Psychiatric Annals

CME Article 

Pharmacological Treatment of Obesity

Cenk Tek, MD; Joseph C. Ratliff, PhD; Lydia Chwastiak, MD, MPH


Losing weight requires permanent changes in behavior. Lifestyle interventions are the most effective obesity treatment we have today. The major limitation of lifestyle interventions is that not everyone can comply with the requirements, and weight lost is usually regained once the intervention is over.1


Losing weight requires permanent changes in behavior. Lifestyle interventions are the most effective obesity treatment we have today. The major limitation of lifestyle interventions is that not everyone can comply with the requirements, and weight lost is usually regained once the intervention is over.1

All authors are with the Department of Psychiatry, Yale University School of Medicine, New Haven, CT. Cenk Tek, MD, is Associate Professor of Psychiatry; Joseph C. Ratliff, PhD, is a Postdoctoral Associate in Psychiatry; and Lydia Chwastiak, MD, MPH, is Associate Professor of Psychiatry.

Drs. Tek, Ratliff, and Chwastiak have disclosed no relevant financial relationships.

Address correspondence to: Cenk Tek, MD, Yale University School of Medicine, Department of Psychiatry, 34 Park St., New Haven, CT 06519-1109; fax: 203-974-7691; email:

Losing weight requires permanent changes in behavior. Lifestyle interventions are the most effective obesity treatment we have today. The major limitation of lifestyle interventions is that not everyone can comply with the requirements, and weight lost is usually regained once the intervention is over.1

Although the effectiveness of lifestyle interventions has been demonstrated repeatedly,2 they are not widely used in the traditional medical settings. Lifestyle programs can be augmented with pharmacological interventions that reduce appetite, reduce food cravings, prevent calorie absorption, or peripherally accelerate metabolism.

The biology of energy metabolism and appetite control is complicated. Both peripheral and central mechanisms involving multiple hormones, neurotransmitters, and signaling proteins ensure against starvation and drive the organism to store energy for use when food is unavailable. Multiple biological systems promote weight gain, but very few mechanisms act against prevention of excess weight, and these are easily overridden by opposing forces. Energy regulation that is biased for storing energy was evolutionarily necessary for the survival of species. In the developed world today, however, starvation is rare. This redundancy of the weight-promoting biological systems is partly responsible for the lack of effective obesity medications, despite decades of research. Yet, pharmacological strategies are only effective when combined with an appropriate behavioral/nutritional program.3

Historical Pharmaceutical Failures

During the past several decades, there have been several weight management drug failures with unfortunate consequences. In the 1940s, methamphetamine was sold as an obesity agent both alone and in combination with barbiturates to manage “jitteriness.” Because it increased the availability of dopamine in the brain, it worked as an appetite suppressant, but the effect was short-lived. The resulting addiction potential, cardiovascular effects (sometimes fatal), and psychiatric complications such as psychosis ended the use of both methamphetamine and other amphetamines as obesity agents.

A more recent example of a drug failure is fenfluramine, a potent serotonin agonist that increased the availability of serotonin in the brain, and was approved for obesity and used throughout the 1990s alone or in combination with phentermine (“fen-phen”). Fenfluramine caused considerable morbidity and mortality, and was withdrawn from the market after it was demonstrated to cause permanent cardiac valvular defects.4

A recent example is sibutramine, a serotonin-noradrenaline reuptake blocker and a weak antidepressant that is thought to promote weight loss by suppressing appetite and activating brown tissue thermogenesis. Sibutramine (10 mg to 20 mg) in combination with behavioral interventions produced an average of 4.5 kg of placebo-adjusted weight loss over 1 year in clinical trials.5 But in 2010, the FDA withdrew sibutramine from the market because of concern over increased risk of stroke and heart attack in patients with cardiac disease.

Based on the observation that recreational cannabis users report increased appetite with cannabis use, rimonabant, a cannabinoid (CB1) receptor blocker, was developed. Rimonabant was effective in multiple studies, but was never approved in the US due to concerns of increased risks of depression and suicidality. It was approved in Europe and used for a few years before it was pulled from the market because of suicide risk.

