Anandamide Is Involved in Appetite-Related Amygdala Hyperactivations in Schizophrenia Patients Treated With Olanzapine: A Functional Magnetic Resonance Imaging Study

To the Editors: In schizophrenia, the prevalence of metabolic syndrome, obesity, and type 2 diabetes is 2 to 3 times more elevated than it is in the general population. The reasons for this elevated prevalence of metabolic disorders in schizophrenia include poor dietary habits, physical inactivity, genetic factors, and antipsychotics. Endogenous cannabinoids (ECBs) have been overlooked as potential mediators of the comorbidity between schizophrenia and metabolic disorders. The main ECBs, anandamide (AEA) and 2-arachydonoylglycerol, bind 2 main cannabinoid receptors: CB1 and CB2. 2 CB1 receptors are found in the brain in the cortex, limbic system, basal ganglia, brain stem, and cerebellum, and are also found in the peripheral metabolic system. CB2 receptors are mostly located in the peripheral immune cells. Palmithylethanolamide and oleylethanolamide (OEA) are 2 noncannabinoid bioactive fattyacid ethanolamides, which do not bind cannabinoid receptors, but bindwith high-affinity peroxisome proliferatorYactivated receptor > (PPAR->). Importantly, mounting evidence suggests that the ECBs and fattyacid ethanolamides play a crucial role in the pathophysiology of both schizophrenia and metabolic disorders. Preliminary evidence suggests that the ECB system is impaired in schizophrenia. Recently, a positron emission tomography study has shown an elevation of CB1 receptor binding in schizophrenia patients across many brain regions. Moreover, cerebrospinal AEA levels have been shown to be increased in schizophrenia patients compared to healthy controls. Peripheral AEA and OEA levels have also been shown to be altered in schizophrenia, albeit inconsistently. Endogenous cannabinoids contribute to weight gain via central and peripheral mechanisms. In animals, ECBs have been shown to be involved in the motivational aspects of food intake at the level of the hypothalamus, the nucleus accumbens, and possibly, the limbic forebrain. Peripheral mechanisms of ECB-induced weight gain have also been highlighted, including increased hepatic triglyceride biosynthesis, impaired pancreatic insulin sensitivity, and decreased glucose uptake in skeletal muscles. As for OEA, it has been shown to inhibit food intake by binding PPAR->. In humans, controlled trials of the CB1 inverse agonist rimonabant for the treatment of obesity have shown considerable reductions in body weight and the prevalence of the metabolic syndrome. Recently, our group has studied the neural correlates of appetite alterations in schizophrenia patients scanned before and after 16-week treatment with olanzapine, using functional magnetic resonance imaging (fMRI). One of the antipsychotics producing the most weight gain, olanzapine was chosen because it simulates appetite in schizophrenia. We found that olanzapine increased loci of activations in limbic regions in schizophrenia. The objective of the current analysis was to explore the associations between plasma AEA and OEA levels and the central mechanisms involved in appetite dysregulation in schizophrenia, during olanzapine treatment. Twenty-four schizophrenia patients (5 women) (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) were recruited (age, 30.0 T 9.4 years). None of them had a substance use disorder. Patients switched from other antipsychotics (except 3 who were drugfree) to olanzapine. Of these patients, 15 participated in both prescanning and postscanning sessions. All subjects signed an informed detailed consent form approved by the local ethics committee. Participants underwent whole-brain fMRI at high field (3 T) while they were in a satiated state (3 hours after the last meal), before and after treatment. In each fMRI session, subjects participated in a passive picture viewing task during Appetizing and Neutral conditions. Psychiatric symptoms, appetite, eating behavior, and body weight were measured before and after treatment, as well as blood levels of fasting glucose, insulin, and lipids. We collected blood samples (heparinized tubes), after an overnight fast, and measured AEA and OEA levels using mass spectrometry. We used the average blood oxygenation levelYdependent (BOLD) signal in the limbic brain regions which became more active to appetizing than neutral stimuli after olanzapine treatment. These regions were located in the left amygdala and right insula (2 activation loci). In these regions, the effect of treatment was a ‘‘hyperactivity’’ in the BOLD signal in patients in response to appetizing images, significantly above levels seen in healthy controls. We evaluated the relationship between ECB levels and the BOLD signal change in these regions. Stepwise multiple regression analysis was used to assess the contribution of ECB levels on the variance observed in brain activity above and beyond the contribution from metabolic markers, since we previously found that changes in appetite-related amygdala activity were associated with changes in glucose and insulin levels over time. During treatment, patients gained weight, had fewer positive symptoms, and had increases in triglycerides and insulin levels. In contrast, plasma AEA and OEA levels did not vary significantly over time (AEAVbefore: 1.62 T 0.68; after: 1.44 T 0.52; Z = j1.42, P = 0.15/ OEAVbefore: 3.16 T 3.45; after: 1.98 T 1.47; Z = j1.70, P = 0.08). The moderation analysis indicated that the relationship between the AEA levels and the brain activity in amygdala in response to foodrelated as compared to neutral visual stimuli was significantly affected by the olanzapine treatment (F1,26 = 8.76, P G 0.01). Specifically, the interaction between AEA levels and treatment explained 21.9% more of variance in amygdala activation than each of these 2 variables alone. Furthermore, after controlling for the influence of glucose and insulin, the addition of AEA levels into the hierarchical regression model in the last step explained a significant proportion of the variability in amygdala activity above and beyond the variability already explained by the metabolites (24.3% when accounting for glucose; 27.9% for insulin; 40%, without metabolites; Ps G 0.05). We found no relationship between plasma OEA levels and the limbic brain regions found to be activated in schizophrenia as a result of olanzapine treatment. In a small sample of schizophrenia patients treated with olanzapine, we found that plasma AEA levels were positively associated with amygdala hyper-activations in response to appetizing food stimuli. This finding is consistent with the growing preclinical literature showing that ECBs, including AEA, are involved in the motivational aspect of food intake. In rodents, it has been shown that the amygdala is LETTERS TO THE EDITORS