromethorphan, and about 105 mg of bupropion hydrochloride or a molar equivalent of another form of bupropion, and wherein the human patient is experiencing major depressive disorder and has above-average impairment in interest-activity compared to other human patients experiencing major depressive disorder, or has been treated with at least one prior treatment during a current major depressive episode. Attached Figure Description

[0006] Figure 1 This shows the components of the interest-activity symptom score. a QIDS-SR items (scoring from 0 to 3) are doubled to have equal weight with MADRS items (scoring from 0 to 6); higher interest-activity symptom scores correspond to more severe symptoms; MADRS stands for Montgomery Åsberg Depression Rating Scale; QIDS-SR stands for Rapid Self-Rating Depression Scale.

[0007] Figure 2A Showing interest-activity symptom scores relative to baseline. a Change, and Figure 2B Showing interest-activity symptom scores from responses. a Variations, where **P < 0.01, ***P < 0.001. No adjustment was made for multiple comparisons. aThe interest-activity symptom score is the sum of three MADRS items (attention, fatigue, and loss of sensation) and three QIDS-SR items (attention, interest, and energy). Higher interest-activity symptom scores correspond to more severe symptoms. b The estimates are derived from MMRM using unstructured covariance, with fixed effects for baseline interest-activity symptom scores, weeks, treatment group, and the interaction term between weeks and treatment group. c A response is defined as an improvement of ≥50% in the interest-activity symptom score relative to baseline. AXS-05 indicates DM / BU.

[0008] Figure 3 Shows the mean slope of the change in baseline interest-activity score relative to baseline MADRS during treatment weeks 1, 2, 3, 4, and 6. AXS-05 indicates DM / BU.

[0009] Figure 4A shows the baseline interest-activity symptom score when using a control group. a The changes in the total MADRS score, and Figure 4B shows the changes in the total MADRS score based on the baseline interest-activity symptom score when using DM / BU. a The interest-activity symptom score is the sum of the three MADRS items (attention, fatigue, and loss of sensation) and the three QIDS-SR items (attention, interest, and energy). Higher interest-activity symptom scores correspond to more severe symptoms. High interest-activity is one SD above the mean baseline interest-activity symptom score, the mean interest-activity score reflects the mean baseline interest-activity symptom score, and low interest-activity score reflects one SD below the mean interest-activity symptom score. b Marginal mean of MADRS change relative to baseline score. AXS-05 indicates DM / BU.

[0010] Figure 5 The study design is shown, where 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 = Short Form Well-being and Quality of Life Questionnaire. AXS-05 represents DM / BU.

[0011] Figure 6A The Q-LES-Q-SF individual items are displayed, with two additional items (medication use and overall life satisfaction) not included in the total score.

[0012] Figure 6BDisplays individual Q-LES-Q-SF scores, where the original total score is the sum of 14 items (14-70 total score), then converted to a percentage score of the maximum possible score.

[0013] Figure 7 Displays the MADRS total score response and remission.

[0014] Figure 8A Shows the change in HAM-A score relative to baseline. * For changes relative to baseline calculated by a two-tailed paired t-test, P < 0.001. a A lower score indicates improvement. b The sample size for week 1 is n = 141; the sample size for week 2 is n = 136; and the sample size for week 6 is n = 124. AXS-05 indicates DM / BU.

[0015] Figure 8B Showing the changes in HAM-A score from the reaction.

[0016] Figure 9 Shows the percentage change in Q-LES-Q-SF score and the total MADRS score relative to baseline. * For changes relative to baseline calculated by two-tailed paired t-tests at all time points, P < 0.001. a A higher score indicates improvement. b A lower score indicates improvement. c The sample size for week 1 is n = 134; the sample size for week 2 is n = 130; and the sample size for week 6 is n = 119. AXS-05 indicates DM / BU.

[0017] Figure 10 The results show consistent improvement in all individual Q-LES-Q-SF items and average item scores relative to baseline, except for physical mobility, which had the highest baseline score (4.04, good). a The Q-LES-Q-SF items are not included in the percentage score. Detailed Implementation

[0018] As mentioned above, this disclosure relates to the administration of the following combinations: 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride, or a molar equivalent of bupropion in its free base or other salt form; and 2) about 40-50 mg, about 44-46 mg, or about 45 mg of dextromethorphan hydrobromide, or a molar equivalent of dextromethorphan in its free base or other salt form. For convenience, this combination is referred to herein as a “subject combination.” In each case of a subject combination mentioned herein, the combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is particularly considered.

[0019] Dextromethorphan hydrobromide is a non-competitive NMDA receptor antagonist and σ-1 receptor agonist.

[0020] The chemical name of dextromethorphan hydrobromide is 3-methoxy-17-methyl-(9α, 13α, 14α)morphinan hydrobromide monohydrate. Dextromethorphan hydrobromide has the empirical formula C1. 18 H 25 NO•HBr•H2O and a molecular weight of 370.33. The structural formula is:

[0021]

[0022] Dextromethorphan hydrobromide powder is a white or off-white crystal and is slightly soluble in water.

[0023] Bupropion hydrochloride is an aminoketone and CYP450 2D6 inhibitor.

[0024] The chemical name of bupropion hydrochloride is (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. Bupropion hydrochloride has the empirical formula C1. 13 H 18 ClNO•HCl and a molecular weight of 276.2. The structural formula is:

[0025]

[0026] Bupropion hydrochloride powder is white and readily soluble in water.

[0027] Other forms of dextromethorphan and bupropion, such as other salt forms or free base forms, can be used.

[0028] The subject matter combination may be contained in oral dosage forms, including tablets, such as sustained-release tablets. In some embodiments, the subject matter combination is contained in a dosage form for oral administration and may be available as a spherical bilayer tablet.

