title: Assessment of safety, tolerability and effectiveness of adjunctive aripiprazole to lithium/valproate in bipolar mania: a 46-week, open-label extension following a 6-week double-blind study.
abstract: OBJECTIVE
  This study evaluated the long-term tolerability and effectiveness of aripiprazole adjunctive to lithium or valproate in partial responders with bipolar mania.
  
  
  METHODS
  Completers of a 6-week double-blind comparison of adjunctive aripiprazole versus placebo in bipolar mania partially responsive to lithium or valproate monotherapy could enter a 46-week extension treatment with open-label adjunctive aripiprazole plus lithium (ARI + LI) or valproate (ARI + VAL). Safety, efficacy and functioning were assessed.
  
  
  BACKGROUND
  CN138-134LT: Study of Aripiprazole in Patients With Bipolar I Disorder; ID number: NCT00257972; registry: www.clinicaltrials.gov.
  
  
  RESULTS
  In total, 283 (ARI + LI n = 108; ARI + VAL n = 175) patients entered and 146 (ARI + LI n = 55; ARI + VAL n = 91) completed the 46-week, open-label extension. Frequently reported adverse events (AEs) that occurred with ARI + LI vs. ARI + VAL were: tremor (17.0% vs. 12.1%), akathisia (6.6% vs. 8.6%), headache (6.6% vs. 4.0%), insomnia (9.4% vs. 10.3%), depression (7.5% vs. 9.2%) and weight increase (11.3% vs. 8.6%). Extrapyramidal symptom-related AEs occurred in 24 (22.6%) ARI + LI- and 38 (21.8%) ARI + VAL-treated patients, with eight discontinuations. The majority of new-onset events of akathisia and insomnia occurred early. Mean (SE) weight change from double-blind endpoint to Week 46 (LOCF) was 2.3 (0.6) kg with ARI + LI and 2.0 (0.4) kg with ARI + VAL. Significant improvements from baseline over the 52 weeks (LOCF) occurred with ARI + LI and ARI + VAL on mean (95%CI) YMRS total score (-16.5 [-18.1; -14.8] and -17.6 [-18.9; -16.3], both p < 0.001 vs. baseline) and MADRS total score (-1.7 [-3.3; -0.1], p < 0.05 vs. baseline vs. -2.7 [-4.0; -1.4], p < 0.001 vs. baseline). Over the 46-week extension, continued aripiprazole provided continued YMRS improvement with ARI + LI (-2.9) and ARI + VAL (-3.3), while mean MADRS total changes were +1.1 and +1.0, respectively, and LIFE-RIFT changes were 0.2 and -0.5, respectively.
  
  
  CONCLUSIONS
  Long-term aripiprazole adjunctive to lithium/valproate in bipolar mania was safe and well tolerated. Improvements in manic symptoms and functioning were maintained. Aripiprazole, adjunctive to either lithium or valproate, appeared to be equally safe and effective combinations for the treatment of bipolar disorder.
  
  
  CONCLUSIONS
  As an open-label extension study with a low completion rate, a conservative interpretation of the findings is warranted. Additionally, the study population was not randomly selected but chosen at the discretion of the investigator, and patients did not maintain therapeutic levels of their mood stabiliser consistently.
authors.affiliation: Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain. evieta@clinic.ub.es
authors.forename: Eduard
authors.initials: E
authors.lastname: Vieta
authors.forename: Randall
authors.initials: R
authors.lastname: Owen
authors.forename: Christine
authors.initials: C
authors.lastname: Baudelet
authors.forename: Robert D
authors.initials: RD
authors.lastname: McQuade
authors.forename: Raymond
authors.initials: R
authors.lastname: Sanchez
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Marcus
mesh_terms: D000328:Adult; D018692:Antimanic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068180:Aripiprazole; D001714:Bipolar Disorder / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D018020:Lithium Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D016896:Treatment Outcome; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*
chemical_list: D018692:Antimanic Agents; D018020:Lithium Compounds; D010879:Piperazines; D015363:Quinolones; D014635:Valproic Acid; D000068180:Aripiprazole