Treatment of depression

Abstract

The present disclosure relates to administering in certain patient populations a combination of: 1) about 100 to 110 mg, about 104 to 106 mg, or about 105 mg of bupropion hydrochloride or a molar equivalent of bupropion in a free base form or another salt form; and 2) from about 40 to 50 mg, from about 44 to 46 mg, or from about 45 mg of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan free base form or another salt form for use in the treatment of pain or neurological disorders such as depression.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 342,960 filed on May 17, 2022, U.S. Provisional Application No. 63 / 345,396 filed on May 24, 2022, U.S. Provisional Application No. 63 / 345,856 filed on May 25, 2022, U.S. Provisional Application No. 63 / 346,083 filed on May 26, 2022, U.S. Provisional Application No. 63 / 346,269 filed on May 26, 2022, and U.S. Provisional Application No. 63 / 347,431 filed on May 31, 2022; all of which are incorporated herein by reference in their entirety. Summary of the invention

[0003] The present disclosure is directed to administering in certain patient populations a combination of: 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride, or a molar equivalent of bupropion in free base form or another 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 free base form or another salt form, for the treatment of pain or a neurological disorder such as depression. BRIEF DESCRIPTION OF THE DRAWINGS

[0004] Figure 1 Flow chart depicting the participants in Example 1 through a Phase 2 trial of dextromethorphan-bupropion for major depressive disorder (a randomized, double-blind, controlled trial).

[0005] Figure 2A Shown are mean changes from baseline in MADRS total scores over time using dextromethorphan-bupropion versus bupropion alone in Example 1. Error bars indicate standard error, and p values ​​are calculated based on least square means. MADRS = Montgomery-Asberg Depression Rating Scale.

[0006] Figure 2B The percentage of patients achieving remission (MADRS total score ≤ 10) over time (in weeks) using dextromethorphan-bupropion compared to bupropion alone in Example 1 is shown. P values ​​are calculated based on least square means. MADRS = Montgomery-Asberg Depression Rating Scale.

[0007] Figure 3 The study procedures in Example 3 are described.

[0008] Figure 4 Describe the time to relapse (in weeks) for dextromethorphan-bupropion compared to placebo in Example 3.

[0009] Figure 5 A graph showing the mean reduction in MADRS total score over time (in months) with dextromethorphan-bupropion treatment in Example 4.

[0010] Figure 6 Graph showing the proportion (in percent) of subjects with clinical response (>50% reduction in MADRS) and remission (MADRS < 10) over time (in weeks and months) with dextromethorphan-bupropion treatment in Example 4.

[0011] Figure 7 A graph showing the proportion (in percent) of subjects with a CGI-S response (≥ 2 category changes) over time (in weeks and months) with dextromethorphan-bupropion treatment in Example 4.

[0012] Figure 8 Shown is the mean reduction in SDS over time (in months) using dextromethorphan-bupropion in Example 4. Error bars indicate standard error.

[0013] Fig. 9 The proportion (in percentage) of subjects in Example 4 with SDS remission (SDS ≤ 6) over time (in weeks and months) under dextromethorphan-bupropion treatment is shown.

[0014] Fig.10 Shown is the mean reduction in Hamilton Anxiety Rating Scale (HAM-A) total score over time (in months) with dextromethorphan-bupropion treatment in Example 5.

[0015] Fig.11 The percentage of patients achieving HAM-A remission (score ≤ 7) over time (in weeks and months) with dextromethorphan-bupropion treatment in Example 5 is shown.

[0016] Fig.12 The percentage of patients achieving a HAM-A response (≥50% improvement from baseline) over time (in weeks and months) with dextromethorphan-bupropion treatment in Example 5 is shown.

[0017] Fig.13 The study design of GEMINI (Phase 3, randomized, double-blind, placebo-controlled, multicenter U.S. trial) using dextromethorphan-bupropion or placebo (NCT04019704) in Example 6 is described.

[0018] Fig.14Shown are mean changes in MADRS total scores from baseline over time (in weeks) using dextromethorphan-bupropion compared with placebo in Example 6. P values ​​were calculated based on LS means.

[0019] Fig.15 Shown are the LS mean changes over time (in weeks) for the MADRS anhedonia subscale using dextromethorphan-bupropion compared to placebo in Example 6.

[0020] Fig.16 The percentage of responders who achieved a ≥50% reduction in the MADRS anhedonia subscale over time (in weeks) using dextromethorphan-bupropion compared to placebo in Example 6 is shown.

[0021] Fig.17 Depicted in Example 7 are patient placements in a Phase 3 trial of dextromethorphan-bupropion for major depressive disorder.

[0022] Fig.18A The mean change in the total MADRS score from baseline over time (in weeks) using dextromethorphan-bupropion compared to placebo in Example 7 is shown. The MADRS score range is 0 to 60, with higher scores indicating more severe depression. The results are expressed as mean values, and the error bars represent standard errors. The P value is calculated based on the least squares mean. MADRS = Montgomery-Asberg Depression Rating Scale, SE = standard error.

[0023] Fig.18B The percentage of patients achieving remission (MADRS total score ≤ 10) over time using dextromethorphan-bupropion versus placebo in Example 7 is shown. P values ​​are calculated by X 2 Test calculated. MADRS = Montgomery-Asberg Depression Rating Scale.

[0024] Fig. 18C The percentage of patients achieving clinical response (reduction in MADRS total score ≥ 50% from baseline) over time with dextromethorphan-bupropion compared with placebo in Example 7 is shown. P values ​​are calculated by X 2 Test calculated. MADRS = Montgomery-Asberg Depression Rating Scale. DETAILED DESCRIPTION

[0025] As described above, the present disclosure is directed to administering a combination of: 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride or a molar equivalent of dextromethorphan in free base form or another 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 free base form or another salt form. For convenience, this combination is referred to herein as the "subject combination." In each instance in which the subject combination is mentioned herein, a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is specifically contemplated.

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

[0027] The chemical name of dextromethorphan hydrobromide is morphinan, 3-methoxy-17-methyl-, (9α, 13α, 14α), hydrobromide monohydrate. The empirical formula of dextromethorphan hydrobromide is C 18 H 25 NO·HBr·H2O, and the molecular weight is 370.33. The structural formula is:

[0028]

[0029] Dextromethorphan hydrobromide powder is white or almost white crystals and is slightly soluble in water.

[0030] Bupropion hydrochloride is an aminoketone and CYP450 2D6 inhibitor.

[0031] The chemical name of bupropion hydrochloride is: (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The empirical formula of bupropion hydrochloride is C 13 H 18 ClNO·HCl, and the molecular weight is 276.2. The structural formula is:

[0032]

[0033] Bupropion hydrochloride powder is white and readily soluble in water.

[0034] 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 may be used as a round bilayer tablet or a round monolayer tablet.

[0035] In some embodiments, each tablet containing the subject combination contains 45 mg of dextromethorphan hydrobromide in an immediate release formulation. In some embodiments, each tablet containing the subject combination contains 105 mg of bupropion hydrochloride in an extended release formulation. In some embodiments, each tablet containing the subject combination contains 45 mg of dextromethorphan hydrobromide in an immediate release formulation and 105 mg of bupropion hydrochloride in an extended release formulation.

[0036] In some embodiments, a tablet comprising the subject combination comprises L-cysteine ​​hydrochloride monohydrate. In some embodiments, a tablet comprising the subject combination comprises carbomer homopolymer. In some embodiments, a tablet comprising the subject combination comprises microcrystalline cellulose. In some embodiments, a tablet comprising the subject combination comprises colloidal silicon dioxide. In some embodiments, a tablet comprising the subject combination comprises cross-linked polyvinylpyrrolidone. In some embodiments, a tablet comprising the subject combination comprises stearic acid. In some embodiments, a tablet comprising the subject combination comprises magnesium stearate.

[0037] In some embodiments, a tablet comprising the subject combination comprises the following inactive ingredients: L-cysteine ​​hydrochloride monohydrate, carbomer homopolymer, microcrystalline cellulose, colloidal silicon dioxide, crospovidone, stearic acid, and magnesium stearate.

[0038] In some embodiments, the starting dose of the subject combination is 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride in one tablet, administered once daily in the morning. In some embodiments, after 3 days, the dose is increased to one tablet (or one dosage form containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride) twice daily, for example, given at least 8 hours apart. In some embodiments, no more than two doses are administered on the same day, each dose containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride.

[0039] The subject combination may be administered orally with or without food. In some embodiments, the tablet is swallowed whole, rather than crushed, split or chewed.

[0040] In the subject combination, bupropion inhibits the metabolism of dextromethorphan via CYP2D6. When co-administered with bupropion, dextromethorphan exhibits nonlinear pharmacokinetics at steady state, with AUC and C of dextromethorphan varying from 30 mg to 60 mg. max The changes in AUC and C of bupropion were greater than dose proportional, and for different doses of bupropion (75 mg to 150 mg), the AUC and C of bupropion were max The change was less than dose proportional.

[0041] When given in combination, steady-state plasma concentrations of dextromethorphan and bupropion were achieved within 8 days. max and AUC 0-12 , the accumulation rates of dextromethorphan at steady state are about 20 and about 32, respectively. max and AUC 0-12 , the accumulation rates of bupropion at steady state were 1.1 and 1.5, respectively.

[0042] After administration of the subject combination, the median T of dextromethorphan was max is about 3 hours, while the median T of bupropion is max The C of hydroxybupropion metabolites max It occurs approximately 3 hours after dosing and is approximately 14 times the peak level of bupropion. The AUC of hydroxybupropion 0-12 It is about 19 times that of bupropion. C of erythro-hydroxybupropion and threo-hydroxybupropion metabolites max The AUC values ​​for erythro-hydroxybupropion and threo-hydroxybupropion are approximately 4 hours after administration and are approximately equal to and 5 times that of bupropion, respectively. 0-12 The values ​​are about 1.2 times and about 7 times that of bupropion, respectively.

[0043] The subject combination may be taken with or without food. When the subject combination is administered with food, dextromethorphan C max and AUC 0-12 remained unchanged and decreased by 14%, respectively, while bupropion C max and AUC 0-12 An increase of 3% and 6% respectively.

[0044] Dextromethorphan is approximately 60-70% bound to plasma proteins, whereas bupropion is 84% ​​bound to plasma proteins. Hydroxybupropion metabolites are protein bound to a similar extent as bupropion, whereas threohydroxybupropion metabolites are protein bound to about half the extent of bupropion.

[0045] Following 8 consecutive days of administration of the subject combination in extensive metabolizers, the mean elimination half-life of dextromethorphan was increased approximately 3-fold to approximately 22 hours compared to dextromethorphan administered without bupropion.

[0046] The mean elimination half-lives of dextromethorphan and bupropion are 22 hours and 15 hours, respectively. The apparent elimination half-lives of hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion metabolites are approximately 35, 44, and 33 hours, respectively.

[0047] The topic combination can be used as an adjunctive treatment for major depressive disorder or depression.

[0048] In addition to major depressive disorder, the subject combinations can also be used to treat other diseases of the condition in the patient population or situation described herein. For example, the subject combinations can be used to treat pain or neurological disorders. Examples of neurological disorders that can be treated with the subject combinations include, but are not limited to, affective disorders, mental disorders, brain dysfunction, movement disorders, dementia, motor neuron disease, neurodegenerative diseases, epilepsy, and headaches.

[0049] Affective disorders that may be treated by the subject combinations include, but are not limited to, depression, major depression, refractory depression, refractory bipolar depression, bipolar disorder including cyclothymia, seasonal affective disorder, mood disorders, chronic depressive disorder (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 disorder and mania, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychotic dysfunction, pseudobulbar mood, and mood lability.

[0050] Depression can be manifested by depressive symptoms. These symptoms can include psychological changes (such as mood changes), feelings of extreme sadness, despair, mental dullness, inattention, pessimistic worries, agitation, anxiety, irritability, guilt, anger, worthlessness, reckless behavior, suicidal thoughts or attempts, and / or self-depreciation. The physical symptoms of depression can include insomnia, anorexia, loss of appetite, weight loss, weight gain, decreased energy and libido, fatigue, irritability, aches, pains, headaches, cramps, digestive problems, and / or abnormal hormonal circadian rhythms.

[0051] Mental disorders that can be treated by the subject combination include, but are not limited to: anxiety disorders, including, but not limited to, phobia, 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, paranoia, schizoaffective disorder, schizotypy, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease. Alzheimer's disease can also be referred to as Alzheimer's dementia. Other neurobehavioral symptoms of Alzheimer's disease that can be treated include disinhibition and emotional indifference.

[0052] Agitation may occur in Alzheimer's disease as the disease progresses. Agitation may present itself as inappropriate verbal, emotional, and / or physical behavior. Inappropriate behavior may include, but is not limited to, incoherent babbling, inappropriate emotional responses, demands for attention, threats, irritability, frustration, screaming, repetitive questioning, mood swings, swearing, abusive language, physical outbursts, emotional distress, restlessness, tearing, sleep disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body movements, hoarding, stalking, hitting, scratching, biting, aggressiveness, hyperactivity, and / or kicking.

[0053] 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 approximately 6 million individuals in the United States, a figure that is expected to increase to approximately 14 million by 2050. It is reported that up to 70% of AD patients suffer from agitation and are characterized by emotional distress, aggressive behavior, destructive irritability, and disinhibition. Managing agitation is a priority for AD. Agitation in AD patients is associated with increased caregiver burden, functional decline, accelerated cognitive decline, premature nursing home placement, and increased mortality. Currently, the FDA has not approved a therapy for the treatment of agitation in AD patients.

[0054] It is known that neurobehavioral symptoms may occur during dementia, and it can be treated by theme combination therapy. Compared to the patient's cognitive impairment, caregivers or family members may feel more unbearable due to the patient's behavior / psychological symptoms. The common form of syndrome includes Alzheimer's disease, vascular dementia, Lewy body (abnormal protein aggregates formed in nerve cells) dementia and a group of diseases causing frontotemporal dementia (degeneration of the frontal lobe of the brain). The symptoms of dementia patients are similar to those of mental disorders, but slightly different from each other. The neurobehavioral symptoms associated with dementia include depression, apathy, agitation, disinhibition, hallucination, delusion, psychosis, impulse, aggressiveness, compulsion, hypersexuality and personality disorder. Neurobehavioral symptoms may also be found in other morbidities (such as traumatic brain injury), such as disinhibition.

[0055] Agitation in patients with Alzheimer's disease can be assessed using the Cohen Mansfield Agitation Inventory or (CMAI). The CMAI assesses a variety of behaviors, including hitting (including self), kicking, grabbing, pushing, throwing, biting, scratching, spitting, hurting self or others, tearing objects or destroying property, making physical advances, pacing, wandering aimlessly, dressing inappropriately or undressing, trying to go to different places, intentionally falling down, eating / drinking inappropriate substances, handling things inappropriately, hiding things, hoarding things, repetitive quirks, general irritability, screaming, making verbal advances, swearing or verbally aggression, repeating sentences or questions, strange noises (weird laughter or crying), complaining, whining, and constant and unprovoked requests for attention or help.