[0029] In some embodiments, each tablet containing the subject combination contains 45 mg of dextromethorphan hydrobromide as an immediate-release formulation. In some embodiments, each tablet containing the subject combination contains 105 mg of bupropion hydrochloride as a sustained-release formulation. In some embodiments, each tablet containing the subject combination contains 45 mg of dextromethorphan hydrobromide as an immediate-release formulation and 105 mg of bupropion hydrochloride as a sustained-release formulation.

[0030] In some embodiments, the tablet containing the theme combination contains L-cysteine ​​hydrochloride monohydrate. In some embodiments, the tablet containing the theme combination contains carbomer homopolymer. In some embodiments, the tablet containing the theme combination contains microcrystalline cellulose. In some embodiments, the tablet containing the theme combination contains colloidal silica. In some embodiments, the tablet containing the theme combination contains crospovidone. In some embodiments, the tablet containing the theme combination contains stearic acid. In some embodiments, the tablet containing the theme combination contains magnesium stearate.

[0031] In some embodiments, tablets containing the theme combination contain the following inactive ingredients: L-cysteine ​​hydrochloride monohydrate, carbomer homopolymer, microcrystalline cellulose, colloidal silica, crospovidone, stearic acid, and magnesium stearate.

[0032] In some embodiments, the starting dose of the 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 a dosage form containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) administered twice daily (e.g., 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 on the same day.

[0033] The combination of tablets can be administered orally with or without food. In some embodiments, the tablets should be swallowed whole and should not be crushed, split, or chewed.

[0034] In some implementations, the subject combination is administered to human patients twice daily until the human patients experience a reduction in their total MADRS score relative to baseline of at least about 7, at least about 11, at least about 13, or at least about 15.9.

[0035] In some implementations, in human patients receiving the subject combination, the total MADRS score reduction relative to baseline experienced by the human patients exceeds the reduction experienced by patients receiving placebo. Human patients receiving the subject combination may experience a greater reduction in MADRS score than those receiving placebo at, for example, 1 week after administration, 2 weeks after administration, 3 weeks after administration, 4 weeks after administration, 5 weeks after administration, 6 weeks after administration, or at other times.

[0036] In some implementations, the selected human patients have 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.

[0037] The Interest-Activity Score is based on the following questions in MADRS: difficulty concentrating, fatigue, and feeling unable to focus; and the following questions in QIDS-SR: attention / decision, general interest, and energy level. These questions are presented in the table below. The QIDS-SR score is doubled, and the sum of the MADRS score and the doubled QIDS-SR score is the Interest-Activity Score.

[0038] Interest - Components of Activity Score

[0039]

[0040] Treatment may result in a decrease in interest-activity scores in human patients of at least 20%, 35%, 45%, 50%, or 58% relative to baseline; and at least 10%, 15%, or 20% compared to placebo administration. These results may be achieved, for example, at 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, etc.

[0041] In individuals with MDD who have substantial impairment of interest and activity, treatment with a combination of dextromethorphan and bupropion may be a particularly effective treatment option. In people with MDD, baseline primary interest-activity symptoms (low interest, reduced activity, indecisiveness, and lack of enjoyment) may be associated with poor response to treatment with serotonergic antidepressants. In some implementations, treatment can significantly improve interest-activity symptom scores compared to control. In some implementations, treatment can demonstrate comparable reductions in depressive symptoms, regardless of the severity of baseline interest-activity symptoms.

[0042] In individuals with MDD who are currently experiencing a major depressive episode (MDE) and are unresponsive to a previous antidepressant, treatment with a combination therapy consisting of dextromethorphan and bupropion for up to one year can rapidly and persistently improve quality of life. Improvements can occur in numerous areas related to quality of life, including overall life satisfaction, well-being, and daily living abilities. The treatment can rapidly and persistently improve symptoms of depression and anxiety. The treatment demonstrates long-term efficacy and safety in this patient population.

[0043] In the combination of the two drugs, bupropion inhibits the metabolism of dextromethorphan via CYP2D6. Dextromethorphan exhibits nonlinear pharmacokinetics at steady state when co-administered with bupropion, and its AUC and C2O values ​​are [not specified in the original text]. max There was a greater-than-dose variation for different doses of dextromethorphan (30 to 60 mg) and a less-than-dose variation for different doses of bupropion (75 to 150 mg).

[0044] Steady-state plasma concentrations of dextromethorphan and bupropion, when administered as a combination, were achieved over 8 days. Based on C... max and AUC 0-12 The steady-state accumulation ratios of dextromethorphan and dextromethorphan are approximately 20 and 32, respectively. Based on C max and AUC 0-12 The cumulative ratios of bupropion at steady state were 1.1 and 1.5, respectively.

[0045] After application of the topical combination, the median T value of dextromethorphan was... max It lasts for about 3 hours, and the median T value of bupropion is... max It takes about 2 hours. The C of the hydroxybupropion metabolite... max It appears approximately 3 hours after administration and is about 14 times the peak level of bupropion. AUC of hydroxybupropion 0-12 The AUC of bupropion 0-12 Approximately 19 times higher than the C of erythrohydroxybupropion and threohydroxybupropion metabolites. max It appeared approximately 4 hours after administration, and was associated with C10 and C20 of bupropion, respectively. max Roughly equal or the C of bupropion max Approximately 5 times higher. The AUC values ​​of erythrohydroxybupropion and threohydroxybupropion... 0-12 The values ​​are the AUC values ​​of bupropion. 0-12 The values ​​are approximately 1.2 times and approximately 7 times.

[0046] The theme combination can be taken with or without food. When the theme combination is taken with food, dextromethorphan C max and AUC 0-12 The values ​​were unchanged and decreased by 14%, respectively, and bupropion C... maxand AUC 0-12 They increased by 3% and 6% respectively.

