Efficacy and safety of noradrenalin reuptake inhibitor augmentation therapy for schizophrenia: A meta-analysis of double-blind randomized placebo-controlled trials

Background: We performed an updated meta-analysis of noradrenalin reuptake inhibitor (NRI) augmentation therapy in patients with schizophrenia treated with antipsychotics based on a previous meta-analysis (Singh etal.). Methods: PubMed, Cochrane Library databases, and PsycINFO citations were searched from their inception to June 10, 2013 without language restrictions. We conducted a systematic review and meta-analysis of individual patient data from randomized controlled trials comparing NRI augmentation therapy with placebo. The outcome measure for efficacy was the psychopathology of schizophrenia and the measures for safety were discontinuation rate and several side effects. We used standardized mean differences (SMD) to estimate treatment effects for continuous variables, and risk ratios (RR) for dichotomous variables, with their 95% confidence intervals (CIs). A random-effects model was used. Results: Nine studies (4 atomoxetine studies, 3 reboxetine studies, 1 reboxetine-betahistine combination study and 1 mazindol study, total n= 298) were identified. No statistically significant effects of NRI augmentation therapy on overall (p= 0.90), positive (p= 0.81), and negative (p= 0.89) symptoms were found. NRI augmentation therapy was marginally superior to placebo for efficacy of depressive symptoms (SMD = -1.08, p= 0.05). Dropout due to all-cause (p= 0.70), inefficacy (p= 0.64), or adverse events (p= 0.18) was similar in both groups. NRI augmentation therapy showed a significantly lower increase or larger reduction in body weight than placebo (SMD = -0.47, p= 0.03). Reboxetine augmentation was associated with less weight gain that placebo in antipsychotic treated schizophrenia patients (SMD = -0.78, p= 0.0001). Conclusion: NRIs may exert an effect on depressive symptoms, and seem to be well-tolerated treatments.