Journal of Psychosocial Nursing and Mental Health Services

Psychopharmacology 

Therapies for Obesity and Medication-Associated Weight Gain

Robert H. Howland, MD

Abstract

Compared to the general population, individuals with psychiatric illness, especially serious and chronic mood and psychotic disorders, are more likely to be overweight or obese, have higher rates of weight-related medical conditions, and have greater non-suicide mortality rates. Lorcaserin (Belviq®), phentermine/topiramate combination (Qsymia®), and bupropion/naltrexone combination have been demonstrated to be effective for the treatment of obesity, as an adjunct to a reduced-calorie diet and physical activity, although their absolute safety has yet to be established with more widespread use or longer use. Bariatric surgery is an effective approach for morbid obesity, but careful psychiatric assessment before and follow up after surgery is necessary. Behavioral lifestyle interventions to promote weight loss are effective and should be implemented along with or instead of drug therapies or surgery.

Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.

The author has disclosed no potential conflicts of interest, financial or otherwise.

Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.

Posted Online: April 18, 2013

Abstract

Compared to the general population, individuals with psychiatric illness, especially serious and chronic mood and psychotic disorders, are more likely to be overweight or obese, have higher rates of weight-related medical conditions, and have greater non-suicide mortality rates. Lorcaserin (Belviq®), phentermine/topiramate combination (Qsymia®), and bupropion/naltrexone combination have been demonstrated to be effective for the treatment of obesity, as an adjunct to a reduced-calorie diet and physical activity, although their absolute safety has yet to be established with more widespread use or longer use. Bariatric surgery is an effective approach for morbid obesity, but careful psychiatric assessment before and follow up after surgery is necessary. Behavioral lifestyle interventions to promote weight loss are effective and should be implemented along with or instead of drug therapies or surgery.

Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.

The author has disclosed no potential conflicts of interest, financial or otherwise.

Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.

Posted Online: April 18, 2013

 

Overweight and obesity, now considered epidemic, are associated with significant morbidity, including increased risks for heart disease, stroke, diabetes, apnea, and certain cancers, and consequent mortality. Compared to the general population, individuals with psychiatric illness, especially serious and chronic mood and psychotic disorders, are more likely to be overweight or obese, have higher rates of weight-related medical conditions, and have greater non-suicide mortality rates. There is no single reason for this disparity. Likely contributing factors include physical inactivity, unhealthy diet, poor health care access and utilization, intrinsic illness-related physiological processes, and psychotropic drug-related effects. The U.S. Food and Drug Administration (FDA) has approved some medications for the treatment of obesity, including two new products described below (Colman et al., 2012). Other medications are known to be associated with weight loss and can be used to promote weight loss or minimize weight gain, although they are not FDA-approved for this indication. As an update to a previous article (Howland, 2008), I will briefly discuss several newer therapeutic approaches for obesity and medication-related weight gain.

Lorcaserin (Belviq®)

Lorcaserin was approved by the FDA in 2012 for the treatment of obesity, as an adjunct to a reduced-calorie diet and physical activity. Lorcaserin is a selective small molecule agonist drug that stimulates the serotonin 2C (5HT2C) receptor. Activation of the 5HT2C receptor decreases food intake by increasing satiety and decreasing hunger. The efficacy of lorcaserin was established in two large randomized, double-blind, placebo-controlled studies (RCTs) of overweight or obese adults (1-year study by Fidler et al., 2011; 2-year study by Smith et al., 2010) and in a large 1-year placebo-controlled RCT of overweight or obese adults with diabetes (O’Neil et al., 2012).

Common side effects of lorcaserin are nausea, dizziness, headache, and fatigue. Hypogylcemia, observed in the diabetes study, can occur. Stimulation of 5HT2C receptors increases prolactin secretion, which may result in galactorrhea, gynecomastia, decreased or irregular menses, or decreased libido, although increased prolactin was not reported in the human studies. There is a potential risk for developing serotonin syndrome if lorcaserin is combined with other serotonergic drugs, but this has not yet been reported. Several drugs previously marketed for obesity (i.e., fenfluramine and dexfenfluramine [Redux®]) were withdrawn because they were associated with the development of valvular heart disease and pulmonary arterial hypertension. These serious adverse events are thought to be mediated by effects on serotonin 2B (5HT2B) receptors. The three lorcaserin studies incorporated cardiac assessments and did not find evidence for significantly increased rates of these adverse events compared to placebo. The lack of these serious adverse effects may be due to the drug’s selectivity for 5HT2C receptors, but this will need to be assessed further with more widespread use of lorcaserin for longer periods of time now that it has been marketed.

