title: A randomized, placebo-controlled study investigating the nicotinic α7 agonist, RG3487, for cognitive deficits in schizophrenia.
abstract: Effective treatments for cognitive impairment associated with schizophrenia (CIAS) remain an unmet need. Nicotinic α7 receptor agonists may be effective in CIAS. This 8-week (week 1, inpatient; weeks 2-8, outpatient), double-blind, randomized study used Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) guidelines to investigate the nicotinic α7 partial agonist RG3487 (formerly MEM3454) in CIAS; 215 patients with chronic stable schizophrenia received placebo or RG3487 (5, 15, or 50 mg) added to ongoing treatment with risperidone, paliperidone, or aripiprazole. Primary end point was baseline to week 8 change in MATRICS Consensus Cognitive Battery (MCCB) composite t-score. Secondary outcomes were change in MCCB domain and negative symptom assessment (NSA) scores. The study did not allow for evaluation of nonsmokers. Each RG3487 dose was evaluated using a mixed-effects model repeated measures approach. Mean (SD) baseline MCCB composite t-score was 28.3 (12.0). No significant effect on MCCB composite t-scores was observed with RG3487 (adjusted mean difference (SE) vs placebo: 5 mg: 0.11 (1.39); 15 mg: -1.95 (1.39); 50 mg: -1.13 (1.37); p = 0.2-0.9). RG3487 did not improve MCCB domain scores. In a post hoc analysis of patients with moderate negative symptoms, 5 and 50 mg RG3487 vs placebo significantly improved NSA total (-4.45 (p = 0.04) and -4.75 (p = 0.02), respectively) and global (-0.39 (p = 0.04) and -0.55 (p = 0.003), respectively) scores. The MCCB did not lead to higher than expected patient withdrawal. RG3487 was generally well tolerated. In patients with stable schizophrenia, RG3487 did not improve cognitive deficits, as assessed by the MCCB; however, in patients with moderate negative symptoms, a post hoc analysis revealed significant improvement of negative symptoms.
authors.affiliation: CNS Research and Early Development, F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Umbricht
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
authors.forename: Richard S E
authors.initials: RS
authors.lastname: Keefe
authors.affiliation: Memory Pharmaceuticals, Montvale, NJ, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Murray
authors.affiliation: 1] Memory Pharmaceuticals, Montvale, NJ, USA [2].
authors.forename: David A
authors.initials: DA
authors.lastname: Lowe
authors.affiliation: 1] CNS Research and Early Development, F. Hoffmann-La Roche, Basel, Switzerland [2].
authors.forename: Richard
authors.initials: R
authors.lastname: Porter
authors.affiliation: CNS Research and Early Development, F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: George
authors.initials: G
authors.lastname: Garibaldi
authors.affiliation: CNS Research and Early Development, F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Santarelli
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001643:Bridged Bicyclo Compounds / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007191:Indazoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000150:complications* / Q000188:drug therapy; D012565:Schizophrenic Psychology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D001643:Bridged Bicyclo Compounds; D007191:Indazoles; D018722:Nicotinic Agonists; C554954:N-((3S)-1-azabicyclo(2.2.2)oct-3-yl)-1H-indazole-3-carboxamide hydrochloride