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Ketamine, escitalopram and amitripyline had a stronger antidepressant effect upon homozygous mice.Amitriptyline and desipramine potentiated glucose elevation in homozygous mice.Escitalopram and bupropion did not affect the glucose concentration of homozygous mice.Ketamine improved the impaired glucose metabolism of homozygous mice.There is significant comorbidity between mood disorders and diabetes. Wolfram syndrome—related to deficient WFS1 gene function—causes diabetes and mood disorders in humans. Mice lacking the Wfs1 gene display impaired emotional behaviour and glucose metabolism. Various antidepressant drugs are used for alleviating the symptoms of mood disorders. For this study the tail suspension test and locomotor activity test were used to compare the effects of different antidepressants upon homozygous Wfs1-deficient, heterozygous Wfs1-deficient and wild-type mice. Mouse glucose metabolism was concurrently studied using the glucose tolerance test.We showed that ketamine(10 mg/kg),NMDA antagonist, escitalopram(2.5–10 mg/kg), selective serotonin reuptake inhibitor(SSRI), and amitriptyline(10 mg/kg), noradrenaline and serotonin reuptake inhibitor, elicited a stronger antidepressant-like effect in homozygous Wfs1-deficient mice compared to wild-type mice. The effect of noradrenaline and serotonin reuptake inhibitor desipramine(10 and 20 mg/kg) did not differ between genotypes. The dopamine and noradrenaline reuptake inhibitor bupropion(5–20 mg/kg) had no significant antidepressant-like effect upon any genotype.Amitriptyline and desipramine potentiated a glucose elevation, escitalopram and bupropion did not affect glucose concentrations, and ketamine improved impaired glucose metabolism in homozygous Wfs1-deficient mice. Therefore, the results of this study suggest that SSRIs are the drugs of choice for the treatment of depressive symptoms in diabetic patients. The efficacy of ketamine for these patients remains to be established. Nonetheless, employing the mechanism of action of ketamine that affected glucose metabolism positively, could be an approach for development of improved antidepressants. Wfs1-deficient mice are likely the good animal model to develop new antidepressants more suitable for depressed patients with diabetes.