[0056] Schizophrenia may be treated by a combination of themes including positive and / or negative symptoms of schizophrenia or residual symptoms of schizophrenia.Other conditions that may be treated include intermittent explosive disorder.

[0057] The brain dysfunction that the subject combination can treat includes, but is not limited to, disorders involving intellectual impairment, such as Alzheimer's disease, Alzheimer's dementia, amnesia, amnesia / amnestic syndrome, epilepsy, impaired consciousness, coma, decreased attention, speech disorders, voice spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperactivity syndrome and schizophrenia. Brain dysfunction also includes disorders caused by cerebrovascular disease, including but not limited to stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head injury, etc., wherein symptoms include impaired consciousness, Alzheimer's disease, coma, decreased attention and speech disorders.

[0058] Substance addictions that can be treated by the subject combination include, but are not limited to, drug dependence, cocaine addiction, psychostimulants (e.g., crack, cocaine, speed, methamphetamine), nicotine, alcohol, opioids, antianxiety 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, cigars and / or pipes, e-cigarettes or vaping, and chewing cigarette addiction.

[0059] Movement disorders that may be treated by the subject combinations 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, chorea rheumatica, 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.

[0060] Dementias that may be treated by the subject combinations include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff Syndrome, and Pick's disease.

[0061] Motor neuron diseases that may be treated by the subject combinations include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophy, Tay-Sachs disease, Sandhoff's disease, and hereditary spastic paraplegia.

[0062] Neurodegenerative diseases that may be treated by the subject 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, 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 dystrophy, Charcot-Marie-Tooth disease, disease, CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0063] Epileptic disorders that may be treated by the subject combinations include, but are not limited to, epileptic seizures, nonepileptic seizures, epilepsy, febrile convulsions; partial seizures, including, but not limited to, simple partial seizures, Jacksonian seizures, complex partial seizures, and epilepsy continua partial; 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.

[0064] Headache types that may be treated by the subject combination include, but are not limited to, migraines, tension headaches, and cluster headaches.

[0065] Other neurological disorders that may be treated by the subject combinations include, but are not limited to, Rett Syndrome, autism, tinnitus, impaired consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy; voice disorders caused by uncontrolled laryngeal muscle spasms, including but not limited to abductorspasmodic dysphonia, adductor spasmodic dysphonia, muscular tension dysphonia, and vocal tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity, such as methotrexate neurotoxicity; incontinence, including but not limited to stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.

[0066] In some embodiments, the subject combinations can be used to treat pain, joint pain, pain associated with sickle cell disease, pseudobulbar mood, depression (including refractory depression), disorders related to memory and cognition, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rhett syndrome, seizures, cough (including chronic cough), and the like.

[0067] In some embodiments, the subject combinations may be administered orally to relieve musculoskeletal pain, including low back pain, and pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatic diseases, periarticular disorders, axial spondyloarthritis (including ankylosing spondylitis), Paget's disease, fibrous dysplasia, SAPHO syndrome, transient hip osteoarthritis, vertebral compression fractures, osteoporosis, and the like.

[0068] In some embodiments, the subject combinations may be administered to relieve inflammatory pain, including musculoskeletal pain, arthritic pain, and complex regional pain syndrome.

[0069] Arthritis refers to inflammatory joint diseases that may be associated with pain. Examples of arthritis pain include pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatism, periarticular disease, neuropathic arthropathy (including Charcot foot), axial spondyloarthritis (including ankylosing spondylitis), and SAPHO syndrome.

[0070] In some embodiments, the subject combinations are used to treat chronic musculoskeletal pain.

[0071] In some embodiments, the subject compositions can be administered to relieve complex regional pain syndrome, such as complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or 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 the limbs, which may be accompanied by edema and autonomic, motor and sensory changes.

[0072] In some embodiments, the subject compositions may be administered orally to relieve neuropathic pain.

[0073] 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, pain caused by 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-related neuropathy, and radiation or chemotherapy-related neuropathy, etc.

[0074] In some embodiments, the subject compositions may be administered to relieve fibromyalgia.

[0075] In some embodiments, the subject combination can prevent relapse in patients with refractory depression (TRD). Generally speaking, about 40% of MDD patients are refractory, defined as no response to two or more correctly administered antidepressants of 2 different classes within the current depressive episode. In TRD patients who eventually achieve remission, MDD relapse is not uncommon, with >40% of patients relapsing within about 4 months of treatment. Relapse is defined by ≥1 of the following: (1) MADRS total score ≥18 for 2 consecutive assessments 7 to 21 days apart; (2) Clinical Global Impression-Severity (CGI-S) increased by ≥2 points from randomization for 2 consecutive assessments 7 to 21 days apart, with a minimum CGI-S score of 4 points; and (3) loss of treatment response, such as: a) hospitalization due to worsening depression or due to suicide risk, b) the researcher determines that additional antidepressant treatment or conversion treatment is needed, and c) the researcher believes that the patient has relapsed.

[0076] In some embodiments, the subject combination can delay the time to recurrence of depressive symptoms compared to placebo in the treatment of refractory depression. In some embodiments, the subject combination can significantly and statistically delay the time to recurrence of depressive symptoms compared to placebo in TRD patients who have achieved stable remission receiving the subject combination (dextromethorphan and bupropion).

[0077] In some embodiments, a TRD patient who continues treatment with the subject combination may not experience a recurrence of depressive symptoms within about 10 weeks, within about 20 weeks, within about 26 weeks, within about 30 weeks, within about 40 weeks, within about 50 weeks, within about 52 weeks, or longer, or within at least 6 months of treatment.

[0078] In some embodiments, the subject combination can significantly prevent depression recurrence in at least 6 months compared to placebo. In some embodiments, treatment with the subject combination can reduce the likelihood of recurrence compared to placebo. In some embodiments, the likelihood of a patient not experiencing depression recurrence when treated with the subject combination is at least 30%, about 30-40%, about 40-50%, or about 36%, or any percentage within the range defined by any one of the above values, compared to receiving a placebo and with a percentage of patients who do not relapse.

[0079] After treatment with theme combination, depressive symptoms can be improved rapidly. The mean change of MADRS total score from baseline may be significant in the 1st week, 2nd week, 4th week or 6th week. The improvement of depression composite symptoms can last for about 3 months, about 6 months, about 1 year or longer. The clinical response (improvement ≥ 50%) in the case of theme combination may be realized in the 1st week, 2nd week, 4th week or 6th week. The relief (≤10) of MADRS in the case of theme combination may be realized in the 1st week, 2nd week, 4th week or 6th week or longer. The antidepressant effect of theme combination may be lasting and last to the 2nd month, 3rd month, 6th month, 9th month, 12th month or longer.

[0080] With the subject combination treatment, a CGI-S response (≥2 category change) may be rapid. A CGI-S response (≥2 category change) may be observed at Week 1, Week 2, Week 4, or Week 6. CGI-S improvements may be durable, at Month 2, Month 3, Month 6, Month 9, Month 12, or longer.

[0081] In the case of treatment with this combination, the average reduction in SDS may be very fast. In the case of treatment with the subject combination, the average reduction in SDS may be significant in the 1st week, 2nd week, 4th week or 6th week. In the case of treatment with the subject combination, the average reduction in SDS may be lasting and continue to the 2nd month, 3rd month, 6th month, 9th month, 12th month or longer. The relief (≤6) of SDS may be realized in the 1st week, 2nd week, 4th week, 6th week, 2nd month, 3rd month, 6th month, 9th month, 12th month or longer.

[0082] In some embodiments, a human patient is selected who has a HAM-A score of at least 10 or at least 15 prior to treatment.

[0083] Treatment with the themed combination may improve anxiety symptoms. Reductions from baseline in mean HAM-A scores may be significant at Week 1, Week 2, Week 4, or Week 6. Improvements in HAM-A may be durable, to Month 2, Month 3, Month 6, Month 9, Month 12, or longer. Treatment with the themed combination may provide rapid relief of anxiety, to Week 1, Week 2, Week 4, or Week 6. Relief may be durable, to Month 2, Month 3, Month 6, Month 9, Month 12, or longer.

[0084] Approximately 15-70% of patients may achieve a HAM-A response (≥50% improvement from baseline) at Week 1, Week 2, Week 4, or Week 6, respectively. Response rates may continue to improve at Months 2, 3, 6, 9, 12, or longer.

[0085] In some embodiments, a human patient is selected who has a MADRS-anhedonia score of at least 15 or at least 19 before treatment. In some embodiments, the subject composition may improve anhedonia symptoms in major depressive disorder (MDD), as assessed by the MADRS anhedonia subscale. Anhedonia is one of the core features of MDD. Anhedonia is considered by patients to be one of the most troubling aspects of MDD, and is associated with functional decline, and is a risk factor for non-response to antidepressant treatment. The MADRS anhedonia subscale includes 5 items: 1) obvious sadness; 2) reported sadness; 3) difficulty concentrating; 4) laziness; and 5) inability to feel.

[0086] In some embodiments, the subject combination can be orally administered to reduce the MADRS anhedonia subscale at week 1, week 2, week 3, week 4, week 5, or week 6 or longer. In some embodiments, administration of the subject combination may result in a mean decrease in MADRS anhedonia subscale score from baseline of about 4-5, 4-6, 6-8, 6-7, 8-10, 8-9, 9-10, about 4.4, about 6.8, about 8.1, about 9.6, about 9.7, or about 10 or more, or any MADRS anhedonia subscale score within a range bounded by any of these values.

[0087] In some embodiments, the mean reduction from baseline in the MADRS anhedonia subscale for oral administration of the subject combination may be significantly greater than that for oral administration of a placebo at week 1, week 2, week 3, week 4, week 5, or week 6 or more. In some embodiments, the mean reduction from baseline in the MADRS anhedonia subscale for oral administration of the subject combination may be about 30%, about 50%, about 60%, about 20-30%, about 30%-35%, about 30%-50%, about 40%-50%, about 50%-55%, about 50-60%, about 60%-65%, or any percentage within the range defined by any of these values, at week 1, week 2, week 3, week 4, week 5, or week 6 or more.

[0088] In some embodiments, the likelihood of a patient becoming a responder (≥50% reduction in the MADRS anhedonia subscale) when orally administered the subject combination at week 1, week 2, week 3, week 4, week 5, or week 6 or longer may be about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 20-25%, about 30-35%, about 40-45%, about 50-55%, about 21%, about 35%, about 42%, about 51%, about 54%, or any likelihood within a range bounded by any of these values.

[0089] In some embodiments, the likelihood of a patient becoming a responder (MADRS anhedonia subscale reduction of ≥ 50%) to the subject combination of dextromethorphan and bupropion may be statistically significantly higher at week 1, week 2, week 3, week 4, week 5, or week 6 or more compared to placebo. In some embodiments, the likelihood of a patient becoming a responder when being administered the subject combination may be about 10-15%, about 15-20%, about 20-25%, about 13%, about 16%, about 18%, about 20%, about 23%, or any percentage within a range bounded by any of these values ​​at week 1, week 2, week 3, week 4, week 5, or week 6 or more than the likelihood of a patient becoming a responder when taking placebo.

[0090] The terms "treatment" or "therapy" include any activity that affects the structure or any function of the body of a human or other animal, including the diagnosis, cure, mitigation, treatment, or prevention of disease.

[0091] Example 1

[0092] Effects of dextromethorphan-bupropion in major depressive disorder: a randomized double-blind controlled trial

[0093] Target:

[0094] Altered glutamatergic neurotransmission has been implicated in the pathogenesis of major depressive disorder. This phase 2 trial evaluated the efficacy and safety of dextromethorphan-bupropion, an oral NMDA receptor antagonist and sigma-1 receptor agonist that utilizes inhibition of CYP2D6 to increase its bioavailability, in the treatment of major depressive disorder.

[0095] method:

[0096] This randomized, double-blind, multicenter, parallel-group trial evaluated dextromethorphan-bupropion versus an active comparator, sustained-release bupropion, in patients aged 18-65 years diagnosed with major depressive disorder of moderate or greater severity. Patients were randomized to receive dextromethorphan-bupropion (45 mg / 105 mg tablets) or bupropion (105 mg tablets) once daily for the first 3 days and twice daily thereafter for a total of 6 weeks. The primary endpoint was the overall treatment effect (mean of the change from baseline in Weeks 1-6) on the Montgomery-Asberg Depression Rating Scale (MADRS) score assessed in all randomized patients whose diagnosis and severity were confirmed by an independent assessor and who received at least one dose of study medication and received at least one post-baseline assessment.

[0097] result:

[0098] Of the 97 patients randomized, 17 did not have a confirmed diagnosis and severity based on independent assessment, resulting in 80 patients in the efficacy population (dextromethorphan-bupropion, N=43; bupropion, N=37). The mean change from baseline in MADRS scores during weeks 1-6 (overall treatment effect) was significantly greater with dextromethorphan-bupropion compared with bupropion (-13.7 points vs. -8.8 points; least squares mean difference = -4.9; 95% CI = -3.1, -6.8). At week 2 and at each time point thereafter, the change in MADRS scores was significantly greater with dextromethorphan-bupropion compared with bupropion (week 6: -17.3 points vs. -12.1 points; least squares mean difference = -5.2, 95% CI = -1.1, -9.3). At week 2 and at every time point thereafter, remission rates were significantly greater with dextromethorphan-bupropion (week 6: 46.5% vs. 16.2%; least squares mean difference = 30.3%, 95% CI = 11.2, 49.4). At week 6, the responder rate (≥50% decrease in MADRS score from baseline) was 60.5% with dextromethorphan-bupropion compared with 40.5% with bupropion (least squares mean difference = 19.9%, 95% CI = -1.6, 41). Most secondary outcomes favored dextromethorphan-bupropion. The most common adverse events with dextromethorphan-bupropion were dizziness, nausea, dry mouth, decreased appetite, and anxiety. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or sexual dysfunction.

[0099] in conclusion:

[0100] Among patients with major depression, dextromethorphan-bupropion significantly improved depressive symptoms compared with bupropion and was well tolerated.

[0101] Major depression is a common and disabling condition and is the leading cause of disability worldwide. Currently approved oral antidepressants work primarily via monoamine pathways. These agents often have partial or inadequate responses, and they usually require several weeks to produce clinically significant effects. In the Sequential Treatment of Depression (STAR*D) trial, approximately two-thirds of depressed patients were unable to achieve remission using first-line treatment, and of the patients who experienced clinical responses, approximately 60% achieved remission only during treatment or after 8 weeks of treatment.

