Memantine augmentation in clozapine-refractory schizophrenia: a randomized, double-blind, placebo-controlled crossover study

Abstract

BackgroundDysfunction of neuroplasticity due to N-methyl-d-aspartate (NMDA) receptor hypofunction may be a causal factor for memory and executive dysfunctioning in schizophrenia. Deregulation of NMDA transmission in the prefrontal cortex may also explain negative and positive symptoms. Clozapine augmentation with memantine targets altered NMDA receptor-mediated neurotransmission in schizophrenia and showed substantial beneficial effects on several symptom domains in a small proof-of-concept study. We evaluate effects of memantine add-on treatment to clozapine for memory and executive function, and negative and positive symptoms in schizophrenia.MethodClozapine-treated patients with refractory schizophrenia were randomly assigned to 12 weeks of double-blind adjunctive treatment with memantine (n = 26) or placebo (n = 26). Crossover occurred after a 2-week placebo wash-out period. Primary endpoints were change from baseline to 12 weeks treatment and 14 weeks to 26 weeks treatment on memory and executive function using the Cambridge Neuropsychological Test Automated Battery (CANTAB), Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression Severity Scale (CGI-S). Side effects were assessed using the Liverpool University Neuroleptic Side-Effect Rating Scale.ResultsWhen compared with placebo, memantine improved a composite memory score comprising verbal recognition memory and paired associates learning task scores on the CANTAB (effect size = 0.30) and PANSS negative subscale score (effect size = 0.29). Side effects were mild and transient.ConclusionsIn patients with clozapine-treated refractory schizophrenia, memantine addition significantly improved verbal and visual memory and negative symptoms without serious adverse effects. These results justify further investigations on long-term memantine augmentation to clozapine in treatment-resistant schizophrenia.

Efficacy of memantine in schizophrenic patients: A systematic review

“…In addition to the study conducted by Veerman et al mentioned in results [34], De Lucena et al reported, in a letter to editor, the efficacy of memantine as add-on therapy to clozapine with large effect sizes for overall symptoms, positive symptoms, negative symptoms, and global cognitive functioning in patients with partial remission of negative symptoms of schizophrenia [46]. In the same study it has been further hypothesized that BDNF may play a role in the effect of memantine in patients with schizophrenia, but inconsistent results have been found [46].…”

“…The positive effects of memantine augmentation to clozapine may be linked to their conjunct action on NMDA receptors. This combination modulates glutamatergic neurotransmission at multiple levels [45], with clozapine inducing both upregulation of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and NMDA receptors [34]. Schaefer et al 2007 described a memantine-mediated decrease of clozapineinduced weight gain using an on-off-on design with a significant increase of weight after discontinuation and again a substantial weight loss after reexposition with memantine [39].…”

“…Krivoy et al observed a 16% reduction in total PANSS and a 21% reduction in PANSS negative subscale [30]. In 2015, a 26-week randomized double-blind, placebo-controlled crossover study conducted on 52 patients showed that PANSS negative symptoms scores significantly improved in subjects treated with clozapine and memantine 10 mg/day compared to those treated with placebo [34]. A 12-week randomized controlled trial conducted on 60 subjects showed higher scores of QLS (quality of life scale) and GAF (global assessment of functioning) in patients treated with memantine compared to the control group [35].…”

“…Veerman et al found that composite memory score significantly improved during memantine add-on of clozapine therapy compared to placebo in resistant schizophrenic patients [34]. Krivoy et al also evaluated neurocognitive aspects of patients taking memantine but NCSE did not show any significant change before and after therapy, as well as scores for CDT (clock drawing test) [30].…”

“…Some patients complained of headache, insomnia, constipation, fatigue, dizziness, and auditory hallucinations [34,37]. Veerman et al found an increase on the Allergic Reactions subscale of the LUNSERS, including rash, sensitivity to sun, unusual skin marks, and itchy skin [34]. Considering metabolic effects of memantine, a case report …”