WO2022094230A1 - Composés pour le traitement de la psychose ou de la dépression - Google Patents

Composés pour le traitement de la psychose ou de la dépression Download PDF

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WO2022094230A1
WO2022094230A1 PCT/US2021/057281 US2021057281W WO2022094230A1 WO 2022094230 A1 WO2022094230 A1 WO 2022094230A1 US 2021057281 W US2021057281 W US 2021057281W WO 2022094230 A1 WO2022094230 A1 WO 2022094230A1
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patient
pimavanserin
interval
administration
daily
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PCT/US2021/057281
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English (en)
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Bryan DIRKS
Srdjan R. Stankovic
Ethan S. Burstein
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Acadia Pharmaceuticals Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • MDD is a serious, often recurrent medical condition associated with an average lifetime incidence of DSM-4 major depressive episodes of 14.6% and a lifetime risk of suicide attempt of 15.9% (Chen YW, Dilsaver SC. Biol. Psychiatry. 1996, 39(10), 896; Bromet et al. BMC Med. 2011, 9:90).
  • Treatment of depression may include psychotherapy, pharmacotherapy, or a combination.
  • Pharmacotherapy of depression usually includes prescription of antidepressant drugs, including, for example, selective serotonin reuptake inhibitors (SSRIs) and serotoninnorepinephrine reuptake inhibitors (SNRIs).
  • Antipsychotics can be used as adjunct treatment of depression but are limited due to potential treatment-limiting toxicities, including movement disorders, metabolic effects, weight gain, motor disorders, and sedation. Thus, while some medications have demonstrated modest efficacy, improvements are needed in both their efficacy and their safety and tolerability profiles.
  • Certain antidepressant drugs for example, citalopram, are known to cause QT prolongation, an ECG abnormality that has been associated with Torsade de Pointes (TdP), ventricular tachycardia, and sudden death.
  • TdP Torsade de Pointes
  • Citalopram Label recommends that citalopram should not be given at doses above 40 mg/day due to the risk of QT prolongation at higher citalopram doses and should also not be used in patients who are taking other drugs that prolong the QT interval, for example, Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QT interval (e.g., pentamidine, levomethadyl acetate, methadone).
  • Class 1A e.g., quinidine, procainamide
  • Class III e.g., amiodarone, sotalol
  • antiarrhythmic medications e.g., chlorpromazine, thioridazin
  • FDA Food and Drug Administration
  • This disclosure provides, in part, a method of treating major depression in a patient in need thereof, wherein the patient is currently taking a daily dose of an SSRI or an SNRI that prolongs the QT interval, comprising administering a daily dose of pimavanserin to the patient and continuing administering the SSRI or the SNRI, and wherein upon the administration of the pimavanserin, the QT interval of the patient does not significantly increase.
  • Methods provided herein also include a method of ameliorating QT prolongation caused by administration of an SSRI or an SNRI to a human patient in need thereof, comprising administering to the patient pimavanserin daily.
  • a method of treating psychosis secondary to neurodegenerative disorders in a patient in need thereof, wherein the patient is currently taking a daily dose of a SSRI or a SNRI that prolongs the QT interval, comprising administering a daily dose of pimavanserin to the patient and continuing administering the SSRI or the SNRI, and wherein upon the administration of the pimavanserin, the QT interval of the patient does not significantly increase.
  • the present disclosure provides a method of treating a neurodegenerative disorder, in a patient in need thereof, wherein the patient is currently taking a daily dose of a SSRI or a SNRI that prolongs the QT interval, comprising administering a daily dose of pimavanserin to the patient and continuing administering the SSRI or the SNRI, and wherein upon the administration of the pimavanserin, the QT interval of the patient does not significantly increase.
  • Another contemplated method provided herein is a method of treating schizophrenia, in a patient in need thereof, wherein the patient is currently taking a daily dose of an SSRI or an SNRI that prolongs the QT interval, comprising administering a daily dose of pimavanserin to the patient and continuing administering the SSRI or the SNRI, and wherein upon the administration of the pimavanserin, the QT interval of the patient does not significantly increase.
  • Also provided herein is a method of treating major depression in patient in need thereof, wherein the patient is currently taking a daily dose of pimavanserin that prolongs the QT interval, comprising administering a daily dose of an SSRI to the patient and continuing administering the pimavanserin and wherein upon the administration of the SSRI, the QT interval of the patient does not significantly increase.
  • the present disclosure provides a method of treating major depression in a patient in need thereof, comprising: identifying a patient currently taking a daily dose of an SSRI or an SNRI that has a prolonged the QT interval, and administering a daily dose of pimavanserin to the patient and continuing administering the SSRI or the SNRI, and wherein upon the administration of the pimavanserin, the QT interval of the patient does not significantly increase.
  • the SSRI is selected from the group consisting of citalopram, escitalopram (LEXAPRO), fluoxetine (PROZAC), fluvoxamine, paroxetine (PAXIL), sertraline, vilazodone, vortioxetine, desvenlafaxine, duloxetine, levomilnacipran, sibutramine, tramadol, milnacipran and venlafaxine.
  • a regular e.g., daily, every 2 weeks, or a monthly
  • the daily dose of pimavanserin is 20 mg or 34 mg daily.
  • FIG. 1 shows LSMean change from baseline to Week 5 for the HAMD-17 total score.
  • FIG. 2 shows LSMean change from baseline to Week 5 for the Sheehan Disability Score (SDS).
  • FIG. 3 shows the response and remission rate with pimavanserin or placebo during Stage 1.
  • FIG. 4 shows LSMean change from baseline to Week 10 for HAMD-17 total score.
  • FIG. 5 shows LSMean change from baseline to Week 10 for the SDS.
  • FIG. 6 shows HAMD-17 total score change in trial Stage 1 among subjects with anxious distress at baseline.
  • FIG. 7 shows HAMD-17 “anxiety somatization” item score change in trial Stage 1.
  • FIG. 8 shows HAMD-17 “anxiety somatization” symptoms score change among the subgroup of subjects with higher anxious distress in trial Stage 1.
  • FIG. 9 shows time to early improvement in Stage 1 with pimavanserin or placebo.
  • FIG. 10 shows effect size and 95% CI for HAMD-17 items at Stage 1 Week 5 of trial.
  • FIG. 11 shows the mean change in HAMD-17 individual item scores from baseline to Week 5 with pimavanserin or placebo.
  • FIG. 12 shows HAMD-17 melancholic symptom subscale score change in trial Stage 1.
  • FIG. 13 shows functional remission rate by visit (week) with placebo or pimavanserin in Stage 1.
  • FIG. 14 shows SDS individual items “work/school,” “social life,” “family life/home responsibilities” score change in Stage 1.
  • FIG. 15 shows SDS item “days unproductive” changes from baseline by visit in Stage 1.
  • FIG. 16 shows change in QTcF from baseline to overall postbaseline maximum in ENHANCE study.
  • FIG. 17 shows change in QTcF from baseline to overall postbaseline maximum in ADVANCE study.
  • FIG. 18 shows change in QTcF from double blind baseline to overall postbaseline maximum in Study 035.
  • Treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.
  • Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds of the disclosure can be administered to a mammal, such as a human, but can also be other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the compounds of the disclosure are administered in therapeutically effective amounts to treat a disease.
  • a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in the treatment of depression.
  • “Hamilton Depression Scale 17-item (HAMD-17)” is a multiple item questionnaire used to provide an indication of depression, and is known to those skilled in the art.
  • the questionnaire is designed for adults to rate the severity of depression by probing mood, feelings of guilt, suicide ideation, insomnia, work and interests, agitation or retardation, anxiety, weight loss, and somatic symptoms.
  • Each item on the questionnaire is scored on a 3 or 5 point scale, depending on the item, and the total score is compared to the corresponding descriptor. A score of 0-7 is considered to be normal. Scores of 14 or higher indicate moderate, severe, or very severe depression. Assessment time is estimated at 20 minutes. (See Guy W. Clinical Global Impressions.
  • HAMD-6 “Hamilton Depression Scale 6-item” is a subscale derived from the 17-item Hamilton Rating Scale for Depression (HAMD-17). HAMD-6 includes the following items: depressed mood, guilt feelings, work and interests, psychomotor retardation, psychic anxiety, and general somatic symptoms (Bech et al. Acta Psychiatr Scand. 1975, 51(3): 161-70).
  • MADRS Montgomery-Asberg Depression Rating Scale
  • Clinical Global Impression (CGI)” scale is a clinician-rated, 7-point scale that is designed to rate the severity of the subject’s depression at the time of assessment using the Investigator’s judgment and past experience with subjects who have the same disorder (i.e., depression with anxious distress).