[0047] Dextromethorphan has a plasma protein binding rate of approximately 60-70%, while bupropion has a rate of 84%. The protein binding rate of the hydroxybupropion metabolite is similar to that of bupropion; while the protein binding rate of the threo-hydroxybupropion metabolite is about half that observed with bupropion.

[0048] Compared to dextromethorphan administered in the absence of bupropion, the mean elimination half-life of dextromethorphan increased by approximately 3 times to approximately 22 hours after 8 days of subject combination administration in strong metabolizers.

[0049] The mean elimination half-lives of dextromethorphan and bupropion were 22 hours and 15 hours, respectively. The apparent elimination half-lives of the metabolites of hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion were approximately 35, 44, and 33 hours, respectively.

[0050] Unlike the combination of quinidine and dextromethorphan, the subject combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide administered twice daily does not prolong the QT interval to any clinically relevant degree. Therefore, QT interval evaluation by electrocardiography is generally not performed in human patients experiencing major depressive disorder who are at risk of QT prolongation and torsades de pointes.

[0051] Thematic combinations can be used as adjunctive therapy for major depressive disorder or depression.

[0052] Besides major depressive disorder, thematic combinations can be used to treat other conditions within the patient populations or situations described herein. For example, thematic combinations can be used to treat pain or neurological disorders. Examples of neurological disorders that can be treated with thematic combinations include, but are not limited to: mood disorders, mental disorders, brain dysfunction, movement disorders, dementia, motor neuron disease, neurodegenerative diseases, seizure disorders, and headaches.

[0053] Mood disorders that can be treated with thematic combination therapy include, but are not limited to, depression, major depressive disorder, treatment-resistant depression, treatment-resistant bipolar depression, bipolar disorder (including cyclothymia), seasonal affective disorder, mood disorders, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual anxiety disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit with hyperactivity disorder (ADDH), and attention deficit / hyperactivity disorder (AD / HD), bipolar manic state, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychogenic sexual dysfunction, pseudobulbar mood, and mood instability.

[0054] Depression can manifest as depressive symptoms. These symptoms can include psychological changes such as mood swings, intense sadness, hopelessness, slowed thinking, difficulty concentrating, pessimism, agitation, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal thoughts or attempts, and / or self-deprecation. Physical symptoms of depression can include insomnia, loss of appetite, decreased appetite, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, aches and pains, headaches, cramps, digestive problems, and / or abnormal hormonal circadian rhythms.

[0055] Mental disorders that can be treated with a combination of themes include, but are not limited to, anxiety disorders, including but not limited to phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD); mania, bipolar disorder, hypomania, unipolar depression, depression, stress disorder, somatic symptom disorder, personality disorder, psychosis, schizophrenia, paranoid disorder, schizoaffective disorder, schizotypal personality disorder, aggression, aggression in Alzheimer's disease, and agitation in Alzheimer's disease. Alzheimer's disease can also be referred to as Alzheimer's dementia. Other treatable neurobehavioral symptoms of Alzheimer's disease include disinhibition and emotional blunting.

[0056] Agitation in Alzheimer's disease occurs as the disease progresses. Agitation may manifest itself as inappropriate verbal, emotional, and / or physical behaviors. Inappropriate behaviors may include, but are not limited to, incoherent rambling, inappropriate emotional reactions, attention-seeking, threatening, irritability, frustration, screaming, repetitive questioning, mood swings, cursing, abusive language, physical outbursts, emotional distress, restlessness, destroying objects, sleep disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive physical movements, hoarding, stalking, hitting, scratching, biting, aggression, hyperactivity, and / or kicking.

[0057] 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 affects an estimated 6 million people in the United States, a number projected to increase to approximately 14 million by 2050. Up to 70% of people with AD report agitation, characterized by mood disturbances, aggressive behavior, disruptive irritability, and disinhibition. Managing agitation is a top priority in AD. Agitation in AD patients is associated with increased caregiver burden, functional decline, accelerated cognitive decline, early admission to nursing homes, and increased mortality. Currently, there are no FDA-approved therapies for treating agitation in people with AD.

[0058] Neurobehavioral symptoms are known to occur during dementia and can be treated in combination. Caregivers or family members may feel more overwhelmed by the patient's behavioral / psychological symptoms than by the patient's cognitive impairment. Common forms of the syndrome include Alzheimer's disease, vascular dementia, Lewy body dementia (abnormal protein aggregates produced inside nerve cells), and a group of diseases that lead to frontotemporal dementia (degeneration of the frontal lobe). The symptoms of dementia are similar to those of mental disorders, but some symptoms differ slightly from one another. Neurobehavioral symptoms associated with dementia include depression, emotional blunting, agitation, disinhibition, hallucinations, delusions, psychosis, impulsivity, aggression, compulsive behaviors, hypersexuality, and personality disorders. Neurobehavioral symptoms such as disinhibition may also be found in other conditions such as traumatic brain injury.

[0059] Agitation in patients with Alzheimer's disease can be assessed using the Cohen Mansfield Agitation Inventory (CMAI). The CMAI assesses a variety of behaviors, including hitting (including hitting oneself), kicking, grabbing others, pushing, throwing, biting, scratching, spitting, harming oneself or others, tearing objects or damaging property, engaging in physical provocation, pacing, aimless wandering, inappropriate clothing or undressing, attempting to go to another place, intentionally falling, eating / drinking inappropriate substances, improper handling of objects, hiding things, hoarding things, repetitive stereotyped behaviors, generalized restlessness, screaming, verbal provocation, cursing or verbal aggression, repeating sentences or questions, making strange noises (strange laughter or crying), complaining, defiant behavior, and persistently unreasonable demands for attention or help.

