OBJECTIVE: The therapeutic success of clozapine and risperidone has
focused attention on the interaction between serotonin and dopamine systems
as an avenue for superior therapeutics in schizophrenia. The authors review
the neurobiological basis for this interaction and its clinical relevance.
METHOD: The authors synthesized information from more than 100 published
articles obtained through electronic and bibliography-directed searches.
FINDINGS: The serotonin system inhibits dopaminergic function at the level
of the origin of the dopamine system in the midbrain as well as at the
terminal dopaminergic fields in the forebrain. Serotonergic antagonists
release the dopamine system from this inhibition. This disinhibition of the
dopamine system in the striatum may alleviate neuroleptic-induced
extrapyramidal symptoms, and a similar disinhibition in the prefrontal
cortex may ameliorate negative symptoms. However, the benefits of combined
serotonergic- dopaminergic blockade may be observed in only a narrow dose
range and may be lost with doses that produce suprathreshold dopaminergic
blockade. CONCLUSIONS: Serotonergic modulation of dopaminergic function
provides a viable mechanism for enhancing therapeutics in schizophrenia,
but much remains unclear. Future research will have to establish the
existence of this interaction in humans in vivo, specify the conditions
under which it leads to optimal therapeutic benefits, and explore the
possibility of using specific serotonergic treatments as flexible adjuncts
to typical neuroleptics, rather than the present trend toward using single
drugs with combined actions.