Improvement of Negative and Positive Symptoms in Treatment-Refractory Schizophrenia: A Double-Blind, Randomized, Placebo-Controlled Trial With Memantine as Add-On Therapy to Clozapine

Background: Glutamate deregulation may be involved in the neuropathology of schizophrenia, mainly through N-methyl-d-aspartate (NMDA) receptor dysfunction. Memantine, a drug approved by the FDA for the treatment of moderate to severe Alzheimer’s disease, acts as a weak nonselective NMDA receptor antagonist. The aim of this study was to examine the efficacy of memantine as an adjunctive treatment to clozapine in patients with refractory schizophrenia.

Method: In this double-blind, placebo-controlled study, outpatients with refractory schizophrenia according to DSM-IV clinical criteria were randomly assigned, from March 2005 to February 2008, to receive either 20 mg/d memantine (n=10) or placebo (n=11), in addition to clozapine, for 12 weeks. The primary outcome measure was the total score on the 18-item Brief Psychiatry Rating Scale (BPRS) and BPRS subscales of positive and negative symptoms. Secondary outcomes were global severity of disease as measured by the Clinical Global Impressions scale (CGI), cognition as assessed by the Mini-Mental State Examination (MMSE), and extrapyramidal symptoms as assessed by the Simpson-Angus Scale (SAS).

Results: Twenty-one participants completed the study and were used in the analysis. Significant improvement (P<.01) on the total BPRS score, its subscales of positive (effect size [ES]=−1.38) and negative (ES=–3.33) symptoms, the CGI score (ES=1.56), and the MMSE score was observed with memantine as compared with placebo. No significant changes in extrapyramidal symptoms were observed.

Conclusions: Memantine add-on to clozapine therapy was associated with improvement in negative and positive symptoms in refractory schizophrenia patients.

Trial Registration: Identifier: NCT00757978

Submitted: December 9, 2008; accepted February 23, 2009.

Corresponding author: Clarissa S. Gama, MD, PhD, Hospital de Clínicas de Porto Alegre, Laboratório de Psiquiatria Molecular, Rua Ramiro Barcelos 2350, Porto Alegre, RS, Brazil, 90035 003 (

J Clin Psychiatry 2009;70(10):1416-1423