Rimonabant and Depression

Very recently, The Lancet published a meta-analysis of four studies on the efficacy of rimonabant, a selective antagonist of the cannabinoid type 1 receptor [2]. The data indicate that patients given rimonabant have a 2.5 times higher risk of discontinuing treatment because of depressive mood disorders than those given placebo, and also a higher risk of developing anxiety. These findings are in line with an FDA report [7] about the safety of rimonabant, which suggested that 26% of people given 20 mg rimonabant daily had developed a psychiatric symptom, compared to 14% of those given placebo (depression: 9 vs. 5%, respectively). There was also a 1.9-fold higher risk for suicide in all studies.

Rimonabant is an interesting compound since it stands for a whole new class of drugs that target the endocannabinoid system. This system may have a strong influence on food intake, smoking and substance use, among other things. Numerous findings from the animal model [3] have shown that rimonabant has positive effects in alcohol-preferring rats. For this reason we recently conducted a double-blind, placebo-controlled study in 258 alcohol-dependent patients [6] to test the efficacy of 20 mg/day rimonabant in preventing relapse in alcoholism. The outcome was slightly but non-significantly better in the rimonabant than in the placebo group. Furthermore, in the rimonabant group there was no evidence of a higher rate of either serious adverse events in general or psychiatric disorders (P: 16.5%, R: 17.6%). We also found no increased rate of depression or depressed mood (P: 2, R: 5 cases, suicide attempts: placebo 3, rimonabant 1). In the rimonabant group, two out of five patients with depression or depressed mood had depression in their medical history. One patient in the placebo and two in the rimonabant group discontinued treatment because of depression. The mean scores of both the Hamilton depression and Hamilton anxiety scales [4] [5] at baseline were indicative of non-symptomatic patients (HAMA and HAMD 3.3 in both groups), and change from baseline was non-significant for HAMA mean scores (0.4 for placebo, 1.1 for rimonabant) and on the threshold of significance (P = 0.051) for HAMD (−0.2 for placebo, 0.8 for rimonabant).

We conclude from these data that susceptibility to depression might differ greatly between patient groups. As pointed out by Christensen et al. [2], other anti-obesity drugs have been withdrawn because of the risk of suicidal ideation and death from suicide [1]. When targeting the endocannobinoid system, the risk for depression (and suicide) may be higher in obese patients than in other groups. The reported data clearly indicate that rimonabant has a substantial risk of inducing depression but may not justify categorising cannabinoid receptor blockers as a dangerous class of drugs per se.

References

• 1 Astrup A, Greenway FL, Ling W. et al . Randomized controlled trials of the D1/D5 antagonist ecopipam for weight loss in obese subjects.  Obesity. 2007;  15 1717-1731
• 2 Christensen R, Kruse Kristensen P, Bartels EM. et al . Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomized trials.  Lancet. 2007;  370 1706-1713
• 3 Colombo G, Orrù A, Lai P, Cabras C, Maccioni P, Rubio M, Gessa GL, Carai MA. The cannabinoid CB1 receptor antagonist, rimonabant, as a promising pharmacotherapy for alcohol dependence: preclinical evidence.  Mol Neurobiol. 2007;  36 102-112
• 4 Hamilton M. The assessment of anxiety states by rating.  Br J Med Psychol. 1959;  32 50-55
• 5 Hamilton M. A rating scale of depression.  J Neurol Neurosurg Psychiatry. 1960;  23 56-62
• 6 Soyka M, Koller G, Schmidt P. et al . Cannabinoid receptor 1 blocker rimonabant (SR 141716) for treatment of alcohol dependence − results from a placebo-controlled double-blind trial.  J Clin Psychopharmacol. 2008;  3 317-324
• 7 US Food and Drug Administration Advisory Committee .FDA briefing document: Zimulti (rimonabant) 20 mg. Rockville: FDA 2007

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