  • CGI-I Clinical Global Impression-Improvement
  • CGI-S Clinical Global Impression-Severity
  • Sheehan Disability Score (SDS)” is used to assess functional disability and improvement in workplace function has been demonstrated with antidepressant therapy in patients with MDD (Lee et al, J Affect Disord. 2018;227:406-415). The SDS is well validated and widely accepted for assessing functional outcomes in patients with MDD (Weiher et al, Neuropsychiatr Dis Treat. 2017;14:103-115). In a systematic review of studies that assessed functional outcomes, the authors suggested that improvements in function (SDS) should be considered for inclusion as co-endpoints with symptomatic assessments when evaluating treatments for MDD (Sheehan et al, J Affect Disord. 2017;215:299-313). Routine assessments of both symptoms and function could be helpful for minimizing residual effects that increase the risk for relapse or recurrence (Sheehan et al, J Affect Disord. 2017;215:299-313).
  • “Functional remission” as used herein refers to remission in functional impairment. Functional remission is defined as a SDS total score of 6 or less at endpoint. (Sheehan et al. Human Psychopharmacology 2016, 31, 53-63).
  • Karolinska Sleepiness Scale is a scale for evaluating subjective sleepiness (Kaida et al. Clinical Neurophysiology 2006, 117, 7, 1574-1581).
  • treatment-resistant major depressive disorder refers to major depressive disorder where the patient had a history of an inadequate response when administered 1 or 2 other antidepressant treatments (e.g., administered an SSRI or SNRI) during e.g., a current depression episode. In some embodiments, the patient had a history of an inadequate response when administered an SSRI and SNRI.
  • “Inadequate response” to an antidepressant may be determined through the administration of the MGH Antidepressant Treatment Response Questionnaire (ATRQ), which is a self-rated scale used to determine treatment resistance in major depressive disorder (Chandler et al. CNS Neurosci Ther. 2010; 16(5):322-325).
  • ATRQ MGH Antidepressant Treatment Response Questionnaire
  • “Early improvement as measured by Hamilton Depression Scale,” as used herein, refers to a reduction from baseline in HAMD-17 total score of 20% or more.
  • a patient with “DMS-5 defined diagnosis of major depressive disorder” has 5 or more of the symptoms as described in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) during a 2-week period and at least one of the symptoms is either 1) depressed mood or 2) loss of interest or pleasure.
  • the symptoms as described in DMS-5 include the following: 1) depressed mood; 2) loss of interest or pleasure; 3) significant weight loss; 4) insomnia or hypersomnia; 5) psychomotor agitation or retardation; 6) fatigue or loss of energy; 7) feelings of worthlessness or excessive or inappropriate guilt; 8) diminished ability to think or concentrate or indecisiveness; and 9) recurrent thoughts of death.
  • Scale of Outcomes in Parkinson’s Disease is a scale developed for research in Parkinson disease to evaluate nighttime sleep and daytime sleepiness and has high internal consistency for the nighttime sleep and daytime sleepiness scales (0.88 and 0.91, respectively), and test-retest reliabilities (0.94 and 0.89, respectively). Scores on the SCOPA Sleep Scale show high correlations between the nighttime sleep scale and the Pittsburgh Sleep Quality Index (0.83), and between the daytime sleepiness scale and the Epworth Sleepiness Scale (0.81). The coefficient of variation of both the nighttime sleep and the daytime sleepiness scale can be higher than that of the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale, indicating a better ability to detect differences between individuals. (Marinus J, Visser M, van Hilten JJ, Lammers GJ, Stiggelbout AM. Sleep. 2003;26(8): 1049-1054.)
  • EuroQol-5 dimensions-5 level (EQ-5D-5L) is a standardized instrument used as a measure of health outcome and measures 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each of which has 5 potential responses.
  • the responses record 5 levels of severity (no problems/slight problems/moderate problems/severe problems/extreme problems) within a particular EQ-5D dimension.
  • Methods Provided herein, in part, is a method of treating major depression in a patient in need thereof, wherein the patient is currently taking a daily dose of an SSRI or an SNRI that prolongs the QT interval, comprising administering a daily dose of pimavanserin to the patient and continuing administering the SSRI or the SNRI, and wherein upon the administration of the pimavanserin, the QT interval of the patient does not significantly increase.
  • the major depression is treatment-resistant.
  • the major depression is depression associated with Parkinson’s disease or Alzheimer’s disease.
  • the patient is concomitantly taking a strong CYP3A4 inhibitor and the daily dose of pimavanserin is 10 mg daily.
  • the strong CYP3A4 inhibitor is selected from the group consisting of ketoconazole, clarithromycin, indinavir, and itraconazole.
  • the QT interval of the patient increases by about 3 msec or less as compared to the QT interval of the patient before the administration of pimavanserin.
  • the QT interval of the patient is about the same as the QT interval of the patient before the administration of pimavanserin.
  • the QT interval of the patient increases by about 2 msec or less as compared to the QT interval of the patient before the administration of pimavanserin.
  • the patient’s QT interval decreases by 1 msec or more after 5 weeks of the daily administration of pimavanserin as compared to the QT interval of the patient before the administration of pimavanserin.
  • the QT interval of the patient upon administration of the pimavanserin, does not increase by 5 msec or less than the QT interval of the patient before the administration of pimavanserin.
  • the QT interval of the patient upon the administration of the pimavanserin, is less as compared to the QT interval of the patient before the administration of pimavanserin in combination with a QT interval of a patient taking pimavanserin alone without current administration of the SSRI or SNRI.
  • the QT interval of the patient is 80% or less as compared to the QT interval of the patient before the administration of pimavanserin in combination with a QT interval of a patient taking pimavanserin alone without current administration of the SSRI or SNRI.
  • the patient is 60 years old or older.
  • the SSRI is citalopram.
  • the patient is currently taking a daily dose of 20 mg, 40 mg or 60 mg citalopram.
  • the SSRI is escitalopram.
  • the patient is currently taking a daily dose of 1.5 mg, 5 mg, 10 mg, 20 mg or 30 mg of escitalopram.
  • the patient is currently taking a daily dose of 40 mg citalopram, and after 5 weeks of the administration of pimavanserin, the QT interval of the patient is prolonged by no more than 14 msec, or no more than 12.6 msec, compared to the QT interval of the patient before the administration of pimavanserin and before the administration of citaplopram.
  • the SSRI is selected from the group consisting of citalopram, escitalopram (LEXAPRO), fluoxetine (PROZAC), fluvoxamine, paroxetine (PAXIL), sertraline, vilazodone, vortioxetine, desvenlafaxine, duloxetine, levomilnacipran, sibutramine, tramadol, milnacipran and venlafaxine.
  • the major depression is treatment-resistant.
  • the major depression is depression associated with Parkinson’s disease or Alzheimer’s disease
  • Contemplated patients suffering from major depressive disorder may also be suffering from anxious distress.
  • the anxious distress is generalized anxiety disorder and the patient is being treated with paroxetine, escitalopram, duloxetine, or venlafaxine.
  • the anxiety distress is post-traumatic stress disorder and the patient is being treated with sertraline or paroxetine.
  • the anxiety distress is obsessive compulsive disorder and the patient is being treated with fluoxetine, fluvoxamine, paroxetine or sertraline.
  • the anxiety distress is panic disorder, and the patient is being treated with fluoxetine, paroxetine, sertraline, or venlafaxine.
  • Contemplated patients that may be treating using disclosed methods may have a DSM-5 defined diagnosis of major depressive disorder and/or may have a history of MDD diagnosis at least 1 year prior to the screening.
  • the patient may have an improved score relative to the baseline in one or more of the Hamilton Depression Scale individual items selected from the group consisting of psychic anxiety, somatic anxiety, gastrointestinal symptoms, general somatic symptoms, work and interest, and hypochondriasis.
  • Such a disclosed method may improve one or more of: feelings of restlessness, tension, loss of control, and /or improve concentration.
  • a patient has anxious distress during a majority of days of a major depressive disorder episode.
  • the anxiety distress is selected from any one of the group consisting of separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, panic attack specifier, agoraphobia, generalized anxiety disorder, substance/medication-induced anxiety disorder, anxiety disorder due to another medical condition, post-traumatic stress disorder, and obsessive compulsive disorder.
  • a method of decreasing the QT interval in a patient being administered an SSRI or an SNRI that prolongs the QT interval in the patient if administered alone, and wherein the patient is in need of a decreased QT interval comprising administering pimavanserin to the patient daily.
  • the patient is being administered 20 mg, 40 mg or 60 mg citalopram.
