Rationale

We examined whether memantine add-on to antipsychotic treatment is beneficial in schizophrenia treatment.

Objective

This systematic review and meta-analysis aimed to achieve stronger evidence on the efficacy and safety of memantine add-on for treating schizophrenia.

Methods

We analyzed double-blind, randomized, placebo-controlled trials of memantine add-on treatment in schizophrenia patients receiving antipsychotics. The primary outcomes were amelioration of negative symptoms and all-cause discontinuation. Dichotomous outcomes are presented as risk ratios (RRs), and continuous outcomes are presented as mean differences (MDs) or standardized mean differences (SMDs).

Results

Eight studies (n = 448) were included. Although memantine add-on treatment was superior to placebo for ameliorating negative symptoms (SMD = −0.96, p = 0.006, I 2 = 88%; N = 7, n = 367) in the Positive and Negative Syndrome Scale general subscale (MD = −1.62, p = 0.002, I 2 = 0%; N = 4, n = 151) and Mini-Mental Status Examination score (MD = −3.07, p < 0.0001, I 2 = 21%; N = 3, n = 83), there were no statistically significant differences in the amelioration of overall (SMD = −0.75, p = 0.06, I 2 = 86%; N = 5, n = 271), positive (SMD = −0.46, p = 0.07, I 2 = 80%; N = 7, n = 367), and depressive symptoms (SMD = −0.127, p = 0.326, I 2 = 0%; N = 4, n = 201); all-cause discontinuation (RR = 1.34, p = 0.31, I 2 = 0%; N = 8, n = 448); and individual adverse events (fatigue, dizziness, headache, nausea, constipation) between the groups. For negative symptoms, the significant heterogeneity disappeared when risperidone studies alone were considered (I 2 = 0%). However, memantine add-on treatment remained superior to placebo (SMD = −1.29, p = 0.00001). Meta-regression analysis showed that patient age was associated with memantine-associated amelioration of negative symptoms (slope = 0.171, p = 0.0206).

Conclusions

Memantine add-on treatment may be beneficial for treating psychopathological symptoms (especially negative symptoms) in schizophrenia patients. The negative-symptom effect size may be associated with younger adult schizophrenia patients.