title: Combined rasagiline and antidepressant use in Parkinson disease in the ADAGIO study: effects on nonmotor symptoms and tolerability.
abstract: OBJECTIVE
  Depression, cognitive impairment, and other nonmotor symptoms (NMSs) are common early in Parkinson disease (PD) and may be in part due to disease-related dopamine deficiency. Many patients with PD are treated with antidepressants for NMSs, and the effect of the combination of PD medications that enhance dopamine neurotransmission and antidepressants on NMSs has not been studied. We report the effects of the addition of a monoamine oxidase B inhibitor, rasagiline, to antidepressant treatment in PD.
  
  
  OBJECTIVE
  To evaluate the effect of rasagiline on depression, cognition, and other PD NMSs in patients taking an antidepressant in the Attenuation of Disease Progression With Azilect Given Once Daily (ADAGIO) study.
  
  
  METHODS
  The ADAGIO study was a double-blind, placebo-controlled, delayed-start trial of rasagiline in de novo PD. In this exploratory post hoc analysis, we analyzed patients taking an antidepressant during the 36-week phase 1 period, in which patients were randomized to rasagiline (1 or 2 mg/d) or placebo.
  
  
  METHODS
  We evaluated the change in NMSs in patients taking an antidepressant and rasagiline compared with those taking placebo. The NMSs were assessed by Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale Nonmotor Experiences of Daily Living, the original Unified Parkinson's Disease Rating Scale, and the Parkinson Fatigue Scale.
  
  
  RESULTS
  A total of 191 of the 1174 patients (16.3%) were treated with antidepressants during phase 1 and provided efficacy data. Depression and cognition scores revealed significantly less worsening in the rasagiline group compared with the placebo group (differences in Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale item-adjusted means [SEs], -0.19 [0.10], P = .048, and -0.20 [0.05], P < .001, respectively). Parkinson Fatigue Scale (mean [SE] difference, -0.42 [0.09], P < .001) and daytime sleepiness (mean [SE] difference, -0.24 [0.09], P = .006) scores also revealed significantly less worsening in the rasagiline group compared with placebo. There was a nonsignificant trend toward less worsening in apathy and no significant between-group differences in anxiety or sleep. The effect on depression remained significant after controlling for improvement in motor symptoms (mean [SE] difference, -0.23 [0.09], P = .009). There were no serious adverse events in the combined rasagiline-antidepressant group suggestive of serotonin syndrome.
  
  
  CONCLUSIONS
  The combination of rasagiline and antidepressants in patients with de novo PD is associated with reduced worsening of a range of NMSs in preliminary analyses. Adverse effects appear uncommon with this combination. These findings suggest a role for dopamine-enhancing therapies in NMSs in early PD and encourage further study and confirmation.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00256204.
authors.affiliation: Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors.forename: Kara M
authors.initials: KM
authors.lastname: Smith
authors.affiliation: Teva Pharmaceutical Industries, Petach Tikva, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Eyal
authors.affiliation: Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia3Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia4Department of Veterans Affairs, Philadelphia VA Medi.
authors.forename: Daniel
authors.initials: D
authors.lastname: Weintraub
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000928:Antidepressive Agents / Q000627:therapeutic use*; D057565:Apathy; D003863:Depression / Q000188:drug therapy* / Q000209:etiology; D018450:Disease Progression; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005221:Fatigue; D005260:Female; D006801:Humans; D007189:Indans / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000150:complications / Q000188:drug therapy*; D011569:Psychiatric Status Rating Scales; D012720:Severity of Illness Index; D012890:Sleep; D016896:Treatment Outcome; D014851:Wakefulness
chemical_list: D000928:Antidepressive Agents; D007189:Indans; D018696:Neuroprotective Agents; C031967:rasagiline