Antipsychotic-Related Weight Gain Explained?

Liam Davenport

February 12, 2015

The brain's cannabinoid system may underlie antipsychotic-related weight gain commonly seen in schizophrenia patients, preliminary research suggests.

Investigators at the Université de Montréal, in Canada, found that plasma levels of anadamide, which binds to cannabinoid receptors in the brain, were positively associated with hyperactivation of the amygdala in response to appetizing stimuli following treatment with the atypical antipsychotic olanzapine (multiple brands).

"Although this is really a pilot study, it might provide a new explanation for the reasons why some patients with schizophrenia will gain weight while receiving antipsychotic treatment," lead author Stéphane Potvin, PhD, told Medscape Medical News.

The study was published in the February issue of the Journal of Clinical Psychopharmacology.

Reduced Life Expectancy

Explaining the motivation behind the study, Dr Potvin told Medscape Medical News: "There is substantially reduced life expectancy in schizophrenia. One of the reasons is tobacco smoking, and the other one is obesity, so there's a need to better understand what's going on."

"Although, of course, we cannot pretend that a biological mechanism will explain the full picture, to have new potential explanations is worthy of future investigation."

For the study, Dr Potvin and colleagues performed whole-brain functional magnetic resonance imaging (fMRI) on 24 schizophrenia patients before and after 26 weeks of treatment with olanzapine, while in a satiated state. During fMRI, the patients were passively exposed to appetizing and neutral pictures.

Patients gained weight during treatment and had fewer positive symptoms.

Average blood oxygenation level-dependent signals revealed that limbic brain regions in the left amygdala and right insula became hyperactive to appetizing rather than neutral images after olanzapine treatment, and increases in activity were significantly higher than in control participants.

These brain changes were associated with increased levels of glucose, triglycerides, and anadamide, the primary cannabinoid neurotransmitter, binding to the cannabinoid 1 (CB1) receptor.

The interaction between anadamide and treatment explained 21.9% of the variance in amygdala activation, and further analysis revealed that plasma anadamide levels were positively associated with amygdala hyperactivation in response to appetizing food stimuli.

"This is consistent with a genetic study showing that there's an association between the cannabinoid 1 CB1 receptor gene and weight gain induced by antipsychotics," said Dr Potvin.

"It's also consistent with the literature showing that if you use a medication blocking CB1 receptors, where anadamide binds in the brain, it will produce significant changes in weight. It will reduce weight."

Cautionary Note

Although describing the study as "well designed" and "intriguing," Thomas W. Sedlak, MD, PhD, assistant professor of psychiatry and behavioral health at Johns Hopkins University School of Medicine, in Baltimore, Maryland, said the findings should be interpreted with caution.

"It is a correlation-based approach that makes it difficult to determine whether there is a cause-and-effect relationship, which the authors do note," he told Medscape Medical News.

"Additional studies in animals might help disentangle whether blocking the endocannabinoid system might alter brain activation patterns in response to food cues. They did not have the opportunity to block the endocannabinoid system in human subjects."

Dr Sedlak continued: "At this point it is difficult to conclude that changes in cannabinoids are the cause antipsychotic weight gain. The study wasn't designed to test that ― for instance, by seeing if greater weight gain was associated with greater changes in cannabinoids and whether the dose of olanzapine had a similar relation."

Novel Therapeutics?

However, the study does open up avenues for research, notably in terms of novel therapeutic approaches.

"The endocannabinoid system remains a ripe target for drug intervention. It has long been known that marijuana causes 'the munchies,' in part via the tetrahydrocannabinol-activating CB1 receptors in the brain," said Dr Sedlak.

"Development of the drug rimonabant was spurred by the goal of blocking those receptors and leading to weight loss. It turns out to have rivaled other weight loss drugs," he added.

However, he noted that a number of study participants left the trial because of severe anxiety and depressive symptoms, "underlining the normal roles that the cannabinoid system plays."

"My understanding is also that Eli Lilly has tried to alter the olanzapine molecule; however, the variants that did not have the risk of weight gain also lost their antipsychotic effect, which is unfortunate and shows how difficult a problem this is," said Dr Sedlak.

Dr Potvin agreed that, thus far, unsuccessful attempts to use the cannabinoid system to manipulate weight gain pose a problem. Consequently, "the next step is not so obvious."

"But it is a first step, pointing at this system as one of the factors of why [schizophrenia patients] are gaining weight. Of course, it's not the only one, and the implications at the moment are not that obvious."

Excitement a "Little Premature"

Nevertheless, there is a great deal of interest in the cannabinoid system in the brain. Dr Sedlak shares some of the excitement about understanding its role, but believes that "some of this excitement is a little premature, especially with regards to 'medical' marijuana."

"For instance, in the US, dronabinol [Marinol, AbbVie, Inc] has been available as a prescription drug since the 1990s," he said. "When such a purified form is available that causes less of a 'high,' why are physicians so quick to embrace smoking cannabis, which is well known to have carcinogenic effects?"

Dr Sedlak continued: "A second issue not discussed often enough is whether people 'function' better on marijuana. It is a real 'no-brainer' that people feel good when using it, but an important goal of treatments is to function better, too ― cognitively, occupationally, physically, emotionally, and socially."

"So whenever there are reports of it possibly having some benefit, the follow-up question might be whether patients will function better on it vs other already existing options."

Citing an example of "feeling" better vs "functioning" better, he concluded: "Generally, one does not 'feel good' immediately after a surgery, but the goal of having it is generally to improve long-term functioning."

The study was conducted as part of investigator-initiated trials funded by Eli Lilly Canada. Endocannabinoid assessments were funded by a grant from the Canadian Institutes of Health. Dr Potvin is holder of the Eli Lilly Chair of Schizophrenia from the University of Montreal and reports receiving grants from the Fonds de Recherche du Québec, the Canadian Institute of Health Research, the Fonds Québécois de la Recherche sur la Nature et les Technologies, the Fonds de Recherche du Québec - Société et Culture, Pfizer, Eli Lilly, Instituts Servier, and Bristol-Myers Squibb.

J Clin Psychopharmacol. 2015;35:82-3. Abstract


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