  • the present disclosure provides a method of decreasing the risk of QT prolongation in a patient being administered an SSRI or an SNRI, and in need of an atypical antipsychotic, comprising administering to the patient pimavanserin daily- 10083]
  • Methods provided herein also include a method of ameliorating QT prolongation caused by administration of an SSRI or an SNRI to a human patient in need thereof, comprising administering to the patient pimavanserin daily.
  • a method of treating psychosis secondary to neurodegenerative disorders in a patient in need thereof, wherein the patient is currently taking a daily dose of a SSRI or a SNRI that prolongs the QT interval, comprising administering a daily dose of pimavanserin to the patient and continuing administering the SSRI or the SNRI, and wherein upon the administration of the pimavanserin, the QT interval of the patient does not significantly increase.
  • psychosis secondary to neurodegenerative disorders is dementia related psychosis.
  • the psychosis secondary' to neurodegenerative disorders is Parkinson’s disease psychosis.
  • a method of treating schizophrenia, in a patient in need thereof, wherein the patient is currently taking a daily dose of an SSRI or an SNRI that prolongs the QT interval comprising administering a daily dose of pimavanserin to the patient and continuing administering the SSRI or the SNRI, and wherein upon the administration of the pimavanserin, the QT interval of the patient does not significantly increase.
  • a contemplated patient may have been treated with SSRI or SNRI for at least 8 weeks, for at least 12 weeks, or for at least 16 weeks, or at least 20 weeks during the current depression episode.
  • the patient has been treated with the same dose of the SSRI or SNRI for at least 4 weeks, at least 8 weeks, at least 12 weeks, or at least 16 weeks during the current depression episode.
  • Exemplary SSRIs include citalopram, escitalopram (LEXAPRO), fluoxetine (PROZAC), fluvoxamine, paroxetine (PAXIL), sertraline, vilazodone, vortioxetine, desvenlafaxine, duloxetine, levomilnacipran, sibutramine, tramadol, milnacipran and venlafaxine.
  • the SSRI is citalopram.
  • the SSRI is escitalopram.
  • the patient is currently taking a daily dose of 1.5 mg, 5 mg, 10 mg, 20 mg or 30 mg of escitalopram.
  • a contemplated patient is currently being treated with citalopram, for example, by taking a daily dose of 20 mg, 40 mg or 60 mg of citalopram.
  • a contemplated patient is currently taking escitalopram, for example, by taking a daily dose of 1.5 mg, 5 mg, 10 mg, 20 mg or 30 mg of escitalopram.
  • a regular dose of an antipsychotic that prolongs the QT interval
  • a regular dose of an antipsychotic that prolongs the QT interval
  • the QTcF of the patient is 500 msec or less, e.g. 480 msec or less.
  • the contemplated antipsychotic may be selected from the group consisting of aripiprazole, asenapine, brexpiprazole, cariprazine, lurasidone, olanzapine, and risperidone.
  • the antipsychotic is aripiprazole.
  • the patient may be being administered daily from 5 mg to 50 mg, e.g., from 5 mg to 30 mg daily, from 7.5 mg to 30 mg daily, 5 mg daily, 5 mg twice daily, 7.5 mg daily, 10 mg daily, 15 mg daily, 10 mg twice daily, 20 mg daily, 22 mg daily, 15 mg twice daily, 20 mg daily, 25 mg daily, 30 mg daily, 40 mg daily, or 50 mg daily, aripiprazole.
  • the patient may be being administered monthly from 200 mg to 800 mg e.g., from 300 mg to 700 mg monthly, 200 mg monthly, 300 mg monthly, 400 mg monthly, 500 mg monthly, 600 mg monthly, 662 mg monthly, 700 mg monthly, or 800 mg monthly, aripiprazole LAI (long-acting injectable), e.g., Abilify Maintena® or Aristada®.
  • aripiprazole LAI long-acting injectable
  • the antipsychotic may be asenapine.
  • the patient may be being administered daily from 10 mg to 50 mg, e.g., 10 mg daily, 20 mg daily, 30 mg daily, 40 mg daily, or 50 mg daily, asenapine.
  • the antipsychotic may be brexpiprazole.
  • the patient may be being administered daily from 1 mg to 10 mg, e.g., from 2 mg to 4 mg daily, 1 mg daily, 2 mg daily, 3 mg daily, 4 mg daily, 5 mg daily, 6 mg daily, 7 mg daily, 8 mg daily, 9 mg daily, or 10 mg daily, brexpiprazole.
  • the antipsychotic may be cariprazine.
  • the patient may be being administered daily from 1 mg to 10 mg, e.g., from 4 mg to 8 mg daily, 1 mg daily, 2 mg daily, 3 mg daily, 4 mg daily, 4.5 mg daily, 5 mg daily, 6 mg daily, 7 mg daily, 7.5 mg daily, 8 mg daily, 9 mg daily, or 10 mg daily, cariprazine.
  • the antipsychotic may be lurasidone.
  • the patient may be being administered daily from 20 mg to 140 mg, e.g., from 40 mg to 120 mg daily, 20 mg daily, 40 mg daily, 60 mg daily, 80 mg daily, 100 gm daily, 120 mg daily, or 140 mg daily, lurasidone.
  • the antipsychotic may be olanzapine.
  • the patient may be being administered daily from 1 mg to 30 mg, e.g., from 5 mg to 20 mg daily, 1 mg daily, 5 mg daily, 7.5 mg daily, 5 mg twice daily, 10 mg daily, 15 mg daily, 10 mg twice daily, 20 mg daily, or 30 mg daily, olanzapine.
  • the antipsychotic may be risperidone.
  • the patient may be being administered daily from 0.5 mg to 20 mg, e.g., from 1 mg to 20 mg daily, from 1 mg to 18 mg daily, 1 mg daily, 2 mg daily, 3 mg daily, 2 mg twice daily, 4 mg daily, 5 mg daily, 2 mg three times daily, 6 mg daily, 4 mg twice daily, 8 mg daily, 9 mg daily, 5 mg twice daily, 3 mg every 6 hours, 12 mg daily, 7 mg twice daily, 8 mg twice daily, or 6 mg three times daily, risperidone.
  • the patient may be being administered every 2 weeks from 20 mg to 60 mg, e.g., 25 mg to 40 mg every 2 weeks, 25 mg every 2 weeks, 37.5 mg every 2 weeks, 40 mg every 2 weeks, or 50 mg every 2 weeks, risperidone LAI or monthly from 50 mg to 150 mg, e.g., 100 mg monthly, risperidone LAI.
  • the daily dose of pimavanserin is 20 mg or 34 mg daily.
  • the patient is concomitantly taking a strong CYP3 A4 inhibitor and the daily dose of pimavanserin is 10 mg daily.
  • the strong CYP3 A4 inhibitor is selected from the group consisting of ketoconazole, clarithromycin, indinavir, and itraconazole.
  • the QT interval of the patient increases by about 3 msec or less as compared to the QT interval before the administration of pimavanserin.
  • the QT interval of the patient is about the same as the QT interval of the patient before the administration of pimavanserin.
  • the QT interval of the patient increases by about 2 msec or less as compared to the QT interval of the patient before the administration of pimavanserin.
  • the patient’s QT interval decreases by 1 msec or more after 5 weeks of the daily administration of pimavanserin as compared to the QT interval of the patient before the administration of pimavanserin.
  • the QT interval of the patient does not increase by 10 msec or 5 msec or less than the QT interval of the patient before the administration of pimavanserin.
  • the QT interval of the patient upon the administration of the pimavanserin, is less as compared to the QT interval of the patient before the administration of pimavanserin in combination with a QT interval of a patient taking pimavanserin alone without current administration of the SSRI or SNRI or the antipsychotic.
  • the QT interval of the patient upon the administration of the pimavanserin, is 80% or less as compared to the QT interval of the patient before the administration of pimavanserin in combination with a QT interval of a patient taking pimavanserin alone without current administration of the SSRI or SNRI or the antipsychotic.
  • a contemplated patient is currently taking a daily dose of 40 mg citalopram, and after 5 weeks of the administration of pimavanserin, the QT interval of the patient is prolonged by no more than 14 msec, or no more than 12.6 msec, compared to the QT interval of the patient before the administration of pimavanserin and before the administration of citaplopram.
  • the patient has an inadequate response to the SSRI or SNRI or the antipsychotic alone.
  • a contemplated patient may have had a history of inadequate response to 1 or 2 antidepressant treatments during the current depression episode.
  • the inadequate response may be determined by MGH ATRQ (Antidepressant Treatment Response Questionnaire).
  • the depression is major depressive disorder. In certain embodiments, the depression is treatment resistant depression.
