Review and meta-analysis of add-on tranylcypromine with antipsychotic drugs for the treatment of schizophrenia with predominant negative symptoms: a restoration of evidence

Background Treatment using add-on antidepressants with antipsychotic drugs in negative symptoms of schizophrenia has been reviewed recently in comprehensive meta-analyses. Tranylcypromine (TCP), an irreversible monoamine oxidase (MAO)-A/B inhibitor applied in treatment resistant depression, was not included because of strict requirements for quality of study design. To get a clear picture of available evidence for this resource in the treatment of schizophrenia, we conducted a review and meta-analysis of add-on TCP in the treatment of predominant negative symptoms of schizophrenia (negative schizophrenia). Methods Seven controlled studies of add-on TCP in schizophrenia with predominant negative symptoms were found in a search of multiple databases. A subset of four studies of the prospective and parallel comparison of add-on TCP with antipsychotic drugs vs. antipsychotic drug monotherapy and meeting minimum quality criteria formed the primary meta-analysis. The effect size was calculated as the natural logarithm of the odds ratio (logOR) of responders and non-responders. Results In the primary meta-analysis, a pooled logOR = 1.092 with 95%CI 0.410-1.774 (I-2 = 43.4%, moderate heterogeneity) was calculated according to a fixed-effect model. Heterogeneity was reduced for three double-blind studies of add-on TCP with trifluoperazine (TFP) vs. TFP-monotherapy and resulted a pooled logOR = 0.916 with 95%CI 0.216-1.616 (I-2 negative, no heterogeneity). A significant logOR = 1.558 with 95%CI 0.340-2.776 was found for TCP/TFP compared to placebo in one study. In a meta-analysis of extrapyramidal adverse effects, studies were very heterogeneous and revealed no significant differences between treatments. The risk of exacerbation of positive symptoms with add-on TCP was found to be very low for a duration of treatment of 12-16 weeks. No cases of hypertensive crisis were reported. The main methodical limitations were insufficient description of randomization or matching of patients without randomization. The main clinical limitation is a gap of data for add-on TCP with second-generation antipsychotics. Conclusion New studies are needed for add-on TCP with antipsychotic drugs in schizophrenia with predominant negative symptoms. Trials of this treatment may be possible in rare and selected cases. The therapeutic effect of add-on TCP may be explained by a strong dopaminergic activity.