This is the first study to our knowledge investigating the short-term effects of the antidepressant mirtazapine on glucose and lipid metabolism in healthy men in a highly controlled in-ward experimental setting with standardized caloric intake, physical activity, and sleep/wake cycles. The rationale of this study was that mirtazapine is suspected to induce weight gain in a substantial number of individuals, which is, in the light of their increased risk of converting to type 2 diabetes or hyperlipidemia, an important clinical issue.

We report 4 major findings. First, in healthy male subjects under standardized conditions, no significant change in REE was observed with mirtazapine. Notwithstanding, weight slightly decreased, while hunger and particularly appetite for sweets increased. Second, even in the context of slightly reduced weight and stable nutrition, mOGTT-assessed insulin and C-peptide release were increased after exposure to mirtazapine, as well as the plasma triglyceride/HDL quotient and HbA1c. Furthermore, a shift in energy substrate partitioning towards carbohydrate substrate preference (as measured by RQ) with mirtazapine highly correlated with increases in hunger and appetite for sweets, nota bene under standardized nutrition. Finally, baseline hunger was predictive for increased hunger and appetite for sweets with mirtazapine.

With respect to mirtazapine’s metabolic effects, the data are generally inconclusive, with mixed results. While several studies have raised concerns about adverse metabolic side effects like hyperlipidemia and weight gain (20–22), other studies suspected a “beneficial” effect on glucose metabolism (7, 8). In particular, decreased fasting glucose levels (7, 23) and increased fasting insulin (8) have been observed in depressed patients treated with mirtazapine. As these changes in glucose metabolism were observed predominantly in patients recovering from depression, a normalization of hypercortisolemia, as frequently observed in acutely depressed patients (further linked to glycogenolysis and hyperglycemic metabolic states) (14, 24), might be one mechanism explaining these findings. Further, a suppressive effect on the hypothalamic/pituitary/adrenocortical (HPA) axis has been observed in depressed patients under mirtazapine independent from the psychopathological state (25).

Mirtazapine blocks noradrenergic α 2 -autoreceptors and -heteroreceptors as well as serotonergic 5-HT 2 and 5-HT 3 receptors (26). Although peripheral mirtazapine α 2 action has not been extensively investigated, it has been shown that blockage of pancreatic β cell α 2 -adrenoceptors with various substances disinhibits insulin secretion and reduces glucagon secretion, both decreasing blood glucose (27). In line with this, α 2 -adrenoceptor antagonists like midaglizole promotes insulin secretion in diabetic and nondiabetic subjects (28). Similarly, decreased fasting glucose and increased fasting insulin blood levels have been reported under mirtazapine in depressed patients (7, 8). Contrasting the observation of increased insulin release with mirtazapine in our study, other noradrenergic antidepressants without α 2 action can reduce glucose tolerance (29), as enhanced noradrenergic signaling inhibits insulin secretion, increases glucagon secretion from the endocrine pancreas, and stimulates gluconeogenesis and glycogenolysis in the liver (30). In the present study, mOGTT insulin and C-peptide increased with mirtazapine in mentally and physically healthy males under clamped dietary conditions, i.e., neither hormonal states (e.g., depression-related elevated stress hormones, hormonal alterations related to the ovarian cycle), preexisting metabolic disturbances, nor alimentary habits can be made responsible for our observations. The correlation of insulin and C-peptide with plasma mirtazapine levels further supports the assumption of direct pharmacodynamic effects, i.e., a desensitization of insulin secretion. Nevertheless, the interpretation of altered insulin response to the test meal is limited and we can neither prove the hypothesis of direct increase of insulin by mirtazapine nor can we rule out that impaired insulin action in terms of insulin resistance plays a role. Indeed, increased insulin in the mOGTT and unchanged glucose would argue for an impaired insulin action. Considering that our subjects were nondiabetic without any metabolic risk factor, the HOMA index was unchanged, and the observation period was short, impaired insulin action is less likely. On the other hand, from the long-term perspective, the disinhibited insulin secretion via α 2 action, as hypothesized here, may similarly result in impaired insulin action in long-term treatment with mirtazapine in patients. Potentially, these two suggested pathophysiological mechanisms — i.e., disinhibited insulin secretion in the short term and impaired insulin action in the long term — may explain controversial findings of improved glucose tolerance in some studies (usually short term) (7, 8) and increased risk for diabetes in long-term clinical observations in others (4).

It must, however, be mentioned that besides the hypothesis of a direct effect of mirtazapine on metabolic parameters, there is a possible alternative hypothesis supposing that mirtazapine’s effects are influenced by the strong effect of mirtazapine on sleep. It is well established that there is a tight association between sleep and insulin resistance and obesity (31). And indeed, we had observed in this study (17) that mirtazapine elicited significant periodic leg movements during sleep (PLMS) in 8 of the 12 participants (7 of the 10 included here). PLMS are associated with arousals during sleep and can significantly affect sleep continuity (32). Theoretically, these differences in sleep continuity affected by mirtazapine could be instrumental in determining changes in insulin metabolism. We have not included sleep parameters in the present manuscript because (a) the effect of mirtazapine on PLMS was counterbalanced by the effect on slow wave sleep, with a significant increase already in the first nights (i.e., corresponding to an increased deep sleep); and (b) both effects — on PLMS and slow wave sleep — were mostly acute effects that decreased over the course of the study. With respect to sleep, disentangling the direct and indirect effects of mirtazapine on metabolism remains therefore a challenging, although promising, task.