  • a contemplated patient is diagnosed with Parkinson’s disease.
  • the patient is undergoing treatment for Parkinson’s disease.
  • the patient is suffering from Parkinson’s disease psychosis.
  • contemplated patients after 2, 4, 6, 8 or 10 weeks of administration of the compound, contemplated patients have an improvement in depression symptoms as measured by the Hamilton Depression Scale, e.g., the Hamilton Depression Scale - 17 items (HAMD-17).
  • the patient is also suffering from Parkinson’s disease dementia.
  • the patient is diagnosed with Parkinson’s disease dementia.
  • the patient is undergoing treatment for Parkinson’s disease dementia.
  • a patient contemplated for methods of treating disclosed herein may have an initial HAMD-17 score before treatment, of more than or equal to 15 at the baseline, or less than or equal to 15.
  • Contemplated treatments can result, in certain embodiments, in the patient having a HAMD-17 score of less than or equal to 10, less than or equal to 9, less than or equal to 8, or less than or equal to 7, for example, in some embodiments, treating results in the patient having a 50% or greater improvement in HAMD- 17 score.
  • treating results in the patient having an improved Scale of Outcomes in PD-Sleep (SCOPA) daytime score, and/or results in the patient having an improved Clinical Global Impression - improvement (CGI-I) score from baseline, e.g., results in the patient having a CGI-I score of 1 or 2 (very much improved or much improved), after 8 weeks or more of administration.
  • CGI-I Clinical Global Impression - improvement
  • treating results in the patient having an improved quality of life as measured by EQ-5D-5L.
  • a contemplated patient who may be treated using contemplated methods has suffered from Parkinson’s disease for one year or more.
  • a contemplated patient may have one or more (e.g. at least 3) of the indications selected from the group consisting of: rest tremor, rigidity, bradykinesia and/or akinesia, and postural and gait abnormalities.
  • Contemplated patients may additionally meet clinical criteria for depression with Parkinson’s disease as listed in the NINDS/NIMH guidelines.
  • the subject is on a stable dose of anti -Parkinson’s medication for 1 month prior to screening.
  • Contemplated patients in some embodiments may or may not have personal or family history or symptoms of long QT syndrome.
  • Patients that may be treating can be for example, 18 years or older, 30 years or older, 35 years or older, 40 years or older, 45 years or older, 50 years or older, or 60 years or older.
  • N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide is administered in the form of a capsule.
  • N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide is administered in the form of a tablet.
  • N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide is administered each day for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, or 3 months, 6 months or more.
  • the compound N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4- (2-methylpropyloxy)phenylmethyl)carbamide may be administered in the form of a pharmaceutically acceptable salt such as a tartrate salt.
  • the QT interval of a contemplated patient increases by about 10 msec, 9msec, 8 msec, 7 msec, 6msec, 5 msec, 4 msec, 3 msec or less as compared to the QT interval before the administration of pimavanserin.
  • the QT interval of a contemplated patient is about the same as the QT interval of the patient before the administration of pimavanserin.
  • the QT interval of a contemplated patient increases by about 2 msec or less as compared to the QT interval of the patient before the administration of pimavanserin.
  • the patient’s QT interval may decrease by 1 msec or more after 5 weeks of the daily administration of pimavanserin as compared to the QT interval of the patient before the administration of pimavanserin.
  • the QT interval of the contemplated patient does not increase by 10 msec or 5 msec or less than the QT interval of the patient before the administration of pimavanserin.
  • the QT interval of a contemplated patient is less as compared to the QT interval of the patient before the administration of pimavanserin in combination with a QT interval of a patient taking pimavanserin alone without current administration of the SSRI or SNRI.
  • the QT interval of the contemplated patient may be 80% or less as compared to the QT interval of the patient before the administration of pimavanserin in combination with a QT interval of a patient taking pimavanserin alone without current administration of the SSRI or SNRI.
  • Also provided herein is a method of treating major depression in patient in need thereof, wherein the patient is currently taking a daily dose of pimavanserin that prolongs the QT interval, comprising administering a daily dose of an SSRI to the patient and continuing administering the pimavanserin and wherein upon the administration of the SSRI, the QT interval of the patient does not significantly increase.
  • the present disclosure provides a method of treating major depression in a patient in need thereof, comprising: identifying a patient currently taking a daily dose of an SSRI or an SNRI that has a prolonged the QT interval, and administering a daily dose of pimavanserin to the patient and continuing administering the SSRI or the SNRI, and wherein upon the administration of the pimavanserin, the QT interval of the patient does not significantly increase.
  • a contemplated methods include a method of treating psychosis secondary to neurodegenerative disorders in a patient in need thereof, comprising identifying a patient currently taking a daily dose of an SSRI or an SNRI that has a prolonged the QT interval, and administering a daily dose of pimavanserin to the patient and continuing administering the SSRI or the SNRI, and wherein upon the administration of the pimavanserin, the QT interval of the patient does not significantly increase.
  • a method of treating a neurodegenerative disorder in a patient in need thereof comprising identifying a patient currently taking a daily dose of an SSRI or an SNRI that has a prolonged the QT interval, and administering a daily dose of pimavanserin to the patient and continuing administering the SSRI or the SNRI, and wherein upon the administration of the pimavanserin, the QT interval of the patient does not significantly increase.
  • the patient has a DSM-5 defined diagnosis of major depressive disorder.
  • the SSRI or SNRI is selected from the group consisting of: citalopram, escital opram, paroxetine, fluoxetine, sertraline, duloxetine, venlafaxine, desvenlafaxine, and fluvoxamine.
  • N'- 4-(2-methylpropyloxy)phenylmethyl)carbamide is administered in the form of a tartrate salt.
  • orally administering comprises administering about 5 mg to about 40 mg, based on the free base form, of N-(4-fluorophenylmethyl)-N-(1- methylpiperidin-4-yl)- N'- 4-(2-methylpropyloxy)phenylmethyl)carbamide daily.
  • orally administering comprises administering 34 mg based on the free base form of N-(4-fluorophenylmethyl)-N-(l -methylpiperidin-4-yl )-N"-(4-(2- methylpropyloxy)phenylmethyl)carbamide daily.
  • the 34 mg is administered in one capsule or two tablets (2 x 17 mg tablets).
  • the patient is concurrently being administered a CYP3 A4 inhibitor, wherein orally administering comprises administering 10 mg of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-A- (4-(2-methylpropyloxy)phenylmethyl)carbamide daily.
  • pimavanserin or pharmaceutically acceptable salt thereof is administered orally to the human subject.
  • a tartrate salt of pimavanserin is administered to the human subject.
  • Pimavanserin or pharmaceutically acceptable salt thereof can, for example, be administered once, twice or three times per day. Pimavanserin or pharmaceutically acceptable salt thereof can, for example, be administered in a daily dose between 0.5 mg to 120 mg, or between 8 mg to 42 mg. For example, the daily dose of pimavanserin may be 20 mg or 34 mg daily.
  • a contemplated patient may be 18 years or older. In some embodiments, a contemplated patient may have had at least one year of history of major depression disorder. In certain embodiments, a patient does not have a psychotic disorder other than MDD. In certain embodiments, the patient does not have a history or symptoms of long QT syndrome.
  • a patient may have a 50% or greater improvement in a HAMD-17 score relative to the baseline.
  • the patient may have a 30% or greater, 40% or greater, 60% or greater, 70% or greater, or 80% or greater improvement in a HAMD-17 score relative to the baseline.
  • the patient may have a HAMD-17 score of less than 14.
  • the patient may have a HAMD-17 score of less than 20, less than 19, less than 18, less than 17, less than 16, less than 15, less than 13, less than 12, less than 10, less than 9, or less than 8.
  • the patient after 5 weeks of daily administration, has an improved Sheehan Disability Score (SDS) relative to the baseline. In certain embodiments, the treating results in increased functional remission compared to a patient treated with a placebo. In some embodiments, the functional remission is a total SDS score of 6 or less. In other embodiments, after 5 weeks of daily administration, the patient has an improved score in the work/school item of the SDS. In certain embodiments, after 5 weeks of daily administration, the patient has an improved score in the social life item of the SDS. In some embodiments, after 5 weeks of daily administration, the patient has an improved score in the family life/home responsibilities item of the SDS. In certain embodiments, after 5 weeks of daily administration, the patient has a reduced number of the days unproductive item of the SDS.
  • SDS Sheehan Disability Score
  • the patient after 5 weeks of daily administration, the patient has a higher improvement in a HAMD-17 score than a patient treated with an SSRI or SNRI alone.
  • the patient may have an early improvement as measured by Hamilton Depression Scale within 7 days of daily administration compared to a patient treated with a placebo.
