title: A double-blind, randomized, placebo-controlled study with JNJ-37822681, a novel, highly selective, fast dissociating D₂ receptor antagonist in the treatment of acute exacerbation of schizophrenia.
abstract: JNJ-37822681 is a novel, highly selective dopamine D₂ receptor antagonist characterized by a rapid dissociation rate from the dopamine D₂ receptor. This profile was hypothesized to confer antipsychotic efficacy and improved tolerability. In this 12-week study, the efficacy and safety of JNJ-37822681 were evaluated in patients with an acute exacerbation of schizophrenia, randomly assigned (1:1:1:1:1) to JNJ-37822681 (10-, 20- or 30-mg bid), olanzapine (15 mg once-daily), or placebo (for 6 weeks followed by olanzapine for 6 weeks). Of 498 randomized patients, 298 (60%) completed the study. All JNJ-37822681 dose groups and the olanzapine group showed significantly greater reduction in PANSS total score from baseline to week 6 versus placebo (all p-values < 0.001). Least-squares adjusted mean changes from baseline to week 6 in PANSS total score were: -6.4 (placebo); -18.4 (10 mg JNJ-37822681), -17.7 (20 mg JNJ-37822681), -20.0 (30 mg JNJ-37822681) and -22.9 (olanzapine). All JNJ-37822681 groups showed significant improvement versus placebo from baseline to week 6 in the PANSS subscales, Marder factors, Clinical Global Impression of Severity, and in the Subjective Well-Being on Neuroleptics scale (all p-values < 0.05). The most common treatment-emergent adverse events with JNJ-37822681 were insomnia (17%) and akathisia (13%). Incidences of extrapyramidal symptoms were dose-related and were comparable for JNJ-37822681 10 mg bid and olanzapine groups. All JNJ-37822681 dose groups showed lesser weight gain compared with olanzapine. The efficacy and tolerability profile of the JNJ-37822681 10 mg bid was consistent with the study hypothesis.
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium. mschmid4@its.jnj.com
authors.forename: Mark E
authors.initials: ME
authors.lastname: Schmidt
authors.forename: Justine M
authors.initials: JM
authors.lastname: Kent
authors.forename: Ella
authors.initials: E
authors.lastname: Daly
authors.forename: Luc
authors.initials: L
authors.lastname: Janssens
authors.forename: Nancy
authors.initials: N
authors.lastname: Van Osselaer
authors.forename: Gitta
authors.initials: G
authors.lastname: Hüsken
authors.forename: Ion-George
authors.initials: IG
authors.lastname: Anghelescu
authors.forename: Luc
authors.initials: L
authors.lastname: Van Nueten
mesh_terms: D000208:Acute Disease / Q000523:psychology; D000328:Adult; D017109:Akathisia, Drug-Induced / Q000453:epidemiology; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000009:adverse effects / Q000627:therapeutic use; D039721:Diagnostic and Statistical Manual of Mental Disorders; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D015994:Incidence; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D010352:Patient Dropouts; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D007319:Sleep Initiation and Maintenance Disorders / Q000139:chemically induced / Q000453:epidemiology
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C576398:N-(1-(3,4-difluorobenzyl)piperidin-4-yl)-6-(trifluoromethyl)pyridazin-3-amine; D010880:Piperidines; D011724:Pyridazines; D017448:Receptors, Dopamine D2; D001569:Benzodiazepines; D000077152:Olanzapine