Over-the-counter (OTC) agents also have been withdrawn from the market by the FDA. Ephedrine and phenylpropanolamine were stimulants that were sold as OTC weight loss supplements and commonly used; but there were very few short- or long-term clinical trials demonstrating weight-loss efficacy. Because these medications were associated with increased risk of stroke and cardiac arrhythmia, the FDA withdrew them from the market in 2002 and 2004, respectively.6

FDA Approval Challenges

Any medication approved for the treatment of obesity likely will be used by a large number of individuals, so even rare complications will be seen in significant numbers. The FDA has therefore appropriately chosen to be conservative in obesity medication reviews. For example, sibutramine was a controlled drug despite its low addiction potential. The FDA guidelines for obesity drug approval7 require either ≥ 5% statistically significant placebo-adjusted weight loss after 1 year of treatment, or weight loss of > 5% of body weight by > 35% of subjects (and approximately twice the amount of weight loss compared to the placebo group, with a difference that is statistically significant). Registration trials require both active and placebo groups to receive nutritional support and behavioral lifestyle intervention. Additionally, the treatment should demonstrate improvement in comorbidities such as plasma lipids, blood pressure, or glucose levels and should not compromise psychiatric or cardiovascular safety. There is specific emphasis during reviews on cardiovascular, psychiatric, and carcinogenic side effects.7

There is one peculiarity of the FDA’s drug approval approach: The FDA defines clinically significant weight loss as 5% of total body weight (TBW) while it defines clinically significant drug-induced weight gain as 7% TBW. This has had unforeseen public health consequences, such as contributing to an obesity epidemic among people with serious mental illness.8

Importance of Medical History

Before starting any medications for obesity, a general medical workup is necessary. The most important reasons for this are that obesity is associated with multiple medical conditions; some medical conditions are associated with weight gain; and available medications (both approved and off-label; see Table, page 490) have multiple organ system side effects. Although the work-up may be different for individual medications, there are some general rules. First, endocrinologic reasons for weight gain such as hypothyroidism — including sub-clinical forms that do not require treatment — and Cushing’s disease need to be ruled out. Second, cardiovascular disease, hypertension, hyperlipidemia, and diabetes — including pre-diabetes conditions such as insulin resistance — need to be identified and treated. A baseline ECG and glycosylated hemoglobin (HbA1c) are useful, in addition to a fasting lipid panel and serum glucose measurement. Baseline liver and kidney function are also important to document. A complete blood count will identify anemia that may be due to a lack of essential nutrients (iron or B vitamins) as a result of dieting. Anemia is not a cause for weight gain, but the associated lack of energy and fatigue may prevent patient adherence with an activity program.

Approved and Off-Label Obesity Medications

Table. Approved and Off-Label Obesity Medications

Finally, all of the medications patients are taking, whether prescribed or OTC, need to be reviewed for weight gain liability. The most frequent offenders are antihistaminic allergy medications;9 as a rule, if an antihistamine sedates, it increases appetite; thus, switching to nonsedating antihistamines might be a pharmacological intervention in itself. Nonsedating agents vary by how much they cross the blood-brain barrier, and sometimes switching between them might be helpful.

Alcohol and drug use also need to be addressed: Marijuana greatly increases appetite; opioids are linked to weight gain; and alcohol is a calorie-dense substance that should be eliminated as part of any weight loss program.

After the initial workup, a review of the patient’s nutrition status and previous weight loss efforts are necessary. A patient never should be started on an obesity medication without first trying a structured lifestyle program. Moreover, lifestyle programs need to be continued after obesity medications are started. A consultation with a registered dietitian is extremely useful to both identify easy targets (such as nondiet soda consumption) and to recommend a diet of modest (500 calories or more) calorie reduction.

As the goal is to produce lasting changes, “crash” diets that might yield initial high weight loss, but which are not easily sustained, are not that useful. The best lifestyle programs are developed by academia (eg, the Diabetes Prevention Program10 [DPP]). However, these are not always widely available and/or reimbursed by insurance companies, and may be more expensive than available commercial programs. Although perhaps not as effective, many nationally available commercial programs11 routinely incorporate elements from academic interventions, provide support, and are fairly affordable.

An activity program such as brisk walking, elimination of elevator use, and parking in far lots, etc, is easy to prescribe in the office-setting and is feasible for incorporation into a patient’s daily routine.

Eating patterns should be investigated and recorded, to identify eating disorders such as binge eating, night eating, or bulimia. Emotional eating should be identified, as well as sleep disorders, since these have been associated with obesity, and can be addressed, preferably by behavioral methods. If a medication must be used, antihistamines should be avoided and the drugs such as zolpidem or eszopiclone need to be used cautiously due to association with sleep eating.12

Medications for Obesity Treatment

Only three medications are currently FDA-approved for the treatment of obesity: two noradrenergic amines that act centrally to decrease appetite; and one lipase inhibitor that acts on the intestinal absorption of fat.