Phentermine/Topiramate Combination (Qsymia®)

Sympathomimetic drugs (directly or indirectly affecting norepinephrine or dopamine) have appetite-suppressing effects that can result in weight loss (Eckel, 2008). Phentermine (Adipex®) is one of several drugs in this class that is FDA-approved for the treatment of obesity.

Topiramate (Topamax®) is an anticonvulsant drug that is FDA-approved for the treatment of certain types of seizures and migraine headaches. Clinical treatment studies in epilepsy and migraine headaches observed that topiramate-treated patients were more likely to lose weight than placebo-treated patients. Five other placebo-controlled RCTs in adults with obesity also found greater weight loss for topiramate compared to placebo (Antel & Hebebrand, 2012). Controlled studies have demonstrated that topiramate can prevent or reduce weight gain associated with antipsychotic drugs (Mahmood et al., 2013). The mechanism of action of topiramate on promoting weight loss is not clearly known.

A fixed-dose phentermine/topiramate combination product was approved by the FDA in 2012 for the treatment of obesity, as an adjunct to a reduced-calorie diet and physical activity. The efficacy of the combination was established in two large 56-week, placebo-controlled RCTs of overweight or obese adults (Allison et al., 2011; Gadde et al., 2011). Additional efficacy and safety information from a 1-year placebo-controlled extension study (2 years total on study drug or placebo) was reported by Garvey et al. (2012) as an extension of the Gadde et al. (2011) RCT. Common side effects observed in the clinical trials were dry mouth, paresthesia, taste alteration, constipation, insomnia, dizziness, headache, and fatigue. Potential side effects related to the phentermine component are anxiety and increased heart rate. Potential side effects from the topiramate component include confusion, word finding difficulties, and other adverse cognitive effects; metabolic acidosis; decreased sweating; kidney stones; and acute narrow angle glaucoma.

Bupropion/Naltrexone Combination

Bupropion (Wellbutrin®) is an anti-depressant drug affecting norepinephrine and dopamine transmission. Compared to other antidepressant drugs, it is more often associated with a decrease in weight. Three placebo-controlled RCTs in obese adults demonstrated that weight loss was significantly greater for bupropion compared to placebo (Plodkowski et al., 2009). Bupropion (Zyban®) also is FDA-approved for smoking cessation, and individuals who stop smoking with bupropion are less likely to gain weight compared to those who stop smoking without the use of bupropion (Richmond & Zwar, 2003).

Naltrexone (Revia®) is a pure opioid receptor antagonist drug (i.e., it has no agonist effects on any opioid receptor subtype). It can be used for rapid detoxification from opioid drug addictions, and has FDA-approved indications for the treatment of opioid dependence and alcohol dependence. Animal studies suggested that endogenous opioid systems regulate feeding behavior, but human studies of food intake and obesity found minimal to no benefit with the use of naltrexone (Nogueiras et al., 2012).

Despite the apparent lack of weight loss benefit for naltrexone in humans, animal studies demonstrating synergistic effects of bupropion plus naltrexone on feeding and weight led to human studies of the bupropion/naltrexone combination (Plodkowski et al., 2009). One 24-week, placebo-controlled, dose-finding study (Greenway et al., 2009) and two larger 56-week, placebo-controlled RCTs (Greenway et al., 2010; Wadden et al., 2011) in obese adults confirmed the efficacy of the combination. Common side effects in these studies were nausea, headache, dizziness, and insomnia. Despite greater weight loss in the combination group, however, reductions in blood pressure were less than in the placebo group. There were no other notable adverse cardiac effects. An FDA advisory group recommended approval of the combination product and recommended that a cardiovascular safety study be conducted after approval, but the FDA decided against approval until a cardiovascular safety study was completed (Billes & Greenway, 2011).

Bariatric Surgery for Obesity

Bariatric surgery has become an accepted intervention for the treatment of morbid obesity. Three RCTs have found that bariatric surgery resulted in greater weight loss and better metabolic effects (e.g., glycemic control) compared to intensive conventional medical therapy alone (Kashyap et al., 2013). Prevalence rates for various psychiatric disorders appear to be high among individuals being evaluated for bariatric surgery (Muhlhans, Horbach, & de Zwaan, 2009). Patients with a psychiatric history also are more likely to not follow through with surgery (Sockalingam et al., 2013). In addition, bariatric surgery patients show higher suicide rates than the general population (Peterhänsel, Petroff, Klinitzke, Kersting, & Wagner, 2013). Given these various findings, careful pre-surgery psychiatric assessment and post-surgery follow up are clearly warranted (Marcus, Kalarchian, & Courcoulas, 2009).