[0102] Data from neuroimaging, cell and clinical studies indicate that the glutamatergic system is involved in the pathogenesis of depression. Dextromethorphan is a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors (ionotropic glutamate receptors) and a σ-1 receptor agonist. Blockade of NMDA receptors and agonism of σ-1 receptors regulate glutamate signaling in the central nervous system. Dextromethorphan is rapidly and extensively metabolized by CYP2D6, resulting in subtherapeutic plasma levels, limiting its clinical practicality. Tablets combining dextromethorphan and bupropion (hereinafter dextromethorphan-bupropion) are formulated to increase the bioavailability and half-life of dextromethorphan, and are developed for the treatment of major depression. The bupropion component increases its plasma concentration by inhibiting the metabolism of dextromethorphan. In March 2019, the US Food and Drug Administration (FDA) granted a breakthrough therapy title for dextromethorphan-bupropion for the treatment of major depression. This designation is given to drug candidates that, based on preliminary clinical data, show benefit over available therapies, and it provides sponsors with increased attention and interaction with FDA staff during the development of their drug candidates.

[0103] Failure rates of signal detection in depression clinical trials have been demonstrated to be high. A large analysis of depression clinical trials submitted for new drug applications over a 25-year period showed a trial failure rate of nearly 50% and a decreasing treatment effect (drug-placebo difference) over that period. Reasons identified in the literature for poor signal detection and high failure rates in depression clinical trials include high and increasing placebo response rates, site rater bias leading to inflated baseline scores, inclusion of patients with less severe symptoms, and failure to exclude patients who were ineligible for study participation. Approaches to address increasing placebo rates include placebo run-in designs and sequential parallel comparison designs, both of which remove subjects with high placebo responders to increase treatment effect. These approaches have had mixed success. Approaches to reduce the inclusion of ineligible or inappropriate patients include the use of a third party to re-interview potential patients to confirm illness severity and eligibility. A limitation of these approaches is that sites are not blinded to the use of independent assessments.

[0104] In this pilot trial, we utilized several measures to potentially address issues leading to poor signal detection. These measures included confirmation of disease severity through independent assessment and comprehensive blinding of participating clinical trial sites.

[0105] method

[0106] Study Design

[0107] This was a 6-week, randomized, double-blind, active-controlled phase 2 trial conducted at four sites in the United States from May to December 2018. The trial used bupropion, an approved antidepressant, as a comparator because it is a component of dextromethorphan-bupropion.

[0108] To address the possibility of inappropriate inclusion of patients due to site assessor bias, this study only evaluated efficacy in patients whose diagnosis and severity of major depressive disorder were confirmed based on clinical review by independent assessors who were blind to treatment allocation. The clinical review utilized only the documents collected by the site at screening and baseline, including a complete medical history and clinician- and patient-reported outcome measures (described below in the efficacy assessment). The independent assessors had no direct contact with the study participants and did not touch any patient data collected after randomization. In order to reduce the researcher's expectation bias and thus reduce the placebo response, the site was blinded to the presence of the primary efficacy variables and independent assessors. A blinding scheme was provided to the site, presenting the trial as a safety study with an exploratory efficacy assessment. A detailed discussion of the efficacy analysis was limited to the statistical analysis plan, which was not provided to the site.

[0109] All sites were approved by an independent review committee, and all patients provided written informed consent before participation. Site researchers collected trial data, and the applicant ensured that all personnel performing the rating scale were qualified and appropriately trained. The trial was conducted in accordance with the International Council for Coordination's guidelines for good clinical practice, the principles of the Declaration of Helsinki, and all regulatory requirements. The clinical trial is listed on ClinicalTrials.gov (NCT03595579).

[0110] Participants

[0111] Patients aged 18-65 years with a confirmed diagnosis of major depressive disorder and a current major depressive episode of moderate or greater severity were evaluated for the study. Diagnosis was established using DSM-5 criteria for major depressive disorder without psychotic features, based on the Structured Clinical Interview for DSM-5 (Clinical Trial Version) and a score of ≥25 on the Montgomery-Asberg Depression Rating Scale (MADRS) and ≥4 on the Clinical Global Impression Severity Scale (CGI-S) as assessed by site investigators. The diagnosis of major depressive disorder and a current major depressive episode of moderate or greater severity were confirmed by a blinded independent assessor based on clinical review prior to database lock and study unblinding.

[0112] Key exclusion criteria included bipolar disorder, panic disorder, obsessive-compulsive disorder, refractory depression (defined as at least two failed adequate antidepressant treatments in the current major depressive episode), substance use disorder within the past year, lifetime history of psychiatric disorder, clinically significant suicide risk, and history of epilepsy. Patients could be treated with antidepressants prior to study entry, but prior to the baseline visit and randomization, they were required to completely stop previous treatment with a washout period of at least 1 week or five half-lives of the drug, whichever was longer. The screening period was up to 4 weeks to allow for any required reduction and washout of previous medications.

[0113] Randomization and Blinding

[0114] Participants were randomized in a 1:1 ratio to receive oral treatment with dextromethorphan-bupropion or sustained-release bupropion. To blind the site investigators to independent diagnosis confirmation, all patients deemed eligible by the site investigators were randomized to receive study drug and were included in the safety population. As prespecified, patients whose diagnosis or severity was not confirmed by independent assessors were excluded from the efficacy population.

[0115] The appearance of dextromethorphan-bupropion tablets and bupropion tablets is identical. The randomization schedule was computer-generated using a permuted block algorithm that randomly assigned study medication to randomization numbers. All patients, investigators, and study staff were blinded to treatment assignment, and the randomization schedule was not accessible to anyone involved in the conduct of the study until treatment assignment was formally unblinded.

[0116] program

[0117] The double-blind treatment period was 6 weeks. Patients received their assigned study drug dextromethorphan-bupropion (45mg / 105mg tablets) or bupropion (105mg tablets), once a day for the first 3 days and twice a day thereafter. The bupropion dose in the control group (210mg per day) was selected to match the dose in dextromethorphan-bupropion to achieve appropriate comparison. During the treatment period, patients tracked their mood by completing a daily visual analogue moodscale. Study visits occurred 1, 2, 3, 4, and 6 weeks after the baseline visit. Safety follow-up occurred at week 7 (1 week after the last dose of study drug). There were no formal interruption criteria; patients could withdraw consent for any reason, and researchers could remove patients from the study for any safety-related reasons. Based on the results of the pharmacokinetic study, the dose of dextromethorphan-bupropion was selected and adjusted stepwise to twice a day. Compliance with study medication was monitored by counting the number of tablets dispensed and returned and by measuring plasma concentrations of bupropion at the end of the study.

[0118] Efficacy evaluation

[0119] The primary efficacy variable was the change in the total MADRS score from baseline to week 6. MADRS is a 10-item clinician-rated questionnaire ranging from 0 to 60, with higher scores indicating more severe depression. The primary hypothesis test was the overall treatment effect on the MADRS score (mean of the change from baseline in weeks 1-6).

[0120] Secondary end points included clinical response (defined as a ≥50% reduction from baseline in the MADRS total score); remission (defined as a MADRS total score ≤10); scores on the Clinical Global Impression of Improvement scale (CGI-I; scores range from 1 [very improved] to 7 [very worse]); scores on the CGI-S (scores range from 1 [normal] to 7 [worst case possible]); scores on the 16-item Quick Inventory of Depressive Symptoms-Self-Rating (QIDS-SR; scores range from 0 to 27, with higher scores indicating more severe depression); and scores on the MADRS-6 (a 10-item subscale of the MADRS that assesses core symptoms of depression: palpable sadness, reported sadness, inner tension, lethargy, inability to feel, and pessimistic thoughts).

[0121] Safety was assessed based on the incidence of adverse events; changes in vital signs, clinical laboratory measurements, physical examinations, and electrocardiograms; and assessment of suicidal ideation and behavior using the Columbia-Suicide Severity Rating Scale (C-SSRS). Adverse events during the treatment period were defined as those occurring from the first dose of dextromethorphan-bupropion or bupropion to 7 days after the last dose.

[0122] Statistical analysis

[0123] Two patient sets were pre-specified for analysis. The safety population included all patients who received at least one dose of study drug. The efficacy population (modified intent-to-treat population) consisted of all patients with a major depressive episode of moderate or greater severity, confirmed by an independent assessor, who were randomized, received at least one dose of study drug, and received at least one post-baseline assessment.

[0124] The main efficacy variable is the change of MADRS total score from baseline, and the main hypothesis test is the overall treatment effect.The overall treatment effect of MADRS is evaluated by calculating the mean value of the change from baseline at each time point (week 1-6) in the study.The change of MADRS scores from baseline is analyzed using a mixed model with repeated measures, including treatment (two levels: one indicates ingot treatment, and two indicate control treatments), number of weeks (five levels: week 1-4 and week 6) and week-by-week treatment interaction as factors, baseline values ​​as covariates, and subjects as random effects.This method is used to analyze and evaluate all other efficacy variables that change from baseline.Missing values ​​are calculated by carrying forward (last-observation-carried-forward) method from the previous observation result.

[0125] The overall treatment effect, the treatment effect of each week after the individual baseline, and the difference between the treatment effects were estimated using the least squares mean estimate and reported together with the bilateral 95% confidence interval of the treatment difference. Efficacy variables (e.g., clinical response and remission rate) related to percentages were analyzed via the chi-square test. The CGI-I was analyzed using the Cochran-Mantel-Haenszel test. The analysis was performed using SAS version 9, and all hypothesis tests were performed at a bilateral alpha level of 0.05.

[0126] If a positive result is found in the primary hypothesis test on MADRS, additional analyses (response, remission) should be performed on this variable to examine clinical relevance. As this is a Phase 2 experimental study, secondary efficacy variables were not adjusted for multiplicity, and nominal p-values ​​for these variables are presented. The sample size assumes that approximately 60 confirmed patients (30 in each group) complete the double-blind period. The sample size of the study was determined based on previously reported experience from trials of similar phase, in similar patient populations, and with similar objectives.

[0127] result

[0128] Patients and placement

[0129] A total of 97 patients were randomized (48 to dextromethorphan-bupropion and 49 to bupropion). Of these, independent assessor assessment could not confirm the diagnosis or severity of 17 patients, resulting in a total of 80 patients in the efficacy (modified intention-to-treat) population (43 in the dextromethorphan-bupropion group and 37 in the bupropion group) ( Figure 1 Of the 17 patients excluded from the sample, 16 were excluded because of discrepancies in depression severity scores (not meeting criteria for at least moderate depression severity), and one was excluded because the patient was not diagnosed with major depression.

[0130] Figure 1 Flowchart showing participants moving through the Phase 2 trial of dextromethorphan-bupropion for major depressive disorder.

[0131] Baseline demographic and clinical characteristics of patients were generally similar for the dextromethorphan-bupropion and bupropion groups (Table 1). The proportion of female black or African American patients and Hispanic or Latino patients in the bupropion group (70.3%, 37.8%, and 29.7%, respectively) was higher than in the dextromethorphan-bupropion group (58.1%, 27.9%, and 14.0%, respectively). Given the small sample size, these observed differences are entirely within random chance (p>0.15). The number of patients who completed the trial in the efficacy population was 34 (79.1%) in the dextromethorphan-bupropion group and 26 (70.3%) in the bupropion group. The completers of the safety population are shown in Figure 1 middle.

[0132] Overall, mean treatment adherence based on tablet counts was high across visits for both the dextromethorphan-bupropion group and the bupropion group in both the safety and efficacy populations (≥90.0% and ≥91.3%, respectively). Consistent with adherence based on tablet counts, 93.1% of the 72 patients in the efficacy population with pharmacokinetic samples had measurable study drug concentrations at the last scheduled study visit.

[0133] effect

[0134] Compared with bupropion, dextromethorphan-bupropion was significantly associated with a decrease in the MADRS total score (Figure 2). The least squares mean change from baseline in the MADRS total score in weeks 1-6 (overall treatment effect) was -13.7 points in the dextromethorphan-bupropion group and 28.8 points in the bupropion group (least squares mean difference = -4.9, 95% CI = -3.1, -6.8; Cohen's d value = 1.2; p < 0.001). Dextromethorphan-bupropion was observed to improve the MADRS total score better than bupropion as early as week 1, and the difference was statistically significant starting from week 2 (least squares mean difference = -4.7, 95% CI = -0.6, -8.8; p = 0.024) and at each time point thereafter. At week 6, dextromethorphan-bupropion was associated with a mean change from baseline in the MADRS total score of -17.3 points, compared with -12.1 points for bupropion (least squares mean difference = -5.2, 95% CI = -1.1, -9.3; Cohen's d = 0.6; p = 0.013). The results of a sensitivity analysis of the primary endpoint (overall treatment effect) using a mixed model for repeated measures without imputation of missing values ​​were consistent with those of the primary analysis (least squares mean difference = -5.1, 95% CI = -3.1, -7.1; p < 0.001).

[0135] Table 1. Baseline Demographics and Clinical Characteristics of Study Participants in the Phase 2 Trial of Dextromethorphan-Bupropion for Major Depressive Disorder a

[0136]

[0137]

[0138] a CGI-S=Clinical Global Impression Severity Scale; MADRS=Montgomery-Asberg Depression Rating Scale.

[0139] A statistically significantly greater percentage of patients achieving remission (defined as a MADRS total score ≤10) was observed in the dextromethorphan-bupropion group compared with the bupropion group at week 2 (25.6% and 2.7%, respectively; least squares mean difference = 22.9%, 95% CI = 8.8, 36.9; p = .004) and at each time point thereafter. Figure 2A and 2B, Table 2). At week 6, the percentage of patients achieving remission was 46.5% in the dextromethorphan-bupropion group and 16.2% in the bupropion group (least squares mean difference = 30.3%, 95% CI = 11.2, 49.4; p = 0.004). Clinical response (defined as a ≥ 50% reduction in MADRS total score) favored the dextromethorphan-bupropion group, with the difference between the groups reaching statistical significance at week 3 (least squares mean difference = 27.2%, 95% CI = 7.2, 47.2; p = 0.012) and week 4 (least squares mean difference = 23.0%, 95% CI = 1.7, 44.3; p = 0.040). At week 6, 60.5% of patients in the dextromethorphan-bupropion group achieved a clinical response compared to 40.5% in the bupropion group (least squares mean difference = 19.9%, 95% CI = -1.6, 41.5; p = 0.075).

[0140] Dextromethorphan-bupropion significantly improved MADRS-6 (core symptom) scores compared to bupropion. The least squares mean change from baseline in MADRS-6 scores over weeks 1-6 (overall treatment effect) was -10.1 points in the dextromethorphan-bupropion group and -6.6 points in the bupropion group (least squares mean difference = -3.4, 95% CI = -2.2, -4.7; p < 0.001) (Table 2). Dextromethorphan-bupropion was observed to improve MADRS-6 scores better than bupropion as early as week 1, and the difference was statistically significant starting from week 2 (least squares mean difference = -3.2, 95% CI = -0.4, -6.0; p = 0.027) and at each time point thereafter.

