ORIGINAL CONTRIBUTION
Does Mirtazapine Interfere With Naturalistic Diabetes Treatment? Hoo Rim Song, MD, Young Sup Woo, MD, PhD, Hee-Ryung Wang, MD, In-hee Shim, MD, Tae-Youn Jun, MD, PhD, and Won-Myong Bahk, MD, PhD
Abstract: Mirtazapine is known to induce weight gain and possibly leads to exacerbation of diabetic profiles. However, many cases of diabetic patients, who complained of insomnia and depression, were treated with mirtazapine in the clinical situations. Thus, this study aimed to assess any negative effects that treatment with mirtazapine may incur in diabetic patients. This study included 33 patients enrolled in naturalistic diabetes treatment that had also been diagnosed with depression and prescribed mirtazapine for at least 6 months. Another 33 diabetic patients who had not taken any psychiatric medicines were included as a control group. Body mass index, fasting plasma glucose, HbA1c, total cholesterol, triglyceride levels, high-density lipoprotein, and low-density lipoprotein were assessed at baseline, 3 months, and 6 months. The dose of mirtazapine at baseline was 24.3 T 14.0 mg/d in the mirtazapine group, and the 2 groups did not differ in any baseline characteristics except for total cholesterol levels. Body mass index increased in both groups, and the change in the mirtazapine group (1.0 T 0.6 kg/m2) was significantly greater than that in the control group (0.3 T 0.4 kg/m2, P G 0.001) at 6 months. Only the control group exhibited a decrease in fasting plasma glucose, whereas both groups showed a decrease in HbA1c, low-density lipoprotein, and total cholesterol, an increase in high-density lipoprotein, and no change in triglyceride levels. None of the differences between the groups were statistically significant. In conclusion, mirtazapine increased the weight gain of diabetic patients; however, other diabetic and lipid markers generally did not worsen during the 6-month treatment period. These results suggest that, at least in the short term, mirtazapine is safe for diabetic patients in a stable state and are undergoing appropriate diabetic treatment. Key Words: mirtazapine, diabetes, BMI, fasting glucose, HbA1c (J Clin Psychopharmacol 2014;34: 588Y594)
S
everal recent studies have raised the possibility that antidepressants may induce weight gain and complicate metabolic issues such as glucose dysregulation.1Y3 In particular, mirtazapine, a widely used noradrenergic and selective serotonergic antidepressant, is associated with these unwanted effects.4As a result,
From the Department of Psychiatry, Yeouido St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. Received November 27, 2013; accepted after revision April 15, 2014. Reprints: Won-Myong Bahk, MD, PhD, Department of Psychiatry, Yeouido St Mary’s Hospital, College of Medicine, The Catholic University of Korea, #62 Yeouido-dong, Yeongdeungpo-gu, Seoul, 150-713, Korea (eadrenergic antagonism, and improvements in depressive symptoms benefit glucose control and that mirtazapine might also exert an effect in terms of improving diabetic profiles.13 The primary aims of this study were to assess the effects of mirtazapine on diabetic patients in a naturalistic setting whether mirtazapine truly does have a negative effect on diabetic symptoms to determine its influence on standard diabetic treatments. If the negative influence of mirtazapine exceeds the efficacy of natural diabetic treatments, it would be difficult to recommend the prescription of mirtazapine to diabetic patients despite its good psychiatric efficacy. Our data suggest a greater increase in BMI in the mirtazapine group, which agrees with previous reports. However, there were no significant findings regarding differences in the changes of FPG, HbA1c, and lipid profiles between groups. This suggests that the effects of mirtazapine on metabolic function did not negatively influence the natural diabetic treatment process during the 6-month treatment period. However, this drug did induce weight gain. It is also possible that the efficacies of diabetes and dyslipidemia treatments outweigh the negative effects of mirtazapine temporarily. Actually, obesity is the fundamental origin of most metabolic issues including insulin resistance,14 and mirtazapine induces significant weight gain, particularly in obese patients (BMI Q25 kg/m2). The negative effects of mirtazapine may manifest slowly and indirectly via weight gain and worsens the long-term course of diabetes. If various medications do indeed mask the metabolic adverse effects of mirtazapine in the short term, the long-term use of mirtazapine in diabetic patients may exacerbate the diabetic process. This research was intended to evaluate the safety of mirtazapine in diabetic patients over a 6-month treatment period in well-controlled experimental situation. However, it is difficult to arrive at a clear conclusion regarding this issue because mirtazapine