[0060] Schizophrenia can be treated in combination, including positive and / or negative symptoms of schizophrenia, or residual symptoms of schizophrenia. Other conditions that can be treated include intermittent fulminant disorder.

[0061] Brain dysfunctions that can be treated with a combination of therapies include, but are not limited to, disorders involving intellectual impairment, such as Alzheimer's disease, memory loss, amnesia / amnesia syndrome, epilepsy, altered consciousness, coma, decreased attention, speech disorders, vocal dysphagia, Parkinson's disease, Lennox-Gastaut syndrome, autism, ADHD, and schizophrenia. Brain dysfunctions also include disorders caused by cerebrovascular diseases, including but not limited to stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, and head injury, among which symptoms include altered consciousness, Alzheimer's disease, coma, decreased attention, and speech disorders.

[0062] Substance addictions / abuses that can be treated with a combination of themes include, but are not limited to, drug dependence and addictions to: cocaine, stimulants (such as crack, cocaine, speed, methamphetamine), nicotine, alcohol, opioids, anti-anxiety and hypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as smoking, smoking cigars and / or pipe smoking, vaping, and chewing tobacco addiction.

[0063] Movement disorders that can be treated with a combination of themes include, but are not limited to, akathisia, dyskinesia, synkinesis, choreoathetosis, ataxia, throwing disorder, hemispheric throwing disorder, bradykinesia, cerebral palsy, chorea, Huntington's disease, Huntington's disease-related chorea, rheumatic chorea, Siddenham's chorea, movement disorders, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, Tourette syndrome, and Wilson's disease.

[0064] Dementia that can be treated with a combination of therapies 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-Korsakov syndrome, and Pick's disease.

[0065] Motor neuron diseases that can be treated with a combination of therapies include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, sequelae of poliomyelitis (PPS), spinal muscular atrophy (SMA), spinal motor atrophy, Ty-Sachs disease, Sandhof disease, and hereditary spastic paraplegia.

[0066] Neurodegenerative diseases that can be treated with thematic combinations include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedreich ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Hey-Draghi syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, autosomal dominant cerebral arteriosclerosis with subcortical infarction and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tous disease (CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatal substantia nigra degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0067] The following seizure disorders can be treated with a combination of themes, including but not limited to epileptic seizures, non-epileptic seizures, epilepsy, febrile seizures; partial seizures, including but not limited to simple partial seizures, Jacksonian seizures, complex partial seizures, and continuous partial epilepsy; generalized seizures, including but not limited to generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

[0068] Headache types that can be treated with thematic combinations include, but are not limited to, migraines, tension headaches, and cluster headaches.

[0069] Other neurological disorders that can be treated with thematic combinations include Rett syndrome, autism, tinnitus, altered consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy; speech disorders caused by uncontrolled spasms of the laryngeal muscles, including but not limited to abductor spasm dysarthria, adductor spasm dysarthria, tonic dysarthria, and vocal tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity (such as methotrexate neurotoxicity); incontinence, including but not limited to stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.

[0070] In some implementations, the combination of themes can be used to treat pain, joint pain, sickle cell disease-related pain, pseudobulbar mood, depression (including treatment-resistant depression), memory and cognitive impairment, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, seizures, cough (including chronic cough), etc.

[0071] In some implementations, the combination of therapies can be administered orally to relieve musculoskeletal pain (including low back pain), as well as pain associated with: rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatic diseases, periarticular diseases, axial spondyloarthritis (including ankylosing spondylitis), Paget's disease, fibrous dysplasia of bone, SAPHO syndrome, transient hip osteoarthritis, vertebral compression fractures, osteoporosis, etc.

[0072] In some implementations, a combination of themes can be applied to relieve inflammatory pain, including musculoskeletal pain, arthritis pain, and complex regional pain syndromes.

[0073] Arthritis refers to inflammatory joint diseases that may be associated with pain. Examples of arthritis pain include pain associated with the following: osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatic diseases, periarticular diseases, neuropathic arthropathy (including Charcot foot), axial spondyloarthritis (including ankylosing spondylitis), and SAPHO syndrome.

[0074] In some implementations, the combination of themes is used to treat chronic musculoskeletal pain.

[0075] In some implementations, the subject composition can be applied to relieve 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 another type of CRPS. CRPS is a type of inflammatory pain. CRPS can also have neuropathic components. Complex regional pain syndrome is a disabling pain syndrome. It is characterized by severe limb pain, possibly accompanied by edema, and autonomic, motor, and sensory changes.

[0076] In some implementations, the subject composition can be administered orally to relieve neuropathic pain.

[0077] Examples of neuropathic pain include pain caused by diabetic peripheral neuropathy or diabetic peripheral neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathy, phantom limb pain, central pain, and pain caused by 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 radiation or chemotherapy-related neuropathy.

[0078] In some implementations, the subject composition can be applied to relieve fibromyalgia.

[0079] The term “treating” or “treatment” includes the diagnosis, cure, relief, treatment or prevention of disease in a person or other animal, or any activity that otherwise affects the structure or any function of the body of a person or other animal.

[0080] The following are examples of implementation schemes that the inventors have specifically considered:

[0081] Implementation Scheme 1. A method for improving interest-activity, the method comprising administering a dosage form to a human patient in need once or twice daily, wherein the dosage form comprises about 45 mg of dextromethorphan hydrobromide or a molar equivalent of another form of bupropion, and about 105 mg of bupropion hydrochloride or a molar equivalent of another form of bupropion, and wherein said human patient is experiencing major depressive disorder.

[0082] Implementation Scheme 2. A method for treating major depressive disorder, the method comprising administering a dosage form once or twice daily to a human patient in need, wherein the dosage form comprises about 45 mg of dextromethorphan hydrobromide or a molar equivalent of another form of bupropion, and about 105 mg of bupropion hydrochloride or a molar equivalent 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.

