Exploring psychotherapeutic issues and agents in clinical practice
Overweight and obesity, associated with significant morbidity and mortality, is an especially important problem among individuals with psychiatric illness, in part due to the adverse metabolic effects of some psychotropic drugs. The U.S. Food and Drug Administration (FDA) has approved a number of medications for the treatment of obesity, and other medications are known to be associated with weight loss and can be used to promote weight loss or minimize weight gain. In this month’s column, I briefly discuss the use of melatonin, liraglutide, and naltrexone/bupropion for obesity and medication-related weight gain.
Melatonin, Energy Metabolism, and the Treatment of Medication-related Weight Gain
Melatonin is an ancient molecule that is found in plants and animals (Cipolla-Neto, Amaral, Afeche, Tan, & Reiter, 2014). In animals, the central endogenous circadian rhythm pacemaker (regulating various 24-hour biological cycles) is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Light influences SCN function via a neural pathway from the retina to the SCN. A pathway also runs from the SCN to the pineal gland, where the synthesis and release of melatonin occurs. Melatonin secretion is regulated internally by the normal autonomous activity of the SCN and regulated externally by light exposure on the retina.
Circulating melatonin is largely provided by the pineal gland, but is also locally synthesized in other tissues. Melatonin receptors are found throughout the body, including the pancreas and adipose tissue (Slominski, Reiter, Schlabritz-Loutsevich, Ostrom, & Slominski, 2012). Evidence from preclinical and clinical studies suggests that melatonin has an important physiological role in energy metabolism and the regulation of body weight (Cipolla-Neto et al., 2014; McMullan, Schernhammer, Rimm, Hu, & Forman, 2013). Experimental studies demonstrate that melatonin is necessary for the synthesis, secretion, and action of insulin. Melatonin is also involved in maintaining an adequate energy balance by regulating energy flow to and from stores, regulating energy expenditure through the activation of brown adipose tissue, and participating in the “browning” of white adipose tissue. White adipose tissue stores excess fuel as triglycerides, whereas brown adipose tissue oxidizes fatty acids to generate heat. Brown adipose tissue is considered metabolically healthy. Cold exposure and exercise have both been found to be associated with the browning of white adipose tissue. Because of the role of melatonin in energy metabolism, there is developing interest in its use for treating or preventing weight gain.
The effect of melatonin 5 mg per day on weight gain and various metabolic and cardiovascular risk factors was evaluated by Romo-Nava et al. (2014) in an 8-week randomized, double-blind, placebo-controlled trial of individuals with bipolar disorder (n = 20) or schizophrenia (n = 24) who were taking an antipsychotic drug (i.e., clozapine [Clozaril®], olanzapine [Zyprexa®], quetiapine [Seroquel®], or risperidone [Risperdal®]). The melatonin group showed a significant attenuation of weight gain and a decrease in blood pressure compared to placebo. Melatonin had a particularly beneficial effect on mean fat mass, blood pressure, and triglyceride level in individuals with bipolar disorder, but not schizophrenia. Melatonin also had a relatively greater attenuating effect on weight gain with quetiapine and risperidone than for clozapine and olanzapine.
In a study that was restricted to a single diagnosis (first-episode schizophrenia) and a single antipsychotic drug (olanzapine), Modabbernia et al. (2014) enrolled 48 medication-free individuals in an 8-week randomized, double-blind, placebo-controlled trial that compared olanzapine plus melatonin 3 mg per day versus olanzapine plus placebo. Compared to placebo, melatonin was associated with significantly less weight gain and had more favorable effects on waist circumference and triglyceride level. In both studies, melatonin was well-tolerated and not associated with adverse neuropsychiatric effects.
Liraglutide, Diabetes, and the Treatment of Obesity
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has a glucose-dependent stimulatory effect on insulin production and secretion and an inhibitory effect on glucagon secretion from the pancreas in response to hyperglycemia (Ng & Wilding, 2014). GLP-1 is mainly produced by L cells in the ileum of the small intestine, and its secretion is stimulated by nutrients passing through the intestine. In addition to binding to GLP-1 receptors in pancreatic islet cells, where it serves to regulate plasma glucose levels, GLP-1 also binds to receptors in the brainstem, hypothalamus, and amygdala, where it may promote satiety and therefore decrease energy intake. Stimulating these GLP-1 receptors might contribute to weight loss.