was confirmed to result in increased weight again. A high BMI and high HbA1c levels are also considered as obstacles when deciding whether to prescribe mirtazapine or not. From a long-term perspective, clinicians should carefully consider of continuing mirtazapine treatment for more than 1 year. The main limitation of this study is that it utilized retrospective tracking in a small sample. Although we tried to narrow demographic differences between 2 groups as far as possible, it is difficult to exclude the effect of depression itself in the mirtazapine group. In addition, the correlation between the change in the severity of depressive symptoms and the diabetic profile was not evaluated because of the lack of adequate scales in the medical records, and thus, the influence of improved depressive symptoms on outcome remains unknown. Moreover, only the laboratory data permitted by Korean National Health Insurance were obtainable, and it was not possible to assess LDL levels in patients without a diagnosis of dyslipidemia. The fact that participants in this study were being actively treated in the university hospital and had relatively better diabetes profiles than uncontrolled or refractory patients should also be considered in the interpretation of the current data. Therefore, the results can be applied only to wellcontrolled diabetic patients. Despite such limitations, this was the first study to examine the metabolic effects of mirtazapine in diabetic patients. Retrospective or observational studies would be an alternative
594
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&
Volume 34, Number 5, October 2014
for patients who cannot be enrolled in prospective clinical trials. Here, the general homogeneity of characteristics between the 2 groups at the baseline of achieving the one-to-one matching strategy was an advantage because the initial influence of depression on metabolic profiles was minimized by selection of similar baseline characteristics. In conclusion, mirtazapine increased weight gain in diabetic patients, but the other diabetic and metabolic markers generally did not worsen over the 6-month treatment period. These results suggest that mirtazapine may be safely used to treat diabetic patients who are suffering from depression, and those patients should have stable state and able to receive appropriate diabetic treatment. Moreover, clinicians should be aware of the weight gain induced by mirtazapine. Further observations for longer than 6 months are needed. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest.
REFERENCES 1. Kivima¨ki M, Hamer M, Batty GD, et al. Antidepressant medication use, weight gain, and risk of type 2 diabetes: a population-based study. Diabetes Care. 2010;33(12):2611Y2616. 2. Yoon JM, Cho E-G, Lee H-K, et al. Antidepressant use and diabetes mellitus risk: a meta-analysis. Korean J Fam Med. 2013;34(4):228Y240. 3. Khoza S, Barner JC, Bohman TM, et al. Use of antidepressants and the risk of type 2 diabetes mellitus: a nested case-control study. Int J Clin Pharm. 2012;34(3):432Y438. 4. Watanabe N, Omori IM, Nakagawa A, et al. Safety reporting and adverse-event profile of mirtazapine described in randomized controlled trials in comparison with other classes of antidepressants in the acute-phase treatment of adults with depression: systematic review and meta-analysis. CNS Drugs. 2010;24(1):35Y53. 5. Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev. 2001;7(3):249Y264. 6. Fisfalen ME, Hsiung RC. Glucose dysregulation and mirtazapine-induced weight gain. Am J Psychiatry. 2003;160(4):797. 7. Himmerich H, Fulda S, Schaaf L, et al. Changes in weight and glucose tolerance during treatment with mirtazapine. Diabetes Care. 2006;29(1):170. 8. Lustman PJ, Anderson RJ, Freedland KE, et al. Depression and poor glycemic control: a meta-analytic review of the literature. Diabetes Care. 2000;23(7):934Y942. 9. Hennings JM, Schaaf L, Fulda S. Glucose metabolism and antidepressant medication. Curr Pharm Des. 2012;18(36):5900Y5919. 10. Fawcett J, Barkin RL. Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression. J Affect Disord. 1998;51(3):267Y285. 11. Chen JL, Spinowitz N, Karwa M. Hypertriglyceridemia, acute pancreatitis, and diabetic ketoacidosis possibly associated with mirtazapine therapy: a case report. Pharmacotherapy. 2003;23(7):940Y944. 12. Hennings JM, Ising M, Grautoff S, et al. Glucose tolerance in depressed inpatients, under treatment with mirtazapine and in healthy controls. Exp Clin Endocrinol Diabetes. 2010;118(2):98Y100. 13. Laakmann G, Hennig J, Baghai T, et al. Mirtazapine acutely inhibits salivary cortisol concentrations in depressed patients. Ann N Y Acad Sci. 2004;1032:279Y282. 14. DeFina LF, Vega GL, Leonard D, et al. Fasting glucose, obesity, and metabolic syndrome as predictors of type 2 diabetes: the Cooper Center Longitudinal Study. J Investig Med. 2012;60(8):1164Y1168.
