Long-term Treatment with a 5-Alpha-Reductase Inhibitor Alleviates Depression-like Behavior in Obese Male Rats.

Several studies have reported side effects of finasteride (FIN), such as anxiety/depression in young men. Obesity is also positively associated with anxiety/depression symptoms; however, the impacts of long-term FIN treatment and FIN withdrawal in young obese individuals are still elusive. The present study aimed to investigate the effect of long-term treatment and its withdrawal on anxiety/depression and brain pathologies in lean and obese adult male rats. Forty-eight male Wistar rats were equally divided into two groups and fed either a normal or high-fat diet. At age 13 weeks, rats in each dietary group were divided into three subgroups: 1) the control group receiving drinking water, 2) the long-term treatment group receiving FIN orally at 5 mg/kg/day for 6 weeks, and 3) the withdrawal group receiving FIN orally at 5 mg/kg/day for 2 weeks followed by a 4-week withdrawal period. Anxiety/depression-like behaviors, biochemical analysis, brain inflammation, oxidative stress, neuroactive steroids, brain metabolites, and microglial complexity were tested. The result showed that lean rats treated with long-term FIN and its withdrawal exhibited metabolic disturbances, depressive-like behavior, and both groups showed increased neurotoxic metabolites and reduced microglial complexity. Obesity itself led to metabolic disturbances and brain pathologies, including increased inflammation, oxidative stress, and quinolinic acid, as well as reduced microglial complexity, resulting in increased anxiety- and depression-like behaviors. Interestingly, the long-term FIN treatment group in obese rats showed attenuation of depressive-like behaviors, brain inflammation, and oxidative stress, along with increased brain antioxidants, suggesting the possible benefits of FIN in obese conditions.

The connection of 5-alpha reductase inhibitors to the development of depression.

Recent literature connects 5-alpha reductase inhibitors (5-ARIs) with neuropsychiatric adverse effects. Several clinical studies have indicated that former 5-ARIs users had a higher incidence of depressive symptoms and neuropsychiatric side effects than non-users. However, the underlying mechanisms involved in the depression in former 5-ARIs patients, a condition known as "post finasteride syndrome (PFS)", are not thoroughly understood. This review aims to summarize and discuss the association between 5-ARIs and depression as well as possible mechanisms. We used PubMed search terms including "depression", "depressive symptoms", "MDD", "anxiety", or "suicidal idea", and "5-alpha reductase inhibitors", "finasteride", "dutasteride", "5-ARIs". All relevant articles from in vivo and clinical studies from 2002 to 2021 were carefully reviewed. Any contradictory findings were included and debated. The potential mechanisms that link 5-ARIs and depression include alteration in neuroactive steroids, dopaminergic dysfunction, reduced hippocampal neurogenesis, increased neuroinflammation, alteration of the HPA axis, and epigenetic modifications. From this review, we hope to provide information for future studies based on animal experiments, and potential therapeutic strategies for depressive patients with PFS.