Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update

C Chaves,A.W Zuardi,S.M Dursun,C Trzesniak,J.E Hallak,J.A.S Crippa,C.R Marque,J.P Machado De Sousa

doi:10.1590/s0100-879x2009001100002

Abstract

Growing consistent evidence indicates that hypofunction of N-methyl-D-aspartate (NMDA) transmission plays a pivotal role in the neuropathophysiology of schizophrenia. Hence, drugs which modulate NMDA neurotransmission are promising approaches to the treatment of schizophrenia. The aim of this article is to review clinical trials with novel compounds acting on the NMDA receptor (NMDA-R). This review also includes a discussion and translation of neuroscience into schizophrenia therapeutics. Although the precise mechanism of action of minocycline in the brain remains unclear, there is evidence that it blocks the neurotoxicity of NMDA antagonists and may exert a differential effect on NMDA signaling pathways. We, therefore, hypothesize that the effects of minocycline on the brain may be partially modulated by the NMDA-R or related mechanisms. Thus, we have included a review of minocycline neuroscience. The search was performed in the PubMed, Web of Science, SciELO, and Lilacs databases. The results of glycine and D-cycloserine trials were conflicting regarding effectiveness on the negative and cognitive symptoms of schizophrenia. D-serine and D-alanine showed a potential effect on negative symptoms and on cognitive deficits. Sarcosine data indicated a considerable improvement as adjunctive therapy. Finally, minocycline add-on treatment appears to be effective on a broad range of psychopathology in patients with schizophrenia. The differential modulation of NMDA-R neurosystems, in particular synaptic versus extrasynaptic NMDA-R activation and specific subtypes of NMDA-R, may be the key mediators of neurogenesis and neuroprotection. Thus, psychotropics modulating NMDA-R neurotransmission may represent future monotherapy or add-on treatment strategies in the treatment of schizophrenia.

Highlights

Schizophrenia is a disabling illness that affects approximately 1% of the world population (1) and is characterized by positive, negative and cognitive symptoms
The most used inclusion criteria were schizophrenia diagnosis according to the Diagnostic and Statistical Manual (DSM), primary deficit syndrome, minimum score of 30 on the Scale for the Assessment of Negative Symptoms (SANS), and use of a stable antipsychotic dose for more than three months
A combination of various scales was used for the evaluation of clinical efficacy: Positive and Negative Symptoms Scale (PANSS), Brief Psychiatric Research Scale (BPRS), SANS, Global Assessment Scale (GAS), and Clinical Global Impression (CGI)

Summary

Introduction

Schizophrenia is a disabling illness that affects approximately 1% of the world population (1) and is characterized by positive, negative and cognitive symptoms. This psychiatric disorder encompasses symptoms such as delusions, hallucinations, disorganized thinking, apathy, and deterioration of social role functioning (1). Patients with schizophrenia experience severe suffering and close to 10% of them commit suicide (1). Conventional dopamine receptor-blocking antipsychotics are effective for positive symptoms, but they have limited effects on negative and cognitive symptoms (2). These symptoms possibly involve other neurotransmitter systems besides dopamine

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