We examined whether noradrenergic and specific serotonergic antidepressants (NaSSAs: mirtazapine and mianserin), as augmentation therapy, have therapeutic potential for schizophrenia treatment. A systematic review was conducted of PubMed, Cochrane Library and PsycINFO in December 2012 and meta-analyses of double-blind, randomized placebo-controlled trials were performed. Standardized mean difference (SMD), risk ratio (RR), number-needed-to-treat (NNT), number-needed-to-harm (NNH) and 95% confidence intervals (CI) were calculated. Results were across 12 studies and 362 patients were included (mirtazapine: seven trials and 221 patients; mianserin: five trials and 141 patients). NaSSA augmentation therapy was superior to placebo in overall symptoms (S.M.D. = -0.75, CI -1.24 to -0.26, p = 0.003, N = 11, n = 301), negative symptoms (S.M.D. = -0.88, CI -1.41 to -0.34, p = 0.001, N = 9, n = 240) and response rate (RR = 0.71, CI 0.57-0.88, p = 0.002, NNT = 4, p<0.00001, N = 6, n = 163). There was no significant difference in positive symptoms, depressive symptoms or discontinuation rate between NaSSAs and placebo treatments. In addition, no patients who received NaSSAs developed worsening psychosis during the study. For individual NaSSAs, mirtazapine was superior to placebo in overall symptoms (S.M.D. = 0.98, CI = -1.74 to -0.22, p = 0.01, N = 7, n = 194), negative symptoms (S.M.D. = -1.25, CI -1.88 to -0.62, p = 0.0001, N = 6, n = 172) and response rate (RR = 0.70, p = 0.04, NNT = 4, p = 0.0004, N = 4, n = 119). Moreover, NaSSAs were associated with reduced akathisia score (p < 0.00001) and extrapyramidal symptom scales (p = 0.01). However, NaSSAs caused drowsiness/sedation/somnolence compared with placebo (RR = 3.52, p = 0.002, NNT = 6, p = 0.01, N = 8, n = 209). Our results indicate that NaSSA (especially mirtazapine) augmentation therapy improved overall and negative symptoms in patients with schizophrenia. Because the included studies were small, the results should be treated with caution.