[0083] Implementation Scheme 3. The method according to Implementation Scheme 1 or 2, wherein the human patient’s interest-activity score is 33, 34, 35 or 36.

[0084] Implementation Scheme 4. The method according to any of the preceding implementation schemes, 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.

[0085] Implementation Scheme 5. The method according to any of the preceding implementation schemes, 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.

[0086] Implementation Scheme 6. The method according to any of the preceding embodiments, wherein the dosage form is a solid dosage form.

[0087] Implementation Scheme 7. The method according to any of the preceding embodiments, wherein the dosage form further comprises a carbomer homopolymer.

[0088] Implementation Scheme 8. The method according to any of the foregoing embodiments, wherein the dosage form further comprises colloidal silica.

[0089] Implementation Scheme 9. The method according to any of the preceding embodiments, wherein the dosage form further comprises crospovidone.

[0090] Implementation Scheme 10. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises glyceryl monocaprylate.

[0091] Implementation Scheme 11. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises L-cysteine ​​hydrochloride monohydrate.

[0092] Implementation Scheme 12. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises magnesium stearate.

[0093] Implementation Scheme 13. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises microcrystalline cellulose.

[0094] Implementation Scheme 14. The method according to any of the preceding embodiments, wherein the dosage form further comprises polyvinyl alcohol.

[0095] Implementation Scheme 15. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises red iron oxide.

[0096] Implementation Scheme 16. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises sodium lauryl sulfate.

[0097] Implementation Scheme 17. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises stearic acid.

[0098] Implementation Scheme 18. The method according to any of the preceding embodiments, wherein the dosage form further comprises talc.

[0099] Implementation Scheme 19. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises titanium dioxide.

[0100] Implementation Scheme 20. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises yellow iron oxide.

[0101] Implementation Scheme 21. The method according to any of the preceding embodiments, wherein the dosage form is a tablet.

[0102] Implementation Scheme 22. The method according to Implementation Scheme 21, wherein the tablet is a bilayer tablet.

[0103] Implementation Scheme 23. The method according to any of the preceding implementation schemes, wherein the dosage form is for oral administration.

[0104] Implementation Scheme 24. The method according to Implementation Scheme 23, wherein the solid dosage form is administered orally in the morning.

[0105] Implementation Scheme 25. The method according to any of the preceding implementation schemes, wherein the dextromethorphan is an immediately released formulation.

[0106] Implementation Scheme 26. The method according to any of the preceding implementation schemes, wherein the bupropion is a sustained-release formulation.

[0107] Implementation Scheme 27. A method for treating major depressive disorder, the method comprising administering a dosage form once or twice daily to a human patient in need, wherein the dosage form comprises about 45 mg of dextromethorphan hydrobromide or a molar equivalent of another form of dextromethorphan, and about 105 mg of bupropion hydrochloride or a molar equivalent 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 during a current major depressive episode.

[0108] Implementation Scheme 28. The method according to Implementation Scheme 27, wherein the total MADRS score of the human patient is at least 30.

[0109] Implementation Scheme 29. The method according to Implementation Scheme 27, wherein the total CGI-S score of the human patient is at least 4.

[0110] Implementation Scheme 30. The method according to Implementation Scheme 27, wherein the human patient has a HAM-A score of at least 15.

[0111] Implementation Scheme 31. The method according to Implementation Scheme 27, wherein the human patient's Q-LES-Q-SF percentage score is less than 42.

[0112] Implementation Scheme 32. The method according to any of the preceding implementation schemes, 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.

[0113] Implementation Scheme 33. The method according to any of the preceding implementation schemes, 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.

[0114] Implementation Scheme 34. The method according to any of the preceding embodiments, wherein the dosage form is a solid dosage form.

[0115] Implementation Scheme 35. The method according to any of the preceding embodiments, wherein the dosage form further comprises a carbomer homopolymer.

[0116] Implementation Scheme 36. The method according to any of the preceding embodiments, wherein the dosage form further comprises colloidal silica.

[0117] Implementation Scheme 37. The method according to any of the preceding embodiments, wherein the dosage form further comprises crospovidone.

[0118] Implementation Scheme 38. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises glyceryl monocaprylate.

[0119] Implementation Scheme 39. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises L-cysteine ​​hydrochloride monohydrate.

[0120] Implementation Scheme 40. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises magnesium stearate.

[0121] Implementation Scheme 41. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises microcrystalline cellulose.

[0122] Implementation Scheme 42. The method according to any of the preceding embodiments, wherein the dosage form further comprises polyvinyl alcohol.

[0123] Implementation Scheme 43. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises red iron oxide.

[0124] Implementation Scheme 44. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises sodium lauryl sulfate.

[0125] Implementation Scheme 45. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises stearic acid.

[0126] Implementation Scheme 46. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises talc.

[0127] Implementation Scheme 47. The method according to any of the preceding embodiments, wherein the dosage form further comprises titanium dioxide.

[0128] Implementation Scheme 48. The method according to any of the preceding implementation schemes, wherein the dosage form further comprises yellow iron oxide.

[0129] Implementation Scheme 49. The method according to any of the preceding embodiments, wherein the dosage form is a tablet.

[0130] Implementation Scheme 50. The method according to Implementation Scheme 49, wherein the tablet is a bilayer tablet.

[0131] Implementation Scheme 51. The method according to any of the preceding implementation schemes, wherein the dosage form is for oral administration.

[0132] Implementation Scheme 52. The method according to Implementation Scheme 51, wherein the solid dosage form is administered orally in the morning.