  • the patient may have an early improvement as measured by Hamilton Depression Scale within 8 days of daily administration compared to a patient treated with a placebo.
  • the patient may have an early improvement as measured by Hamilton Depression Scale within 9 days of daily administration compared to a patient treated with a placebo.
  • the patient may have an early improvement as measured by Hamilton Depression Scale within 10 days of daily administration compared to a patient treated with a placebo.
  • the patient may have an improved score in the psychic anxiety item of the Hamilton Depression Scale.
  • the patient has an improved score in the somatic anxiety item of the Hamilton Depression Scale.
  • the patient has an improved score in the work and interest item of the Hamilton Depression Scale.
  • the patient has an improved score in the gastrointestinal symptoms item of the Hamilton Depression Scale.
  • the patient has an improved score in the general somatic symptoms item of the Hamilton Depression Scale.
  • the patient has an improved score in the hypochondria item of the Hamilton Depression Scale.
  • a contemplated patient before administration of N-(4- fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2- methylpropyloxy)phenylmethyl)carbamide, may wake up 2 hours earlier than usual.
  • the patient before administration of N-(4-fluorophenylmethyl)-N-(1- methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide, the patient has observable psychomotor retardation or agitation.
  • the patient before the administration of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2- methylpropyloxy)phenylmethyl)carbamide, the patient has significant weight loss or anorexia.
  • a disclosed method may improve, in a patient suffering from major depressive disorder, one or more of: depression that is worse in the morning, waking up 2 or more hours earlier than usual, psychomotor retardation or agitation, weight loss or anorexia, and excessive or inappropriate guilt.
  • the patient may have a 50% or greater improvement in a HAMD-6 score relative to the baseline, where the HAMD-6 consists of the following individual items: depressed mood, guilt feelings, work and interests, psychomotor retardation, psychic anxiety, and general somatic symptoms.
  • the patient may have a higher improvement in a HAMD-6 score than a patient treated with an SSRI or SNRI alone, wherein the HAMD-6 consists of the following individual items: depressed mood, guilt feelings, work and interests, psychomotor retardation, psychic anxiety, and general somatic symptoms.
  • the patient has an improved score in the depressed mood item of the Hamilton Depression Scale.
  • the patient has an improved score in the guilt item of the Hamilton Depression Scale.
  • the patient has an improved score in the work and interest item of the Hamilton Depression Scale.
  • the patient has an improved score in the psychomotor retardation item of the Hamilton Depression Scale.
  • the patient has an improved score in the gastrointestinal symptoms item of the Hamilton Depression Scale.
  • the patient after 5 weeks of daily administration, has improved daytime sleepiness and/or improved nighttime sleep disturbance.
  • the improved sleep disturbance is measured by at least a -1.5 change from baseline of the Karolinska Sleepiness Scale.
  • the patient after 5 weeks of daily administration, the patient has an improved score in the psychic anxiety item of the Hamilton Depression Scale. In certain embodiments, after 5 weeks of daily administration, the patient has an improved score in the somatic anxiety item of the Hamilton Depression Scale. In other embodiments, after 5 weeks of daily administration, the patient has an improved score in the work and interest item of the Hamilton Depression Scale.
  • N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide is administered in the form of a tartrate salt.
  • orally administering comprises administering about 5 mg to about 40 mg, based on the free base form, of N-(4-fluorophenylmethyl)-N-(1- methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide daily.
  • orally administering may comprise administering 34 mg based on the free base form of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2- methylpropyloxy)phenylmethyl)carbamide daily.
  • the 34 mg is administered in one capsule or two tablets (2 x 17 mg tablets).
  • the contemplated patient may also be concomitantly taking a strong CYP3 A4 inhibitor, and the daily dose of pimavanserin is 10 mg daily.
  • exemplary’ strong CYP3A4 inhibitors include but are not limited to ketoconazole, clarithromycin, indinavir, and itraconazole.
  • the human subject with MDD is taking a SSRI or SNRI to treat MDD.
  • the pimavanserin or pharmaceutically acceptable salt thereof is administered daily to the human subject for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more weeks.
  • a subject can be a mammal, a primate, a monkey or a human. In certain embodiments of the methods provided herein, the subject is a human subject.
  • the human subject is a female or male human subject.
  • the human subject is a female human subject. In other embodiments, the human subject is a male human subject.
  • the age of the human subject is 45 years or older, 50 years or older, or 55 years or old, or 60 years or older, or 65 years or older, or 70 years or older at baseline. In another embodiment, the age of the patient is 60 years or older. In another embodiment, the age of the patient is less than 60 years old.
  • N-(4-Fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'- 4-(2- methylpropyloxy)phenylmethyl)carbamide is also known as pimavanserin; N-[(4- fluorophenyl)methyl]-N-(1-methy1-4-piperidinyl)-A’-[[4-(2-methylpropoxy)phenyl]methyl]- urea, 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)-3-[4-(2-methylpropoxy)benzyl]urea or ACP-103 and is represented by the chemical formula:
  • N-(4-Fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2- methylpropyloxy)phenylmethyl)carbamide maybe administered as a tartrate salt, which is urea, N-[(4-fluorophenyl)methyl]-N-(1-methy1-4-piperidinyl)-N’-[[4-(2- methylpropoxy)phenyl]methyl]- ,(27?,37?)-2,3-dihydroxybutanedioate (2: 1), and represented by the chemical formula:
  • Pimavanserin i.e., N-(4-Fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'- (4-(2-methylpropyloxy)phenylmethyl)carbamide
  • Pimavanserin i.e., N-(4-Fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'- (4-(2-methylpropyloxy)phenylmethyl)carbamide
  • Pimavanserin can be obtained in a number of salt and crystalline forms.
  • Exemplary pharmaceutically acceptable salts include the tartrate, hemi -tartrate, citrate, fumarate, maleate, malate, phosphate, succinate, sulphate, and edisylate (ethanedi sulfonate) salts.
  • Pimavanserin, and salts thereof including the aforementioned ions, among others, are described, for example, in International Patent Publication WO 2008/144326, U.S. Patent Publication Nos. 2006-0111399 and 2010-0305329, and International Patent Application WO20 17015272, the entirety of which is incorporated herein by reference.
  • pimavanserin is the tartrate salt of pimavanserin.
  • pimavanserin is the crystalline form of the tartrate salt of pimavanserin Form A.
  • pimavanserin is the crystalline form of the tartrate salt of pimavanserin Form C.
  • pimavanserin or a pharmaceutically acceptable salt thereof is administered to the subject in an oral dosage form, such as, for example, a tablet, a capsule, or a lozenge and the like.
  • the drug product is formulated with standard pharmaceutical excipients at a 34 mg pimavanserin (40 mg of pimavanserin tartrate) in capsules for oral administration.
  • the capsule formulation includes inactive ingredients magnesium stearate and microcrystalline cellulose.
  • the following inactive ingredients can, for example, be present as components of the capsule shell: black iron oxide, FD&C blue #1, hypromellose, titanium dioxide, and yellow iron oxide.
  • pimavanserin or a pharmaceutically acceptable salt thereof is orally administered to the subject in a capsule, wherein the amount of pimavanserin or pharmaceutically acceptable salt in the capsule is between 2 mg to 80 mg, between 5 mg to 45 mg, or between 9 mg to 42 mg.
  • pimavanserin or a pharmaceutically acceptable salt thereof is orally administered to the subject in a tablet, wherein the amount of pimavanserin or pharmaceutically acceptable salt in the tablet is between 2 mg to 80 mg, between 5 mg to 45 mg, or between 9 mg to 42 mg.
  • Disclosed method include administration of N-(4-fluorophenylmethyl)-N-(1- methylpiperidin-4-yl)-N'- 4-(2-methylpropyloxy)phenylmethyl)carbamide orally by table or capsule (34 mg of compounds).
  • Tablets may contain 20 mg of pimavanserin tartrate, which is equivalent to 17 mg of pimavanserin free base, or 11.8 mg of pimavanserin tartrate, which is equivalent to 10 mg of pimavanserin free base.
  • pimavanserin is in crystalline and/or amorphous form.
  • Pimavanserin or a pharmaceutically acceptable salt thereof may be administered in the form of a capsule, e.g. a capsule may contain 40 mg of pimavanserin tartrate, which is equivalent to 34 mg of pimavanserin free base, or 20 mg of pimavanserin tartrate, which is equivalent to 17 mg of pimavanserin free base, or 11.8 mg of pimavanserin tartrate, which is equivalent to 10 mg of pimavanserin free base.