[0141] Dextromethorphan-bupropion treatment was associated with significantly greater improvements in CGI-S compared with bupropion. The overall treatment effect (mean improvement from baseline over weeks 1-6) on CGI-S was -1.6 in the dextromethorphan-bupropion group compared with -1.0 in the bupropion group (least squares mean difference = -0.5, 95% CI = -0.3, -0.8; p < 0.001) (Table 2). At all time points, dextromethorphan-bupropion was superior to bupropion in CGI-S, with the difference between the groups reaching statistical significance at week 2 (least squares mean difference = -0.9, 95% CI = 0.0, -1.0; p = 0.049) and at every time point thereafter (including week 6; least squares mean difference = -0.5, 95% CI = 0.0, -1.1; p = 0.038). A statistically significantly greater proportion of patients in the dextromethorphan-bupropion group demonstrated moderate to marked improvement on the CGI-I at both Week 1 (LSMD=14.3%, 95% CI=1.5, 28.3; p=0.045) and Week 4 (LSMD=28.1%, 95% CI=4.1, 52.1; p=0.025) compared to the bupropion group.

[0142] The dextromethorphan-bupropion group also showed statistically significant improvements on the patient-rated QIDS-SR compared to the bupropion group. The least squares mean change from baseline in weeks 1-6 on the QIDS-SR (overall treatment effect) was -6.0 in the dextromethorphan-bupropion group and -4.8 in the bupropion group (least squares mean difference = -1.2, 95% CI = -0.2, -2.2; p = 0.017). The proportion of patients who achieved remission (defined as a score of ≤5) on the QIDS-SR at week 6 in the dextromethorphan-bupropion group (46.5%) was statistically significantly greater than that in the bupropion group (21.6%) (least squares mean difference = 24.9%, 95% CI = 4.9, 44.8; p = 0.020).

[0143] Figure 2A and 2B Shown are MADRS total scores and remission over time in a phase 2 trial of dextromethorphan-bupropion for major depressive disorder. Figure 2A Shows the mean change from baseline in MADRS total score over time; Figure 2B The percentage of patients achieving remission (MADRS total score ≤ 10) over time is shown. MADRS stands for Montgomery-Asberg Depression Rating Scale. Error bars indicate standard error, and p-values ​​are calculated via chi-square test.

[0144]

[0145] a CGI-S5 = Clinical Global Impression Severity Scale; LS = least squares; MADRS = Montgomery-Asberg Depression Rating Scale; MADRS-6 = 6-item Montgomery Asberg Depression Rating Scale; NNT = number needed to treat; ns = not significant. Changes from baseline variables were analyzed using a mixed model with repeated measures. This analysis of covariance mixed-effects model with repeated measures included treatment, week, and week-by-week treatment interaction as factors, baseline value as covariate, and patient as a random effect. Treatment effects and treatment differences at each time point were estimated using least squares mean estimates. Efficacy variables related to percentages were analyzed via chi-square tests. All hypothesis tests were performed at a two-sided alpha level of 0.05.

[0146] Security

[0147] The percentage of patients who experienced any adverse event during the treatment period was 72.9% in the dextromethorphan-bupropion group and 64.6% in the bupropion group. The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, dry mouth, decreased appetite and anxiety. In the bupropion group, the most commonly reported adverse events were nausea, headache, dry mouth, decreased appetite and constipation. The intensity of most adverse events was mild or moderate. Three patients in the dextromethorphan-bupropion group (two patients dizziness; one patient drowsiness, nausea and anxiety) and one patient in the bupropion group (psychiatric disorder) reported adverse events rated as severe in intensity. There were no major adverse events (including hospitalization) in the trial. The incidence of adverse events leading to study drug discontinuation was the same in the dextromethorphan-bupropion group and the bupropion group (12.5%). Two patients in the dextromethorphan-bupropion group discontinued the study drug due to dizziness and anxiety, respectively, and one patient in the bupropion group discontinued due to psychiatric disturbances. Dextromethorphan-bupropion was not associated with increased psychotomimetic effects, weight gain, or sexual dysfunction (Table 3).

[0148] Mean changes from baseline in clinical laboratory parameters and vital signs were small and similar between treatment groups. Two patients in the dextromethorphan-bupropion group had adverse events of weight loss, and one patient in the bupropion group had an adverse event of increased blood pressure, all of which resolved. The adverse event of weight loss was not major and was mild in severity.

[0149] There was no signal of increased suicidality in this study as assessed by the change from baseline on the C-SSRS. At baseline, five patients (10.4%) in the dextromethorphan-bupropion group and four patients (8.2%) in the bupropion group responded positively to item 1 (desire to die) of the C-SSRS. At week 1, only two patients in the dextromethorphan-bupropion group responded positively to item 1, compared with five in the bupropion group. At week 6, one patient in each treatment group responded positively to item 1 of the C-SSRS.

[0150] Table 3. Summary of Adverse Events in the Phase 2 Trial of Dextromethorphan-Bupropion for Major Depressive Disorder a

[0151]

[0152] a The safety population included all randomized patients who received at least one dose of dextromethorphan-bupropion or bupropion. Adverse events occurring during the treatment period were defined as those that began or worsened from the first dose of dextromethorphan-bupropion or bupropion to 7 days after the last dose.

[0153] b A major adverse event was defined as any adverse event that resulted in death, was immediately life-threatening, led to inpatient hospitalization or prolongation of hospitalization, or caused persistent or clinically significant disability or incapacity.

[0154] c Serious adverse events were defined as any event that interfered with activities of daily living, or significantly affected clinical status, or required intensive treatment intervention.

[0155] discuss

[0156] In this randomized, controlled trial, dextromethorphan-bupropion demonstrated rapid, dramatic, and statistically significant antidepressant efficacy compared with the active comparator, bupropion, on the primary efficacy variable (MADRS total score) and multiple other clinician- and patient-reported measures of depression severity. Given the known challenges in achieving signal detection in depression clinical trials, design features were implemented in this study to increase assay sensitivity and ensure assessment of an appropriate patient population. To address possible site assessor bias for inclusion of inappropriate patients, only patients whose diagnosis and severity of major depressive disorder were confirmed by blinded independent assessors based on clinical review were assessed in this study. Another important design feature implemented to increase the ability to detect efficacy signals in this Phase 2 trial was to blind site investigators to the efficacy objectives of the trial to reduce expectation bias.

[0157] As early as Week 1, dextromethorphan-bupropion rapidly reduced depressive symptoms as measured by the MADRS total score, with statistically significant differences over bupropion observed at Week 2 and at every time point thereafter. The treatment difference on MADRS (change in dextromethorphan-bupropion minus change in bupropion) was large and consistent over time, approximately 5 points (range 4.5-5.6 points) at each time point from Week 2 to Week 6. This treatment effect over the active comparator is superior to the average difference of approximately 2.5 points from placebo seen at Weeks 6-8 in antidepressant studies in the FDA database.

[0158] Symptom remission is considered a desirable goal of depression treatment because it is associated with better daily functioning and better long-term prognosis. The remission rate on MADRS (total score ≤ 10) was statistically significantly greater in the dextromethorphan-bupropion group starting at week 2 (p = 0.004) and at each time point thereafter. The remission rate on the patient-rated QIDS-SR (total score ≤ 5) at week 6 similarly favored dextromethorphan-bupropion (p = 0.020), indicating that clinician- and patient-reported outcomes were consistent.

[0159] The MADRS core symptom subscale (MADRS-6) was assessed because it has been suggested that core symptoms may be more sensitive to changes from antidepressant treatment. Results on the MADRS-6 were consistent with those on the 10-item MADRS, showing greater improvement in the dextromethorphan-bupropion group compared with the bupropion group, with both measures achieving statistical significance beginning at week 2 and at every time point thereafter.

[0160] Results from the clinician's global assessment were consistent with those from the symptom-specific scales and favored dextromethorphan-bupropion. Clinician-reported reductions in illness severity (as measured by the CGI-S) were rapid and consistently greater with dextromethorphan-bupropion compared with bupropion, and were statistically significant beginning at Week 2 (p=0.049) and at every subsequent time point, including Week 6 (p=0.038).

[0161] Dextromethorphan-bupropion showed rapid onset of effect on depressive symptoms and global measures, with statistically significant improvements observed on several measures compared to bupropion starting from week 2, but the sample size of the study was small. Starting from week 2, dextromethorphan-bupropion showed a statistically significant decrease from baseline in the MADRS total score compared to bupropion (p=0.024). Starting from week 2, the remission rate in the dextromethorphan-bupropion group on MADRS was statistically significantly superior compared to the bupropion group (26% vs. 3%; p=0.004). Global measures showed rapid improvement with dextromethorphan-bupropion, with statistically significant changes observed on CGI-I (p=0.045) at week 1 and on CGI-S (p=0.049) at week 2.

[0162] This study is the first controlled trial of dextromethorphan-bupropion in patients with depression. Murrough et al. reported the results of the combination of dextromethorphan and quinidine in the treatment of patients with refractory depression. However, this is an open-label trial without a control group, which limits the interpretation. The development of a combination of deuterated dextromethorphan and quinidine for the treatment of severe depression was stopped because the results of the Phase 2 placebo-controlled trial of this indication (NCT02153502) did not provide evidence of efficacy sufficient to justify continued development. In the Phase 2 trial of the present invention, the performance of the bupropion group (210 mg / day) was in line with expectations, resulting in a substantial reduction (12 points) in the total MADRS score from baseline at week 6. In contrast, in an 8-week, randomized placebo-controlled trial of 362 patients, treatment with bupropion at a dose of 150 mg / day or 300 mg / day resulted in a decrease of approximately 10 points from baseline in the Hamilton Depression Rating Scale (HAM-D) score of each of the two doses at week 8. This 10-point change in HAM-D means an approximately 12-point change in MADRS, which is consistent with the bupropion results in the Phase 2 trial of the present invention. The bupropion dose in the trial of the present invention was selected to match the dose in dextromethorphan-bupropion to achieve an appropriate comparison. This dose is lower than the usual target dose of 300 mg / day as monotherapy stated in the FDA prescribing information for bupropion.

[0163] Dextromethorphan-bupropion was safe and well tolerated in this trial. The incidence of adverse events was generally similar between the two groups, except for dizziness, which was reported in 20.8% of the dextromethorphan-bupropion group compared with 4.2% of the bupropion group. To estimate the true incidence of dizziness with dextromethorphan-bupropion, a larger study was conducted (ClinicalTrials.gov identifier: NCT04019704). Discontinuation rates due to adverse events were similar in the two treatment groups.

[0164] Unlike other NMDA receptor antagonists, dextromethorphan-bupropion is not associated with psychotomimetic effects. This tolerability may be related to the significantly faster rate of unclogging of NMDA receptor channels reported for dextromethorphan compared with other NMDA antagonists. In this trial, dextromethorphan-bupropion was not associated with abuse-related adverse events. Although the duration of dosing in this trial was only 6 weeks, in long-term open-label safety trials, dextromethorphan-bupropion has been administered for up to 1 year (ClinicalTrials.gov Identifier: NCT04039022). In this trial and other larger controlled trials, dextromethorphan-bupropion has not been abused to date. In this 6-week trial, dextromethorphan-bupropion was not associated with increased weight gain or sexual dysfunction.

[0165] Limitations of this trial include the exclusion of patients with insufficient symptom severity, psychosis or other psychiatric disorders, substance use disorders, clinically significant suicide risk, or severe medical comorbidity. These exclusions, as well as the prohibition of certain concomitant medications, may limit the generalizability of the study results. In addition, treatment was performed according to the trial protocol by dedicated clinicians at experienced trial sites, along with frequent clinical assessments, which may not reflect general practice. Although most secondary outcomes supported the superiority of dextromethorphan-bupropion over bupropion, the confidence intervals for the between-group differences were not adjusted for multiple comparisons. A larger number of patients in the bupropion group were excluded by independent assessment compared with the dextromethorphan-bupropion group, which may have affected the overall results. Imputation of missing values ​​by the previous observation carried forward method may have affected the results for categorical variables such as response and remission. Finally, the trial duration was limited to 6 weeks. The effect of long-term treatment with dextromethorphan-bupropion has been evaluated in a separate study. In this Phase 2 randomized clinical trial, treatment with dextromethorphan-bupropion achieved clinically meaningful and statistically significant improvements in depressive symptoms compared with the active comparator, bupropion, and was well tolerated. The reduction in depressive symptoms with dextromethorphan-bupropion was statistically significant at Week 2 and at every time point thereafter compared with bupropion alone.

[0166] Example 2

[0167] Dextromethorphan-bupropion Achieves Primary and Key Secondary Endpoints in the Phase 2 MERIT Trial of Dextromethorphan-Bupropion in Treatment-Resistant Depression

[0168] Dextromethorphan-bupropion significantly delayed the time to relapse of depression compared with placebo (p=0.002, primary endpoint).

[0169] Dextromethorphan-bupropion significantly prevented relapse of depression for at least 6 months compared with placebo (p=0.004, a key secondary endpoint).

[0170] Dextromethorphan-bupropion, a novel, oral, investigational NMDA receptor antagonist with multimodal activity, met the primary and key secondary endpoints in the Phase 2 MERIT (Mechanisms of Response Evaluation in TRD) trial and significantly and statistically significantly prevented relapse of depressive symptoms compared with placebo in patients with treatment-resistant depression (TRD). The MERIT study was a randomized, double-blind, placebo-controlled, relapse prevention, multicenter U.S. trial that evaluated 44 patients with TRD. Patients who were in stable remission after treatment with dextromethorphan-bupropion were randomized to continue treatment with dextromethorphan-bupropion or to interrupt dextromethorphan-bupropion and switch to placebo.

[0171] Dextromethorphan-bupropion met the primary endpoint by significantly and statistically significantly delaying the time to relapse of depressive symptoms compared to placebo (p=0.002), with no relapses observed with dextromethorphan-bupropion over at least 6 months of double-blind treatment. Dextromethorphan-bupropion also met the key secondary endpoint of relapse prevention based on the relapse rate during the double-blind treatment period (0.0% for dextromethorphan-bupropion patients, 36.4% of patients switched from dextromethorphan-bupropion to placebo, p=0.004).

[0172] Dextromethorphan-bupropion was well tolerated in the trial. There were no treatment-emergent adverse events reported in >1 patient in the dextromethorphan-bupropion group. One subject in the dextromethorphan-bupropion group experienced two major adverse events (gout and bacteremia), both of which were considered unrelated to the study drug.

[0173] About the MERIT Study

[0174] MERIT is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study evaluating dextromethorphan-bupropion versus placebo in preventing relapse of depressive symptoms in patients with treatment-resistant depression (TRD). Refractory is defined as persistent depressive symptoms despite treatment with two or more antidepressants during a current major depressive episode. Patients with TRD were enrolled in MERIT from a long-term, open-label Phase 3 trial of dextromethorphan-bupropion and were required to be in stable remission prior to randomization. Stable remission was defined as at least two consecutive Montgomery-Asberg Depression Rating Scale (MADRS) scores ≤12, separated by at least 4 weeks.