Phentermine is an amphetamine derivative that activates the secretion of norepinephrine and produces weight loss by stimulating a decrease in caloric intake and an increase in resting energy expenditure.13 Phentermine is approved by the FDA for short-term use (generally considered 3 months) and is one of the most prescribed weight-loss medications. Phentermine (15 mg to 30 mg) produces an average of 3.6 kg of placebo-adjusted weight loss over 2 to 24 weeks.5 The most common side effects include insomnia, dry mouth, constipation, hypertension, and tachycardia. Psychosis risk is present although infrequent; other psychiatric side effects include behavior change, agitation, anxiety, even mania. Phentermine use is contraindicated in patients with a history of psychosis. Phentermine was part of the phen-fen combination that was linked to cardiac valvular defects; caution should be exercised in its use. Although it has low addiction potential, misuse has been reported and should be monitored.


Diethylpropion is another noradrenergic amine that is related to the antidepressant bupropion. It is approved for short-term use as an appetite suppressant in conjunction with diet and exercise. Diethylpropion (75 mg) produces an average of 3 kg of placebo-adjusted weight loss over 6 months.5 Side effects are similar to those observed with phentermine use and similar caution should be exercised when prescribing it.


Orlistat is a gastric and pancreatic lipase inhibitor that blocks intestinal absorption of up to 30% of ingested fat. It is approved for use for up to 1 year. It does not have any central nervous system or appetite effects. Orlistat (360 mg) produces an average of 2.8 kg of placebo-adjusted weight loss over 1 year.5 Additionally, weight loss with orlistat treatment is associated with improvements in plasma lipids and blood pressure when combined with a lifestyle program. The most common side effects include gastrointestinal discomfort, diarrhea/soiling, and deficiencies of the fat-soluble vitamins. Orlistat is available as an OTC medication at a lower dose; this formulation is much less expensive. Orlistat is not appropriate for patients who are able to curb their fat intake through dietary changes.

Off-Label Medications that May Produce Weight Loss


Metformin is a biguanide antihyperglycemic medication approved for the treatment of type 2 diabetes. Metformin reduces blood glucose levels by decreasing hepatic glucose production and enhancing insulin sensitivity. It may also decrease appetite through its effect on the hypothalamus. During the DPP, a study of several thousand overweight people at risk for diabetes, those receiving metformin treatment (850 mg twice daily) who did not develop diabetes lost an average of 2.9 kg.14 Possible side effects include nausea, gastrointestinal discomfort, and lactic acidosis. Metformin is very well-tolerated, inexpensive, and may be useful for patients with developing insulin resistance — both for modest weight loss, and also to delay the onset of diabetes.


Exenatide is a glucagon-like peptide 1 (GLP-1) receptor agonist that is FDA-approved for treating type 2 diabetes. GLP-1 is secreted in response to food ingestion and slows down gastric emptying and stimulates insulin secretion. In clinical trials, exenatide (10 μg) produced a 4.1 kg placebo-adjusted weight loss and a significant reduction in HbA1c over 26 weeks.15 Common side effects include nausea, headache, and pancreatitis. It is administered only as a subcutaneous injection, and therefore may not be practical for obesity treatment.


Bupropion is a dopamine and nor-adrenaline reuptake inhibitor that is approved for the treatment of depression and smoking cessation. Over 6 to 12 months, bupropion (300 mg to 400 mg) produces a 2.8 kg placebo-adjusted weight loss.5 Side effects include seizures, dry mouth, insomnia, and nausea. Similar to many antidepressants, it carries a suicide warning. This may be the antidepressant of choice in obese individuals, but it is less useful as an obesity treatment in nondepressed individuals, given the associated risks.


Topiramate is approved for the treatment of epilepsy and migraines, and may be the treatment of choice for obese patients with these disorders. Topiramate (96 mg to 196 mg) produces an average of 6.6 kg of placebo-adjusted weight loss over 6 months.5 It does not appear that any additional benefit is obtained beyond a dose of 200 mg. Although the mode of action for weight loss is uncertain, it is hypothesized that its role as a weak carbonic anhydrase inhibitor may produce weight loss through inhibition of lipogenesis. Topiramate should be used with caution, as it carries a suicidality warning, and metabolic acidosis and kidney stone formation can occur. More common side effects include paresthesia, dizziness, insomnia, and cognitive impairment. In our clinical experience, the cognitive side effects limit the usefulness of topiramate as a weight-loss medication.


