261. THE ASSOCIATION BETWEEN BROWN ADIPOSE TISSUE (BAT)-BRAIN AXIS ACTIVITY AND THE RISK OF METABOLIC ADVERSITIES IN PATIENTS WITH SCHIZOPHRENIA TREATED WITH ANTIPSYCHOTIC DRUGS (APDS)

Abstract Background Patients with schizophrenia are at an increased risk of developing metabolic syndrome (MS) compared to the general population. Recent studies have implicated the BAT-brain axis in metabolic regulation. BAT, which has a high mitochondrial density, plays a role in thermogenesis and energy expenditure through sympathetic stimulation (Chondronikola and Sidossis, 2019). Bone morphogenetic protein 8b (BMP8b), a batokine secreted by mature BAT and presents in the hypothalamus, is positively correlated with BAT activity (Whittle et al., 2012). Orexin-A, a neuropeptide secreted by the lateral hypothalamic area, stimulates BAT activity via the sympathetic nervous system (Messina et al., 2018, Shirasaka et al., 1999). Both circulating orexin-A (Strawn et al., 2010) and BMP8b (Urisarri et al., 2021) levels are correlated with cerebrospinal fluid (CSF) concentrations, reflecting BAT-brain axis activity. Aims & Objectives This series of studies investigated the association between BAT-brain axis activity and the risk of MS in patients with schizophrenia, as well as the effects of APDs on BAT-brain axis activity. Method Blood levels of BMP8b and orexin-A, as representatives of BAT-brain axis activity, and metabolic profiles were compared among patients treated with clozapine, those treated with aripiprazole, and drug-free patients or non-psychiatric controls. The association between BMP8b or orexin-A levels and metabolic outcomes was examined using regression models. Additionally, the effects of APD treatment on BMP8b and orexin-A levels were assessed. Results In the first study, higher BMP8b levels were associated with a lower risk of MS after adjusting for BMI and APDs type. Multivariate regression analysis showed that APD treatment, particularly clozapine (β = −164.7; 95% CI, −248.5 to −80.9; P < .001), led to a more significant reduction in BMP8b levels than aripiprazole (β = −132.9; 95% CI, −226.5 to −39.3; P < .01) compared to APD-free status. In the next study, regression analyses indicated that higher orexin-A levels were associated with a significantly lower risk of MS. Adjusted odds ratios (OR) for MS in the second and third tertiles of orexin-A were 0.05 (95% CI: 0.01–0.24) and 0.06 (95% CI: 0.01–0.30) compared to the first tertile, respectively,. Furthermore, orexin-A levels were significantly higher in patients taking less obesogenic antipsychotics, followed by those treated with clozapine and non-psychiatric controls (F = 104.6, P < 0.01), after adjusting for variables such as age, sex, smoking history, type of APD, treatment duration, and disease severity. In the third study, APD-free patients were included to explore the effects of APD on orexin-A regulation independent from schizophrenia disease effect. Results showed that patients treated with APDs had higher orexin-A levels compared to APD-free patients, with the aripiprazole group displaying higher levels than the clozapine group. Discussion & Conclusions Our findings suggest that increased BAT-brain axis activity, as indicated by elevated orexin-A and BMP8b levels, is associated with better metabolic profiles in patients with schizophrenia. APD treatment, especially clozapine, is linked to reduced BAT activity, while orexin-A levels appear upregulated as a compensatory mechanism in the brain. These results highlight the protective role of BAT-brain axis activation in preventing metabolic disturbances in patients undergoing antipsychotic treatment.