The interplay between inflammation and neural plasticity determines serotoninergic antidepressant efficacy

Major Depressive Disorder (MDD) is a multifaceted disorder that imposes an enormous medical, societal and economic burden. Selective Serotonin Reuptake Inhibitors (SSRIs) are the most commonly prescribed antidepressant drugs. However, their efficacy is variable and incomplete and there is still limited understanding of the factors determining their beneficial action. With the purpose to identify these factors and develop more effective therapeutic strategies for MDD, we carried out preclinical studies exploiting a multidisciplinary strategy, spanning from molecular to cellular and behavioral assessment. We focused on inflammation and neural plasticity because, though these have been widely reported as key factors in determining SSRI outcome, their interplay has been limitedly explored. The results obtained show, on the one hand, that the increased neural plasticity induced by SSRI administration regulates inflammation counterbalancing both the activation and suppression of immune response, and, on the other, that any deviation towards an extreme immune activation or suppression results in reduced neural plasticity. These findings indicate that neural plasticity and inflammation are mutually regulating processes and that inflammatory levels should be kept within a strict physiological range to be permissive for neural plasticity. As further step, we explored a polypharmacological strategy aimed at increasing SSRI efficacy through the add-on treatment with metformin, a drug able to improve metabolic profile, which has been shown to be implicated in antidepressant efficacy. This approach is aimed at producing two concerted effects –increasing neural plasticity (i.e. SSRI) and regulating metabolism (i.e. metformin)—that together should lead to a more effective therapeutic strategy for MDD than the SSRI alone. The results suggest that the combined treatment has an improved efficacy and that multifactorial disorders such as MDD may be more effectively treated with strategies able to targeting several biological processes. Overall, our findings underpin the implementation of the precision medicine paradigm in the psychiatric field. Indeed, information concerning not only the patients’ mood but also selected physiological endpoints (e.g. inflammatory levels and metabolic profile) should be considered for an effective antidepressant therapeutic strategy.