  • the drug product is formulated with standard pharmaceutical excipients at a 17 mg strength (20 mg of pimavanserin tartrate) in immediate- release tablets for once-daily oral administration.
  • the drug product is formulated with standard pharmaceutical excipients at a 10 mg strength (11.8 mg of pimavanserin tartrate) in immediate-release tablets for once-daily or twice-daily oral administration.
  • Pimavanserin once daily as 10 mg tablet can, for instance, be administered to the subject when a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin, indinavir, and itraconazole) is also being administered to the subject.
  • a strong CYP3A4 inhibitor e.g., ketoconazole, clarithromycin, indinavir, and itraconazole
  • the dose for the indication of adjunctive treatment of MDD indication is 34 mg pimavanserin taken orally as two 17 mg tablets once daily.
  • the dose and pharmaceutical composition of pimavanserin are those disclosed in International Application No. PCT7US2018/048096, which is incorporated herein for all purposes.
  • Pimavaserin can be in a crystalline form. Such forms have been described as Forms A, B, C, D, etc., e.g. in WO 2006/037043, WO 2007/133802 and WO 2008/144326.
  • the pharmaceutical composition comprises granulated pimavanserin tartrate, Form C which may include a small percentage of Form A, including a pharmaceutically acceptable diluent, binder or excipient, or combination thereof.
  • the pharmaceutical compositions are provided as a two-piece hard shell capsules made of gelatin (fish, mammalian, or vegetable sourced) or other combinations.
  • the two-piece hard shell capsules may contain the pimavanserin granules with a filler/diluent and/or lubricants.
  • the capsules are size 3 or 4 capsules.
  • the capsules are size 4 capsules.
  • the capsules are two-piece capsules of gelatin or hydroxypropyl methylcellulose (HPMC).
  • HPMC hydroxypropyl methylcellulose
  • the doses referred to herein refers to pimavanserin free base. In some embodiments, the doses referred to herein refers to pimavanserin tartrate Form C (e.g., 40 mg of pimavanserin tartrate, equivalent to 34 mg pimavanserin free base). In some embodiments, the doses refer to pimavanserin tartrate Form C encapsulated in capsules of size 3 or 4, such as capsules of size 4.
  • pimavanserin granulated
  • microcrystalline cellulose for example Avicel PH302 or an equivalent microcrystalline cellulose
  • magnesium stearate for example vegetable grade
  • compositions described herein includes pimavanserin tartrate granulation without binder, dried, and thereafter blended with less than 60% w/w microcrystalline cellulose such as Avicel PH302 or equivalent microcrystalline cellulose, and about 1% w/w magnesium stearate.
  • compositions described herein comprise granulated pimavanserin and microcrystalline cellulose is at least 20 % w/w microcrystalline cellulose, such as 30 % w/w microcrystalline cellulose, such as 40 % w/w microcrystalline cellulose, such as 50 % w/w microcrystalline cellulose, such as 50-89 % w/w microcrystalline cellulose, such as 20-94 % w/w, such as 50-94 % w/w, such as 57-94 % w/w, such as 57-89 % w/w microcrystalline cellulose, such as 57-79 % w/w microcrystalline cellulose, or 57-60 % w/w microcrystalline cellulose, or 57-59.5 % w/w microcrystalline cellulose, or 58.5-59.5 % w/w microcrystalline cellulose, or 59 % w/w microcrystalline cellulose.
  • compositions described herein comprise granulated pimavanserin and microcrystalline cellulose and magnesium stearate, such as 0.1-3 % w/w, such as 0.5-2 % w/w magnesium stearate, or 0.5-1.5 % w/w magnesium stearate, or 1 % w/w magnesium stearate.
  • compositions described herein comprise granulated pimavanserin (5, 10, 20 or 34 mg) and microcrystalline cellulose is at least 20 % w/w microcrystalline cellulose, such as 30 % w/w microcrystalline cellulose, such as 40 % w/w microcrystalline cellulose, such as 50 % w/w microcrystalline cellulose, such as 50-89 % w/w microcrystalline cellulose, such as 20-94 % w/w, such as 50-94 % w/w, such as 57- 94 % w/w, such as 57-89 % w/w microcrystalline cellulose, such as 57-79 % w/w microcrystalline cellulose, or 57-60 % w/w microcrystalline cellulose, or 57-59.5 % w/w microcrystalline cellulose, or 58.5-59.5 % w/w microcrystalline cellulose, or 59 % w/w microcrystalline cellulose and magnesium stearate, such as 0.1-3
  • compositions disclosed herein comprise pimavanserin and additional compatible excipients, e.g. sugars, sucrose, mannitol, sorbitol, polysaccharides (e.g. from com, wheat, rice, potato), as well as pregelatinized or partially pregelatinized starches (e.g. STARCH 1500®), cellulose preparations such as microcrystalline cellulose (MCC) (e.g.
  • silicified microcrystalline cellulose e.g. PROSOL V® 50, PROSOL V® 90, PROSOL V® HD90
  • lactose cellulose blends e.g. CELLATOSE® 80, CELLATOSE® 90, PROSOL V® EASYtab SP
  • hydroxypropylmethyl cellulose hydroxy
  • microcrystalline cellulose such as microcrystalline cellulose having a particle size distribution (D90) of 180 - 340 pm, for example Avicel PH302 or an equivalent microcrystalline cellulose, and/or magnesium stearate, for example vegetable grade are encapsulated in a capsule of size 4, for example a two-piece capsule.
  • [00181] Provided are also embodiments wherein 10 or 20 mg pimavanserin (granulated), microcrystalline cellulose, for example Avicel PH302 or an equivalent microcrystalline cellulose, and/or magnesium stearate, for example vegetable grade are encapsulated in a capsule of size 4, for example a two-piece capsule.
  • microcrystalline cellulose for example Avicel PH302 or an equivalent microcrystalline cellulose
  • magnesium stearate for example vegetable grade
  • compositions comprising a capsule of pimavanserin and one or more pharmaceutically acceptable excipient(s) as provided herein, wherein the composition is formulated such that at least 80% of pimavanserin is released in 30 minutes upon administration to a subject.
  • compositions comprising a capsule of pimavanserin and one or more pharmaceutically acceptable excipient(s) as provided herein, wherein the composition is formulated such that at least 80% of the pimavanserin is released from the composition within 30 minutes upon in vitro dissolution testing according to USP ⁇ 711> (apparatus 1 (basket apparatus)).
  • a pharmaceutically acceptable salt of pimavanserin is administered to the patient.
  • a tartrate salt of pimavanserin is administered to the patient.
  • the pharmaceutically acceptable salt of pimavanserin comprises an anion selected from the group consisting of phosphate, sulphate, nitrate, diphosphate, besylate, bicarbonate, carbonate, clavulanate, edisylate, isothionate, borate, halide including e.g., chloride and bromide, nitrate, acetate, succinate, lactate, lactobionate, laurate, mandelate, malate, citrate, fumarate, maleate, oleate, oxalate, ascorbate, nicotinate, benzoate, mesylate, salicylate, stearate, tannate, tosylate, valerate, methanesul
  • the tartrate salt of pimavanserin is administered daily. In some embodiments, the tartrate salt of pimavanserin is administered once daily. In some embodiments, the tartrate salt of pimavanserin is formulated for oral administration as a unit dose.
  • pimavanserin is administered orally.
  • pimavanserin is orally administered in a daily dose from about 0.5 mg to about 90 mg, or from about 8 mg to about 42 mg, or about 10 mg to about 60 mg.
  • pimavanserin is orally administered in a daily dose from about 0.5 mg to about 120 mg, or from about 8 mg to about 42 mg, or about 10 mg to about 60 mg.
  • the above ranges are for pimavanserin free base. In certain embodiments, the above ranges are for a pharmaceutically acceptable salt, e.g., a tartrate salt of pimavanserin or any of the salts listed above.
  • a pharmaceutically acceptable salt e.g., a tartrate salt of pimavanserin or any of the salts listed above.
  • pimavanserin tartrate is orally administered in a daily dose of about 40 mg.
  • the daily dose is 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg,
  • the daily dose of pimavanserin tartrate is administered once, twice or three times per day, for example a 40 mg dose of pimavanserin tartrate is administered once a day, or 20 mg pimavanserin tartrate is administered twice daily.
  • pimavanserin is orally administered in a daily dose of about 34 mg or 20 mg.
  • the daily dose is 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 68 mg, 80 mg, 88 mg or 102 mg.
  • the daily dose of pimavanserin is administered once, twice or three times per day, for example a 34 mg dose of pimavanserin is administered once a day, a 20 mg dose of pimavanserin once or twice daily, or 17 mg pimavanserin is administered twice daily, a 20 mg dose of pimavanserin once or twice daily, or a 10 mg dose pimavanserin is administered twice daily.