[0175] A total of 44 TRD patients who experienced stable remission after open-label treatment with dextromethorphan-bupropion (45 mg dextromethorphan-105 mg bupropion) tablets twice daily for up to 12 months were randomized 1:1 in a double-blind fashion to continue dextromethorphan-bupropion or to discontinue dextromethorphan-bupropion and switch to placebo for at least 26 weeks or until depressive symptoms relapsed. Relapse was defined in the study by one or more of the following: MADRS total score ≥18 on 2 consecutive assessments; an increase of ≥2 points in Clinical Global Impression severity from randomization on 2 consecutive assessments, with a minimum CGI-S score of 4; hospitalization for worsening depression or suicide risk; or investigator-determined relapse or need for additional antidepressant medication or change in treatment.

[0176] The primary endpoint of the study was time from randomization to relapse calculated by Kaplan-Meier estimates and hazard ratios. The key secondary endpoint evaluating relapse prevention was the percentage of patients who remained relapse-free.

[0177] About Major Depressive Disorder

[0178] Major depressive disorder (MDD) is a debilitating, chronic, biologically based disorder characterized by depression, inability to feel happiness, feelings of guilt and worthlessness, low energy, and other emotional and physical symptoms, and it impairs social, occupational, educational, or other important functions. In severe cases, MDD may lead to suicide. According to the National Institutes of Health, it is estimated that 7% of American adults, or about 19 million people, experience MDD each year. According to the World Health Organization (WHO), depression is the leading cause of disability worldwide and the leading cause of the overall global burden of disease. Nearly two-thirds of patients diagnosed and treated do not experience adequate treatment responses using currently available first-line therapies, highlighting the need for additional therapies with new mechanisms of action. Most of the first ineffective second-line treatments are also ineffective. If a patient diagnosed with MDD does not respond to two or more antidepressant therapies, they are defined as suffering from refractory depression (TRD).

[0179] About Dextromethorphan-Bupropion

[0180] Dextromethorphan-bupropion is a novel, oral, patented, investigational NMDA receptor antagonist with multimodal activity being developed for the treatment of major depressive disorder and other central nervous system (CNS) disorders. Dextromethorphan-bupropion utilizes proprietary formulations and dosages of dextromethorphan and bupropion and the applicant's metabolic inhibition technology to regulate the delivery of the components. The dextromethorphan component of dextromethorphan-bupropion is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, also known as a glutamate receptor modulator, which is a novel mechanism of action, meaning that its mode of action is different from currently approved oral therapies for major depressive disorder. The dextromethorphan component of dextromethorphan-bupropion is also a sigma-1 receptor agonist. The bupropion component of dextromethorphan-bupropion is used to increase the bioavailability of dextromethorphan and is a norepinephrine and dopamine reuptake inhibitor. Dextromethorphan-bupropion has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for the treatment of MDD and for the treatment of agitation in Alzheimer's disease.

[0181] Example 3

[0182] Efficacy and safety of the oral NMDA receptor antagonist dextromethorphan-bupropion in preventing relapse in patients with treatment-resistant depression:

[0183] Results from the double-blind, placebo-controlled relapse prevention trial MERIT

[0184] introduce

[0185] Major depressive disorder (MDD) is a serious condition: MDD is a chronic, disabling, pervasive, biologically based condition and a leading cause of suicide.

[0186] Treatment-resistant depression (TRD): Approximately 40% of MDD patients are treatment-resistant, defined as failure to respond to two or more properly administered antidepressants of two different classes in the current depressive episode.

[0187] Relapse of MDD is not uncommon among TRD patients who ultimately achieve remission, with >40% of patients relapsing within approximately 4 months of treatment.

[0188] The need for novel mechanistic approaches: Currently approved oral antidepressants act primarily through monoaminergic mechanisms.

[0189] Glutamatergic hypothesis of MDD: Clinical and preclinical evidence points to dysfunction of glutamatergic neurotransmission in the pathophysiology of MDD, suggesting a role for NMDA receptor antagonists in the treatment of MDD.

[0190] There is an urgent clinical need for new, more effective, faster-acting, mechanistically novel, and well-tolerated MDD treatments.

[0191] Dextromethorphan-bupropion is a novel, oral, investigational NMDA receptor antagonist with multimodal activity:

[0192] The dextromethorphan component of dextromethorphan-bupropion is an antagonist of NMDA receptors, ionotropic glutamate receptors, and sigma-1 receptors.

[0193] These actions modulate glutamatergic neurotransmission.

[0194] The bupropion component of dextromethorphan-bupropion is primarily used to increase the bioavailability of dextromethorphan and is a norepinephrine and dopamine reuptake inhibitor.

[0195] MERIT Trial Objectives

[0196] MERIT (Mechanistic Evaluation of Response in TRD) is a phase 2, randomized, double-blind, placebo-controlled, relapse prevention study designed to evaluate dextromethorphan-bupropion versus placebo in preventing relapse of depressive symptoms in patients with TRD.

[0197] This trial is registered with ClinicalTrials.gov (NCT04608396).

[0198] Study Procedure

[0199] TRD patients (N=44) in stable remission following treatment with dextromethorphan-bupropion were randomized to continue treatment with dextromethorphan-bupropion or to discontinue dextromethorphan-bupropion and switch to placebo for up to 52 weeks or until relapse.

[0200] TRD patients who achieved stable remission in an open-label, long-term study of dextromethorphan-bupropion ("COMET") were eligible for enrollment in MERIT.

[0201] Stable remission was defined as at least two consecutive Montgomery-Asberg Depression Rating Scale (MADRS) scores ≤ 12, separated by at least 4 weeks.

[0202] Figure 3 Displays the study procedures.

[0203] Eligibility Criteria

[0204] Key inclusion criteria:

[0205] Stable responders were defined as at least two consecutive MADRS scores ≤ 12, separated by at least 4 weeks.

[0206] Prior to entry into COMET, participants had treatment-resistant depression, defined as previous enrollment in a study evaluating dextromethorphan-bupropion in patients with prospectively defined TRD (NCT02741791), or

[0207] Subjects enrolled in COMET had received 2 or more prior antidepressants during a major depressive episode prior to entering COMET

[0208] Key exclusion criteria:

[0209] History of electroconvulsive therapy, vagus nerve stimulation, transcranial magnetic stimulation, or any experimental central nervous system treatment during the current episode or within the past 6 months;

[0210] Schizophrenia, bipolar disorder, obsessive-compulsive disorder; and

[0211] Psychiatric symptoms secondary to any other general medical condition.

[0212] Efficacy evaluation

[0213] Primary endpoint: Time from randomization to recurrence calculated by Kaplan-Meier estimation

[0214] Subjects who withdrew for reasons other than relapse were considered to have not relapsed and were censored.

[0215] Key secondary endpoint: Percentage of subjects without relapse

[0216] Relapse was defined by ≥ 1 of the following:

[0217] MADRS total score ≥18 for 2 consecutive assessments, with an interval of 7 to 21 days;

[0218] Clinical Global Impression Severity (CGI-S) increase of ≥2 points since randomization, 2 consecutive assessments, 7 to 21 days apart, with a minimum CGI-S score of 4 points;

[0219] Loss of response to treatment, such as:

[0220] (i) Hospitalization due to worsening depression or due to suicide risk.

[0221] (ii) The investigators determine that additional antidepressant treatment or a switch in treatment is needed.

[0222] (iii) The patient relapsed in the opinion of the investigator.

[0223] result

[0224] Demographics and Baseline Characteristics

[0225] Table 4 shows the demographic data and baseline characteristics.

[0226] Table 4.

[0227]

[0228] CGI-S = Clinical Global Impression - Severity; values ​​are mean (SD) unless otherwise stated.

[0229] DM = dextromethorphan; BUP = bupropion.

[0230] A total of 22 subjects were randomized to each treatment group.

[0231] The mean age in both treatment groups was approximately 50 years.

[0232] Most subjects were white and female.

[0233] Subjects were in remission with a mean MADRS score <6 and a CGI-S score <2.

[0234] Primary endpoint: time from randomization to relapse

[0235] Figure 4 Displays the time to relapse in weeks.

[0236] like Figure 4 As shown, the following is observed.

[0237] Dextromethorphan-bupropion achieved the primary endpoint by delaying the time to recurrence of depressive symptoms.

[0238] Subjects continuing treatment with dextromethorphan-bupropion exhibited a significant and statistically delayed time to recurrence of depressive symptoms compared to subjects randomized to the placebo group (p=0.0023).

[0239] Key secondary endpoint: Percentage of patients without relapse

[0240] The percentages of relapse-free patients in the dextromethorphan-bupropion group and the placebo group are shown in Table 5.

[0241]

[0242] Treatment with dextromethorphan-bupropion prevented relapse in a statistically significantly greater proportion of subjects compared with placebo.

[0243] During the evaluation period, no subjects treated with dextromethorphan-bupropion relapsed compared to 8 subjects receiving placebo (36.4%), a difference in relapse rate of 36.4% (p=0.004).

[0244] Percentage of subjects meeting each relapse criterion

[0245] The recurrence criteria are shown in Table 6.

[0246]

[0247] The most common reason for relapse in the placebo group was MADRS ≥ 18 at two consecutive visits.

[0248] No subject in the dextromethorphan-bupropion group met the MADRS relapse criteria or any other final criteria.

[0249] Seven subjects in the dextromethorphan-bupropion group had a 2-point increase in the CGI-S but did not meet relapse criteria because their scores did not exceed 3 ("mild depression") and / or the deviation was temporary (not sustained between two consecutive assessments).

[0250] Safety and Tolerability

[0251] Table 7 shows the treatment-emergent adverse events (TEAEs).

[0252]

[0253] Long-term treatment with dextromethorphan-bupropion was well tolerated.

[0254] One subject in the dextromethorphan–bupropion group experienced two major adverse events (gout, positive staphylococcus test), both of which were considered unrelated to study drug, and one subject in the dextromethorphan–bupropion group had a TEAE that led to discontinuation of study drug (anxiety).

[0255] in conclusion

[0256] Among TRD patients who achieved stable remission on dextromethorphan-bupropion, dextromethorphan-bupropion substantially and statistically significantly delayed the time to recurrence of depressive symptoms compared with placebo.

[0257] No relapses were observed in patients continuing dextromethorphan-bupropion during at least 6 months of double-blind treatment.

[0258] Dextromethorphan-bupropion was well tolerated in the trial, and no new safety signals were observed.

[0259] These data support the continued development of dextromethorphan-bupropion in TRD and provide additional evidence of the long-term effectiveness of dextromethorphan-bupropion in treating MDD.

[0260] Example 4

[0261] Dextromethorphan-bupropion improves depressive symptoms and functioning in patients who have previously failed treatment: results from the long-term open-label EVOLVE study

[0262] introduce

[0263] Major depressive disorder (MDD) is a serious condition: MDD is a chronic, disabling, pervasive, biologically based condition and a leading cause of suicide.

[0264] MDD is difficult to treat: In the largest open-label study conducted, STAR*D, only about one-third of MDD patients achieved remission with up to 12 weeks of therapy with the SSRI citalopram.

[0265] Second-line therapy: In STAR*D, after failure to respond to an SSRI, second-line therapy resulted in a response rate of approximately 25%, regardless of whether a switch strategy was used: switching to a different SSRI (sertraline), switching to an SNRI (venlafaxine), or switching to an NDRI (bupropion).

[0266] The need for mechanistically novel approaches: The reduced remission rates seen with STAR*D may be due in part to the lack of pharmacological diversity among the different treatments; for example, all antidepressants used are thought to act in largely the same way: through monoamine modulation.

[0267] Glutamatergic hypothesis of MDD: Clinical and preclinical evidence points to dysfunction of glutamatergic neurotransmission in the pathophysiology of MDD, suggesting a role for NMDA receptor antagonists in the treatment of MDD.

[0268] There is an urgent clinical need for new, more effective, faster-acting, mechanistically novel, and well-tolerated MDD treatments.

[0269] Target

[0270] The objective was to evaluate the safety and efficacy of dextromethorphan-bupropion in patients with MDD who had been treated with one prior therapy for their current major depressive episode.

[0271] Study Design: EVOLVE

[0272] EVOLVE (Evaluating NMDA Modulation in Depressive Episodes) was an open-label US trial in which patients were treated with dextromethorphan-bupropion (45 mg dextromethorphan hydrobromide-105 mg bupropion hydrochloride) twice daily for up to 15 months.

[0273] Eligible patients were enrolled after completion of a previous dextromethorphan-bupropion study (MERIT), or directly enrolled, and had a DSM-5 diagnosis of MDD, a MADRS score ≥ 25, and were treated with at least 1 prior antidepressant in the current major depressive episode.

[0274] A total of 186 patients were enrolled, consisting of 35 transferred patients and 146 directly enrolled patients. Here we present the results for the directly enrolled patients.

[0275] Newly enrolled subjects whose MADRS scores do not decrease by ≥25% at Week 6 will be discontinued from the study.

[0276] Efficacy Outcome Measures:

[0277] The primary efficacy analyses were changes from baseline to Week 6 (primary time point) and Weeks 1 and 2 (key secondary time points):

[0278] 1) Montgomery-Asberg Depression Rating Scale (MADRS):

[0279] Clinical response (reduction of MADRS total score by ≥50%);

[0280] Clinical remission (MADRS total score ≤ 10).

[0281] 2) Sheehan Disability Scale (SDS):

[0282] Functional clinical response (SDS total score ≤ 12);

[0283] SDS remission (total score ≤ 6).

[0284] Statistical analysis:

[0285] Efficacy analyses were performed on the mITT population, which consisted of all patients who received at least 1 dose of dextromethorphan-bupropion and provided at least 1 post-baseline efficacy measurement.

[0286] Safety analyses were performed on the safety population, which included all patients who received at least 1 dose of dextromethorphan-bupropion.

[0287] Changes from baseline P values ​​were analyzed using paired t-test.

[0288] Table 8 shows the key inclusion and exclusion criteria.

[0289]

[0290] Table 9 shows the demographic data and baseline characteristics.

[0291] Table 9. Demographic data and baseline characteristics a

[0292]

[0293] a Data are mean (SD) unless otherwise stated.

[0294] Baseline illness severity represented a moderate to severe depression group.

[0295] result

[0296] Figure 5 Shows rapid improvement in depressive symptoms.

[0297] Table 10 shows the mean improvement from baseline in MADRS total score with dextromethorphan-bupropion treatment. As shown in Table 10, the following were observed.

[0298] After treatment with dextromethorphan-bupropion, depressive symptoms improved rapidly.

[0299] The mean changes in MADRS total score from a baseline of 32.2 at weeks 1, 2, and 6 were -9.1±7.64 (p<0.001), 13.3±8.58 (p<0.001), and -20.4±7.79 (p<0.001), respectively.

[0300] Improvements in depressive symptoms lasted for 1 year.

[0301]

[0302] Clinical response and remission

[0303] Figure 6 Clinical responses and remissions are shown over time.

[0304] like Figure 6 As shown, the following is observed.

[0305] Clinical response (≥50% improvement) was achieved by 17.7% of patients at week 1, 39.0% at week 2, and 74.2% at week 6, respectively.

