Neuropathic pain can be a predictor of severe emotional distress, up to full-blown depressive states. In these patients, it is important to move beyond the sole treatment of pain, to recognize depressive symptoms, and to ultimately improve the quality of life. We systematically searched for published and unpublished clinical trials assessing the efficacy and tolerability of antidepressants vs placebo on depression, anxiety and quality of life in patients with neuropathic pain, and pooled data in a meta-analysis. A total of 37 studies fulfilled eligibility criteria and 32 provided data for meta-analysis. Antidepressants were more effective than placebo in improving depressive symptoms (standardized mean difference -0.11; 95% confidence interval -0.20 to -0.02), although the magnitude of effect was small, with a number needed to treat of 24. No significant difference emerged between antidepressants and placebo in reducing anxiety. Quality of life seemed improved in patients on antidepressants, as did pain. Acceptability and tolerability were higher in patients on placebo. To the best of our knowledge, this is the first meta-analysis specifically focusing on the effect of antidepressants on psychiatric symptoms and quality of life in patients with neuropathic pain. Our findings suggest that despite their potential benefit in patients with neuropathic pain, antidepressants should be prescribed with particular care because they might be less tolerable in such a fragile population. However, our findings warrant further research to explore how a correct use of antidepressants can help patients to cope with the consequences of neuropathic pain on their psychosocial health and quality of life.