Liraglutide (Victoza®; Saxenda®) is a long-acting GLP-1 receptor agonist drug that is a structural analog of GLP-1. By activating GLP-1 receptors, it stimulates insulin release and inhibits glucagon secretion only in response to hyperglycemia. As such, it lowers plasma glucose without typically causing hypoglycemia. Liraglutide was first approved by the FDA in 2010 (under the brand name Victoza) as a treatment for type 2 diabetes (“Liraglutide…,” 2010). Studies in patients with type 2 diabetes found that liraglutide was associated with significant weight loss (Du, Wang, Yang, Zhao, & Han, 2014). Based on additional clinical studies (Ng & Wilding, 2014), the FDA subsequently approved the drug (under the brand name Saxenda) in December 2014 as a treatment for non-diabetic–associated obesity.
The efficacy of liraglutide (Saxenda) for overweight and obesity was established in two randomized, double-blind, placebo-controlled, 56-week trials in non-diabetic individuals (Astrup et al., 2012; Wadden et al., 2013). Body weight and various metabolic and cardiovascular risk factors improved significantly with liraglutide compared to placebo. The drop-out rate in these two studies was approximately 30%. Based on studies for obesity (Ng & Wilding, 2014) and type 2 diabetes (Du et al., 2014), the most common adverse effects of liraglutide are nausea, vomiting, dyspepsia, constipation, and diarrhea. Hypoglycemia is possible, but rarely occurs. There are no notable adverse cardiac effects.
Liraglutide must be administered subcutaneously due to its pharmacology and mechanism of action. Because it slows gastric emptying, the rate and extent of absorption of other drugs might be decreased. Studies in rodents found a dose-dependent and treatment-duration–dependent increase in thyroid tumors (Ng & Wilding, 2014). Although the FDA believes that lira-glutide poses a low risk in humans for thyroid cancer, the agency is requiring additional animal studies and the establishment of a thyroid cancer registry (Ng & Wilding, 2014). Another potential safety concern that has been raised with liraglutide and other GLP-1 receptor drugs is the risk of pancreatitis or pancreatic cancer. After reviewing all published and unpublished preclinical and clinical studies, the FDA and European Medicines Agency have stated that a causal relationship between GLP-1 receptor drugs and pancreatitis or pancreatic disorders cannot be established from these data, but these agencies will continue to evaluate this risk through ongoing monitoring and other clinical studies (Egan et al., 2014).
Cardiovascular Safety of Naltrexone/Bupropion Combination for Obesity
The combination of an opioid receptor antagonist drug naltrexone (ReVia®) and the antidepressant and smoking cessation drug bupropion (Wellbutrin®; Zyban®) has been investigated for the treatment of obesity. The efficacy of a naltrexone/bupropion fixed-dose combination drug (Contrave®) was established in four randomized, double-blind, placebo-controlled, 56-week trials in overweight or obese individuals who also had hypertension, dyslipidemia, or type 2 diabetes (Apovian et al., 2013; Greenway et al., 2010; Hollander et al., 2013; Wadden et al., 2011). Body weight, waist circumference, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride level, hemoglobin A1C, and insulin resistance improved significantly with naltrexone/bupropion compared to placebo. The drop-out rate among these four studies was approximately 50%. The most common adverse effects were nausea, headache, constipation, dizziness, vomiting, dry mouth, insomnia, and diarrhea. Changes in blood pressure and resting heart rate tended to be more favorable for placebo-treated individuals than for naltrexone/bupropion-treated individuals, although the magnitude of the difference was small. There were no other notable adverse cardiac effects.
A New Drug Application for naltrexone/bupropion combination was submitted to the FDA in March 2010. An FDA advisory group recommended approval of the combination product and suggested that a cardiovascular safety study be conducted after marketing approval. However, the FDA decided against marketing approval in February 2011, deferring a final decision until a large (9,000 subject) cardiovascular safety study (the Light Study; NCT01601704 on www.ClinicalTrials.gov) was completed.