Behavioral Weight-Loss Interventions

That all patients should receive ongoing counseling about dietary and physical activity weight management strategies is easier said than done. Lifestyle intervention trials in the general population have shown significant benefits, although the benefits are modest and there are always concerns about long-term adherence to lifestyle changes. Psychiatric patient populations have unique needs and often are excluded from such studies, although they are at higher risk for overweight/obesity and associated medical complications. Daumit et al. (2013) recently published their findings from a large multisite community-based behavioral weight-loss intervention program for patients with serious mental illness. They observed a significantly greater weight reduction for the intervention group compared to the control group during the 18 months of the study, demonstrating that severely ill individuals are able to make meaningful lifestyle changes. Obviously, the feasibility of implementing this type of intervention into routine clinical practice across various mental health settings is uncertain, given funding limitations and priorities. Another important factor for lifestyle interventions with patients is the relevance of personal lifestyle behaviors among health care providers (HCPs). Shai et al. (2012), for example, found that HCPs’ personal lifestyles are directly correlated with their clinical health promotion performance among patients, and that changing HCPs’ personal behaviors led to favorable changes in their health promotion to the patients.

Conclusion

Overweight, obesity, and their associated or consequent medical effects is an important public health problem, especially among patients with mental disorders. Several weight-loss drugs or drug combination products have been approved or are in the pipeline, but they have not necessarily been specifically studied in psychiatric patient populations or for medication-related weight gain. The drugs in these combination products can be prescribed individually, and it is therefore possible to co-prescribe them individually for patients in situations where the combination product is unavailable or is not covered by insurance. Bariatric surgery also is an effective approach, but careful psychiatric assessment before and follow up after surgery is imperative. Finally, behavioral lifestyle interventions for weight loss are effective, and they should be implemented along with or instead of drug therapies or surgery, but such interventions should target providers as well as patients. Nurses should be familiar with drug, surgical, and behavioral therapies for overweight and obesity, as they can have a central role in their use.

