Add-on mirtazapine enhances antipsychotic effect of first generation antipsychotics in schizophrenia: a double-blind, randomized, placebo-controlled trial

Mirtazapine, an antidepressant with a broad spectrum of receptor affinity may, if combined with first generation antipsyhotics (FGAs), improve clinical profile of the FGAs. However, potentiation of the antipsychotic effect by mirtazapine has not been reported thus far. We explored the efficacy of adjunctive mirtazapine on symptoms of schizophrenia in patients having an insufficient response to different FGAs.

Schizophrenia-diagnosed patients with a prolonged disease and a history of a poor response to numerous antipsychotics, who were at least moderately ill despite their FGAs treatment, received add-on mirtazapine (n=20) or placebo (n=19) in a 6-week double-blind randomized controlled trial (RCT). The analysis was made on a Modified Intent-to-Treat (MITT) basis with Last Observations Carried Forward (LOCF).

Mirtazapine outranged placebo on almost all measures. The clear-cut clinical relevance of this finding was demonstrated by a large effect size of 1.00 (95% CI 0.23-1.67, p=0.003) on the total Positive and Negative Syndrome Scale (PANSS) scores (the primary outcome). The PANSS positive subscale scores decreased by 17.2% with mirtazapine vs. 1.6% with placebo (p<0.001), and the PANSS negative subscale scores by 12% and 3% (p<0.001), correspondingly.

This is the first RCT reporting a robust additive antipsychotic effect of an adjunctive antidepressant. Mirtazapine-FGAs combination appears to be a safe, well-tolerated and efficacious treatment option in this challenging population. These findings are important due to the current re-emerging attention to FGAs. The focus of further studies should be expanded to include combinations with or switching to novel antipsychotics, different subpopulations of patients with schizophrenia, finding of optimal doses, and comparison with clozapine.