Neurotransmitter interactions in psychotropic drug action: beyond dopamine and serotonin.

A frequent topic of discussion among research clinicians and other scientists engaged in basic psychiatric research is the extent of real advances in approaches to drug therapy in psychiatry. After the serendipitous discovery of some major avenues of drug treatment for psychiatric disorders in the 1950s, a wide range of prescription drugs became available for treating mood disorders and schizophrenia. Nevertheless, it is difficult to deny that the most significant advances have been in reducing the unwanted side effects of these therapeutic agents. The provocative argument that we have really seen relatively little advance in therapeutic mechanisms for drug treatment is often based on the striking observation that many of the primary neural targets for treating depression and schizophrenia remain unchanged. Soon after the introduction of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants, noradrenaline and serotonin emerged as the primary candidates for the biochemicals that may be imbalanced and underlie depression. The MAOIs and tricyclics act primarily to increase functional availability of brain serotonin and catecholamines (particularly noradrenaline, in this context). Looking across the years, our approach appears to have turned full circle. This is clear from a comparison of early tricyclics such as imipramine with drugs such as venlafaxine. Imipramine is a strong inhibitor of serotonin and noradrenaline uptake into the presynaptic terminal, and the major primary metabolite, desmethylimipramine (desipramine), is a very potent inhibitor of synaptic noradrenaline uptake, with less effect on serotonin. Venlafaxine blocks the synaptic uptake of both serotonin and noradrenaline and has a much “cleaner” spectrum of action in terms of improved side-effect profile compared with tricyclic antidepressants. Some elegant studies indicate that serotonin plays a significant role in the regulation of mood. For many drugs, antidepressant response appears to be related to increased serotonin neurotransmission. Although some antidepressants induce a primary increase in noradrenaline transmission, this effect may also lead to altered serotonin function. In the context of schizophrenia, since the extensive early drug design work of Paul Janssen and others, our principal focus for the neurochemicals to target in the treatment of psychosis has remained on dopamine and serotonin. Some of the main neuroleptics that are still widely used today, such as haloperidol and chlorpromazine, were introduced at a very early stage. Although the precise therapeutic mechanisms of antipsychotic drugs remain to be established, the newer drugs that are considered “atypical” because of a reduced side-effect profile appear to block receptors for both dopamine and serotonin. There was considerable interest in the atypical antipsychotic drug clozapine as a serotonin 5-HT2A/C receptor-blocking compound that appeared to have relatively little affinity for dopamine D2 receptors. More recent work, however, has clearly placed this effective antipsychotic drug back in the lineup of atypical antipsychotic drugs that block both the D2 and 5-HT2A/C