Individuals with insulin resistance, such as those with Type II Diabetes Mellitus (T2DM), have a significantly elevated risk of suffering from concomitant depression and anxiety (Bădescu et al., 2016). Hence, by intuition, pharmacological treatments for insulin resistance could potentially alleviate these symptoms as well. As it turns out, recent findings by Zemdegs et al. (2019) indicated that, in mice exhibiting insulin resistance, intervention with the anti-diabetic drug metformin elicited reduced anxiety as well as antidepressant effects in these mice when compared to controls. This was believed to be mediated at the level of the serotonin pathway in the brain.
The authors replicated the metabolic conditions of insulin resistance by administering a high fat diet to mice. They observed that these mice exhibited impaired neuronal activity of serotonergic neurons and lowered serotonin concentrations at the level of the hippocampus, which was linked to the anxiety that this metabolic condition may trigger.
Conversely, when mice were given metformin, they displayed an increase in both serotonin neuronal activity and hippocampal concentrations of this neurotransmitter. The biochemical mechanism underlying metformin’s action is proposed to be a reduction in levels of branched-chain amino acids (BCAAs) that would otherwise inhibit the entry of the amino acid tryptophan, the precursor of serotonin (AKA 5-hydroxytryptamine), into the brain.
With lower levels of BCAAs, there is much greater intake of tryptophan into the brain, and hence, elevated levels of serotonin. This phenomenon was implicated in eliciting an anxiolytic and antidepressant effect in the mice. This is in line with the theory underlying selective serotonin reuptake inhibitors (SSRIs) as treatments for depression. What this shows is that metformin could potentially be the key therapeutic to address comorbid conditions of metabolic insulin resistance and the mental health issues of depression and anxiety.
Potential of Metformin
The potential of metformin as a mental health therapeutic has actually been exhibited in previous studies. As a drug that alters the nervous system metabolism, particularly as it is able to penetrate the blood-brain barrier, metformin has been found to potential the antidepressant effect of the SSRI fluoxetine, via increasing the expression of the gene for the insulin growth factor protein, IGF2, which has manifested phenotypically in mice as reductions in anhedonic behavior.
The increased expression of this protein is implicated in facilitating increases in hippocampal synaptic plasticity and long-term potentiation, which is linked to improvements in neurocognitive function, and reductions in depression and anxiety (Lennox et al., 2014).
The usefulness of metformin as a pharmacological adjunct in mental health is not limited to patients with diabetes. Any patient with a condition that is associated with insulin resistance carries an inherent risk of suffering comorbid depression or anxiety. One such demographic is females with polycystic ovary syndrome (PCOS). Adolescent females with PCOS and associated insulin resistance, when treated with metformin for 90 days, have reported markedly decreased levels of anxiety and depression when administered Beck’s Anxiety (BAI) and Depression Inventories (BDI-II) (Erensoy et al., 2019).
Based on the effect (or many effects) that metformin has been found to elicit at the molecular level within the central nervous system, there is great reason for optimism for the use of this drug in individuals with anxiety and depression. Many of these individuals also suffer from insulin resistance, a condition which continues to be on the rise in this country, in large part because of diet and sedentary lifestyle, but also because of genetic predisposition.
Based on the literature thus far, it would seem that metformin would be best suited to patients with depression and anxiety who suffer from concurrent insulin resistance, rather than those solely suffering from the mental health condition itself.
In addition to the actual neurobiological effects of the drug, another potential and intuitive way of looking at the beneficial effect of metformin on mental health may be that, through addressing the condition of insulin resistance, one’s physical health and well-being improved markedly. This positive experience of better health could go on to further perpetuate one’s improved mood and general mental state independent of the neurobiological underpinnings of the drug.
What I must also stress here is that I am not advocating for Metformin as a ‘magic pill’ for mental health. Rather, I am trying to tie into the metabolism-mental health link, and how this can be a pharmacological adjunct to treating a demographic with mental health issues concurrent with metabolic conditions such as insulin resistance.
While much more substantive research in clinical trials with actual human patients is needed, metformin could be the proof of principle: that metabolic conditions can also have a pathophysiological effect at the level of mental health, and by treating the root cause of the metabolic condition, we can treat mental health issues as well.
Bădescu, S., Tătaru, C., & Kobylinska, L. (2016). The association between diabetes mellitus and depression. J Med Life, 9(2), 120-125.
Erensoy, H., Niafar, M., Ghafarzadeh, S., Aghamohammadzadeh, N., & Nader, N. D. (2018). A pilot trial of metformin for insulin resistance and mood disturbances in adolescent and adult women with polycystic ovary syndrome. Gynecological Endocrinology, 35(1), 72-75.
Lennox, R., Porter, D. W., Flatt, P. R., Holscher, C., Irwin, N., & Gault, V. A. (2014). Comparison of the independent and combined effects of sub-chronic therapy with metformin and a stable GLP-1 receptor agonist on cognitive function, hippocampal synaptic plasticity and metabolic control in high-fat fed mice. Neuropharmacology, 86, 22-30.
Zemdegs, J., Martin, H., Pintana, H., Bullich, S., Manta, S., Marqués, M., . . . Guiard, B. (2019). Metformin promotes anxiolytic and antidepressant-like responses in insulin-resistant mice by decreasing circulating branched-chain amino acids. The Journal of Neuroscience, 2904-18.