Adjunctive memantine in clozapine-treated refractory schizophrenia: an open-label 1-year extension study

Psychol Med. 2017 Jan;47(2):363-375. doi: 10.1017/S0033291716002476. Epub 2016 Oct 25.

Abstract

Background: In a recent placebo-controlled, double-blind crossover trial (n = 52), significant beneficial effects on memory (d = 0.30) and negative symptoms (d = 0.29) were found after 12 weeks of memantine augmentation in patients with clozapine-refractory schizophrenia. In this open-label 1-year extension study we report the long-term effects and tolerability of memantine add-on therapy to clozapine.

Method: Completers of the first trial who experienced beneficial effects during 12 weeks of memantine treatment received memantine for 1 year. Primary endpoints were memory and executive function using the Cambridge Neuropsychological Test Automated Battery, the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression Severity Scale (CGI-S).

Results: Of 31 randomized controlled trial completers who experienced beneficial effects from memantine, 24 received memantine for 1 year. The small improvement in memory found in the memantine condition in the placebo-controlled trial remained stable in the extension study. Executive function did not improve. After 26 weeks of memantine add-on therapy to clozapine, PANSS negative symptoms (r = 0.53), PANSS positive symptoms (r = 0.50) and PANSS total symptoms (r = 0.54) significantly improved. Even further significant improvement in all these measures was observed between 26 weeks and 52 weeks of memantine, with effect sizes varying from 0.39 to 0.51. CGI-S showed a non-significant moderate improvement at 26 weeks (r = 0.36) and 52 weeks (r = 0.34). Memantine was well tolerated without serious adverse effects.

Conclusions: In the 1-year extension phase the favourable effect of adjunctive memantine on memory was sustained and we observed further improvement of negative, positive and overall symptoms in patients with clozapine-treated refractory schizophrenia.

Keywords: Clozapine; cognitive functioning; glutamate antagonists; memantine; therapy-resistant schizophrenia.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antipsychotic Agents / pharmacology*
  • Clozapine / pharmacology*
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / etiology
  • Drug Resistance
  • Drug Synergism
  • Drug Therapy, Combination
  • Excitatory Amino Acid Antagonists / administration & dosage
  • Excitatory Amino Acid Antagonists / adverse effects
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Executive Function* / drug effects
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Memantine / administration & dosage
  • Memantine / adverse effects
  • Memantine / pharmacology*
  • Memory Disorders / drug therapy*
  • Memory Disorders / etiology
  • Middle Aged
  • Schizophrenia / complications
  • Schizophrenia / drug therapy*

Substances

  • Antipsychotic Agents
  • Excitatory Amino Acid Antagonists
  • Clozapine
  • Memantine