  • the SSRI is selected from the group consisting of citalopram, escitalopram (LEXAPRO), fluoxetine (PROZAC), fluvoxamine, paroxetine (PAXIL), sertraline, vilazodone, vortioxetine, desvenlafaxine, duloxetine, levomilnacipran, sibutramine, tramadol, milnacipran and venlafaxine.
  • the SNRI is selected from the group consisting of desvenlafaxine, duloxetine, levomilnacipran, sibutramine, tramadol, milnacipran and venlafaxine.
  • the antidepressant given to the subject can, for example, be doxepin, clomipramine, amoxapine, amitriptyline, maprotiline, desipramine, nortriptyline, doxepin, trimipramine, imipramine, protriptyline, pipof ezine or noxiptiline.
  • the antidepressant is a tricyclic antidepressant.
  • Tricyclic antidepressants are known in the art.
  • the antidepressant is an antipsychotic.
  • the antidepressant can be bupropion or nefazodone.
  • EXAMPLE 1 Study of Adjunctive Pimavanserin in Patients With Major Depressive Disorder and an Inadequate Response to Therapy
  • the study consisted of an 8- to 21 -day screening period, a 10-week double- blind treatment period, and a safety follow up period of up to 30 days.
  • Screening assessments consisted of the SAFER Interview (Desseilles et al, Harv Rev Psychiatry. 2013;21(5):269- 74), which included the MADRS, CGI-S, and MGH ATRQ.
  • the study utilized a 2-stage Sequential Paralle1-Comparison Design (SPCD) (Fava et al, Psychother Psychosom. 2003; 72:115-127) whereby, following screening, eligible patients were randomized in Stage 1 in a 3 : 1 ratio to placebo or pimavanserin added to their current SSRI or SNRI therapy for 5 weeks.
  • SPCD Sequential Paralle1-Comparison Design
  • placebo non- responders HAMD-17 total score >14 and ⁇ 50% reduction in score from baseline
  • pimavanserin (1 : 1 ratio
  • MDE major depressive episode
  • SCID-5- CT Structured Clinical Interview for DSM-5, Clinical Trials Version
  • Eligible patients had a history of MDD for ⁇ 1 year prior to screening, a MADRS total score >20, and a CGI-S score >4 (moderately ill or worse) at both screening and baseline.
  • Eligible patients also had a history of an inadequate response to 1 or 2 antidepressant treatments during the current depression episode. Inadequate treatment response was determined through the administration of the MGH ATRQ administered during the SAFER interview.
  • the NNT for response and remission in Stage 1 was 3.6 and 8.1, respectively.
  • response and remission rates were significantly (p ⁇ 0.05) greater with pimavanserin vs. placebo from Week 2 through Week 5 (FIG. 3).
  • Pimavanserin was well tolerated in this study.
  • the AE profile was consistent with previous studies of pimavanserin for Parkinson’s disease psychosis and Alzheimer’s disease psychosis and discontinuations for AEs were lower with pimavanserin than with placebo (1.2% vs. 3.2%).
  • EXAMPLE 2 Study of Safety and Efficacy of Pimavanserin Treatment in Adults with Parkinson’s Disease and Depression
  • An 8-week, open-label, single arm study evaluating the safety and efficacy of 34 mg pimavanserin treatment of depression in adults with Parkinson’s disease is conducted. Subjects can receive treatment as either monotherapy or adjunctively if inadequately controlled with SSRI/SNRI monotherapy.
  • a primary endpoint of the study is change from baseline to Week 8 in the Hamilton Depression Scale 17-item (HAMD-17) total score. Secondary endpoints include Clinical Global Impression (CGI) scales (improvement and severity), Scale of Outcomes in PD-Sleep (SCOP A), and quality of life as measured by EuroQo1-5 dimensions-5 levels (EQ-5D-5L).
  • Pimavanserin 34 mg (provided as two 17 mg NUPLAZID® tablets) were administered orally as a single dose once daily.
  • Subjects were assessed for eligibility and prohibited medications were discontinued. After all screening assessments were completed, eligible subjects returned to the clinic for Baseline evaluation. After Baseline assessments were completed, subjects were enrolled and received the first dose of pimavanserin. Study medication were provided to the subjects to take home with instructions to take the medication approximately the same time each day, and return all used containers and unused study drug as scheduled.
  • the subject has a clinical diagnosis of idiopathic Parkinson’s disease with a minimum duration of 1 year, defined as the presence of at least three of the following cardinal features, in the absence of alternative explanations or atypical features: 1) rest tremor 2) rigidity 3) bradykinesia and/or akinesia and 4) postural and gait abnormalities.
  • the HAMD-17 total score was analyzed using mixed model for repeated measures (MMRM).
  • MMRM mixed model for repeated measures
  • the model included effects for visit, Baseline HAMD-17 total score, and the Baseline HAMD-17 total score-by-visit interaction.
  • An unstructured covariance matrix was used to model the within-subject errors and the Kenward-Roger approximation was used to adjust the denominator degrees of freedom.
  • the treatment effect for the primary endpoint was estimated as the least-squares mean change from Baseline to Week 8, and was tested at a significance level of 0.05.
  • the treatment effect was also estimated at each of the other time points (Weeks 2, 4, and 6) using the same MMRM model described above, and was considered secondary analyses.
  • Continuous secondary efficacy endpoints (CGI-I, CGI-S, SCOP A, and EQ- 5D-5L) were analyzed using similar MMRM models as for the primary efficacy endpoint, except that the Baseline value of the endpoint being analyzed was included in the model as a covariate instead of the Baseline HAMD-17 total score.
  • CGI-I the response is the CGI-I score (as opposed to the change from Baseline), and the Baseline CGI-S score was used as the covariate.
  • HAMD-17 responder endpoints >50% reduction from Baseline in HAMD-17 total score
  • the proportion of responders was summarized by visit, including 95% confidence intervals. Observed cases (subjects with missing values at a given visit are excluded) as well as missing values imputed as non-responders was presented.
  • 5 -HT 2A receptors represent important targets for depression.
  • a variety of studies have shown antidepressant activity from compounds with potent antagonist or inverse agonist activity at 5-HT 2A receptors, and to varying degrees 5-HT 2c receptors, but low affinity to serotonin transporter, norepinephrine transporter, and dopamine transporter, either alone or when coadministered with SSRIs (Table 7).
  • Pimavanserin with its potent activity as a 5-HT 2A antagonist/inverse agonist and lesser activity as a 5-HT 2c antagonist/inverse agonist, has a similar receptor profile to many compounds with antidepressant activity.
  • Current research continues to investigate novel molecular and cellular mechanisms of augmentation of antidepressant therapies.
  • 5-HT 2A receptors represent important targets for depression.
  • a variety of studies have shown antidepressant activity from compounds with potent antagonist or inverse agonist activity at 5-HT 2A receptors, and, to varying degrees, 5-HT 2c receptors, but low affinity to serotonin transporter, norepinephrine transporter, and dopamine transporter.
  • Antidepressant activity from these compounds has been found when taken alone or when coadministered with SSRIs, however, with some compounds (e.g., ritanserin, volinanserin, pruvanserin) their ability to alleviate SSRI antidepressant side effects is not known.
  • V OL volinanserin .
  • K i affinity ( K i ) in nM of the indicated ligands and transporters/receptors.
  • K i values are provided in parentheses. “Low” denotes a K i >1000 nM.
  • SSRIs and serotonin-norepinephrine reuptake inhibitors elevate synaptic levels of 5-HT, they indirectly activate all 14 5-HT receptor subtypes including 5-HTIA, 5-HT2A, 5-HT2C and 5-HT3 receptors. Efficacy of SSRIs is thought to be primarily mediated through activation of 5-HTIA serotonin receptors (Samuels et al., 2015, Nat Neurosci., 18(11): 1606-1616).
  • Study ACP-103-042 was a Phase 2, multicenter, randomized, double-blind, placebo-controlled, 2-stage SPCD study to evaluate the efficacy and safety of adjunctive pimavanserin in adult patients with inadequate treatment response to SSRI or SNRI antidepressant. Patients were required to be receiving a stable regimen of treatment with an SSRI/SNRI antidepressant as treatment for MDD to which they had exhibited an inadequate response. Each subject entering Stage 1 was randomly assigned (1 :3) to receive either 34 mg pimavanserin (52 subjects) or placebo (155 subjects) once daily (QD).