The primary outcome of the Light Study was the occurrence of major adverse cardiovascular events (MACEs: death, non-fatal stroke, and non-fatal myocardial infarction) for naltrexone/bupropion versus placebo during 4 years of follow up (Cleveland Clinic, 2015). According to an agreement between the study sponsor and FDA, a confidential interim data analysis would be conducted after 25% of MACEs had occurred (approximately 100 events). If these interim results demonstrated that naltrexone/bupropion was not associated with a doubling of risk compared to placebo, the combination product would be considered by the FDA for marketing approval while continuing recruitment in the Light Study. Based on the results from the 25% interim data analysis (completed in November 2013), the FDA approved naltrexone/bupropion for marketing in September 2014, with the stipulation that enrollment in the Light Study continue.
Although the results of the interim analysis were intended to be confidential (restricted to a data safety monitoring committee and the FDA), the findings apparently were more widely released to employees within Orexigen Therapeutics (the drug developer) and Takeda Pharmaceuticals (the company licensed to market the product in the United States). The interim analysis results were also publicly announced in March 2015 by Takeda and Orexigen. According to the 25% interim analysis, naltrexone/bupropion was associated with a 41% reduction in MACEs compared to placebo (35 events for drug versus 59 events for placebo). In May 2015, the executive steering committee of the Light Study recommended that the study be halted, not because of these seemingly favorable results, but because unblinding the “confidential” interim results (by publicly disclosing them) had compromised the integrity of the study (Cleveland Clinic, 2015).
A subsequent interim data analysis, conducted after 50% of MACEs had occurred, found that naltrexone/bupropion was associated with a much smaller 12% reduction in MACEs compared to placebo (90 events for drug versus 102 events for placebo). Hence, during the second 25% of the study, 43 MACEs occurred with placebo and 55 occurred with the drug (Cleveland Clinic, 2015). This finding illustrates that the cardiovascular safety of naltrexone/bupropion derived from only the first 25% of collected data is misleading. Another finding from the 50% analysis was that 26 non-cardiovascular deaths occurred in the naltrexone/bupropion group and 17 occurred in the placebo group. Because enrollment into the Light Study has been halted, the FDA is requiring that a new cardiovascular outcomes study be conducted.
Melatonin, liraglutide, and naltrexone/bupropion are examples of drugs with different mechanisms of action that have favorable effects on obesity or medication-related weight gain. Melatonin has a favorable side effect profile and is available over-the-counter. Although more studies of melatonin are needed, I consider it appropriate to recommend melatonin for any patient who will be started on a psychotropic drug that is potentially associated with weight gain or other adverse metabolic effects. By contrast, the use of naltrexone/bupropion may be problematic in patients with bipolar disorder or schizophrenia because of the potential adverse effects of the bupropion component of the combination. Except possibly for patients with depression, I recommend against the general use of naltrexone/bupropion in psychiatric patients until additional studies are conducted. Finally, I believe that liraglutide is reasonably safe to consider for a broad range of psychiatric patients, but this drug also deserves further study, especially in those patients taking antipsychotic medications. Nurses should become familiar with the clinical studies and safety concerns of these drugs when used for the treatment of overweight and obesity.
