Mirtazapine has often been prescribed as add-on treatment for schizophrenia in patients with suboptimal response to conventional treatments. In this review, we evaluate the existing evidence for efficacy and effectiveness of add-on mirtazapine in schizophrenia and reappraise the practical and theoretical aspects of mirtazapine-antipsychotic combinations. In randomized controlled trials (RCTs), mirtazapine demonstrated favourable effects on negative and cognitive (although plausibly not depressive) symptoms, with no risk of psychotic exacerbation. Mirtazapine also may have a desirable effect on antipsychotic-induced sexual dysfunction, but seems not to alleviate extrapyramidal symptoms, at least if combined with second-generation antipsychotics. It is noteworthy that all published RCTs have been underpowered and relatively short in duration. In the only large pragmatic effectiveness study that provided analyses by add-on antidepressant, only mirtazapine was associated with both decreased rate of hospital admissions and number of in-patient days. Mirtazapine hardly affects the pharmacokinetics of antipsychotics. However, possible pharmacodynamic interactions (sedation and metabolic offence) should be borne in mind. The observed desired clinical effects of mirtazapine may be due to its specific receptor-blocking properties. Alternative theoretical explanations include its possible neuroprotective effect. Further well-designed RCTs and real-world effectiveness studies are needed to determine whether add-on mirtazapine should be recommended for difficult-to-treat schizophrenia.
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