References

  • Allison, D.B., Gadde, K.M., Garvey, W.T., Peterson, C.A., Schwiers, M.L., Najarian, T. & Day, W.W. (2011). Controlled-release phentermine/topiramate in severely obese adults: A randomized controlled trial (EQUIP). Obesity, 20, 330–342. doi:10.1038/oby.2011.330 [CrossRef]
  • Antel, J. & Hebebrand, J. (2012). Weight-reducing side effects of the antiepileptic agents topiramate and zonisamide. Handbook of Experimental Pharmacology, 209, 433–466. doi:10.1007/978-3-642-24716-3_20 [CrossRef]
  • Billes, S.K. & Greenway, F.L. (2011). Combination therapy with naltrexone and bupropion for obesity. Expert Opinion on Pharmacotherapy, 12, 1813–1826. doi:10.1517/14656566.2011.591382 [CrossRef]
  • Colman, E., Golden, J., Roberts, M., Egan, A., Weaver, J. & Rosebraugh, C. (2012). The FDA’s assessment of two drugs for chronic weight management. New England Journal of Medicine, 367, 1577–1579. doi:10.1056/NEJMp1211277 [CrossRef]
  • Daumit, G.L., Dickerson, F.B., Wang, N.Y., Dalcin, A., Jerome, G.J., Anderson, C.A. & Appel, L.J. (2013). A behavioral weight-loss intervention in persons with serious mental illness. New England Journal of Medicine. Advance online publication. doi:10.1056/NEJMoa1214530 [CrossRef]
  • Eckel, R.H. (2008). Nonsurgical management of obesity in adults. New England Journal of Medicine, 358, 1941–1950. doi:10.1056/NEJMcp0801652 [CrossRef]
  • Fidler, M.C., Sanchez, M., Raether, B., Weissman, N.J., Smith, S.R., Shanahan, W.R. & Anderson, C.M. (2011). A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: The BLOSSOM trial. Journal of Clinical Endocrinology and Metabolism, 96, 3067–3077. doi:10.1210/jc.2011-1256 [CrossRef]
  • Gadde, K.M., Allison, D.B., Ryan, D.H., Peterson, C.A., Troupin, B., Schwiers, M.L. & Day, W.W. (2011). Effects of low-dose controlled-release phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): A randomized placebo-controlled phase 3 trial. Lancet, 377, 1341–1352. doi:10.1016/S0140-6736(11)60205-5 [CrossRef]
  • Garvey, W.T., Ryan, D.H., Look, M., Gadde, K.M., Allison, D.B., Peterson, C.A. & Bowden, C.H. (2012). Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): A randomized placebo-controlled phase 3 extension study. American Journal of Clinical Nutrition, 95, 297–308. doi:10.3945/ajcn.111.024927 [CrossRef]
  • Greenway, F.L., Dunayevich, E., Tollefson, G., Erickson, J., Guttadauria, M., Fujioka, K. & Cowley, M.A. (2009). Comparison of combined bupropion and naltrexone therapy for obesity with monotherapy and placebo. Journal of Clinical Endocrinology and Metabolism, 94, 4898–4906. doi:10.1210/jc.2009-1350 [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 multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 376, 595–605. doi:10.1016/S0140-6736(10)60888-4 [CrossRef]
  • Howland, R.H. (2008). Pharmacotherapy for psychotropic drug-related weight gain. Journal of Psychosocial Nursing and Mental Health Services, 46(7), 15–18 doi:10.3928/02793695-20080201-06 [CrossRef] .
  • Kashyap, S.R., Bhatt, D.L., Wolski, K., Watanabe, R.M., Abdul-Ghani, M., Abood, B. & Schauer, P.R. (2013). Metabolic effects of bariatric surgery in patients with moderate obesity and type 2 diabetes. Diabetes Care. Advance online publication. doi:10.2337/dc12-1596 [CrossRef]
  • Mahmood, S., Booker, I., Huang, J. & Coleman, C.I. (2013). Effect of topiramate on weight gain in patients receiving atypical antipsychotic agents. Journal of Clinical Psychopharmacology, 33, 90–94. doi:10.1097/JCP.0b013e31827cb2b7 [CrossRef]
  • Marcus, M.D., Kalarchian, M.A. & Courcoulas, A.P. (2009). Psychiatric evaluation and follow-up of bariatric surgery patients. American Journal of Psychiatry, 166, 285–291. doi:10.1176/appi.ajp.2008.08091327 [CrossRef]
  • Muhlhans, B., Horbach, T. & de Zwaan, M. (2009). Psychiatric disorders in bariatric surgery candidates: A review of the literature and results of a German prebariatric surgery sample. General Hospital Psychiatry, 31, 414–421. doi:10.1016/j.genhosppsych.2009.05.004 [CrossRef]
  • Nogueiras, R., Romero-Picó, A., Vazquez, M.J., Novelle, M.G., López, M. & Diéguez, C. (2012). The opioid system and food intake: Homeostatic and hedonic mechanisms. Obesity Facts, 5, 196–207 doi:10.1159/000338163 [CrossRef] .
  • O’Neil, P.M., Smith, S.R., Weissman, N.J., Fidler, M.C., Sanchez, M., Zhang, J. & Shanahan, W.R. (2012). Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: The BLOOM-DM study. Obesity, 20, 1426–1436. doi:10.1038/oby.2012.66 [CrossRef]
  • Peterhänsel, C., Petroff, D., Klinitzke, G., Kersting, A. & Wagner, B. (2013). Risk of completed suicide after bariatric surgery: A systematic review. Obesity Reviews. Advance online publication. doi:10.1111/obr.12014 [CrossRef]
  • Plodkowski, R.A., Nguyen, Q., Sundaram, U., Nguyen, L., Chau, D.L. & St. Jeor, S. (2009). Bupropion and naltrexone: A review of their use individually and in combination for the treatment of obesity. Expert Opinion on Pharmacotherapy, 10, 1069–1081. doi:10.1517/14656560902775750 [CrossRef]
  • Richmond, R. & Zwar, N. (2003). Review of bupropion for smoking cessation. Drug and Alcohol Review, 22, 203–220 doi:10.1080/09595230100100642 [CrossRef] .
  • Shai, I., Erlich, D., Cohen, A.D., Urbach, M., Yosef, N., Levy, O. & Shahar, D.R. (2012). The effect of personal lifestyle intervention among health care providers on their patients and clinics: The Promoting Health by Self Experience (PHASE) randomized controlled intervention trial. Preventive Medicine, 55, 285–291. doi:10.1016/j.ypmed.2012.08.001 [CrossRef]
  • Smith, S.R., Weissman, N.J., Anderson, C.M., Sanchez, M., Chuang, E., Stubbe, S. & Shanahan, W.R. (2010). Multicenter, placebo-controlled trial of lorcaserin for weight management. New England Journal of Medicine, 363, 245–256. doi:10.1056/NEJMoa0909809 [CrossRef]
  • Sockalingam, S., Cassin, S., Crawford, S.A., Pitzul, K., Khan, A., Hawa, R. & Okrainec, A. (2013). Psychiatric predictors of surgery non-completion following suitability assessment for bariatric surgery. Obesity Surgery, 23, 205–211. doi:10.1007/s11695-012-0762-5 [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, 19, 110–120. doi:10.1038/oby.2010.147 [CrossRef]

10.3928/02793695-20130411-01

Sign up to receive

Journal E-contents