Author Affiliations: Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York (Dr Hill); and Department of Psychology, University of British Columbia, Vancouver, Canada (Dr Gorzalka).
A recent release from the European Medicines Agency has recommended the suspension of the weight-reducing drug rimonabant (which was also in trials for the treatment of nicotine dependence) from the market due to the development of undesirable psychiatric side effects, particularly symptoms of depression.1 This decision follows a similar one regarding rimonabant made by the US Food and Drug Administration last year for the same reasons. In November 2008, Sanofi-Aventis announced it was suspending marketing of rimonabant.2 Soon thereafter, Pfizer announced that it was terminating clinical trials with otenabant, a diet drug with a similar mechanism of action.3
Pharmacologically, rimonabant and otenabant act through antagonism of the cannabinoid CB1 receptor; thus, these clinical developments suggest that blockade of the CB1 receptor exerts adverse effects on emotional behavior and mood regulation. Given the therapeutic potential of these drugs for the treatment of obesity and nicotine dependence, the emerging psychiatric consequences of CB1 receptor blockers are quite unfortunate; however, the termination of these compounds should not hamper future research examining alternative targets for the treatment of these disorders. Regardless, this serendipitous clinical finding may further the medical community's understanding of the role of CB1 receptor signaling in the etiology of depressive illness and the potential of this receptor system in the development of a new class of pharmaceutical treatment for depression.
The reported symptoms of depression following treatment with these CB1 receptor antagonists are not entirely surprising. The cannabinoid CB1 receptor was originally characterized as the receptor to which Δ9-tetrahydrocannabinol (THC) binds to produce its psychoactive effects.4 For centuries, cannabis has been used by individuals for its mood-elevating and stress-reducing properties, responses that are mediated via THC activating the CB1 receptor.4 With the development of transgenic animals lacking the cannabinoid CB1 receptor, a notable feature of these animals was enhanced symptoms on behavioral indices of anxiety and depression and a heightened sensitivity to stressful stimuli.5 Ongoing research revealed that the CB1 receptor also had endogenous ligands termed endocannabinoids4 (just as endorphins represent an endogenous substrate for the mu opioid receptor through which morphine and other opioids exert their effect). In contrast to what was seen in studies of mice lacking the CB1 receptor, agents that inhibited the metabolism of endocannabinoids by the enzyme fatty acid amide hydrolase (FAAH) exhibited stress-reducing, antianxiety, and antidepressive effects in an array of preclinical models.6 - 8 Importantly, FAAH inhibitors (which augment endocannabinoid neurotransmission) were found to be devoid of the reinforcing properties seen with THC,8 - 9 suggesting that these compounds may not share the risk of dependence or addiction that are a concern for the therapeutic use of THC.
Bridging these findings was the fact that CB1 receptor activity in brain regions (such as the hippocampus) implicated in depression was reduced in a preclinical animal model of depression.10 Based on these findings, we predicted that deficits in endocannabinoid activity could produce a symptomatic profile reminiscent of depressive illness.11 In line with this hypothesis, we recently demonstrated that circulating levels of endocannabinoid ligands are significantly reduced in a population with major clinical depression.12 Collectively, these data suggest that deficits in endocannabinoid/CB1 receptor signaling may be biological phenomena that are conducive to depression. Viewed in this light, it is not surprising that negative emotional reactions and symptoms of depression were adverse effects of treatment with rimonabant.
Decades ago, clinical use of the putative antihypertensive agent reserpine (which causes vesicular depletion of monoaminergic transmitters) produced symptoms of depression in a noteworthy proportion of individuals taking the drug. This and congruent findings were a foundation for the monoamine theory of depression as well as the development of modern conventional antidepressants that function to increase the synaptic availability of monoamine neurotransmitters. Analogously, the clinical reactions documented following rimonabant administration provide the first human data that impairments in endocannabinoid/CB1 receptor activity can directly result in the development of depressive symptoms. However, these data may also speak to the therapeutic potential of the endocannabinoid system for the development of a novel class of antidepressants. As mentioned, agents that increase endocannabinoid neurotransmission produce antidepressant, antianxiety, and stress-reducing effects in preclinical models.6 - 8 Conventional antidepressant treatments increase CB1 receptor expression in limbic brain regions involved in depression, such as the hippocampus and amygdala.13 - 14 Thus, if impairments in endocannabinoid/CB1 receptor activity can promote symptoms of depression, it follows that augmentation of endocannabinoid/CB1 receptor activity could reduce symptoms of depression.
Depressive illness is a devastating mental disorder for which the physical and financial burden is often underappreciated. The World Health Organization currently ranks depression as the fourth leading contributor to global morbidity, disability, and early mortality and predicts that it will become the second leading contributor by 2020.15 Accordingly, the search for novel treatments for depressive illness is a high priority, particularly considering that conventional treatments for depression are often suboptimal. The clinical and preclinical evidence briefly reviewed herein demonstrates that endocannabinoid signaling is impaired in depressive illness, antidepressant treatments enhance endocannabinoid activity, and agents that pharmacologically potentiate endocannabinoid signaling may possess antidepressant properties. The fact that administration of CB1 receptor antagonists evoked symptoms of depressive illness in a significant proportion of participants in clinical trials argues that the endocannabinoid system is a critical regulator of emotion, mood, and stress responsivity in humans and that dysregulation of this system may be integral to the pathogenesis of mood disorders.
On the basis of preclinical research and the adverse clinical responses to CB1 receptor antagonists, it can be anticipated that inhibition of FAAH (or alternate pharmacological means to enhance endocannabinoid neurotransmission) will soon become a target for research and development on the treatment of depression. It will be interesting to see if drugs that augment endocannabinoid activity will eventually provide a new option for the treatment of depression.
Corresponding Author: Matthew N. Hill, PhD, Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Ave, New York, NY 10021 (mhill@rockefeller.edu).
Financial Disclosures: None reported.
Funding/Support: This article was written with the support of a Canadian Institute of Health Research (CIHR) operating grant to Dr Gorzalka and a CIHR postdoctoral fellowship to Dr Hill.
Role of the Sponsors: Beyond financial support, these agencies had no role in the preparation, review, or approval of this article.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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