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More Serotonin: Not as Simple as It Seems

Serotonin is a current obsession of psychopharmacologists, and not without reason. The atypical antipsychotic drugs clozapine and risperidone potently antagonize serotonin receptors as well as dopamine D, family receptors. (Clozapine differs from risperidone in its relative selectivity for the D,/DZc receptor compared with the D.JD,* receptor.) There is increasing evidence to suggest that serotonin subsystems in the brain may be involved in aggression. Further, it has long been known that the major shared property of LSD-like hallucinogens (once again increasing in rates of abuse) is serotonin receptor agonism. However, the serotonin system has achieved greatest prominence in the field of psychopharmacology because of the success of selective serotoninreuptake inhibitors (SSRIs): in aggregate, these agents have become the most widely prescribed antidepressants in the United States. SSRIs also appear to be therapeutically effective in a remarkably broad range of conditions including panic disorder, obsessive-compulsive disorder, and bulimia. As the name SSRI implies, the initial biological action of these agents upon entering the nervous system is to inhibit the serotonin-reuptake transporter and thus to prolong the life of serotonin in synapses. At therapeutic concentrations these drugs have no significant direct agonist or antagonist effects on any known serotonin receptors. In fact, the actual therapeutic mechanism of action of the SSRIs (and other antidepressants) remains mysterious, with the long lag between initiation of drug therapy and therapeutic efficacy still unexplained. However, the therapeutic effect is almost certainly initiated by reuptake blockade, resulting in increased stimulation of serotonin receptors. What is not always realized is that the neurobiological