Preclinical studies suggest that downregulation of &bgr;-adrenoceptors in the CNS in animals can be achieved with short term administration of high doses of antidepressants. Similarly, the function of the serotonergic system has been shown in preclinical studies to undergo rapid changes during antidepressant administration. However, the relevance of these observations to clinical antidepressant effects remains speculative.While manipulation of these 2 neurotransmitter systems has provided the rationale for several strategies for ‘rapid onset’ antidepressants, other neurotransmitter systems are undoubtedly involved in the mechanism of action. Dopaminergic, peptidergic and glucocorticoid receptors may provide a new focus for the rapid onset of antidepressant action.Nevertheless, some clinical studies with existing agents suggest that antidepressant responses in patients are evident within 1 week of the commencement of treatment. The limiting step in achieving such a rapid onset may be the drug doses required. Intolerance to the adverse effects precludes the use of the high doses needed. There is, therefore, a need to develop drugs with less troublesome adverse effects in order to test the hypothesis that high therapeutic doses of antidepressants may lead to a rapid clinical response.