Receptor Mechanisms in the Treatment of Schizophrenia

There remain many limitations to the treatment of schizophrenia. In addition to the poor response of negative and cognitive symptoms to antipsychotics, and the substantial proportion of poor- or non-responders, there are a variety of unpleasant and restricting side-effects of these drugs. The introduction of several 'atypical' drugs, with diminished propensity to cause extrapyramidal motor effects (EPS), has greatly improved the tolerability of antipsychotic treatments. The pharmacology of atypical antipsychotics is varied and, although dopamine D2 receptor antagonism is common to all antipsychotics, the mechanisms of a typicality are complex and not fully understood. Thus, antagonism at 5-HT2 and/or other receptors, weak dopamine receptor affinity and, most recently, partial agonism at dopamine D2 receptors, have been variously implicated. However, because EPS have diminished with improvements in drug treatment, drug-induced weight gain has emerged as a major concern, and the pharmacological basis of this problem, involving effects at 5-HT2c and perhaps other receptors, is yielding to investigation. Some drugs, notably the D2 partial agonists, can provide antipsychotic effects without the emergence of several of the seproblematic side-effects, which bodes well for future treatment.