  • Stage 1 At the end of Stage 1 (Week 5), subjects initially randomized to placebo and who had met the criteria for a non- responder (i.e., HAMD-17 total score at Week 5 > 14 and a reduction from baseline in HAMD-17 total score of ⁇ 50%) were randomly assigned (1 : 1) to pimavanserin 34 mg/day (29 subjects) or placebo (29 subjects). The determination of the subject’s status and eligibility for randomization in Stage 2 was made in a double-blind manner. Subjects who did not meet criteria for randomization into Stage 2 continued with the assigned treatment from Stage 1 for an additional 5-week period (until the end of the study double-blind treatment).
  • CGI-I Clinical Global Impression-Improvement
  • CGI-S Clinical Global Impression-Severity
  • KSS Karolinska Sleepiness Scale
  • BMS Barratt Impulsiveness Scale
  • MCS SF-12 Mental Component Summary
  • MGH-SFI Massachusetts General Hospital Sexual Functioning Index
  • pimavanserin was generally wel1-tolerated.
  • One subject in each of pimavanserin and placebo groups reported serious adverse events, deemed not related by investigator to study drug. These resolved and both these subjects completed the study.
  • the U.S. Food and Drug Administration (FDA) warns healthcare professionals and patients that the antidepressant Celexa (citalopram hydrobromide) should not be used at doses greater than 40 mg per day because of increase in the QT interval.
  • Celexa citalopram hydrobromide
  • Citalopram Label (Celexa®) recommends that citalopram should not be given at doses above 40 mg/day due to the risk of QT prolongation at higher citalopram doses.
  • Pimavanserin taken alone is associated with QTc interval of ⁇ 5-8 msec in patients receiving once-daily doses of NUPLAZID 34 mg.
  • NUPLAZID label describes that concomitant use of drugs which prolong the QT interval may add to the QT effects of NUPLAZID and should be avoided.
  • QTcF refers to QT interval corrected using Fridericia’ s method
  • QTcB refers to QT interval corrected using Bazett' s method
  • SD refers to standard deviation
  • SE refers to standard error.
  • Stage 1 subjects not re-randomized to pimavanserin and followed through to Week 10. As demonstrated in Tables 12, 13, 16, and 17, no subjects showed clinical significant increase in QTcF (either > 60 msec increase from baseline or > 500 msec duration) among subjects receiving concomitant pimavanserin and citalopram or escitalopram compared to citalopram or escitalopram and placebo in Stage 1.
  • Baseline is Study Week 0 and Week 5 is Study Week 5.
  • Baseline is Study Week 5 and Week 5 is Study Week 10.
  • the denominator is the number of subjects with at least 1 post-Baseline value for the given treatment group in the given Safety Analysis Set.
  • Table 12 summarizes data for 5 weeks of Stage 1 and Stage 2.
  • the denominator is the number of subjects with at least 1 post-Baseline value for the given treatment group in the given Safety Analysis Set. Table 13 summarizes data for 5 weeks of Stage 1 and Stage 2.
  • Baseline is Study Week 5 and Week 5 is Study Week 10.
  • the denominator is the number of subjects with at least 1 post-Baseline value for the given treatment group in the given Safety Analysis Set. This table summarizes data for 5 weeks of Stage 1 and Stage 2.
  • pimavanserin when used adjunctively with citalopram or escitalopram showed no additive effect on mean QTc interval beyond what is expected from label descriptions for either drug. It also demonstrates reduction in expected mean QTcF increase for subjects taking pimavanserin and citalopram concurrently.
  • This study was a Phase 3, multicenter, placebo-controlled, double blind trial to examine the safety and efficacy of pimavanserin in the treatment of psychosis in Parkinson’s Disease.
  • a total of 199 patients were enrolled in the study and randomized on a one-to-one basis to receive either 40 mg of pimavanserin or placebo once daily for six weeks, following a two-week screening period including brief psycho-social therapy.
  • Patients also received stable doses of their existing anti -Parkinson’s therapy throughout the study.
  • the trial was conducted on an outpatient basis with visits performed as follows: Screening Visit 1, Day 1 (Baseline), Day 15, Day 29 and Day 43 with a follow-up visit (Day 71) 4 weeks after the last regular study visit for those subjects who did not continue into an open-label extension protocol.
  • Patients were male or female of 40 years of age or older and were required to have a clinical diagnosis of Parkinson's disease with a minimum duration of 1 year with psychotic symptoms developed after Parkinson's disease diagnosis was established and show a presence of visual and/or auditory hallucinations, and/or delusions, occurring during the four weeks prior to study screening.
  • the patients on anti-Parkinson's medication must have been on a stable dose for 1 month prior to Study Day 1 (Baseline) and during the trial.
  • Baseline Study Day 1
  • Each subject was assigned to receive either 40 mg of pimavanserin tartrate (i.e., 34 mg of pimavanserin) (105 subjects) or placebo (94 subjects) once daily (QD) by mouth for 6 weeks.
  • CGI Clinical Global Impression Scale
  • CGI-S Clinical Global Impression Scale
  • CGI-I Improvement of psychosis.
  • Exploratory Endpoints the Caregiver Burden Scale, and Scales for Outcomes in Parkinson’s Disease - Sleep scale (SCOPN-Sleep).
  • Pimavanserin met the key secondary endpoint for motoric tolerability as measured using Parts II and III of the UPDRS. Pimavanserin conferred antipsychotic activity while maintaining motor control.
  • SAPS-PD assessments were performed by blinded, independent centralized raters.
  • MMRM mixed model repeated measures
  • citalopram (10 mg, 20 mg, or 40 mg per day) with pimavanserin or placebo were monitored for changes in the QT interval.
  • Citalopram Label (Celexa®) recommends that citalopram should not be given at doses above 40 mg/day due to the risk of QT prolongation at higher citalopram doses.
  • expected mean QTcF interval increase based upon prescribing information may not occur with concomitant use of pimavanserin and citalopram compared to citalopram and placebo.
  • Negative symptoms of schizophrenia are associated with adverse clinical outcomes, but effective treatments are lacking.
  • Three clinical trials (Table 16) were designed to assess effects of adjunctive pimavanserin, a selective 5-HT2A inverse agonist/antagonist, on negative symptoms of schizophrenia.
  • ENHANCE study and the ADVANCE study (Table 16) were designed, there were no published data from randomized clinical trials that investigated the treatment of negative symptoms of schizophrenia with a selective 5- hydroxytryptamine 2A (5-HT2A) receptor inverse agonists/antagonist.
  • 5-HT2A 5- hydroxytryptamine 2A
  • EOS end of study
  • ET early termination
  • OL open label
  • QTcF QT interval using Fridericia’s correction method.
  • aripiprazole including long-acting injectable [LAI], Abilify Maintena®, Aristada®), asenapine, brexpiprazole, cariprazine, lurasidone, olanzapine, risperidone (including LAI).
  • LAI long-acting injectable
  • the dosage of the antipsychotic is as shown in Table 17 and Table 18. No dose change of oral AP was permitted within 4 weeks prior to screening; no dose change of LAI AP was permitted within 16 weeks prior to screening.
  • APs The 3 most frequently used APs were aripiprazole (including LAI), risperidone (including LAI), and olanzapine.
  • LAI aripiprazole
  • risperidone including LAI
  • olanzapine A no risperidone subgroup was also analyzed to understand the effects of APs with low or moderate risk of QTc prolongation. This group included patients who were treated with either aripiprazole, asenapine, brexpiprazole, cariprazine, lurasidone, or olanzapine.
  • Electrocardiograms were unblinded from completed trials in which pimavanserin or placebo were added to main APs over 6 weeks (ENHANCE), 26 weeks (ADVANCE), and up to 78 weeks (ongoing 52-week, open-label rollover 035 study) of treatment.
  • N subjects randomized to a given treatment
  • n subjects with at least one postbaseline value for the given treatment group
  • PBO placebo
  • PIM pimavanserin
  • QTcF QT interval using Fridericia’s correction method
  • SE standard error.
  • N subjects randomized to a given treatment
  • n subjects with at least one postbaseline value for the given treatment group
  • PBO placebo
  • PIM pimavanserin
  • QTcF QT interval using Fridericia’s correction method
  • SE standard error.

Abstract

La présente invention concerne, en partie, un procédé de traitement de la dépression majeure, de la psychose secondaire aux troubles neurodégénératifs ou de la schizophrénie chez un patient en ayant besoin, le patient prenant actuellement une dose quotidienne d'un SSRI ou d'un SNRI qui prolonge l'intervalle QT, comprenant l'administration d'une dose quotidienne de pimavansérine au patient et la poursuite de l'administration du SSRI ou du SNRI, et, lors de l'administration de la pimavansérine, l'intervalle QT du patient n'augmente pas significativement.
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