Consistent with common complaints of patients (33), we observed an increase in hunger, and in particular a craving for sweets. This effect was observable even after the first dose of mirtazapine (Figure 2). Nevertheless, weight gain — normally accompanied with increased hunger in patients even with short-term treatment (7, 20–22) — was missing when caloric intake was restricted in our subjects, and individuals even slightly lost weight. Repeated assessments (and adjustments) of caloric need, hunger, and postprandial satiety during the preparatory phase did not suggest nutrition shortness as an origin of the loss of weight. Thus, increased insulin and C-peptide in the mOGTT occurred despite a small decrease in weight, further indicating a direct drug-induced effect on energy metabolism. Although fasting and stimulated glucose as an initiator of food intake were not reduced, increased insulin could further have an influence on increased hunger and appetite for sweets under mirtazapine. In addition, beside its effect on 5-HT receptors, H1-antihistaminergic action has been related to increased appetite under mirtazapine (34). The correlation analysis in our study further showed that those individuals that have more hunger or appetite for sweets exhibit a metabolic shift towards carbohydrate substrate preference in energy metabolism. In a combined microdialysis and indirect calorimetry study, Boschmann et al. (35) attributed an increase of carbohydrate oxidation rate to sensitization of adipose tissue to β-adrenergic stimulation by NET inhibition with the noradrenergic antidepressant reboxetine under costimulation with isoproterenol. In their study, energy expenditure did not differ between reboxetine and placebo treatment, while isoproterenol significantly increased energy expenditure with both reboxetine and placebo treatment. Extrapolated to our study, α 2 stimulation by mirtazapine might not sufficiently address energy expenditure (compared with isoproterenol) but may modulate adrenergic signaling in target cells shifting towards carbohydrate oxidation. Thus, we hypothesize that a shift in energy metabolism induced by mirtazapine is the cause rather than the consequence of elevated appetite for sweet, and — extrapolated to unrestricted condition — of increased caloric intake.

Total cholesterol and LDL slightly decreased with mirtazapine in our study, which is in contrast to previous studies (21, 36) reporting hyperlipidemia under mirtazapine. We only found a rise in the so-called atherogenic index, i.e., the triglyceride/HDL quotient, which might be related to the desensitized insulin release mentioned above (37). In the present study, the observation period might have been too short to detect a further increase of triglycerides and the standardized diet might have prevented changes in lipids. However, even an only slight elevation of insulin could have significant effects on lipid metabolism in the long term (i.e., stimulation of triglyceride synthesis, inhibition of lipolysis) that have not been detected here.

Our study enrolled a relatively small sample of healthy volunteers that were investigated within a short observation period, raising the risk of spurious findings on the one hand and missed metabolic effects under long-term medication with mirtazapine on the other hand. Various comparisons did not pass the threshold of conservative Bonferroni correction for multiple comparisons (e.g., data presented in Table 1 and Supplemental Table 2). This is most likely due to the small sample size, as the change-score effect sizes indicated moderate to strong effects for those variables (such as body weight and lipid parameters) with a P below 0.05 but above the respective Bonferroni-corrected value. However, due to the highly standardized setting, our study has some important strengths. We applied a proof-of-concept design testing the hypothesis that metabolic parameters under mirtazapine would not change in very healthy men under standardized conditions including restricted food intake. Of note, even in the context of dietary restriction and weight loss, we observed metabolic changes under mirtazapine that cannot be attributed to increased food intake, changes in nutrient composition, physical activity, or sleeping behavior. The correlation of plasma mirtazapine levels with metabolic effects in our study further supports the assumption of direct pharmacological effects of mirtazapine on metabolism. Our findings therefore imply direct and weight-gain-independent effects of mirtazapine on energy, and lipid and glucose metabolism, a finding which may have important implications for long-term treatment with mirtazapine.

We observed weight-gain-independent metabolic effects of mirtazapine on glucose and lipid metabolism in exceptionally healthy men of European descent under highly standardized conditions. Following treatment with mirtazapine, insulin and C-peptide increased in response to a standardized test meal, likely to be mediated by mirtazapine’s α 2 -adrenergic–induced desensitization of insulin secretion or increased insulin resistance. Increased hunger and appetite for sweets correlated with a shift in energy substrate partitioning, with increased carbohydrate oxidation rates despite stable nutrient composition and energy balance. These changes in glucose and energy metabolism were independent of body weight and occurred even during short-term exposure to mirtazapine.

These findings provide insights into the specific effects of mirtazapine on energy metabolism, and add to our understanding of effects on clinically relevant metabolic changes by this widely prescribed antidepressant medicine.