October 2010

Exercise in Schizophrenia
Regular exercise can positively affect mental and physical health in people with schizophrenia.

Recognizing and Mitigating Delirium
Preventing delirium in hospitalized older patients saves lives and decreases dementia.

Lorcaserin: A New Drug for Weight Loss?
Lorcaserin has a better safety and adverse event profile but no greater efficacy than currently available weight loss agents.

In Brief
Bupropion during Pregnancy May Increase Risk of ADHD in Offspring; Bipolar Disorder Screening Recommended for Patients with Fibromyalgia

Treating Bipolar II Depression
Only quetiapine (Seroquel) is established as a first-line treatment for bipolar II depression; lithium, selective serotonin reuptake inhibitors (SSRIs), lamotrigine (Lamictal), and pramipexole (Mirapex and others) are second-line options.

Lorcaserin: A New Drug for Weight Loss?

October 2010

A considerable public health problem in the United States, obesity increases rates of cardiovascular disease and diabetes, exacerbates bone and joint problems as people age, and can diminish self-esteem and social comfort. People with depression or other psychiatric disorders may be at greater risk for obesity. Moreover, many classes of psychiatric medications, most notably antipsychotics, independently cause weight gain.

In a recent editorial, Astrup observes a worrisome pattern in the history of pharmacologic treatment of obesity.1 Most drugs approved for marketing have subsequently been withdrawn because of serious adverse effects. The cannabinoid-receptor antagonist rimonabant was withdrawn from European markets because it increased depression, anxiety, and suicidal thinking (BTP 2008;31:5). Three other cannabinoid-receptor antagonists also were withdrawn from clinical investigation. In 2010, the serotonin and norepinephrine reuptake inhibitor (SNRI) sibutramine (Meridia and others) was removed from the European market. Later this year, the US Food and Drug Administration (FDA) expects to complete a review of sibutramine's benefits versus its risks. In patients with cardiovascular disease and type II diabetes, sibutramine is associated with an increased risk of serious, nonfatal cardiovascular events, such as stroke and myocardial infarction. While the FDA currently is allowing sibutramine to remain on the market, the manufacturer has to add labeling that patients with a history of cardiovascular disease should not take it.

Fenfluramine and dexfenfluramine, two other weight loss agents, cause the release of endogenous serotonin from neurons and platelets. Fenfluramine was approved by the FDA in 1973 and dexfenfluramine, in 1996. Both became popular in combination with phentermine (Phentrol and others), which provided additive weight loss benefits. Both fenfluramine compounds were withdrawn from the market in 1997 following reports of valvular heart disease, which caused regurgitation. Fenfluramine has been associated also with increased risk of pulmonary arterial hypertension.

Valvulopathy and pulmonary arterial hypertension are believed to reflect serotonin effects on the 5-HT2B receptor. By contrast, appetite suppression is thought to be mediated by the 5-HT1B and 5-HT2C receptors.

Lorcaserin is a new compound that selectively affects central 5-HT2C receptors, with very weak effects on 5-HT2A and 5-HT2B receptors. In a study funded by lorcaserin's manufacturer, Smith and others randomly assigned more than 3000 overweight or obese patients to lorcaserin or placebo, in combination with a program of diet and exercise.2 After 1 year of treatment, 47.5% of those receiving lorcaserin but only 20.3% in the placebo group had lost 5% or more of their body weight (P < .001). Weight loss was approximately 4 kg (8.9 lb) greater on average in the lorcaserin group than in the placebo cohort.

For the second year, patients who had been taking lorcaserin were randomly assigned in a 2-to-1 ratio to either continue receiving active drug or switch to placebo. Those who switched to placebo gained back the weight they had lost and, at 2 years, had roughly the same body weight as those who had taken placebo for the entire study. Those who took lorcaserin for both years, by contrast, gained back less weight and, at the end of the study, had lost approximately 2 kg (4.4 lb) more than subjects in the placebo group.

For comparison, Astrup points out that lorcaserin's efficacy in promoting weight loss is slightly less than or equivalent to that of the lipase inhibitor orlistat (Alli and others) and slightly less than that of sibutramine, the other two weight loss compounds on the market in the United States. However, the overall safety profile of lorcaserin appears superior to both orlistat and sibutramine. Lorcaserin does not seem to increase the risk of valvulopathy, pulmonary hypertension, depression, or suicidal thinking. Its most common adverse events are upper respiratory infections, headache, dizziness, and nausea. In the Smith et al study, the discontinuation rate in the lorcaserin group was marginally greater than in the placebo group. Astrup notes that phase III studies would be required to confirm lorcaserin's adverse effect profile in larger populations.

Also of interest, lorcaserin was associated with a slight but clinically relevant improvement in most surrogate markers of diabetes and cardiovascular risk. Drugs such as rimonabant and sibutramine do not improve blood pressure, heart rate, and levels of low density lipoprotein cholesterol—factors that would be expected and hoped for with weight loss.

Astrup emphasizes that, if lorcaserin is approved for marketing, its advantage will not be greater efficacy than other agents but a better safety and adverse event profile, along with apparent beneficial effects on risk factors for type II diabetes and cardiovascular disease. Two key questions are: Can lorcaserin be combined safely and effectively with other weight loss drugs that have different mechanisms of action? How will it fit into a clinical algorithm, which obviously must continue to emphasize diet and exercise? The editorialist ends by calling for caution with any new weight loss drug, as the history of compounds in this class is fraught with late discovery of serious adverse effects.

1Astrup A: Drug management of obesity—Efficacy versus safety. N Engl J Med 2010;363:288–290.

2Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, Bays H, Shanahan WR, the Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) study group: Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010;363:245–256.