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The reasons that some of the atypical antipsychotic drugs regularly prescribed to schizophrenic patients cause weight gain is unknown. It is thought that the dorsal vagal complex (DVC) in the ancient part of the brain, the brainstem, and the endocannabinoid system, an array of receptors and agonists that play a role in metabolism, homeostasis, mood, appetite, and many other processes, are involved.
This study investigated the potential interaction of antipsychotic drugs with the endocannabinoid system and the possible alteration of cannabinoid receptor binding density in this part of the brain. The drugs investigated were aripiprazole, haloperidol, and olanzapine. The subjects were female rats. Using brain scanners, the “binding density” of the DVC’s cannabinoid receptors was measured upon administration of the drug.
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One drug was found to decrease receptor binding by nearly 40% in short term (1 week) and nearly 50% in the long term (12 weeks). Both the others had no effect in the short term and only one other had an effect in the long term.
Because the ECS is known to be involved in appetite regulation, it is hypothesized that this is part of the mechanism by which at least one of the drugs studied induces weight gain. The mechanism is not explored or elucidated, leading to calls for more research to be carried out.
Olanzapine was the drug assayed that had the most pronounced effect on cannabinoid binding in this study. It reduced binding by up to 50% in chronic use cases, leading to dysregulation that is believed to be responsible for the increased appetite and weight gain.
The other two drugs, aripiprazole and haloperidol do not produce weight gain as much as olanzapine and they do not decrease cannabinoid binding as much as olanzapine. Haloperidol had little effect on appetite and no effect on the endocannabinoid system in short term and long term applications. Aripiprazole has a less severe effect on the ECS than olanzapine and a less pronounced effect on appetite. Only olanzapine was found to be both ECS affecting and appetite dysregulating.
Now that the mechanism by which olanzapine (and potentially other weight gain inducing antipsychotic drugs) induces weight gain by increasing appetite has been partially explored, the potential for using existing cannabinoid antagonists or agonists to preemptively act against the chemically induced downregulation of cannabinoid binding is open to exploration. This could help people with schizophrenia and other psychotic disorders to keep their weight at a healthy level.
The study raises some substantial questions. Can the ECS be targeted for therapeutic effect in combination with olanzapine, can the appetite increasing effect be reduced safely, and how else does the drug affect the ECS? Furthermore, because the ECS is so widespread and involved with so many different metabolic and regulatory functions, are there other, less pronounced effects through this induced dysregulation of the ECS by these drugs?
The safety profile of these three drugs has been updated but there is substantial work that needs to be carried out before the full interaction of them and the ECS has been elucidated. For example, the mechanism by which this decrease in cannabinoid receptor binding is achieved is still completely unknown. Through understanding this interaction, it will be possible to potentially target the drug itself more appropriately and to use ameliorative therapy to lessen or eliminate side effects.
In conclusion, the understanding of the role of the ECS in appetite has been strengthened and the interaction of three antipsychotic drugs with the ECS has been elucidated in part. This raises the hopes of possible ECS-targeted drug intervention to prevent appetite increase and weight loss while taking olanzapine.