Schizophrenia: Attention Deficits and the NMDA Hypothesis

Abstract

Schizophrenic patients reveal positive symptoms, negative symptoms, and cognitive impairment. Among them, attention deficit is considered one of the schizophrenic endophenotypes. Serotonin-dopamine antagonists (SDAs) are beneficial for positive and negative symptoms as well as certain cognitive deficits. However, neither risperidone (a commonly used SDA) nor typical antipsychotics improve attention in schizophrenic patients. Hypofunction of the N-methyl-D-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. A recent study showed that sub-anesthetic doses of ketamine (an NMDA antagonist) could produce positive symptoms, negative symptoms, and attention deficits in healthy volunteers. Therefore, the relationship between NMDA hypofunction and impaired attention in schizophrenia deserves investigation. Pilot studies demonstrated adjunctive effects of NMDA-enhancing agents (e.g., D-serine and D-alanine, both endogenous amino acids) in certain schizophrenic patients who were concomitantly receiving other antipsychotics. Nonetheless, the attention (and other cognitive) effects and clinical responses of these agents (particularly as monotherapy) in the treatment of schizophrenia require further investigation. Furthermore, the mechanism of NMDA hypofunction in schizophrenia remains unclear. In the human brain, several proteins (including serine racemase, subunits of NMDA receptors, and others) could determine the NMDA's function; the impacts of their genetic variances on attention and other cognitive domains also warrant elucidation. (Tzu Chi Med J 2003; 15:141-148)