[0306] 5.7%, 16.2% and 46.0% of patients achieved remission (≤10) on MADRS at weeks 1, 2 and 6, respectively.

[0307] The antidepressant effect was long-lasting and lasted until month 12.

[0308] CGI-S scores were highly correlated with changes in MADRS over time

[0309] Figure 7 CGI-S responses over time are shown.

[0310] like Figure 7 As shown, the following is observed.

[0311] Responses (≥2 category changes) on the CGI-S were rapid, with 19.1% of patients responding at week 1, 38.2% of patients responding at week 2, and 71.0% of patients responding at week 6.

[0312] CGI-S improvements were durable, with 77.9% of patients responding at 6 months and 79.5% responding at 12 months.

[0313] Rapid improvement in function and relief of SDS

[0314] Figure 8 Shown are the average reductions in SDS over time.

[0315] Fig. 9 Proportion of subjects showing SDS remission over time.

[0316] The baseline SDS score was 17.5±6.08. The mean reductions in the total SDS score at weeks 1, 2, and 6 were 2.9±5.39, 5.0±5.78, and 8.3±6.71 points, respectively (all p<0.001)( Figure 8 ).

[0317] At week 1, 8.5% of patients achieved SDS remission (≤6), at week 2, 18.4% achieved it, and at week 6, 39.5% achieved it. Fig. 9 ).

[0318] The improvement in SDS was durable and persisted at month 12 ( Fig. 9 ).

[0319] Safety and Tolerability

[0320] Table 11 shows adverse events (AEs) in ≥ 5.0% of patients.

[0321] Table 11.

[0322]

[0323] Long-term treatment with dextromethorphan-bupropion was well tolerated.

[0324] COVID-19 infection, nausea, and headache were the most common AEs (Table 11).

[0325] The discontinuation rate due to AEs was 8.9%.

[0326] Following long-term treatment with dextromethorphan-bupropion, the incidence of major adverse events was low (5 patients; 3.4%); no more than 1 patient experienced a SAE.

[0327] in conclusion

[0328] Dextromethorphan-bupropion results in rapid and sustained improvements in depressive symptoms and functioning in patients who were refractory to one previous antidepressant in their current major depressive episode.

[0329] High rates of clinical response and remission on MADRS and functional response on SDS were achieved and maintained up to 12 months of treatment.

[0330] These data further support the use of dextromethorphan-bupropion in the treatment of depressed individuals, including those who have received a prior treatment during a major depressive episode.

[0331] Example 5

[0332] Improvement of anxiety symptoms in depressed patients treated with dextromethorphan-bupropion: results from the EVOLVE open-label, long-term study

[0333] introduce

[0334] Major depressive disorder (MDD) is a serious condition: MDD is a chronic, disabling, pervasive, biologically based condition and a leading cause of suicide.

[0335] MDD is difficult to treat: In the largest open-label study conducted, STAR*D, only about one-third of MDD patients achieved remission with up to 12 weeks of therapy with the SSRI citalopram.

[0336] Anxiety in MDD: Anxiety is reported in up to 50% of depressed individuals and is associated with greater difficulty in treating depression.

[0337] Second-line therapy: In STAR*D, after failure to respond to an SSRI, second-line therapy resulted in a response rate of approximately 25%, regardless of whether a switch strategy was used: switching to a different SSRI (sertraline), switching to an SNRI (venlafaxine), or switching to an NDRI (bupropion).

[0338] There is a need for mechanistically novel approaches: the reduced remission rates with STAR*D may be due in part to the lack of pharmacological diversity between different treatments, for example, all antidepressants used are thought to act in largely the same way: monoamine modulation.

[0339] Glutamatergic hypothesis of MDD: Clinical and preclinical evidence points to dysfunction of glutamatergic neurotransmission in the pathophysiology of MDD, suggesting a role for NMDA receptor antagonists in the treatment of MDD.

[0340] There is an urgent clinical need for new, more effective, faster-acting, mechanistically novel, and well-tolerated MDD treatments.

[0341] Target

[0342] The objective was to evaluate the effects of dextromethorphan-bupropion (45 mg dextromethorphan hydrobromide-105 mg bupropion hydrochloride) on anxiety in patients with MDD who were treated with at least 1 prior antidepressant in a current major depressive episode.

[0343] Study Design: EVOLVE

[0344] EVOLVE (Evaluating NMDA Modulation in Depressive Episodes) was an open-label US trial in which patients were treated with dextromethorphan-bupropion twice daily for up to 15 months.

[0345] Eligible patients were enrolled after completing a previous dextromethorphan-bupropion study or were enrolled directly.

[0346] All patients had a DSM-5 diagnosis of MDD, a MADRS score ≥25, and were treated with at least 1 previous antidepressant in the current major depressive episode.

[0347] A total of 186 patients were enrolled, consisting of 35 patients transferred from the previous dextromethorphan-bupropion study (MERIT) and 146 patients directly enrolled. Here we present the results of the patients directly enrolled.

[0348] Newly enrolled subjects whose MADRS scores do not decrease by ≥25% at Week 6 will be discontinued from the study.

[0349] Efficacy Outcome Measures:

[0350] 1) Montgomery-Asberg Depression Rating Scale (MADRS);

[0351] 2) Hamilton Anxiety Rating Scale (HAM-A) score; and

[0352] 3) Sheehan Disability Scale (SDS).

[0353] Statistical analysis:

[0354] Efficacy analyses were performed on the mITT population, which consisted of all patients who received at least 1 dose of dextromethorphan-bupropion and provided at least 1 post-baseline efficacy measurement.

[0355] Safety analyses were performed on the safety population, which included all patients who received at least 1 dose of dextromethorphan-bupropion.

[0356] Changes from baseline P values ​​were analyzed using paired t-test.

[0357] Table 12 shows the key inclusion and exclusion criteria.

[0358]

[0359] Demographics and baseline characteristics (mITT population)

[0360] Table 13 shows the demographics and baseline characteristics (mITT population).

[0361] Table 13. a

[0362]

[0363] a Data are mean (SD) unless otherwise stated.

[0364] Baseline depression severity indicated a moderate to severe depression group.

[0365] Baseline anxiety severity indicated mild to moderate anxiety.

[0366] result

[0367] Fig.10 and Table 14 shows the reduction in Hamilton Anxiety Rating Scale (HAM-A) scores over time.

[0368]

[0369] like Fig.10 As shown in Table 14, the following was observed.

[0370] Treatment with dextromethorphan-bupropion resulted in significant improvement in anxiety symptoms.

[0371] The mean score of HAM-A at week 6 was <7, indicating a reduction in anxiety symptoms.

[0372] The reductions from baseline at weeks 1, 2, and 6 were 3.4±5.34 (p<0.001), 5.5±5.81 (p<0.001), and 8.6±5.75 (p<0.001), respectively.

[0373] The improvement in HAM-A was sustained at 6 months (-10.2±6.47; p<0.001) and 12 months (-10.2±6.33; p<0.001).

[0374] Fig.11 The percentage of patients achieving remission (score ≤ 7) on HAM-A is shown over time. Fig.11 As shown, the following is observed:

[0375] Treatment with dextromethorphan-bupropion resulted in a rapid rate of relief of anxiety.

[0376] By week 4, more than 50% of patients achieved relief of anxiety symptoms.

[0377] Responses were durable, with 74.7% of patients responding at month 6 and 78.3% responding at month 12.

[0378] Fig.12 The percentage of patients achieving a HAM-A response (≥50% improvement from baseline) is shown over time.

[0379] As shown in FIG.12, the following are observed:

[0380] 18.4%, 27.9% and 62.1% of patients achieved a response on HAM-A at weeks 1, 2 and 6, respectively.

[0381] The response rate continued to increase at month 6 (73.7%) and month 12 (77.1%).

[0382] Safety and Tolerability

[0383] Table 15 shows adverse events (AEs) in ≥ 5% of patients.

[0384] Table 15.

[0385]

[0386]

[0387] Long-term treatment with dextromethorphan-bupropion was well tolerated.

[0388] COVID-19 infection, nausea, and headache were the most common AEs.

[0389] The discontinuation rate due to AEs was 8.9%.

[0390] The incidence of major adverse events was low following long-term treatment with dextromethorphan-bupropion (5 patients; 3.4%). No more than 1 patient experienced a SAE.

[0391] in conclusion

[0392] Treatment with dextromethorphan-bupropion reduces anxiety symptoms in patients with MDD.

[0393] Response and relief of anxiety symptoms were achieved as early as 1 week after treatment with dextromethorphan-bupropion.

[0394] These data are consistent with integrated data from controlled trials of dextromethorphan-bupropion, which demonstrated a reduction in MADRS intrapersonal stress item scores at week 1 compared with the control group.

[0395] Long-term treatment with dextromethorphan-bupropion is generally safe and well tolerated.

[0396] These data provide additional evidence for the efficacy of dextromethorphan-bupropion in MDD, including those with prior treatment and those with anxious features.

[0397] Example 6

[0398] Effects of oral NMDA receptor antagonist dextromethorphan-bupropion on anhedonia symptoms in major depressive disorder

[0399] introduce

[0400] Major depressive disorder (MDD) is a serious condition: MDD is a chronic, disabling, pervasive, biologically based condition and a leading cause of suicide.

[0401] MDD is difficult to treat: 63% of MDD patients have an inadequate response to current first-line oral therapies (STAR*D trial results), and the majority of these inadequate responders also fail to respond to second-line treatments (69%).

[0402] Apathy is one of the core features of major depressive disorder (MDD) and is present in up to 75% of individuals diagnosed with MDD.

[0403] Apathy is viewed by patients as one of the most distressing aspects of MDD, is associated with decreased functioning, and is a risk factor for nonresponse to antidepressant treatment.

[0404] It takes time to respond to treatment: Current oral antidepressants are associated with prolonged times to clinically meaningful responses (up to 6-8 weeks).

[0405] The need for novel mechanistic approaches: Currently approved oral antidepressants act primarily through monoaminergic mechanisms.

[0406] Glutamatergic hypothesis of MDD: Clinical and preclinical evidence points to dysfunction of glutamatergic neurotransmission in the pathophysiology of MDD, suggesting a role for NMDA receptor antagonists in the treatment of MDD.

[0407] There is an urgent clinical need for new, more effective, faster-acting, mechanistically novel, and well-tolerated MDD treatments.

[0408] Target

[0409] GEMINI was a phase 3, randomized, double-blind, placebo-controlled, multicenter U.S. trial in which 327 adults diagnosed with moderate to severe MDD were randomized to dextromethorphan-bupropion or placebo (NCT04019704).

[0410] Post hoc analyses were conducted to determine the effects of dextromethorphan-bupropion compared with placebo on the 5-item MADRS anhedonia subscale.

[0411] The objective was to evaluate the effect of dextromethorphan-bupropion compared with placebo in improving anhedonia symptoms in MDD as assessed by the MADRS anhedonia subscale.

[0412] Study Design: GEMINI

[0413] Fig.13 Shows the study design for GEMINI.

[0414] Primary endpoint: Change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at week 6.

[0415] Key secondary endpoints: Change from baseline in MADRS at Weeks 1 and 2.

[0416] MADRS Anhedonia Subscale: Change from baseline and response rate as measured by the MADRS Anhedonia subscale, which consists of 5 items:

[0417] 1) Obvious sadness;

[0418] 2) reported sadness;

[0419] 3) Difficulty concentrating;

[0420] 4) Laziness;

[0421] 5) Unable to feel.

[0422] Previous research has shown that the MADRS anhedonia subscale is highly correlated with the Snaith-Hamilton Pleasure Scale, a validated measure of hedonic mood.

[0423] Table 16 shows the key inclusion and exclusion criteria. Table 17 shows the demographic data and baseline characteristics.

[0424]

[0425]

[0426] Baseline illness severity represented a moderate to severe depression group.

[0427] Demographic data were similar in the dextromethorphan-bupropion and control groups.

[0428] result

[0429] Fig.14 Shown are the mean changes from baseline in MADRS total score with dextromethorphan-bupropion versus placebo.

[0430] like Fig.14 As shown in Table 18, the following was observed.

[0431] The primary endpoint was achieved - a statistically significant decrease from baseline in MADRS total score at Week 6 compared to placebo (-16.6 vs. -11.9, p=0.002).

[0432] Compared with placebo, there was a rapid and statistically significant reduction in MADRS total score by Week 1 (first measured time point) (p=0.007), Week 2 (p<0.001), and at all time points thereafter.

[0433] Table 18 shows the change from baseline in MADRS total score at Week 1 and Week 2.

[0434]

[0435] Fig.15 Shown are LS mean changes over time in the MADRS anhedonia subscale with dextromethorphan-bupropion compared with placebo.

[0436] like Fig.15 As shown, the following is observed:

[0437] At week 1 (the first measurement time point), treatment with dextromethorphan-bupropion resulted in a statistically significant mean reduction from baseline in MADRS anhedonia subscale scores of 4.44 points compared to 2.69 points for placebo (p<0.001).

[0438] By week 6, the mean reduction from baseline in the MADRS anhedonia subscale was 9.70 in the dextromethorphan-bupropion group compared to 7.22 in the placebo group (p=0.001).

[0439] Fig.16 Shown is the percentage of responders who achieved a ≥50% reduction in the MADRS anhedonia subscale.

[0440] like Fig.16 As shown, the responder rate (MADRS anhedonia subscale improvement ≥ 50%) was statistically significantly greater with dextromethorphan-bupropion compared with placebo at week 1 (p<0.001) and at each time point thereafter.

[0441] By Week 6, 54% of the dextromethorphan-bupropion patients were responders, compared to 36% of the placebo patients at Week 6 (p=0.002).

[0442] Safety and Tolerability

[0443] Table 19 shows adverse events (AEs) with dextromethorphan-bupropion compared with placebo.

[0444] Table 19.

[0445]

[0446] The most commonly reported AEs were dizziness, nausea, and headache.

[0447] The discontinuation rate due to AEs was 6.2% for dextromethorphan-bupropion and 0.6% for placebo.

[0448] in conclusion

[0449] Dextromethorphan-bupropion is a novel oral NMDA receptor antagonist that rapidly and statistically significantly improves depressive symptoms at weeks 1 and 2.

[0450] Treatment with dextromethorphan-bupropion rapidly and significantly reduced anhedonia symptoms as well as overall depressive symptoms.

[0451] Dextromethorphan-bupropion was generally safe and well tolerated.

[0452] These data support the efficacy of dextromethorphan-bupropion across a broad range of symptoms in patients with MDD.

[0453] Example 7

[0454] Efficacy and safety of dextromethorphan-bupropion (Dextromethorphan-bupropion) in patients with major depressive disorder: a phase 3 randomized clinical trial (GEMINI)

[0455] Synopsis

[0456] Objective: Altered glutamatergic neurotransmission is implicated in the pathogenesis of depression. This trial evaluated the efficacy and safety of an oral N-methyl-D-aspartate (NMDA) receptor antagonist and sigma1 receptor agonist, dextromethorphan-bupropion, in the treatment of major depressive disorder (MDD).