[0133] Implementation Scheme 53. The method according to any of the preceding implementation schemes, wherein the dextromethorphan is an immediately released formulation.

[0134] Implementation Scheme 54. The method according to any of the preceding implementation schemes, wherein the bupropion is a sustained-release formulation.

[0135] Example

[0136] Example 1

[0137] Evaluation of DM / BU (dextromethorphan-bupropion) in major depressive disorder using the interest-activity domain.

[0138] Key issues

[0139] Does DM / BU improve interest-activity symptoms in people with MDD?

[0140] Does the severity of interest-activity symptoms at baseline affect the outcome of depression treated with DM / BU?

[0141] in conclusion

[0142] In people with MDD, baseline primary interest-activity symptoms (low interest, reduced activity, indecisiveness, and lack of enjoyment) were associated with poor treatment response to serotonergic antidepressants.

[0143] This post-hoc analysis evaluated interest-activity symptom scores, using updated measures derived from MADRS and QIDS-SR.

[0144] Compared with the control, DM / BU (oral NMDA receptor antagonist and σ-1 receptor agonist) significantly improved interest-activity symptom scores.

[0145] DM / BU showed a comparable reduction in depressive symptoms, regardless of the severity of baseline interest-activity symptoms.

[0146] These results suggest that DM / BU may be a particularly effective treatment option in individuals with MDD whose interests and activities are substantially impaired.

[0147] Introduction

[0148] Major depressive disorder (MDD) is a very common chronic disability disorder and a leading cause of suicide.

[0149] In people who respond to monoaminergic antidepressants, it typically takes several weeks to observe a clinically meaningful improvement in depressive symptoms.

[0150] Serotonergic antidepressants have been shown to have reduced effectiveness in individuals with depression who exhibit the main symptoms of impaired interest and activity (low interest, reduced activity, indecisiveness, and lack of pleasure), a finding that has been replicated in several studies, including:

[0151] 1) Genome-based therapeutics for depression (GENDEP; N = 811);

[0152] 2) Sequential therapy alternatives for alleviating depression (STAR*D; subgroup of N = 3637); and

[0153] 3) Canadian Depression Biomarker Integration Network Trial 1 (CAN-BIND-1; N = 211).

[0154] Therefore, there is a need for alternative antidepressants with novel mechanisms of action for individuals with MDD whose interests and activities are impaired.

[0155] DM / BU: A novel oral NMDA receptor antagonist

[0156] DM / BU (dextromethorphan-bupropion [Auvelity]) ® Sustained-release tablets are a novel oral N-methyl-D-aspartate (NMDA) receptor antagonist and σ-1 receptor agonist approved by the U.S. Food and Drug Administration for the treatment of adult MDD.

[0157] Dextromethorphan is an antagonist of NMDA receptors and a σ-1 receptor agonist.

[0158] Bupropion is an inhibitor of aminoketones and cytochrome P450 2D6, which increases the bioavailability of dextromethorphan.

[0159] Methods and Research Design

[0160] This post-hoc analysis combined data from two double-blind, randomized, controlled 6-week trials of DM / BU in individuals with moderate to severe MDD:

[0161] 1) The GEMINI trial (NCT04019704) was a placebo-controlled trial (DM / BU, n = 156; placebo, n = 162); and

[0162] 2) The ASCEND test (NCT03595579) used bupropion as an active control (DM / BU, n = 43; bupropion, n = 37).

[0163] Both studies met their primary endpoints, with DM / BU showing a statistically significant improvement on the Montreal Asperger's Depression Rating Scale (MADRS) compared to controls.

[0164] This analysis examined interest-activity symptom scores, which had been previously used and defined as the sum of three MADRS items (attention, fatigue, and loss of feeling) and three QIDS-SR items (attention, interest, and energy). Figure 1 ).

[0165] The post-hoc meta-analysis evaluated two hypotheses (Table 1).

[0166]

[0167] Note: MADRS = Montreal-Asperger's Depression Rating Scale; MMRM = Mixed Model of Repeated Measures.

[0168] Key findings

[0169] patient group

[0170] Baseline demographic and clinical characteristics were similar across groups (Table 2).

[0171]

[0172] a Due to rounding, the sum may not be 100%. b This includes Native Americans or Alaskan Natives, Native Hawaiians or Pacific Islanders, multiple races, other races, or unreported groups. c Individuals with treatment-resistant depression (defined as those who have not responded to ≥ 2 appropriate antidepressant treatments in their current MDE) were excluded from the ASCEND and GEMINI tests. MADRS = Montreal Asperger's Depression Rating Scale; MDE = Major Depressive Episode.

[0173] Hypothesis 1. Compared to the control, DM / BU will produce greater improvements in interest-activity aspects.

[0174] At each time point, compared with placebo, DM / BU treatment significantly improved the change in interest-activity symptom score relative to baseline (score reduction). Figure 2A ).

[0175] At each time point, compared with placebo, a significantly larger percentage of people using DM / BU achieved an interest-activity symptom score response. Figure 2B ).

[0176] Assumption 2. The effectiveness of DM / BU will be maintained regardless of the baseline severity of the individual's interest-activity score.

[0177] In the control group, higher baseline interest-activity impairment was associated with smaller improvements in total MADRS score (simple slope b, 0.27; 95% CI, 0.02 to 0.52; P < 0.05). Figure 3 )

[0178] In the DM / BU group, there was no significant correlation between baseline interest-activity symptom scores and total MADRS scores (simple slope b, -0.04; 95% CI, -0.24 to 0.31; P = 0.787).

[0179] At any treatment week, in the DM / BU group, there was no correlation between baseline interest-activity symptom score and change in MADRS relative to baseline (all P values ​​> 0.05).

