Augmentation With Antidepressants in Schizophrenia Treatment Appears Safe and Efficacious

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In terms of depressive and negative symptoms, in the present meta-analysis, researchers estimate that 1 in 9 patients with schizophrenia will improve with add-on antidepressants.
In terms of depressive and negative symptoms, in the present meta-analysis, researchers estimate that 1 in 9 patients with schizophrenia will improve with add-on antidepressants.

The prevalence of depressive symptoms in individuals diagnosed with schizophrenia is estimated at approximately 25%. The rate of antidepressant medication prescriptions for patients with schizophrenia has steadily risen over time. The key question is whether the benefits outweigh the health risks in this clinical population when antidepressants are used concomitantly with antipsychotic drugs.

The findings of a systematic review and meta-analysis, published in The American Journal of Psychiatry, indicate that the use of antidepressants in patients with schizophrenia who are concurrently being treated with antipsychotics appears safe (in terms of exacerbation of psychosis) and efficacious (in terms of quality of life, depressive, negative, positive, and overall symptoms).

The researchers identified 82 randomized controlled trials (RCTs), with a total of 3 608 individuals, which compared the efficacy of antidepressant use with controls (placebo or no-treatment) in patients with schizophrenia who are also being treated with antipsychotic drugs. More than 90% of studies that were included in this meta-analysis were double-blind, and all of the studies included were published between 1964 and 2014.

The studies that were included in the present meta-analysis analysis used a variety of add-on antidepressants [eg, monoamine oxidase inhibitors (MAOs), norepinephrine-dopamine reuptake inhibitors, norepinephrine reuptake inhibitors, serotonin antagonists and reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), tricyclic and tetracyclic antidepressants], as well as both first- and second-generation antipsychotics.

As but a single example, the mean dose in fluoxetine equivalents for add-on antidepressant medications was 31.2 mg/day (SD=14.5; range 5.9-86.1), and the mean dose in chlorpromazine equivalents for antipsychotic medications was 603.6 mg/day (SD=323.5; range 240-1 603).

In terms of efficacy [standardized mean difference (SMD)], findings indicate that, add-on antidepressants appear [significantly] more efficacious than controls (ie, placebo or no treatment) for depressive symptoms (-0.25, 95% CI, -0.38 to -0.12), negative symptoms (-0.30, 95% CI, -0.44 to -0.16), overall symptoms (-0.24, 95% CI, -0.39 to -0.09), positive symptoms (-0.17, 95% CI, -0.33 to -0.01), and quality of life (-0.32, 95% CI, -0.57 to -0.06).

For depressive symptoms, in terms of individual antidepressants, there were no subgroup differences [standardized mean difference (SMD)], but findings indicate that trazodone (-0.98, 95% CI, -1.51 to -0.44), duloxetine (-0.80, 95% CI, -1.45 to -0.16), and sertraline (-0.51, 95% CI, -0.91 to -0.12) appear most efficacious, compared with controls.

Also for depressive symptoms, in terms of drug classes, there were no subgroup differences [standardized mean difference (SMD)], but findings indicate that MAOs (-0.40, 95% CI, -0.78 to -0.01) appear most efficacious, compared with controls.

For negative symptoms, in terms of drug classes, subgroup differences [standardized mean difference (SMD)] were significant. Specifically, SSRIs (-0.25, 95% CI, -0.43 to -0.07) and tetracyclic antidepressants (-0.63, 95% CI, -1.03 to -0.24) appear most efficacious, compared with controls.

In terms of safety (risk ratio), findings indicate that, there were no significant differences between add-on antidepressants and controls (ie, placebo or no treatment) for exacerbation of psychosis (1.03, 95% CI, 0.60 to 1.75), or dropouts due to any reason; (0.98, 95% CI, 0.83 to 1.15), dropouts due to inefficacy; (0.73, 95% CI, 0.45 to 1.19), and dropouts due to side effects; (1.36, 95% CI, 0.88 to 2.10).

Taken together, available data indicate that, “add-on antidepressants are efficacious for negative and depressive symptoms in patients with schizophrenia, but the effect sizes were small;” however, “effect sizes were higher when only patients with pronounced depressive and predominant negative symptoms were included,” the authors noted.

“Given the high prevalence and heavy burden of schizophrenia in general and negative and depressive symptoms in particular, even if only 1 in 9 patients will improve, as suggested by our estimation, it could be regarded as clinically meaningful,” the authors concluded in their publication.

Reference

Helfer B, Samara MT, Huhn M, et al. Efficacy and safety of antidepressants added to antipsychotics for schizophrenia: a systematic review and meta-analysis. Am J Psychiatry. 2016. doi: 10.1176/appi.ajp.2016.15081035.

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