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Does Mirtazapine Interfere With Naturalistic Diabetes Treatment? Hoo Rim Song, MD, Young Sup Woo, MD, PhD, Hee-Ryung Wang, MD, In-hee Shim, MD, Tae-Youn Jun, MD, PhD, and Won-Myong Bahk, MD, PhD
Abstract: Mirtazapine is known to induce weight gain and possibly leads to exacerbation of diabetic profiles. However, many cases of diabetic patients, who complained of insomnia and depression, were treated with mirtazapine in the clinical situations. Thus, this study aimed to assess any negative effects that treatment with mirtazapine may incur in diabetic patients. This study included 33 patients enrolled in naturalistic diabetes treatment that had also been diagnosed with depression and prescribed mirtazapine for at least 6 months. Another 33 diabetic patients who had not taken any psychiatric medicines were included as a control group. Body mass index, fasting plasma glucose, HbA1c, total cholesterol, triglyceride levels, high-density lipoprotein, and low-density lipoprotein were assessed at baseline, 3 months, and 6 months. The dose of mirtazapine at baseline was 24.3 T 14.0 mg/d in the mirtazapine group, and the 2 groups did not differ in any baseline characteristics except for total cholesterol levels. Body mass index increased in both groups, and the change in the mirtazapine group (1.0 T 0.6 kg/m2) was significantly greater than that in the control group (0.3 T 0.4 kg/m2, P G 0.001) at 6 months. Only the control group exhibited a decrease in fasting plasma glucose, whereas both groups showed a decrease in HbA1c, low-density lipoprotein, and total cholesterol, an increase in high-density lipoprotein, and no change in triglyceride levels. None of the differences between the groups were statistically significant. In conclusion, mirtazapine increased the weight gain of diabetic patients; however, other diabetic and lipid markers generally did not worsen during the 6-month treatment period. These results suggest that, at least in the short term, mirtazapine is safe for diabetic patients in a stable state and are undergoing appropriate diabetic treatment. Key Words: mirtazapine, diabetes, BMI, fasting glucose, HbA1c (J Clin Psychopharmacol 2014;34: 588Y594)
S
everal recent studies have raised the possibility that antidepressants may induce weight gain and complicate metabolic issues such as glucose dysregulation.1Y3 In particular, mirtazapine, a widely used noradrenergic and selective serotonergic antidepressant, is associated with these unwanted effects.4As a result,
From the Department of Psychiatry, Yeouido St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. Received November 27, 2013; accepted after revision April 15, 2014. Reprints: Won-Myong Bahk, MD, PhD, Department of Psychiatry, Yeouido St Mary’s Hospital, College of Medicine, The Catholic University of Korea, #62 Yeouido-dong, Yeongdeungpo-gu, Seoul, 150-713, Korea (eadrenergic antagonism, and improvements in depressive symptoms benefit glucose control and that mirtazapine might also exert an effect in terms of improving diabetic profiles.13 The primary aims of this study were to assess the effects of mirtazapine on diabetic patients in a naturalistic setting whether mirtazapine truly does have a negative effect on diabetic symptoms to determine its influence on standard diabetic treatments. If the negative influence of mirtazapine exceeds the efficacy of natural diabetic treatments, it would be difficult to recommend the prescription of mirtazapine to diabetic patients despite its good psychiatric efficacy. Our data suggest a greater increase in BMI in the mirtazapine group, which agrees with previous reports. However, there were no significant findings regarding differences in the changes of FPG, HbA1c, and lipid profiles between groups. This suggests that the effects of mirtazapine on metabolic function did not negatively influence the natural diabetic treatment process during the 6-month treatment period. However, this drug did induce weight gain. It is also possible that the efficacies of diabetes and dyslipidemia treatments outweigh the negative effects of mirtazapine temporarily. Actually, obesity is the fundamental origin of most metabolic issues including insulin resistance,14 and mirtazapine induces significant weight gain, particularly in obese patients (BMI Q25 kg/m2). The negative effects of mirtazapine may manifest slowly and indirectly via weight gain and worsens the long-term course of diabetes. If various medications do indeed mask the metabolic adverse effects of mirtazapine in the short term, the long-term use of mirtazapine in diabetic patients may exacerbate the diabetic process. This research was intended to evaluate the safety of mirtazapine in diabetic patients over a 6-month treatment period in well-controlled experimental situation. However, it is difficult to arrive at a clear conclusion regarding this issue because