[0180] In the DM / BU treatment group, the change in total MADRS score relative to baseline was similar among participants with low, average, and high baseline interest-activity symptom scores throughout the trial, but was different in the control treatment group (Figures 4A and 4B).

[0181] In the control group, high baseline interest-activity symptom scores were associated with smaller improvements in depressive symptoms.

[0182] Security

[0183] The most frequently reported adverse reactions when using DM / BU (≥ 5% and twice the rate of placebo) are dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis.

[0184] Example 2

[0185] Effects of DM / BU (dextromethorphan-bupropion) on depressive symptoms, anxiety, and quality of life in patients with a prior treatment failure: Results from the EVOLVE long-term open-label study

[0186] Key issues

[0187] In individuals with depression currently experiencing a major depressive episode (MDE) and treated with at least one prior therapy, how does long-term DM / BU treatment affect depressive symptoms, anxiety, and quality of life?

[0188] in conclusion

[0189] In individuals with MDD who are unresponsive to a previous antidepressant in the current MDE, treatment with DM / BU for up to 1 year resulted in rapid and lasting improvements in quality of life.

[0190] Improvements occur in many areas related to quality of life, including overall life satisfaction, well-being, and daily living skills.

[0191] In natural environments, DM / BU treatment also provides rapid and lasting improvement in symptoms of depression and anxiety.

[0192] Long-term treatment with DM / BU is generally well tolerated.

[0193] These data support the long-term efficacy and safety of DM / BU in this patient population.

[0194] Introduction

[0195] People with major depressive disorder (MDD) have a significantly impaired quality of life, which is lower than that of people with other chronic diseases.

[0196] In the STAR*D trial, only 41% of patients responded to first-line SSRI treatment, and the response rate decreased from 25.5% for first-line treatment to 10.4% for fourth-line treatment.

[0197] In individuals who respond to monoaminergic antidepressants, it typically takes several weeks to observe clinically meaningful improvements in depression, and improvements in quality of life usually lag behind improvements in symptoms.

[0198] For most people, even those who have recovered from depression, treatment with antidepressants does not restore their quality of life to normal.

[0199] There is a need for rapid and effective methods with novel mechanisms for the treatment of depression, which also improve quality of life.

[0200] AXS-05: A novel oral NMDA receptor antagonist

[0201] AXS-05 (dextromethorphan-bupropion [Auvelity]) ® Sustained-release tablets are a novel oral N-methyl-D-aspartate (NMDA) receptor antagonist and σ-1 receptor agonist approved by the U.S. Food and Drug Administration for the treatment of adult MDD.

[0202] Dextromethorphan is an antagonist of NMDA receptors and a σ-1 receptor agonist.

[0203] Bupropion is an inhibitor of aminoketones and cytochrome P450 2D6, which increases the bioavailability of dextromethorphan.

[0204] Methods and Research Design

[0205] EVOLVE (evaluation of NMDA-mediated depression, NCT04634669) is an open-label phase 2 US trial that studied DM / BU patients with MDD treated with at least one prior therapy in the current MDE. Figure 5 )

[0206] This analysis presented efficacy endpoints in de novo participants who were directly enrolled (n = 146 safety group, n = 145 modified intention-to-treat group), with a focus on endpoints such as those presented by the Brief Well-being and Quality of Life Satisfaction Questionnaire (Q-LES-Q-SF). Figure 6A ) and rating ( Figure 6B (Measured quality of life)

[0207] Key findings

[0208] patient group

[0209] At baseline, participants had moderate to severe depression, mild to moderate anxiety, and severely impaired quality of life (Table 3).

[0210]

[0211] a A Q-LES-Q score ≥ 70.5% is within the normal range, while a score ≤ 55.7% indicates severe impairment.

[0212] CGI-S: Clinical Global Impression Scale – Severity; HAM-A: Hamilton Anxiety Rating Scale; MADRS: Montreal-Asperger's Depression Rating Scale; mITT: Modified Intention to Treatment Group; Q-LES-Q-SF: Minimal Well-being and Quality of Life Satisfaction Questionnaire.

[0213] Depression and anxiety symptoms

[0214] DM / BU treatment significantly improved depressive symptoms as early as week 1 and showed durable improvement during the 12-month open-label treatment period.

[0215] The response and remission rates of the Montreal Asperger's Depression Rating Scale (MADRS) typically increase in studies. Figure 7 ).

[0216] At each visit, anxiety symptoms were significantly reduced relative to baseline, and this continued until the 12th month. Figure 8A ).

[0217] Hamilton Anxiety Rating Scale (HAM-A) response and remission increased over the duration of the study ( Figure 8B ).

[0218] Quality of life

[0219] DM / BU treatment also rapidly improved quality of life, with significant improvement in Q-LES-Q-SF percentage scores relative to baseline at each visit, reflecting improvement in depressive symptoms. Figure 9 )

[0220] All individual Q-LES-Q-SF items showed consistent improvement relative to baseline, except for physical mobility, which had the highest baseline score (4.04, good). Figure 10 )

[0221] Security

[0222] Long-term DM / BU treatment is well tolerated

[0223] 64.4% of participants experienced treatment-related adverse events (TEAEs), and 41.1% experienced drug-related TEAEs.

[0224] No deaths occurred during the study; 5 participants (3.4%) experienced severe TEAEs, and 13 participants (8.9%) discontinued the study due to TEAEs.

[0225] The most common (≥ 5%) TEAEs were COVID-19 infection (8.9%), nausea (8.9%), headache (7.5%), dry mouth (6.2%), insomnia (5.5%), and dizziness (5.5%).