[0457] Methods: This double-blind phase 3 trial was conducted between June and December 2019. Patients with a DSM-5 diagnosis of MDD were randomized in a 1:1 ratio to receive dextromethorphan-bupropion (45 mg-105 mg tablets) or placebo, orally (once daily on days 1-3, then twice daily) for 6 weeks. The primary endpoint was the change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Other efficacy endpoints and variables included change from baseline in MADRS at weeks 1 and 2, clinical remission (MADRS score ≤ 10), clinical response (MADRS score reduction ≥ 50% from baseline), clinician- and patient-rated global assessment, Quick Inventory of Depressive Symptoms-Self-Rating, Sheehan Disability Scale, and quality of life measures.

[0458] Results: A total of 327 patients were randomized: 163 patients received dextromethorphan-bupropion and 164 patients received placebo. The mean baseline MADRS total scores were 33.6 and 33.2 in the dextromethorphan-bupropion and placebo groups, respectively. The least squares mean change from baseline to week 6 in the MADRS total score was -15.9 points in the dextromethorphan-bupropion group and -12.0 points in the placebo group (least squares mean difference, -3.87; 95% confidence interval [CI], -1.39 to -6.36; P = 0.002). Dextromethorphan-bupropion had superior MADRS improvement than placebo at all time points, including week 1 (P = 0.007) and week 2 (P < 0.001). At week 6, 39.5% of patients taking dextromethorphan-bupropion achieved remission, compared with 17.3% of patients taking placebo (treatment difference, 22.2; 95% CI, 11.7 to 32.7; P<0.001), and clinical response was 54.0% vs. 34.0%, respectively (treatment difference, 20.0%; 95% CI, 8.4%, 31.6%; P<0.001). Results for most secondary endpoints with dextromethorphan-bupropion were significantly better than with placebo at almost all time points (e.g., least squares mean difference in CGI-S at week 6, -0.48; 95% CI, -0.48 to -0.79; P=0.002). The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, headache, somnolence, and dry mouth. Dextromethorphan-bupropion was not associated with increased psychotomimetic effects, weight gain, or sexual dysfunction.

[0459] Conclusions: In this phase 3 trial in patients with MDD, treatment with dextromethorphan-bupropion resulted in significant improvements in depressive symptoms compared with placebo starting 1 week after the start of treatment and was generally well tolerated.

[0460] Trial registration: ClinicalTrials.gov Identifier: NCT04019704

[0461] Major depressive disorder (MDD) is a common, disabling, chronic, biologically based condition that impairs social, occupational and educational functioning. It is the leading cause of disability worldwide and is associated with increased suicide risk, morbidity and mortality. Currently approved oral antidepressants act primarily via monoamine pathways. These agents often have partial or inadequate responses, and they typically require several weeks to produce clinically significant effects. In the Sequential Treatment of Depression (STAR*D) trial, approximately two-thirds of depressed patients were unable to achieve remission using first-line treatment, and of those experiencing clinical responses, approximately 60% achieved remission only during treatment or after 8 weeks of treatment.

[0462] Data from neuroimaging, cellular, and clinical studies suggest that the glutamatergic system is involved in the pathogenesis of depression. This evidence includes the use of magnetic resonance spectroscopy to find abnormal glutamate levels in the cortex of patients with depressive disorders and the observation of abnormal N-methyl- D -aspartate (NMDA) receptor expression and signaling, and demonstration of antidepressant efficacy in studies using parenteral administration of the NMDA receptor antagonist ketamine.

[0463] Dextromethorphan is a noncompetitive antagonist of NMDA receptors (ionotropic glutamate receptors) and a σ1 receptor agonist. Blockade of NMDA receptors and agonism of σ1 receptors regulate glutamate signaling in the central nervous system. Dextromethorphan is rapidly and extensively metabolized by cytochrome P450 (CYP) 2D6, resulting in subtherapeutic plasma levels, limiting its clinical usefulness in humans. Tablets combining dextromethorphan and bupropion (hereinafter dextromethorphan-bupropion) are formulated to increase the bioavailability and half-life of dextromethorphan, and are developed for the treatment of MDD. The bupropion component increases the plasma concentration of dextromethorphan by inhibiting its metabolism. In March 2019, the U.S. Food and Drug Administration granted a breakthrough therapy designation for dextromethorphan-bupropion for the treatment of MDD. The goal of this Phase 3 trial is to evaluate the efficacy and safety of dextromethorphan-bupropion compared with placebo in the treatment of patients with MDD.

[0464] Clinical Points

[0465] Currently available oral antidepressants act primarily via monoamine pathways, can be associated with partial or inadequate responses, and often require weeks to produce clinically meaningful effects.

[0466] In this large, randomized, controlled trial, orally administered dextromethorphan–bupropion, an NMDA-receptor antagonist and σ1-receptor agonist, rapidly reduced depressive symptoms and induced remission in patients with major depressive disorder. Dextromethorphan–bupropion was well tolerated.

[0467] method

[0468] Trial Design and Oversight

[0469] The GEMINI (Glutamatergic and Monoaminergic Modulation of Depression) study was a phase 3, randomized, double-blind, placebo-controlled, 6-week trial conducted at 40 centers in the United States from June to December 2019. The trial was conducted in accordance with the International Council for Harmonization guidelines for good clinical practice and the principles of the Declaration of Helsinki. Site investigators collected trial data, and the sponsor ensured that all personnel administering the rating scale were qualified and appropriately trained. All sites were approved by independent review committees, and all patients provided written informed consent before participation.

[0470] Patient population

[0471] Patients were male or female, aged 18-65 years, with a primary diagnosis of MDD, experiencing a major depressive episode lasting at least 4 weeks, and a total score of 25 or higher on the Montgomery-Asberg Depression Rating Scale (MADRS), corresponding to moderate or higher severity, with higher scores indicating more severe depression. Patients also required a score of 4 or higher on the Clinician Global Impression-Severity (CGI-S) scale (ranging from 1 to 7, with higher scores indicating more severe conditions). The diagnosis of depression was based on a structured clinical interview, determined using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which is a standard for MDD without psychotic features, and it has been shown that structured clinical interviews are more conservative in diagnosing MDD than other structured interviews. As part of the screening process, independent assessors confirmed the eligibility and symptom severity of each patient. The assessment consisted of a clinical review of all available documents, including a complete medical history, and outcome measures reported by clinicians and patients.

[0472] Major exclusion criteria included bipolar disorder, psychotic disorder, panic disorder, obsessive-compulsive disorder, treatment-resistant depressive disorder (defined as failure of ≥2 adequate antidepressant treatments in the current major depressive episode), alcohol / substance use disorder within the past year, clinically significant suicide risk, and history of epilepsy.

[0473] Experimental Design and Procedures

[0474] Eligible patients were randomly assigned in a 1:1 ratio to receive dextromethorphan-bupropion (45mg-105mg) or placebo orally for 6 weeks. Randomization was performed via a central interactive web response system. The study medication was provided by the trial sponsor and was identical in form and appearance; all researchers, patients, and research staff involved in the study were blinded to the study treatment. Patients received the designated study medication once a day for 3 days and then twice a day. Study visits occurred 1, 2, 3, 4, and 6 weeks after the baseline visit. Safety follow-up occurred at week 7 (1 week after the last dose of study medication). There were no formal discontinuation criteria; however, patients could withdraw consent for any reason, and researchers could remove patients from the study for any safety-related reason. Based on the results of the pharmacokinetic study, the dose of dextromethorphan-bupropion was selected and adjusted stepwise to twice a day. The clinical trial is listed on ClinicalTrials.gov (NCT04019704).

[0475] end

[0476] The primary endpoint was the change in MADRS total score from baseline to week 6. MADRS is a 10-item clinician-rated questionnaire ranging from 0 to 60, with higher scores indicating more severe depression. Key secondary endpoints were the change from baseline in MADRS total score at week 1; the change from baseline in MADRS total score at week 2; remission at week 2, defined as a MADRS total score ≤ 10; and clinical response at week 6, defined as a ≥50% reduction in MADRS total score.

[0477] Other secondary endpoints included Clinician Global Impression of Improvement (CGI-I; scores range from 1 [very improved] to 7 [very worse]) 19 ; CGI-S (scores range from 1 [normal state] to 7 [worst case]); Patient Global Impression of Improvement (PGI-I; scores range from 1 [much improved] to 7 [very bad]); Quick Inventory of Depressive Symptoms-Self-Rating (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating more severe depression); Sheehan Disability Scale (SDS; scores range from 0 to 30, with higher scores indicating more severe disability); Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF; scores are based on a percentage of the maximum total score, with higher percentages indicating greater satisfaction); and MADRS-6 (a subscale of the 10-item MADRS that assesses core symptoms of depression [obvious sadness, reported sadness, inner tension, lethargy, inability to feel, and pessimistic thoughts]).

[0478] Safety was assessed based on the incidence of adverse events; changes in vital signs, clinical laboratory measurements, physical examinations, and electrocardiograms; assessment of suicidal ideation and behavior using the Columbia-Suicide Severity Rating Scale (C-SSRS); and assessment of withdrawal-related symptoms using the Physician Withdrawal Checklist. Adverse events during the treatment period were defined as those occurring from the first dose of dextromethorphan-bupropion or placebo to 7 days after the last dose.

[0479] Statistical analysis

[0480] The safety analysis set includes all patients who received at least 1 dose of study drug. The modified intention-to-treat population was subjected to efficacy analysis, which was composed of all patients who were randomized, received at least 1 dose of study drug and received at least 1 baseline efficacy assessment. The main efficacy variable, i.e., the change of MADRS from baseline, was analyzed using a mixed model of repeated measures. The analysis of the covariance mixed effects model of repeated measures included treatment, week number, and week-by-week treatment interaction as factors, baseline values ​​as covariates, and patients as random effects. All other changes in the efficacy variables from baseline were analyzed using this method. The treatment effect and treatment difference at each time point were evaluated using the least squares mean estimate. The observed cases were subjected to efficacy variables (e.g., clinical response and remission rates, CGI-I, PGI-I) associated with percentages, and were analyzed by χ 2 Analyses were performed using SAS version 9.4, and all hypothesis tests were performed at a two-sided alpha level of 0.05.

[0481] If a positive result was found on the MADRS primary endpoint, additional analyses (response, remission) should be performed on this variable to examine clinical relevance. To adjust for multiplicity, if the primary endpoint was determined, key secondary endpoints were examined in the following order using stratified hypothesis testing in a prespecified fixed sequence procedure (we stopped after reaching a nonsignificant result): change from baseline to week 2 in MADRS total score; percentage of patients who achieved remission at week 2, defined as a MADRS total score ≤10; change from baseline to week 1 in MADRS total score; percentage of patients who achieved a clinical response at week 6, defined as a reduction of ≥50% in MADRS total score; CGI-I at week 6; change from baseline to week 6 in CGI-S; CGI-I at week 1; percentage of patients who achieved remission at week 1; and change from baseline to week 6 in SDS. For all other secondary endpoints, no adjustment for multiplicity was performed, and nominal P values ​​for these endpoints are presented.

[0482] No imputation was performed for missing data for the primary or secondary endpoints. Sensitivity analyses of the primary efficacy variables were performed based on random replacement and tipping point methods.

[0483] A sample size of approximately 150 patients per treatment group would provide 90% power to detect a treatment difference in the primary efficacy variable of MADRS change at a two-sided significance level of 0.05, assuming an effect size of 0.31.

[0484] result

[0485] Patient characteristics

[0486] A total of 617 patients were screened, of whom 327 were randomized in a 1:1 ratio to receive dextromethorphan-bupropion (163 patients) or placebo (164 patients) ( Fig.17 ). The modified intention-to-treat population consisted of 156 patients in the dextromethorphan-bupropion group and 162 patients in the placebo group. 2 The baseline demographics and clinical characteristics of the two trial groups were generally similar (Table 20). There were more men in the dextromethorphan-bupropion group than in the placebo group (39.1% vs. 27.8%; P=0.033). At baseline, the mean MADRS total score in the dextromethorphan-bupropion group was 33.6 and in the placebo group was 33.2, and the mean CGI-S score in both groups was 4.6. The number of patients who completed the trial was 123 in the dextromethorphan-bupropion group and 147 in the placebo group.

[0487] Fig.17 Shown is the placement of patients in a phase 3 trial of dextromethorphan-bupropion for major depressive disorder.

[0488] Table 20. Baseline Characteristics of the Phase 3 Trial of Dextromethorphan-Bupropion in Major Depressive Disorder (mITT)

[0489]

[0490] a Significantly more males were enrolled in the dextromethorphan-bupropion group compared with the placebo group (P=0.033).

[0491] b Scores on the MADRS range from 0 to 60, with higher scores indicating more severe depression.

[0492] c Scores on the CGI-S range from 1 to 7, with higher scores indicating more severe illness.

[0493] Abbreviations: BMI=body mass index, CGI-S=Clinical Global Impression-Severity, MADRS=Montgomery-Asberg Depression Rating Scale, SD=standard deviation.

[0494] effect

[0495] Dextromethorphan-bupropion significantly reduced MADRS total scores at all assessment time points compared with placebo ( Fig.18A , 18B and 18C). The least squares mean change from baseline to week 6 in the MADRS total score was -15.9 points in the dextromethorphan-bupropion group and -12.0 points in the placebo group (least squares mean difference, -3.87; 95% confidence interval [CI], -1.39 to -6.36; P = 0.002). The results of the sensitivity analysis of the change from baseline to week 6 in the MADRS total score were also statistically significant, supporting that dextromethorphan-bupropion had a treatment difference of similar magnitude to that in the primary analysis. At week 1, the first time point, the least squares mean change from baseline in the MADRS total score was -7.20 points in the dextromethorphan-bupropion group and -4.97 points in the placebo group (least squares mean difference, -2.23; 95% CI, -0.60 to -3.86; P = 0.007). At week 2, the least squares mean change from baseline in the MADRS total score was -11.09 points in the dextromethorphan-bupropion group and -7.66 points in the placebo group (least squares mean difference, -3.44; 95% CI, -1.40 to -5.47; P < 0.001).

[0496] Fig.18A Show the change of MADRS total score from baseline over time. The score range of MADRS is 0 to 60, and the higher the score, the more severe the depression. The results are represented by mean values, and the error bars represent standard errors. The P value is calculated based on the least squares mean. Fig.18B The percentage of patients achieving remission (MADRS total score ≤ 10) is shown over time. P values ​​are calculated by X 2 Check calculated. Fig. 18C The percentage of patients achieving clinical response (MADRS total score reduction from baseline >50%) over time is shown. P values ​​are calculated by X 2 MADRS denotes Montgomery-Asberg Depression Rating Scale, and SE denotes standard error.

