February 2008

Rimonabant Causes Depression and Anxiety
Rimonabant works as a weight loss agent but may cause depression and anxiety.

Selegiline Augmentation for Negative Symptoms of Schizophrenia
Patients with schizophrenia who take selegiline (Eldepryl, Emsam) in addition to antipsychotic drugs may have greater improvement in negative symptoms.

Managing Psychosis in Parkinson's Disease and DLB
Psychosis in Parkinson’s disease or dementia with Lewy bodies is difficult to treat, and patients are sensitive to side effects of drugs used for these conditions.

New Medicines for GAD: Duloxetine and Quetiapine
Duloxetine (Cymbalta) and quetiapine (Seroquel) are effective in treating generalized anxiety disorder.

In Brief
FDA Warns About Varenicline Psychiatric Adverse Effects; Index Ranks States on Prevalence of Depression and Suicide

Norepinephrine Uptake Inhibition
Atomoxetine (Strattera) inhibits norepinephrine uptake at lower doses than does venlafaxine (Effexor and others) or paroxetine (Paxil and others).

Rimonabant Causes Depression and Anxiety

February 2008

Obesity continues to be a serious threat to health in the United States and elsewhere. When diet and exercise are insufficient, doctors often turn to medicine to help patients lose weight.

Marijuana stimulates appetite, which suggests that endogenous cannabinoids may be involved in energy balance. The first endogenous cannabinoid was isolated in the early 1990s, and soon after, two endocannabinoid receptors were identified—CB1 and CB2.1 Rimonabant is a CB1 inverse agonist, which essentially blocks the function of the CB1 receptor. It is the first such agent to be approved anywhere in the world to reduce appetite. Rimonabant is available in a number of countries but not yet in the United States.

Christensen and others recently conducted a meta-analysis of four double-blind, randomized controlled trials comparing rimonabant, 20 mg/day, with placebo in more than 4000 participants.2 It worked as hoped: patients who took it lost an average of 4.7 kg (10.4 lb) more weight after 1 year than those who received placebo (P < .0001). However, those who received the active compound had 40% more adverse events and 40% more serious adverse events than those given placebo. In particular, rimonabant-treated subjects were 2.5 times more likely to discontinue treatment due to depression (P = .01) and 3.0 times more likely to drop out because of anxiety (P = .03). Subjects taking rimonabant were 3.0 times more likely to show significant increases in anxiety symptoms.

In an independent analysis of the same four studies, the US Food and Drug Administration (FDA) found that 26% of participants who received rimonabant had some adverse psychiatric event, most commonly anxiety or depression, versus 14% in the placebo group.3 These adverse psychiatric events tended to occur early in the course of treatment. In a larger group of studies examined by the FDA, suicidal ideation or suicide attempts were almost twice as likely in patients taking rimonabant.

In addition to causing the "munchies," cannabis also has antidepressant and anxiolytic properties—one reason it is popular. In animal models, blocking the CB1 receptor can reverse antidepressant and anxiolytic effects.

Where rimonabant is available for human use (and many drugs can be purchased via the Internet), clinicians should carefully monitor psychiatric symptoms. Psychiatrists seeing anxiety and depression in a patient who is taking rimonabant may consider stopping this agent. The "silver lining" here is that these observations could point the way to better treatments in the future, both for obesity and for mood and anxiety disorders.

1Mitchell PB, Morris MJ: Depression and anxiety with rimonabant. Lancet 2007;370:1671–1672.

2Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A: Efficacy and safety of the weight-loss drug rimonabant: A meta-analysis of randomised trials. Lancet 2007;370:1706–1713.

3US Food and Drug Administration Advisory Committee. FDA briefing document: Zimulti (rimonabant) Tablets, 20 mg. (Accessed January 3, 2008).