Combined Fluoxetine and Metformin Treatment Potentiates Antidepressant Efficacy Increasing IGF2 Expression in the Dorsal Hippocampus

Abstract

An increasing number of studies show that selective serotonin reuptake inhibitors (SSRIs) exert their therapeutic action, at least in part, by amplifying the influence of the living environment on mood. As a consequence, when administered in a favorable environment, SSRIs lead to a reduction of symptoms, but in stressful conditions, they show limited efficacy. Therefore, novel therapeutic approaches able to neutralize the influence of the stressful environment on treatment are needed. The aim of our study was to test whether, in a mouse model of depression, the combined administration of SSRI fluoxetine and metformin, a drug able to improve the metabolic profile, counteracts the limited efficacy of fluoxetine alone when administered in stressful conditions. Indeed, metabolic alterations are associated to both the onset of major depression and the antidepressant efficacy. To this goal, adult C57BL/6 male mice were exposed to stress for 6 weeks; the first two weeks was aimed at generating a mouse model of depression. During the remaining 4 weeks, mice received one of the following treatments: vehicle, fluoxetine, metformin, or a combination of fluoxetine and metformin. We measured liking- and wanting-type anhedonia as behavioral phenotypes of depression and assessed the expression levels of selected genes involved in major depressive disorder and antidepressant response in the dorsal and ventral hippocampus, which are differently involved in the depressive symptomatology. The combined treatment was more effective than fluoxetine alone in ameliorating the depressive phenotype after one week of treatment. This was associated to an increase in IGF2 mRNA expression and enhanced long-term potentiation, specifically in the dorsal hippocampus, at the end of treatment. Overall, the present results show that, when administered in stressful conditions, the combined fluoxetine and metformin treatment may represent a more effective approach than fluoxetine alone in a short term. Finally, our findings highlight the relevance of polypharmacological strategy as effective interventions to increase the efficacy of the antidepressant drugs currently available.

Metformin Enhances Antidepressant/Antipsychotic Combination Therapy of Schizophrenia With Comorbid Depression in a Murine Model

“…Both of the triple-drug combinations gave moderate improvements of depressive and schizophrenia-related behaviors. To further improve efficacy, we added metformin because murine models suggest that it exerts antipsychotic (Wang et al, 2019), anxiolytic, and antidepressant activities (Zemdegs et al, 2019); and enhances the antidepressant activity of fluoxetine, a serotonin reuptake inhibitor (Poggini et al, 2019). Our results supported our hypothesis by showing that the addition of metformin to both triple-drug psychotropic combinations brought further behavioral benefit.…”

“…A notable finding of our study is that metformin significantly augmented both the physiological and behavioral effects of both antidepressant/antipsychotic combinations. Murine studies suggest that metformin has direct psychotropic effects by metabolic regulation of circulating branched-chain amino acid levels (Zemdegs et al, 2019) and potentiates antidepressants by activating the IGF2 pathway (Poggini et al, 2019). Potential complications of second-generation antipsychotics (SGAs) include obesity and development of the metabolic syndrome (Brooks et al, 2009;Luo et al, 2019).…”

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids

“…In light of these data, clinical and preclinical studies are also warranted to further evaluate the efficacy of such a potentiation strategy in depressed patients or in relevant animal models without metabolic comorbidities. In this prospect, a recent study shows that Met produces antidepressant-like activities given either alone (Liu et al, 2019) or in combination with Flx (Poggini et al, 2019) in chronically stressed animals.…”

Insulin-Like Growth Factor 2 As a Possible Neuroprotective Agent and Memory Enhancer—Its Comparative Expression, Processing and Signaling in Mammalian CNS

“…However, these genes do not have similar effects in hippocampus-dependent recent fear memory formation [ 104 ]. Igf2 expression may also be stimulated artificially by selective serotonin reuptake inhibitors administration, as was shown in experiments with murine model of depression [ 105 ].…”