[0497] The percentage of patients achieving remission (defined as a MADRS total score of ≤10) was significantly greater in the dextromethorphan-bupropion group compared with the placebo group at week 2 (16.9% and 7.5%, respectively; treatment difference, 9.4%, 95% CI, 1.9%-16.8%; P=0.013) and at each time point thereafter. At week 6, the percentage of patients achieving remission was 39.5% in the dextromethorphan-bupropion group and 17.3% in the placebo group (treatment difference, 22.2%, 95% CI, 11.7%-32.7%; P<0.001). At all time points, the percentage of patients achieving a clinical response (defined as a reduction of ≥50% in the MADRS total score) was significantly greater in the dextromethorphan-bupropion group compared with the placebo group. At week 6, the percentage of patients achieving a clinical response was 54.0% in the dextromethorphan-bupropion group and 34.0% in the placebo group (treatment difference, 20.0%; 95% CI, 8.4%-31.6%; P<0.001) (Table 21).

[0498] Table 21. Primary and Secondary Outcomes in the Phase 3 Trial of Dextromethorphan-Bupropion in Major Depressive Disorder (mITT) a,b

[0499]

[0500] a Changes from baseline variables were analyzed using mixed models for repeated measures. This analysis of covariance mixed-effects model for repeated measures included treatment, week, and week-by-week treatment interaction as factors, baseline value as a covariate, and patient as a random effect. Treatment effects and treatment differences at each time point were estimated using least squares mean estimates. 2 The test analyzed the efficacy variables related to percentages. All hypothesis tests were performed at a two-sided alpha level of 0.05.

[0501] b The MADRS is a 10-item clinician-rated questionnaire ranging from 0 to 60, with higher scores indicating more severe depression. CGI-I scores range from 1 (much improved) to 7 (very bad). CGI-S scores range from 1 (normal state) to 7 (worst case). MADRS-6 is a subscale of the 10-item MADRS that assesses the core symptoms of depression (obvious sadness, reported sadness, inner tension, laziness, inability to feel, and pessimistic thoughts). QlDS-SR-16 scores range from 0 to 27, with higher scores indicating more severe depression. PGI-I scores range from 1 (much improved) to 7 (very bad). Q-LES-Q-SF scores are based on a percentage of the highest total score, with higher percentages indicating higher satisfaction. SDS scores range from 0 to 30, with higher scores indicating more severe disability.

[0502] c Nominal P value.

[0503] Abbreviations: CGI-1 = Clinical Global Impression of Improvement, CGI-S = Clinical Global Impression-Severity, CI = confidence interval, MADRS-6 = 6-item Montgomery-Asberg Depression Rating Scale, LS mean = least squares mean, PGI-I = Patient Global Impression-Improvement, QlDS-SR-16 = Quick Inventory of Depressive Symptoms-Self-Rating, Q-LES-Q-SF = Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form, SDS = Sheehan Disability Scale, SE = standard error.

[0504] At all time points assessed, the percentage of patients achieving marked or moderate improvement on CGI-I was significantly higher in the dextromethorphan-bupropion group compared with the placebo group (Table 21). At week 6, the percentage of patients achieving marked or moderate improvement on CGI-I was 57.6% in the dextromethorphan-bupropion group, compared with 43.0% in the placebo group (treatment difference, 14.6%; 95% CI, 2.9%-26.4%; P=0.016). Dextromethorphan-bupropion significantly reduced CGI-S scores at all assessment time points compared with placebo. The least squares mean change from baseline to week 6 in the CGI-S score was -1.69 points in the dextromethorphan-bupropion group and -1.29 points in the placebo group (least squares mean difference, -0.48; 95% CI, -0.48 to -0.79; P=0.002).

[0505] At all time points tested, the least squares mean improvements from baseline on the QIDS-SR-16, MADRS-6 subscales, and Q-LES-Q-SF were statistically significantly greater in the dextromethorphan-bupropion group compared with the placebo group, and the percentage of patients with much or very much improvement on PGI-I was statistically significantly higher. At Week 2 and at each time point thereafter, the least squares mean improvements from baseline on the SDS were statistically significantly greater in the dextromethorphan-bupropion group compared with the placebo group (Table 21). Due to the lack of adjustment for the multiplicity of these results, the P values ​​for these endpoints are nominal.

[0506] Security

[0507] The percentage of patients experiencing adverse events during the treatment period was 61.7% in the dextromethorphan-bupropion group and 45.1% in the placebo group. The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, headache, somnolence and dry mouth. There was 1 major adverse event in the trial, a case of pancreatitis in the dextromethorphan-bupropion group, which the investigators determined was unrelated to the study drug. One adverse event rated as serious (migraine) was observed in the dextromethorphan-bupropion group, while 2 events rated as serious (back pain, finger fracture repair) were reported in the placebo group. 6.2% of patients in the dextromethorphan-bupropion group experienced adverse events leading to discontinuation of the study drug, while 0.6% of patients in the placebo group experienced adverse events leading to discontinuation of the study drug. Dextromethorphan-bupropion was not associated with psychosis-mimicking effects, weight gain or increased sexual dysfunction (Table 22). There were no adverse events or suicidal behaviors related to suicide on C-SSRS in any treatment group. One patient in each treatment group reported involuntary suicidal ideation on the C-SSRS at Week 6. There were no withdrawal signs after discontinuation of dextromethorphan-bupropion.

[0508] Table 22. Summary of Adverse Events in the Phase 3 Trial of Dextromethorphan-Bupropion for Major Depressive Disorder (Safety Population a )

[0509]

[0510] a The safety population included all randomized patients who received at least one dose of dextromethorphan-bupropion or placebo. Adverse events occurring during the treatment period were defined as those that began or worsened from the first dose of dextromethorphan-bupropion or placebo to 7 days after the last dose.

[0511] b A major adverse event was defined as any adverse event that resulted in death, was immediately life-threatening, led to inpatient hospitalization or prolongation of hospitalization, or caused persistent or clinically significant disability or incapacity.

[0512] c Serious adverse events were defined as any event that interfered with activities of daily living, or significantly affected clinical status, or required intensive treatment intervention.

[0513] discuss

[0514] In this randomized, placebo-controlled trial, dextromethorphan-bupropion demonstrated statistically significant antidepressant efficacy on primary endpoints and most secondary endpoints in multiple symptom-specific and global measurements. Starting from the 1st week and continuing at each time point thereafter, treatment with dextromethorphan-bupropion resulted in a statistically significant greater decrease in the total score of MADRS compared to placebo. At all time points, the drug-placebo difference of dextromethorphan-bupropion on the change of MADRS was large, about 2-3 points in the 1st and 2nd weeks, and increased to about 4-5 points in the 4th and 6th weeks. This treatment effect is superior to the average difference of about 2.5 points from placebo seen in the antidepressant study in the FDA database at 6 to 8 weeks.

[0515] Symptom relief is considered to be a desired goal of depression treatment because it is associated with better daily function and better long-term prognosis. Dextromethorphan-bupropion treatment leads to earlier and substantial remission on MADRS (total score ≤ 10), with statistically significant separation from placebo at week 2 and each subsequent time point. At week 6, the percentage of patients achieving remission in the dextromethorphan-bupropion group was 39.5%, compared to 17.3% in the placebo group (P = 0.004). At week 1 and each subsequent time point, clinical responses (≥ 50% reduction from baseline) on MADRS were also observed to be early and objective, with statistical significance, compared to placebo. At week 6, the percentage of patients achieving clinical responses in the dextromethorphan-bupropion group was 54.0%, compared to 34.0% in the placebo group (P < 0.001).

[0516] The early efficacy of dextromethorphan-bupropion was further demonstrated by statistically significant benefits compared to placebo on a number of other clinically relevant measures, including MADRS-6, CGI-S, CGI-I, PGI-I, QIDS-SR-16, and Q-LES-Q-SF, at Week 1 and all subsequent time points. Improvements in functional disability were also observed early, with statistical significance achieved on the SDS at Week 2 and at each time point thereafter.

[0517] Dextromethorphan–bupropion was safe and well tolerated in this trial, with a low rate of discontinuations due to adverse events. The magnitude of the difference in the incidence of adverse events and the superior discontinuation rate due to adverse events between the two treatment groups in the trial may reflect the much lower-than-expected incidence of these events in the placebo group. For example, the overall adverse event rate in the dextromethorphan–bupropion group was 61.7%, which is consistent with the mean of 76.4% reported in the antidepressant group in a large meta-analysis of placebo-controlled depression trials. In contrast, the adverse event rate for placebo in this trial was 45.1%, which is lower than the mean of 63.0% reported in the placebo group in the same meta-analysis. Similarly, the discontinuation rate due to adverse events in the dextromethorphan–bupropion group was 6.2%, which is consistent with the mean of 7% reported in the antidepressant group in another large meta-analysis of placebo-controlled depression trials. In contrast, the discontinuation rate due to adverse events for placebo in our trial was 0.6%, which is substantially lower than the mean of 4% reported in the placebo group in the same meta-analysis. Unlike other NMDA receptor antagonists, dextromethorphan-bupropion is not associated with psychotomimetic effects. This tolerability may be related to the significantly faster rate of cleavage of NMDA receptor channels reported for dextromethorphan compared with other NMDA antagonists. Dextromethorphan-bupropion is not associated with increased weight gain or sexual dysfunction.

[0518] Limitations of this trial include the exclusion of patients with psychosis or other psychiatric disorders, alcohol / substance use disorders, clinically significant suicide risk, or severe medical comorbidity. These exclusions, as well as the prohibition of certain concomitant medications, may limit the generalizability of the study findings. In addition, treatment was provided by dedicated clinicians at experienced trial sites according to the trial protocol, along with frequent clinical assessments, which may not reflect general practice. The dropout rate in the dextromethorphan-bupropion group was 24.1%, approximately twice that in the placebo group. However, this rate is consistent with the mean of 24.3% reported in the antidepressant group in a large meta-analysis of published placebo-controlled depression trials. In contrast, the dropout rate in the placebo group in this trial was 10.4%, which is substantially lower than the mean of 24.0% reported in the same meta-analysis. Multiplicity adjustment was applied only to key secondary efficacy end points; however, the nominal P values ​​for most other secondary end points were <.05. Finally, the trial duration was limited to 6 weeks. The effects of long-term treatment with dextromethorphan-bupropion have been evaluated in separate studies.

[0519] In conclusion, this study showed that treatment with dextromethorphan-bupropion resulted in clinically meaningful and statistically significant improvements in depressive symptoms compared with placebo in patients with MDD starting at week 1 and was well tolerated. The efficacy of dextromethorphan-bupropion was supported by significant improvements compared with placebo on multiple clinically relevant endpoints in both symptom-specific and global measures, demonstrating the internal consistency of the study findings.

[0520] Unless otherwise indicated, all numbers used in the specification and claims to indicate quantities of components, properties such as amounts, percentages, etc. should be understood in all cases to indicate the exact value shown and to be modified by the term "about". Therefore, unless otherwise indicated, the numerical parameters listed in the specification and the attached claims are approximate values, which may vary depending on the desired properties to be obtained. At the very least, and without attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be interpreted in accordance with the number of reported significant digits and applying customary rounding techniques.

[0521] Unless otherwise indicated herein or clearly contradicted by context, the terms "one", "a", "said" and similar references used in the context of describing embodiments (especially in the context of the following claims) should be interpreted as covering singular and plural references. Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order. The use of any and all embodiments or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the embodiments and does not limit the scope of any claim. Any language in this specification should not be interpreted as indicating that any unclaimed element is necessary to practice the claims.

[0522] The grouping of alternative elements or embodiments disclosed herein should not be interpreted as limiting. Each group member may be mentioned and claimed individually, or mentioned and claimed in any combination with other members of the group or other elements found herein. For reasons of convenience and / or accelerating the application process, it is contemplated that one or more members of the group may be included in the group or deleted from the group. When any such inclusion or deletion occurs, this specification is deemed to include the modified group, and therefore satisfies the written description of all Markush groups used in the appended claims.

[0523] Certain embodiments are described herein, including the best mode known to the inventors for implementing the claimed embodiments. Of course, variations of these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect that the skilled person will adopt such variations as appropriate, and the inventors expect that the claimed embodiments can be practiced in ways other than those specifically described herein. Therefore, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. In addition, any combination of the above elements in all possible variations is covered unless otherwise indicated herein or clearly contradicted by the context.

[0524] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Therefore, by way of example and not limitation, alternative embodiments may be used in accordance with the teachings herein. Therefore, the claims are not limited to the embodiments exactly shown and described.

Claims

1. A method of treating anxiety in a human patient experiencing major depressive disorder, comprising: Human patients experiencing anxiety and major depressive disorder were selected; and administering to the human patient a combination of 45 mg of dextromethorphan hydrobromide or a molar equivalent of another salt of dextromethorphan or the free base form of dextromethorphan and 105 mg of bupropion hydrochloride or a molar equivalent of another salt of bupropion or the free base form of bupropion.

2. The method of claim 1, wherein the human patient is selected to have a Hamilton Anxiety Rating Scale (HAM-A) score of at least 10 prior to treatment.

3. The method of claim 2, wherein the human patient is selected to have a HAM-A score of at least 15 prior to treatment.

4. The method of any one of the preceding claims, wherein the human patient's HAM-A score is reduced by about 3 to about 4 after 1 week of treatment.

5. The method of any one of the preceding claims, wherein after 2 weeks of treatment, the human patient's HAM-A score is reduced by about 5 to 6.

6. The method of any one of the preceding claims, wherein the human patient's HAM-A score is reduced by about 8 to 9 after 6 weeks of treatment.

7. The method of any one of the preceding claims, wherein after one or more weeks of treatment, the human patient achieves relief from anxiety based on the human patient's HAM-A score.

8. A method of treating anhedonia in a human patient experiencing major depressive disorder, comprising: Selecting human patients experiencing anhedonia and major depressive disorder; and administering to the human patient a combination of 45 mg of dextromethorphan hydrobromide or a molar equivalent of another salt of dextromethorphan or the free base form of dextromethorphan and 105 mg of bupropion hydrochloride or a molar equivalent of another salt of bupropion or the free base form of bupropion.

9. The method of claim 8, wherein the human patient is selected to have a CGI-S score of at least 4 prior to treatment.

10. The method according to claim 8 or 9, wherein the human patient is selected to have a Montgomery-Asberg Depression Rating Scale (MADRS) anhedonia score of at least 15 prior to treatment.

11. The method of claim 8 or 9, wherein the human patient is selected who has a MADRS anhedonia score of at least 19 prior to treatment.

12. The method of claim 8, 9, 10 or 11, wherein the human patient's MADRS anhedonia score is reduced by about 4 to about 5 after 1 week of treatment.

13. The method of claim 8, 9, 10, 11 or 12, wherein the human patient's MADRS anhedonia score is reduced by about 9 to about 10 after 6 weeks of treatment.

14. The method according to any one of the preceding claims, wherein the combination is administered twice daily.

15. The method according to any one of the preceding claims, wherein the human patient is selected to have a MADRS score of at least 25 prior to treatment.

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