Serotonin-dopamine antagonists and treatment of negative symptoms

This review aims to examine the basis of the hypothesis that simultaneously modifying serotonergic and dopaminergic neurotransmission is effective in schizophrenia and to assess critically clinical efficacy data with respect to negative symptoms. A variety of serotonin and dopamine agonists can induce psychosis, so it is to be expected that certain serotonin and dopamine antagonists could have antipsychotic effects. It is known that serotonergic afferent neurons synapsing with dopaminergic neurons exert an inhibitory effect. Because hypodopaminergic pathophysiology has been postulated as being responsible for negative symptoms, serotonin antagonists may be therapeutic. A number of clinical trials provide data on the effect of adding serotonergic drugs to conventional neuroleptics in the treatment of schizophrenia, and there are now studies with drugs that combine serotonin and dopamine antagonism in the same molecule. There may be a modest enhancement of the antipsychotic effect of antagonism at postsynaptic dopamine D2 receptors. The effects of serotonin antagonism on negative symptoms are, however, more encouraging, although the issue is complicated because methodologic difficulties confound the interpretation of the results of these studies. The weight of the evidence suggests that negative symptoms improve when the treatment of schizophrenia includes drugs that diminish serotonergic activity. However, this may be because of indirect effects, such as an enhanced antipsychotic action, diminished extrapyramidal side effects, increased activation, or decreased depression--all features associated with secondary negative symptoms. The challenge is to address primary negative symptoms, and this has been attempted in a small number of patients; the results are not very encouraging.(ABSTRACT TRUNCATED AT 250 WORDS)