Clinical Pharmacology in Schizophrenia

Clinical Pharmacology in Schizophrenia

Pharmacologic data collected from living persons with schizo-phrenia has implicated two neurotransmitter systems in the pathophysiology of the illness. These include both the midbrain dopamine system and the cortical NMDA-sensitive glutamate system. For dopamine-mediated neurotransmission, compre-hensive evidence exists that blockade of dopamine-mediated in animals, for example, rodents. In general, such behavior differs from the activity pattern caused by exposing normal animals to a new environment in that it is more primitive neurotransmission in the central nervous system reduces the psychosis of schizophrenia (Davis, 1969; Seeman, 1995), thus suggesting the involvement of dopamine dynamics in psychosis pathways. Because other strategies to diminish dopaminergic transmission, e.g., partial dopamine agonist action (Tamminga 2002), and dopamine synthesis blockade (Walinder et al., 1976), are also antipsychotic, the hypothesis has broad pharmacologi-cal support. Indeed, a treatment based on the action of a low intrinsic-activity partial dopamine agonist is now on the mar-ket, namely aripiprazole. Moreover, the recent data that schizo-phrenia is associated with increased dopamine release (Laruelle et al., 1996) are consistent with the hypothesis that a hyperactive dopamine system may be a pivotal part of the pathophysiology in schizophrenia.

A putative role for glutamatergic transmission at the NMDA receptor in schizophrenia is based on more recent pharmacologic observations. The action of NMDA-sensitive glutamate antago-nists (specifically, the noncompetitive antagonist ketamine) in causing psychotomimetic symptoms in normal persons (Krystal et al., 1994; Lahti et al., 2001; Malhotra et al., 1996) and in wors-ening psychosis in schizophrenia (Lahti et al., 1995) implicates this system in mediating psychosis. These data suggest that re-duced glutamatergic transmission at the NMDA receptor in the brain could be associated with psychosis in schizophrenia, espe-cially given the supportive tissue histology (Harrison, 1999) and neurochemistry (Gao et al., 2000). Most studies suggest that it is in the limbic cortex, including the anterior cingulate, hippocam-pus and ventral striatum, where this change is most critical.