Effect of mirtazapine on glucose metabolism and resting energy expenditure: Observations in “super-healthy” men under highly standardized conditions

Introduction:

Weight gain and metabolic changes during treatment with antidepressant drugs have emerged as an important concern, particularly in long-term treatment. It is still a matter of ongoing debate whether weight gain and metabolic perturbations with antidepressant use are the consequence of increased appetite and weight gain, respectively, or represents direct pharmacological effects of the drug on metabolism. In addition, depression itself is an independent risk factor for metabolic disorders such as metabolic syndrome and diabetes, further complicating the interpretation of metabolic changes under antidepressant therapy.

Methods:

We therefore conducted a proof-of-concept study (NCT00878540), hypothesizing that in exceptionally healthy men no change of metabolic parameters would occur under mirtazapine, when environmental factors such as nutrition, sleep and physical exercise are controlled. Over a 3-week preparation phase, 10 healthy, young men were attuned to a standardized diet adjusted to their individual caloric need, to a regular sleep/wake cycle and moderate exercise. Continuing this protocol, we administered 30 mg mirtazapine daily for 7 days.

Results:

While no significant weight gain or changes in resting energy expenditure were observed under these conditions, hunger and appetite for sweets increased with mirtazapine, accompanied by a shift in energy substrate partitioning towards carbohydrate substrate preference as assessed by indirect calorimetry. Furthermore, with mirtazapine, insulin and C-peptide release increased in response to a standardized meal.

Conclusion:

Our findings provide important insights into weight-independent metabolic changes associated with mirtazapine and allow a better understanding of the long-term metabolic effects observed in patients treated with antidepressant drugs.