Can Memantine Clear the Remaining Fog of Schizophrenia? 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 receptor (NMDAR) dysfunction. Memantine, which is approved for Alzheimer's disease, acts as a nonselective NMDAR antagonist. There have been some mixed results in some preliminary studies about adding memantine to antipsychotics in patients with schizophrenia in terms of improvement in symptoms. Objective: To add memantine to clozapine to investigate whether it would be effective, primarily for the negative symptoms of schizophrenia. Design: Double-blind, placebo-controlled, randomized trial. Participants/Methods: The sample consisted of 21 adult outpatients in Brazil with a history of treatmentrefractory schizophrenia being treated with clozapine for the past 10 years, with partial remission of negative symptoms. The subjects were randomized to a 12-week trial of memantine or placebo in addition to clozapine treatment as usual. Memantine was dosed twice daily with the following titration schedule: week 1, 5 mg/d; week 2, 10 mg/d; week 3, 15 mg/d; and weeks 4 to 12, 20 mg/d. Primary outcome measures were the positive and negative symptoms of schizophrenia as measured by the 18-item version of the Brief Psychiatric Rating Sale (BPRS). Secondary outcomes included the Clinical Global Impressions (CGI) scale, and the Mini-Mental State Examination (MMSE). The assessments were conducted at baseline and at weeks 4, 8 and 12. Results: The memantine-treated group reported significant decreases in BPRS total scores, the positive symptoms subscale score, and the negative symptom subscale score compared to the placebo group. The memantine group also reported significantly greater improvement in overall functioning on the CGI. At week 12, patients who received memantine (compared with those who received placebo) showed a significantly greater improvement in their cognitive symptoms scored by the MMSE. Conclusions: Memantine appears to improve positive and negative symptoms, overall level of functioning, and possibly even cognition in clozapine-treated patients with schizophrenia. Reviewer's Comments: Memantine is a fast off-rate (low affinity) type of uncompetitive NMDAR antagonist that blocks only pathological receptor activity and could, theoretically, restore abnormal neurons to a homeostatic state. Clozapine, remarkably, increases the expression of NMDARs. Clozapine also appears to stabilize dopaminergic neurons, dampening both hyperactivity and hypoactivity via an agonist and antagonistic action, respectively, at the NMDA/glycine site. Therefore, it may be that clozapine and memantine, through their NMDA and dopamine modulating properties, may be a match made in psychopharmacological heaven for optimal treatment of refractory schizophrenia. (Reviewer-John G. Koutras, MD).