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.