mirtazapine was confirmed to result in increased weight again. A high BMI and high HbA1c levels are also considered as obstacles when deciding whether to prescribe mirtazapine or not. From a long-term perspective, clinicians should carefully consider of continuing mirtazapine treatment for more than 1 year. The main limitation of this study is that it utilized retrospective tracking in a small sample. Although we tried to narrow demographic differences between 2 groups as far as possible, it is difficult to exclude the effect of depression itself in the mirtazapine group. In addition, the correlation between the change in the severity of depressive symptoms and the diabetic profile was not evaluated because of the lack of adequate scales in the medical records, and thus, the influence of improved depressive symptoms on outcome remains unknown. Moreover, only the laboratory data permitted by Korean National Health Insurance were obtainable, and it was not possible to assess LDL levels in patients without a diagnosis of dyslipidemia. The fact that participants in this study were being actively treated in the university hospital and had relatively better diabetes profiles than uncontrolled or refractory patients should also be considered in the interpretation of the current data. Therefore, the results can be applied only to wellcontrolled diabetic patients. Despite such limitations, this was the first study to examine the metabolic effects of mirtazapine in diabetic patients. Retrospective or observational studies would be an alternative
594
www.psychopharmacology.com
&
Volume 34, Number 5, October 2014
for patients who cannot be enrolled in prospective clinical trials. Here, the general homogeneity of characteristics between the 2 groups at the baseline of achieving the one-to-one matching strategy was an advantage because the initial influence of depression on metabolic profiles was minimized by selection of similar baseline characteristics. In conclusion, mirtazapine increased weight gain in diabetic patients, but the other diabetic and metabolic markers generally did not worsen over the 6-month treatment period. These results suggest that mirtazapine may be safely used to treat diabetic patients who are suffering from depression, and those patients should have stable state and able to receive appropriate diabetic treatment. Moreover, clinicians should be aware of the weight gain induced by mirtazapine. Further observations for longer than 6 months are needed. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest.
REFERENCES 1. Kivima¨ki M, Hamer M, Batty GD, et al. Antidepressant medication use, weight gain, and risk of type 2 diabetes: a population-based study. Diabetes Care. 2010;33(12):2611Y2616. 2. Yoon JM, Cho E-G, Lee H-K, et al. Antidepressant use and diabetes mellitus risk: a meta-analysis. Korean J Fam Med. 2013;34(4):228Y240. 3. Khoza S, Barner JC, Bohman TM, et al. Use of antidepressants and the risk of type 2 diabetes mellitus: a nested case-control study. Int J Clin Pharm. 2012;34(3):432Y438. 4. Watanabe N, Omori IM, Nakagawa A, et al. Safety reporting and adverse-event profile of mirtazapine described in randomized controlled trials in comparison with other classes of antidepressants in the acute-phase treatment of adults with depression: systematic review and meta-analysis. CNS Drugs. 2010;24(1):35Y53. 5. Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev. 2001;7(3):249Y264. 6. Fisfalen ME, Hsiung RC. Glucose dysregulation and mirtazapine-induced weight gain. Am J Psychiatry. 2003;160(4):797. 7. Himmerich H, Fulda S, Schaaf L, et al. Changes in weight and glucose tolerance during treatment with mirtazapine. Diabetes Care. 2006;29(1):170. 8. Lustman PJ, Anderson RJ, Freedland KE, et al. Depression and poor glycemic control: a meta-analytic review of the literature. Diabetes Care. 2000;23(7):934Y942. 9. Hennings JM, Schaaf L, Fulda S. Glucose metabolism and antidepressant medication. Curr Pharm Des. 2012;18(36):5900Y5919. 10. Fawcett J, Barkin RL. Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression. J Affect Disord. 1998;51(3):267Y285. 11. Chen JL, Spinowitz N, Karwa M. Hypertriglyceridemia, acute pancreatitis, and diabetic ketoacidosis possibly associated with mirtazapine therapy: a case report. Pharmacotherapy. 2003;23(7):940Y944. 12. Hennings JM, Ising M, Grautoff S, et al. Glucose tolerance in depressed inpatients, under treatment with mirtazapine and in healthy controls. Exp Clin Endocrinol Diabetes. 2010;118(2):98Y100. 13. Laakmann G, Hennig J, Baghai T, et al. Mirtazapine acutely inhibits salivary cortisol concentrations in depressed patients. Ann N Y Acad Sci. 2004;1032:279Y282. 14. DeFina LF, Vega GL, Leonard D, et al. Fasting glucose, obesity, and metabolic syndrome as predictors of type 2 diabetes: the Cooper Center Longitudinal Study. J Investig Med. 2012;60(8):1164Y1168.
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
