CLINICAL HANDBOOK OF SCHIZOPHRENIA

3. Biological Theories 29unchanged receptor levels, depending on the radiotracer used. It has been proposed thatincreases may actually reflect compensation for low prefrontal dopamine levels; thiswould make the significance of either an increase or decrease unclear.It is possible that the ongoing controversies over the role of dopamine in positive andnegative symptoms results in part from the crudeness of available measuring techniques.Dopamine is thought to help define and “sharpen” cortical representations of sensationand action, enhancing salient patterns and dampening nonsalient ones. Attempting to explainbrain dysfunction in terms of simple increases or decreases in dopamine may thereforebe as futile as trying to measure the accuracy of a drawing by how much ink it contains.Subtle dysregulation of dopamine, whether in prefrontal cortex or striatum, couldcause major deficits in information processing without overall excess or lack of dopamine.The Glutamate HypothesisThe glutamate hypothesis proposes that dysfunction of the N-methyl-D-aspartate (NMDA)glutamate receptor is the primary deficit underlying all the positive, negative, and cognitivesymptoms of schizophrenia. Glutamate is the major excitatory neurotransmitter inthe CNS. The NMDA receptor plays key roles in attention, perception, and cognition.Importantly, this receptor also plays critical roles in developmental processes such asaxonal guidance, synaptic pruning, and plasticity, both in utero and during adolescence.For these reasons, the NMDA receptor is an attractive target for schizophrenia research.As with the dopamine hypothesis, the glutamate hypothesis originates in early findingsof low glutamate levels in the CSF of patients with schizophrenia, and in the observationthat the effects of NMDA antagonist drugs (ketamine, phencyclidine [PCP]) mimicsome of the positive, negative, and cognitive features of schizophrenia. Postmortem studiesshow changes in the expression of NMDA receptors and their related proteins inschizophrenia. Many genes conferring schizophrenia risk appear to interact with theNMDA receptor in some way (such as GRM3, described earlier). Recent PET imagingalso suggests reduced hippocampal NMDA receptor binding in schizophrenia.Glutamate models may be able to accommodate existing dopamine-centered hypotheseson schizophrenia. In one model, reduced prefrontal glutamate neurotransmissionleads to reduced prefrontal activity. This results in decreased mesocortical activity, causingnegative and cognitive symptoms. It also results in a loss of regulation in themesolimbic projections. This pathway becomes hyperresponsive to stress or pharmacologicalchallenge, leading to acute episodes of psychosis. Of note here, cannabis reducescorticostriatal glutamate release, while D 2 receptor blockade increases glutamate release.Dopamine–glutamate models may be able to explain how cannabis and dopamineagonists provoke psychosis, and how D 2 antagonists improve positive symptoms.Glutamate-centered theories offer a potential means of unifying genetic, developmental,neuropathological, and neurochemical understanding of schizophrenia. Lines ofsupporting evidence for NMDA-related dysfunction in schizophrenia are beginning toemerge. Research over the next few years should determine whether this trend continues,and whether the glutamate hypothesis can inspire new approaches to treatment.MECHANISM OF ACTION OF ANTIPSYCHOTIC DRUGSHistory of Antipsychotic DrugsThe first antipsychotic drugs were discovered serendipitously. In 1950, the French chemistCharpentier synthesized chlorpromazine as an intended surgical sedative. The surgeonLaborit noted that it induced a profound state of “indifference” to surroundings. He per-