- Apovian, C.M., Aronne, L., Rubino, D., Still, C., Wyatt, H., Burns, C. & Dunayevich, E. (2013). A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity (Silver Spring), 21, 935–943. doi:10.1002/oby.20309 [CrossRef]
- Astrup, A., Carraro, R., Finer, N., Harper, A., Kunesova, M., Lean, M.E. & Van Gaal, L. (2012). Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. International Journal of Obesity, 36, 843–854. doi:10.1038/ijo.2011.158 [CrossRef]
- Cipolla-Neto, J., Amaral, F.G., Afeche, S.C., Tan, D.X. & Reiter, R.J. (2014). Melatonin, energy metabolism, and obesity: A review. Journal of Pineal Research, 56, 371–381. doi:10.1111/jpi.12137 [CrossRef]
- Cleveland Clinic. (2015, May12). Clinical trial testing safety of obesity drug Contrave halted; 50 percent interim data released by the study’s executive committee [Press release]. Retrieved from http://my.clevelandclinic.org/about-cleveland-clinic/newsroom/releases-videos-newsletters/2015-5-12-clinical-trial-testing-safety-of-obesity-drug-contrave-halted
- Du, Q., Wang, Y.J., Yang, S., Zhao, Y.Y. & Han, P. (2014). Liraglutide for the treatment of type 2 diabetes mellitus: A meta-analysis of randomized placebo-controlled trials. Advances in Therapy, 31, 1182–1195. doi:10.1007/s12325-014-0164-2 [CrossRef]
- Egan, A.G., Blind, E., Dunder, K., de Graeff, P.A., Hummer, B.T., Bourcier, T. & Rosebraugh, C. (2014). Pancreatic safety of incretin-based drugs—FDA and EMA assessment. New England Journal of Medicine, 370, 794–797. doi:10.1056/NEJMp1314078 [CrossRef]
- Greenway, F.L., Fujioka, K., Plodkowski, R.A., Mudaliar, S., Guttadauria, M., Erickson, J. & Dunayevich, E. (2010). Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. Lancet, 376, 595–605. doi:10.1016/S0140-6736(10)60888-4 [CrossRef]
- Hollander, P., Gupta, A.K., Plodkowski, R., Greenway, F., Bays, H., Burns, C. & Fujioka, K. (2013). Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes. Diabetes Care, 36, 4022–4029. doi:10.2337/dc13-0234 [CrossRef]
- Liraglutide (Victoza) for type 2 diabetes. (2010). The Medical Letter on Drugs and Therapeutics, 52 (1335), 25–27.
- McMullan, C.J., Schernhammer, E.S., Rimm, E.B., Hu, F.B. & Forman, J.P. (2013). Melatonin secretion and the incidence of type 2 diabetes. Journal of the American Medical Association, 309, 1388–1396. doi:10.1001/jama.2013.2710 [CrossRef]
- Modabbernia, A., Heidari, P., Soleimani, R., Sobhani, A., Roshan, Z.A., Taslimi, S. & Modabbernia, M.J. (2014). Melatonin for prevention of metabolic side-effects of olanzapine in patients with first-episode schizophrenia: Randomized double-blind placebo-controlled study. Journal of Psychiatric Research, 53, 133–140. doi:10.1016/j.jpsychires.2014.02.013 [CrossRef]
- Ng, S.Y.A. & Wilding, J.P.H. (2014). Liraglutide in the treatment of obesity. Expert Opinion on Biological Therapy, 14, 1215–1224. doi:10.1517/14712598.2014.925870 [CrossRef]
- Romo-Nava, F., Alvarez-Icaza González, D., Fresán-Orellana, A., Saracco Alvarez, R., Becerra-Palars, C., Moreno, J. & Buijs, R.M. (2014). Melatonin attenuates antipsychotic metabolic effects: An eight-week randomized, double-blind, parallel-group, placebo-controlled clinical trial. Bipolar Disorders, 16, 410–421. doi:10.1111/bdi.12196 [CrossRef]
- Slominski, R.M., Reiter, R.J., Schlabritz-Loutsevich, N., Ostrom, R.S. & Slominski, A.T. (2012). Melatonin membrane receptors in peripheral tissues: Distribution and functions. Molecular and Cellular Endocrinology, 351, 152–166. doi:10.1016/j.mce.2012.01.004 [CrossRef]
- Wadden, T.A., Foreyt, J.P., Foster, G.D., Hill, J.O., Klein, S., O’Neil, P.M. & Dunayevich, E. (2011). Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: The COR-BMOD trial. Obesity (Silver Spring), 19, 110–120. doi:10.1038/oby.2010.147 [CrossRef]
- Wadden, T.A., Hollander, P., Klein, S., Niswender, K., Woo, V., Hale, P.M. & Aronne, L. (2013). Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: The SCALE Maintenance randomized study. International Journal of Obesity, 37, 1443–1451. doi:10.1038/ijo.2013.120 [CrossRef]