Zonisamide is approved for the treatment of epilepsy, and similar to topiramate, is hypothesized to produce weight loss as a weak carbonic anhydrase inhibitor. Over 16 weeks, zonisamide (up to 600 mg titrated) produced a 5 kg placebo-adjusted weight loss.5 Side effects include fatigue, nausea, dizziness, and cognitive impairment.

Combinations of Generic Medications

Combinations of available medications with differing mechanisms are currently in development; none of these patented combinations has received FDA approval. These medications are available as single agents; consideration may be given to some combinations.

Naltrexone and Bupropion

The combination of the opioid receptor antagonist naltrexone and the dopamine and noradrenaline reuptake inhibitor bupropion has been developed. Naltrexone decreases desire for foods rich in fat and sugars in animals and humans but has not been found effective for weight loss as a single agent.16 In a 56-week phase 3 trial, a combination of sustained-release naltrexone 32 mg and bupropion 360 mg resulted in a 4.7 kg placebo-adjusted weight loss, as well as improvements in lipid metabolism.17 Naltrexone is available in a generic immediate-release form as 50 mg tablets. Bupropion is available as a sustained release formulation in different dosages. In the study, the most common side effects were nausea, constipation, and dizziness. In 2011, the FDA did not approve this combination, citing the necessity for long-term cardiovascular outcome trials.

Phentermine and Topiramate

The rationale for the combination of phentermine and topiramate is to reduce the side effects of the individual medications. In a 56-week phase 3 trial, phentermine 15 mg taken with topiramate controlled-release 92 mg resulted in an 8.8 kg placebo-adjusted weight loss, as well as reductions in blood pressure, triglycerides, and HbA1c.18 The most common side effects were dry mouth, paresthesia, and constipation. Cognitive impairment was also more common in the experimental group compared to placebo. Despite its impressive efficacy, this medication was denied approval in 2010 due to concerns about increased heart rates and possible teratogenic properties, leading to the planning of more long-term clinical trials. Data for kidney stone formation with this combination is unavailable, but they likely occur at rates similar to those of treatment with the single agents.

Bupropion and Zonisamide

The rationale for this combination is that zonisamide may decrease bupropion-induced seizures, while bupropion may negate some of the psychiatric symptoms of zonisamide. Although the results of early phase clinical trials have yet to be published, a 12-week, randomized, open-label study with the combination of bupropion (200 mg/day) and zonisamide (400 mg/day) resulted in a 7.2 kg weight reduction in 18 obese women.19 The most frequent side effects were nausea, headache, and insomnia. This combination has not yet begun phase 3 trials. Zonisamaide is available in an immediate-release formulation, while bupropion is available in both sustained and immediate-release formulations.

Prospective Drug Candidates

Many pharmacological agents with both central and peripheral action mechanisms are in the early phase of development. Time will tell which one of these will be efficacious enough to make it to the market. Lorcaserin, a selective 5-HT2C serotonergic agonist that reduces food intake to promote weight loss, seems close to FDA approval. A multicenter trial found that lorcaserin (10 mg twice daily) induced a 3.6 kg placebo-adjusted weight loss and was associated with significant improvements in blood pressure, insulin resistance, and lipids.20 The most frequent adverse events were headache, dizziness, and nausea. In 2010, the FDA did not approve lorcaserin because its weight loss efficacy did not outweigh its possible carcinogenic properties. Further studies are in progress.

Over-the-Counter Supplements

There are many OTC weight-loss supplements available in the US, but very few studies are available on them. These agents usually purport to be appetite reducers, or metabolism enhancers, natural stimulants, or diuretics. These supplements usually include a mild stimulant such as very high doses of caffeine. Chromium piccolinate is a frequent component; however, a meta-analysis found an average of only 1.1 kg weight loss over 3 months associated with this ingredient.21 Similarly, an African cactus product, Hoodia gordonii, is speculated to suppress appetite based on its use by the Zulu for long travels on foot, but its efficacy was not verified by studies.22 It is important to question patients for OTC supplement use since naturally occurring substances are pharmacologically active, making drug interactions likely. High doses of caffeine, for example, can increase levels of prescription medications through hepatic microsomal enzyme inhibition.

Weight Loss for Psychiatric Patients

Many psychiatric medications cause weight gain. The advent of the second-generation antipsychotic agents (SGAs) such as olanzapine has caused an obesity epidemic among psychiatric patients.8 But antipsychotic medications are not the only psychiatric medications associated with weight gain. Antidepressants such as mirtazapine, and mood stabilizers such as valproate and lithium, also cause clinically significant weight gain.

