Insulin Resistance and Antidepressant Effectiveness: Insight from Clinical and Pre-Clinical Studies

Depression affects over 300 million people. However, 30% of affected patients show resistance to commonly used antidepressants. Therefore, there exists a pressing need for new antidepressant treatments. An association between insulin resistance (IR) and depression has been reported, with IR inducing an increase in depression symptoms’ severity. The aim of the thesis was to investigate the potential role of IR in mediating antidepressant treatment resistance by evaluating available clinical evidence and conducting in vivo pre-clinical studies. A systematic review and meta-analysis on the effect of insulin sensitivity-enhancing lifestyle and dietary (non-pharmacological) adjuncts on antidepressant treatment response was completed. The insulin sensitizing adjuncts assessed were exercise, supplementation with any of zinc, vitamin D, probiotics, magnesium and omega-3-polyunsaturated fatty acids. Randomised controlled trials which assessed the effect, on antidepressant treatment response, of adjunctive therapy were included. The results showed an overall improvement in antidepressant treatment response with adjunctive use of these interventions, suggesting improvements in glucose handling may enhance antidepressant response. Pre-clinical studies were conducted in the Wistar Kyoto rat (WKY), an animal model of resistant depression. Oral glucose tolerance test and insulin tolerance test were used to evaluate glucose handling. Results showed that the WKY has impaired glucose handling which was not affected by chronic fluoxetine treatment but alleviated following chronic pioglitazone (insulin sensitizer) treatment. Improvement in insulin sensitivity was better achieved with fluoxetine and adjunctive pioglitazone treatment. Hippocampal long-term potentiation (LTP) was also assessed in this model as a surrogate marker of antidepressant effectiveness. High frequency stimulation induced LTP in the WKY. This was impaired following chronic monotherapy with either fluoxetine or pioglitazone but restored with fluoxetine and adjunctive pioglitazone treatment. Collectively, these results indicate that IR may contribute to antidepressant resistance and that antidepressant treatment response may be improved via correction of any underlying IR in affected depressed patients.