Abstract
Treatments for negative symptoms and cognitive dysfunction in schizophrenia remain issues that psychiatrists around the world are trying to solve. Their mechanisms may be associated with N-methyl-D-aspartate receptors (NMDARs). The NMDAR hypofunction hypothesis for schizophrenia was brought to the fore mainly based on the clinical effects of NMDAR antagonists and anti-NMDAR encephalitis pathology. Drugs targeted at augmenting NMDAR function in the brain seem to be promising in improving negative symptoms and cognitive dysfunction in patients with schizophrenia. In this review, we list NMDAR-targeted drugs and report on related clinical studies. We then summarize their effects on negative symptoms and cognitive dysfunction and analyze the unsatisfactory outcomes of these clinical studies according to the improved glutamate hypothesis that has been revealed in animal models. We aimed to provide perspectives for scientists who sought therapeutic strategies for negative symptoms and cognitive dysfunction in schizophrenia based on the NMDAR hypofunction hypothesis.
Highlights
Schizophrenia is a psychiatric disorder afflicting approximately 1% of the population worldwide (Perala et al, 2007)
The general effects of N-methyl-D-aspartate receptors (NMDARs)-targeted drugs were small to moderate in negative symptoms, and small or nonsignificant in cognitive dysfunction in schizophrenia
Can we conclude that the starting point in schizophrenia pathology is neither dopamine disorder nor NMDAR hypofunction? Not yet
Summary
Schizophrenia is a psychiatric disorder afflicting approximately 1% of the population worldwide (Perala et al, 2007). It has multiple overlapping symptom clusters including positive symptoms (i.e., delusions, hallucinations), negative symptoms (i.e., social withdrawal, anhedonia), and cognitive impairments (i.e., deficits in attention, working memory, and executive function) (van Os and Kapur, 2009). Negative symptoms and cognitive dysfunction have recently attracted psychiatrists’ attention. The majority of positive symptoms have been relieved by mainstream antipsychotics (the first and second generation of antipsychotics), while most negative symptoms and cognitive dysfunction remain unaffected and may even worsen with the development of schizophrenia (Lieberman et al, 2005; Lieberman, 2007; Leucht et al, 2009). MECHANISMS OF NEGATIVE SYMPTOMS AND COGNITIVE DYSFUNCTION IN SCHIZOPHRENIA. There are five negative symptom domains: (1) blunted affect (diminished emotional expression); (2) alogia (diminished quantity of words spoken and spontaneous elaboration); (3) asociality
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