[0226] Unless otherwise indicated, all figures used in the specification and claims to represent quantities, properties (such as amounts), percentages, etc., of ingredients should in all cases be understood to represent both exact values ​​as shown and to be modified by “about.” Therefore, unless otherwise indicated, the numerical parameters set forth in the specification and appended claims are approximate values ​​and may vary depending on the desired characteristics sought to be obtained. At least and without attempt to limit the application of the doctrine of equivalence to the claims, each numerical parameter should be interpreted at least as being based on the number of significant figures reported and by applying ordinary rounding techniques.

[0227] The use of the terms “comprising” or “comprises” in this document is also considered in its place as “consisting essentially of”, “consistses essentially of”, “consisting of”, or “consists of”.

[0228] Any affirmative statement about an element in this document should be understood to consider both cases where the element is included and cases where it is excluded.

[0229] The terms “a,” “an,” “the,” and similar designations used in the context of describing the embodiments (particularly in the context of the following claims) shall be construed as covering both the singular and the plural, unless otherwise indicated herein or the context clearly contradicts. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or the context clearly contradicts otherwise. The use of any and all examples or exemplary language (e.g., “such”) provided herein is intended only to better illustrate the embodiments and does not impose any limitation on the scope of any claim. No language in the specification should be construed as indicating that any unclaimed element is necessary for the practice of the claims.

[0230] The grouping of alternative elements or embodiments disclosed herein should not be considered limiting. Each member of a group may be mentioned and claimed individually or in any combination with other members of other groups or other elements discovered herein. It is contemplated that one or more members of a group may be included in or removed from the group for convenience and / or to expedite the examination process. In the event of any such inclusion or removal, the specification shall be deemed to contain the group as amended, thereby satisfying the written description of all Markush groups (if used in the appended claims).

[0231] Certain embodiments are described herein, including the best mode known to the inventors for carrying out the claimed embodiments. Of course, changes to these said embodiments will become clear to those skilled in the art after reading the foregoing description. The inventors anticipate that those skilled in the art may adopt such changes as needed, and the inventors intend to practice the claimed embodiments in ways not explicitly described herein. Therefore, the claims include all modifications and equivalents of the subject matter listed in the claims as permitted by applicable law. Furthermore, any combination of the foregoing elements in all possible modifications should be considered unless otherwise indicated herein or the context clearly contradicts otherwise.

[0232] Finally, it should be understood that the embodiments disclosed herein illustrate the principles of the claims. Other modifications may be adopted within the scope of the claims. Therefore, alternative embodiments may be utilized, for example but not as limited, in accordance with the teachings herein. Thus, the claims are not limited to the embodiments precisely shown and described.

Claims

1. A method for improving interest-activity, the method comprising administering a dosage form once or twice daily to a human patient in need, wherein the dosage form comprises about 45 mg of dextromethorphan hydrobromide or a molar equivalent of another form of bupropion, and about 105 mg of bupropion hydrochloride or a molar equivalent of another form of bupropion, and wherein said human patient is experiencing major depressive disorder.

2. A method for treating major depressive disorder, the method comprising administering a dosage form once or twice daily to a human patient in need, wherein the dosage form comprises about 45 mg of dextromethorphan hydrobromide or a molar equivalent of another form of dextromethorphan, and about 105 mg of bupropion hydrochloride or a molar equivalent 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 with other human patients experiencing major depressive disorder.

3. A method for treating major depressive disorder, the method comprising administering a dosage form once or twice daily to a human patient in need, wherein the dosage form comprises about 45 mg of dextromethorphan hydrobromide or a molar equivalent of another form of dextromethorphan, and about 105 mg of bupropion hydrochloride or a molar equivalent 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 during a current major depressive episode.

4. The method according to claim 1, 2 or 3, wherein the human patient's interest-activity score is 33, 34, 35 or 36.

5. The method of claim 3, wherein the total MADRS score of the human patient is at least 30.

6. The method of claim 3, wherein the human patient has a total CGI-S score of at least 4.

7. The method of claim 3, wherein the human patient has a HAM-A score of at least 15.

8. The method of claim 3, wherein the human patient's Q-LES-Q-SF percentage score is less than 42.

9. The method according to any of the preceding claims, 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.

10. The method according to any of the preceding claims, 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.

11. The method according to any of the preceding claims, wherein the dosage form is a solid dosage form.

12. The method according to any of the preceding claims, wherein the dosage form further comprises a carbomer homopolymer.

13. The method according to any of the preceding claims, wherein the dosage form further comprises colloidal silica.

14. The method according to any of the preceding claims, wherein the dosage form further comprises crospovidone.

15. The method according to any of the preceding claims, wherein the dosage form further comprises glyceryl monocaprylate.

16. The method according to any of the preceding claims, wherein the dosage form further comprises L-cysteine ​​hydrochloride monohydrate.

17. The method according to any of the preceding claims, wherein the dosage form further comprises magnesium stearate.

18. The method according to any of the preceding claims, wherein the dosage form further comprises microcrystalline cellulose.

19. The method according to any of the preceding claims, wherein the dosage form further comprises polyvinyl alcohol.

20. The method according to any of the preceding claims, wherein the dosage form further comprises red iron oxide.

21. The method according to any of the preceding claims, wherein the dosage form further comprises sodium lauryl sulfate.

22. The method according to any of the preceding claims, wherein the dosage form further comprises stearic acid.

23. The method according to any of the preceding claims, wherein the dosage form further comprises talc.

24. The method according to any of the preceding claims, wherein the dosage form further comprises titanium dioxide.

25. The method according to any of the preceding claims, wherein the dosage form further comprises yellow iron oxide.

26. The method according to any of the preceding claims, wherein the dosage form is a tablet.

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

28. The method according to any of the preceding claims, wherein the dosage form is for oral administration.

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

30. The method according to any of the preceding claims, wherein the dextromethorphan is an immediately released formulation.

31. The method according to any of the preceding claims, wherein the bupropion is a sustained-release formulation.

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