title: Randomized Controlled Trials of Add-On Antidepressants in Schizophrenia.
abstract: BACKGROUND
  Despite adequate treatment with antipsychotics, a substantial number of patients with schizophrenia demonstrate only suboptimal clinical outcome. To overcome this challenge, various psychopharmacological combination strategies have been used, including antidepressants added to antipsychotics.
  
  
  METHODS
  To analyze the efficacy of add-on antidepressants for the treatment of negative, positive, cognitive, depressive, and antipsychotic-induced extrapyramidal symptoms in schizophrenia, published randomized controlled trials assessing the efficacy of adjunctive antidepressants in schizophrenia were reviewed using the following parameters: baseline clinical characteristics and number of patients, their on-going antipsychotic treatment, dosage of the add-on antidepressants, duration of the trial, efficacy measures, and outcomes.
  
  
  RESULTS
  There were 36 randomized controlled trials reported in 41 journal publications (n=1582). The antidepressants used were the selective serotonin reuptake inhibitors, duloxetine, imipramine, mianserin, mirtazapine, nefazodone, reboxetin, trazodone, and bupropion. Mirtazapine and mianserin showed somewhat consistent efficacy for negative symptoms and both seemed to enhance neurocognition. Trazodone and nefazodone appeared to improve the antipsychotics-induced extrapyramidal symptoms. Imipramine and duloxetine tended to improve depressive symptoms. No clear evidence supporting selective serotonin reuptake inhibitors' efficacy on any clinical domain of schizophrenia was found. Add-on antidepressants did not worsen psychosis.
  
  
  CONCLUSIONS
  Despite a substantial number of randomized controlled trials, the overall efficacy of add-on antidepressants in schizophrenia remains uncertain mainly due to methodological issues. Some differences in efficacy on several schizophrenia domains seem, however, to exist and to vary by the antidepressant subgroups--plausibly due to differences in the mechanisms of action. Antidepressants may not worsen the course of psychosis. Better designed, larger, and longer randomized controlled trials are needed.
authors.affiliation: Kellokoski Hospital, Kellokoski, Finland (Dr Terevnikov); Department of Psychiatry, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Helsinki, Finland (Drs Joffe and Stenberg). viacheslav.terevnikov@hus.fi.
authors.forename: Viacheslav
authors.initials: V
authors.lastname: Terevnikov
authors.affiliation: Kellokoski Hospital, Kellokoski, Finland (Dr Terevnikov); Department of Psychiatry, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Helsinki, Finland (Drs Joffe and Stenberg).
authors.forename: Grigori
authors.initials: G
authors.lastname: Joffe
authors.affiliation: Kellokoski Hospital, Kellokoski, Finland (Dr Terevnikov); Department of Psychiatry, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Helsinki, Finland (Drs Joffe and Stenberg).
authors.forename: Jan-Henry
authors.initials: JH
authors.lastname: Stenberg
mesh_terms: D000928:Antidepressive Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D006801:Humans; D017063:Outcome Assessment, Health Care; D016032:Randomized Controlled Trials as Topic; D012559:Schizophrenia / Q000188:drug therapy*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D017367:Selective Serotonin Reuptake Inhibitors
keywords: add-on treatment; antidepressants; antipsychotics; schizophrenia