Effect of mirtazapine on metabolism and energy substrate partitioning in healthy men

Abstract

Background: 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.

Methods: We therefore conducted a proof-of-concept, open-label clinical trial, 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 were controlled and kept constant. 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.

Clinicaltrials: gov NCT00878540.

Funding: Nothing to declare.

Keywords: Glucose metabolism; Metabolism; Neuroscience; Pharmacology; Psychiatric diseases.

Conflict of interest statement

Conflict of interest: FH is cofounder of the biotech company HolsboerMaschmeyerNeuroChemie GmbH (HMNC GmbH) in Germany. FH and MU are co-inventors on the following patent applications: “FKBP5: a novel target for antidepressant therapy” (international application number WO 2005/054500) and “Polymorphisms in ABCB1 associated with a lack of clinical response to medicaments” (international application number PCT/EP2005/005194).

Figures

Figure 1. Overview of the study.

(A) Study flow diagram. (B) Study protocol. Note that the narrowing bars in the upper part of B are intended to symbolize the extent of standardization means, i.e., instructions for regular sleep, exercise, and nutrition at the screening visit, control of hunger/satiety, adaptation of caloric need, sleep diaries, and activity protocols at control visits during the preparatory phase, and, finally, the continuation of standardized diet, sleep/wake cycle, and physical activity during the laboratory phase under continuous 24 hours/day visual control.

Figure 2. Appetite and satiety under baseline and mirtazapine.

Hunger (A), satiety (B), appetite for sweets (C) and fatty and salty food (D and E) are shown using mean intraday visual analog scales (VAS, 0–100 mm). The mean of 3 consecutive baseline days (baseline) is subsequently followed by drug days (M1 = day after the first given dose of mirtazapine; M2 = day after the second given dose of mirtazapine; and so forth). A repeated-measures ANOVA with a Greenhouse-Geisser correction indicated statistically significant day-to-day differences for hunger and satiety ratings (F[2.59, 23.30] = 5.27, P = 0.008 and F[2.57, 23.16] = 7.55, P = 0.002, respectively), with asterisks in A and B indicating significant differences compared with baseline ratings (post hoc Bonferroni corrected). *P < 0.05, **P < 0.01, ***P < 0.001. There was no statistically significant time effect for ratings of appetite for sweets and salty and fatty food in the repeated-measures ANOVA (P = 0.072, P = 0.067, P = 0.063, respectively). Individual values are indicated as circles. Lower and upper hinges of box plots represent first and third quartiles. Whisker lines correspond to highest and lowest values no further than 1.5 interquartile range from the hinges; outliers are beyond this line. Median lines are indicated across the boxes, and mean values are indicated with an ×.

Figure 3. Indirect calorimetry.

Individual values of the resting energy expenditure (REE) (A) and the respiratory quotient (RQ) (B) are depicted before and after mirtazapine. P values refer to a paired t statistic comparing the mean REE (1,558 kcal/24 h ± 188.08 vs. 1,615 kcal/24 h ± 180.69; t = –1.24; P = 0.246) and the mean RQ (0.83 ± 0.10 vs. 0.87 ± 0.08; t = –1.40; P = 0.195) before and after mirtazapine, respectively.

Figure 4. Oral glucose tolerance testing.

Mean plasma glucose (A), insulin (B), and C-peptide (C) are depicted before (–15 and 0 minutes) and after (15, 30, 60, 90, 120, 150, and 180 minutes) ingestion of a standardized test meal. P values refer to group comparison of areas under the concentration curve (AUC) before (black line) and after (gray line) mirtazapine treatment (AUC glucose: 15,366.9 mg/dl ± 2,390.4 SD vs. 16,515.6 mg/dl ± 1,726.7 SD; t = –1.593; P = 0.146; AUC insulin: 777.6 μU/ml ± 357.0 SD vs. 1,086.8 μU/ml ± 404.0 SD; t = –2.423; P = 0.038; AUC C-peptide: 168.8 nmol/l ± 36.7 vs. 196.9 nmol/l ± 34.6 SD; t = –2.769; P = 0.022 (paired t test; n = 10). Error bars are standard errors of the mean. A medium to high effect (change score; see ref. 18) was found for the change of the AUC for insulin and C-peptide (0.77 [0.65–0.89] and 0.88 [0.74–1.01], respectively). The effect sizes for the change of the glucose AUC was 0.5 (0.41–0.6). In a 2-way repeated-measures ANOVA with a Greenhouse-Geisser correction, we found significant effects of mirtazapine for insulin and C-peptide (F[1, 9] = 6.69, P = 0.029 and F[1, 9] = 8.56, P = 0.017, respectively), but not for glucose (F[1, 9] = 2.27, P = 0.166). The time effect was significant in glucose, insulin, and C-peptide (F[7, 63] = 22.56, P = 1.14 × 10–8, P = 0.029, (F[7, 63] = 16.94, P = 2.95 × 10–5 and (F[7, 63] = 41.09, P = 1.86 × 10–8, respectively) while the mirtazapine × time interaction effects were not significant (F[7, 63] = 1.78, P = 0.188, (F[7, 63] = 2.41, P = 0.092 and (F[7, 63] = 2.01, P = 0.138, respectively). Bonferroni-corrected post hoc tests of mirtazapine × time effects were not significant for any laboratory value.

Figure 5. Correlation analyses.

Correlations for the change in the respiratory quotient (ΔRQ) and the change in the resting energy expenditure (ΔREE) under mirtazapine with baseline hunger (A and E), baseline appetite for sweets (B and F), hunger under mirtazapine (C and G), and appetite for sweets under mirtazapine (D and H). Note the significant correlations (r, Spearman’s rank coefficient; n = 10) with ΔRQ (A–D), but not with ΔREE (E–H).