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.

Efficacy and Safety of Antidepressants Added to Antipsychotics for Schizophrenia: A Systematic Review and Meta-Analysis

“…To identify any further studies and additional data, we contacted pharmaceutical companies manufacturing antidepressants, sent e-mails to corresponding authors of all included studies for which data were missing, and searched the reference lists of included studies and of previous reviews (1,19,(22)(23)(24)(26)(27)(28)(29). We included randomized controlled trials involving 1) people with schizophrenia or schizophrenia (-like) psychosis (e.g., schizophreniform and schizoaffective disorders), irrespective of the diagnostic criteria used, 2) people treated with any add-on antidepressants marketed in at least one country, administered by any mode (oral tablets, oral liquid) and at any dose, and 3) people treated with any antipsychotics (any dose or mode of administration).…”

“…Should they be administered during the acute episode or exclusively in the postpsychotic phase? Recent narrative reviews did not answer these crucial questions and delivered unclear conclusions (1,19,20). Crucially, previous systematic reviews and meta-analyses addressed only specific subgroups of patients with schizophrenia or particular adjunctive medications (cognitive impairment [21], negative symptoms [22][23][24][25], postpsychotic depression [26], add-on noradrenergic and specific serotonergic antidepressants ajp in Advance ajp.psychiatryonline.org 1…”

Add-on Antidepressants in the Naturalistic Treatment of Schizophrenia Spectrum Disorder – When, Who, and How?

“…As already mentioned in the introduction, the value of antidepressant treatment is discussed controversially, and current results from clinical and controlled studies are inconsistent [5,11,50]. In their naturalistic study on concomitant medication in 53 tapers, improvements in 3, and worsening in 1, concluding that the efficacy of concomitant antidepressant treatment is limited [51]. Längle et al studied the effects of polypharmacy on outcome in 374 patients with schizophrenia and schizoaffective disorder in routine psychiatric treatment before discharge and after 6, 12, 18, and 24 months of follow-up and found 16 % of the patients receiving antipsychotics combined with antidepressants with less improvement in the non-monotherapy patients [52].…”

“…Längle et al studied the effects of polypharmacy on outcome in 374 patients with schizophrenia and schizoaffective disorder in routine psychiatric treatment before discharge and after 6, 12, 18, and 24 months of follow-up and found 16 % of the patients receiving antipsychotics combined with antidepressants with less improvement in the non-monotherapy patients [52]. Also, in a very recent review of 36 randomized controlled trials, the vast majority of publications reported no favorable effect of add-on antidepressants on the schizophrenia symptom domains [53].…”

Duloxetine Add-On to Risperidone for Treatment of Negative Symptoms in Patients with Stable Schizophrenia: Randomized Double-Blind Placebo-Controlled Study

“…Even though partially beneficial, antipsychotics do not have a satisfying effect on alleviation of the negative symptoms and no drug has received Food and Drug Administration (FDA) approval for treatment of these symptoms [5]. In this regard, the efficacy of antidepressant agents has also been studied in these patients with as yet inconclusive results [6]. Aside from pharmacotherapy, cognitive behavioral therapy is also recommended for the management of negative symptoms but is only moderately effective in these patients.…”