Several lines of evidence have indicated that the prevalence of psychiatric disorders in diabetic subjects is higher than that in the general population, however, little information is available on the effects of antidepressants in diabetes. In the present review, we summarized the effect of diabetes on the central serotonergic systems and the efficacy of serotonergic antidepressants. Streptozotocin-induced diabetic mice showed prolonged duration of immobility compared to non-diabetic mice in the tail suspension test. This behavioral change was unrelated to the transient increases in blood glucose concentrations or decreased body weights by diabetes. Fluoxetine, a selective serotonin (5-HT) reuptake inhibitor, reduced the duration of immobility in both non-diabetic and diabetic mice. However, a selective 5-HT1A receptor antagonist WAY-100635 reversed the antidepressant-like effect of fluoxetine only in non-diabetic mice. In addition, a 5-HT1A receptor agonist 8-OH-DPAT reduced the duration of immobility in non-diabetic mice, but not in diabetic mice. These results suggest a possibility that the antidepressant-like effect mediated by the activation of 5-HT1A receptors may be attenuated by diabetes.