Mental health status is also important when deciding the pharmacological strategy, since most obesity medications are centrally acting and it is possible to benefit from these effects or avert disasters due to them. As an example, adrenergic amines may be the choice for depressed patients who might benefit from the stimulant effect, while they would be contraindicated for psychotic spectrum patients. Bupropion is the clear choice as an antidepressant for obese patients; since obesity is associated with depression, this scenario is not very unusual. Polypharmacy is frequent, and perhaps necessary, in psychiatry. Thus drug-drug interactions should be reviewed before starting any medication.

All antipsychotic medications, including those with low liability for weight gain, can cause significant weight gain, especially among medication-naïve patients, as demonstrated in first episode psychosis studies.23 It is therefore important to emphasize that it is much easier to prevent weight gain than to lose weight once one is obese. However, it is a herculean task to lose weight while taking a medication that increases appetite. Antipsychotics should be used with caution — or not used at all — among patients with insomnia and anxiety.

Proven low-weight liability strategies can be tried for treatment-resistant depression. These include thyroid augmentation or electroconvulsive therapy instead of augmentation with antipsychotic agents. Psychosis in bipolar disorder, if present, is often episodic and antipsychotic use can be limited to episodes. Not all antipsychotics have the same weight liability, and low weight-gain liability options should be chosen (including older agents such as perphenazine or loxapine). Significant weight gain is a good reason to switch from antipsychotic agents (and other psychotropics) to those with lower weight-gain liability. Those with serious mental illness often benefit from behavioral weight-loss programs and nutrition interventions,24 but are less likely to be referred to these programs.


Behavioral programs and dieting should always be tried first to remediate obesity. A careful risk-benefit analysis is especially relevant in obesity treatment due to problematic multi-organ side effects of medications and frequent pre-existing medical conditions among overweight patients. Medications should be the last resort and should always accompany a well drafted nutritional and behavioral program. When all else fails, for patients with extreme obesity or significant medical complications, bariatric surgery may be indicated.


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Approved and Off-Label Obesity Medications

MedicationDoseWeight lossSide effects
Approved for the treatment of obesity
Phentermine15 to 30 mg P.O. qD3.6 kg over 2 to 24 weeksInsomnia, dry mouth, constipation, hypertension, tachycardia, behavior change, anxiety, agitation, psychosis.
Diethylpropion75 mg P.O. qD3.0 kg over 6 monthsInsomnia, dry mouth, constipation, hypertension, tachycardia, behavior change, anxiety, agitation, psychosis.
Orlistat360 mg P.O. qD2.8 kg over 1 yearGastrointestinal discomfort, diarrhea/soiling, deficiencies of fat-soluble vitamins.
Approved for other indications and may cause weight loss
Metformin850 mg P.O. BID2.9 kg over 2.5 yearsNausea, gastrointestinal discomfort, lactic acidosis.
Exenatide10 μg subcutaneous4.1 kg over 26 weeksNausea, headache, pancreatitis.
Bupropion300 mg to 400 mg P.O. qD2.8 kg over 6 to 12 monthsSeizure, dry mouth, insomnia, nausea, suicidality.
Topiramate96 mg to 196 mg P.O. qD6.6 kg over 24 weeksParesthesia, dizziness, insomnia, kidney stones, metabolic acidosis, cognitive impairment, suicidality.
Zonisamide600 mg P.O. qD4.1 kg over 26 weeksFatigue, nausea, dizziness, metabolic acidosis, cognitive impairment, suicidality.

CME Educational Objectives

  1. Know what information is necessary before starting pharmacological treatment of obesity.

  2. To become familiar with the risks and benefits of current pharmacological treatments of obesity.

  3. To understand how to facilitate weight loss for psychiatric patients.


All authors are with the Department of Psychiatry, Yale University School of Medicine, New Haven, CT. Cenk Tek, MD, is Associate Professor of Psychiatry; Joseph C. Ratliff, PhD, is a Postdoctoral Associate in Psychiatry; and Lydia Chwastiak, MD, MPH, is Associate Professor of Psychiatry.

Drs. Tek, Ratliff, and Chwastiak have disclosed no relevant financial relationships.

Address correspondence to: Cenk Tek, MD, Yale University School of Medicine, Department of Psychiatry, 34 Park St., New Haven, CT 06519-1109; fax: 203-974-7691; email:


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