Clinical studies have not yet determined a common mechanism of action for antidepressant drugs, which have primary sites of action on a variety of different neurotransmitter systems. However, a large body of evidence from animal studies demonstrates that sensitisation of D2-like dopamine receptors in the mesolimbic dopamine system may represent a 'final common pathway' in antidepressant action. The present study aimed to determine whether, consistent with data from animal studies, the clinical antidepressant action of selective serotonin reuptake inhibitors (SSRIs) is reversed by acute administration of a receptor antagonist selective for D2-like receptors in the mesolimbic dopamine system. The participants were patients diagnosed with major depressive disorder (n = 8) who had been treated successfully (Hamilton Depression Scale < 10) with selective serotonin uptake inhibitors (fluoxetine, citalopram or paroxetine); and age-matched, non-depressed, untreated volunteers (n = 10). They attended a psychiatric research ward on an out-patient basis, and received double-blind acute administration of either placebo, or a low dose of the selective dopamine D2/D3 receptor antagonist sulpiride (200 mg), in a counterbalanced order. Mood and psychomotor effects were assessed using visual analogue scales and the Fawcett-Clark Pleasure Capacity Scale. Sulpiride slightly improved subjective well-being in the control group, but in the antidepressant-treated patients, sulpiride caused a substantial reinstatement of depressed mood. These data are consistent with the hypothesis that sensitisation of D2-like receptors may be central to the clinical action of SSRIs.