Antipsychotic Drug-Induced Hyperleptinemia Identified as Key Contributor to Weight Gain and Metabolic Dysfunction


a woman measuring her waist

Psychotic disorders, including schizophrenia, schizoaffective disorders, brief psychotic disorders, and delusional disorders, pose significant challenges to affected individuals, and therapeutic approaches often involve second-generation atypical antipsychotic drugs. While these drugs effectively alleviate symptoms, they are associated with common side effects, such as notable weight gain and hyperglycemia.

Recent research has delved into the mechanisms behind these side effects. Studies have identified various factors, including multiple neuron engagement and inflammatory processes, contributing to the detrimental effects of antipsychotic drugs. Notably, a serotonin receptor 2C–specific agonist has been shown to reverse olanzapine-induced weight gain and hyperglycemia, highlighting the complex interplay of neurotransmitters in these conditions.

Hypothalamic melanocortin 4 receptor (MC4R) has been implicated in risperidone-induced weight gain, emphasizing the role of specific neural pathways. Additionally, alterations in appetite-regulating neurons, such as proopiomelanocortin (Pomc) and neuropeptide Y (Npy), further underscore the intricate neural circuitry affected by these medications.

Inflammation has emerged as a significant player in antipsychotic drug–induced metabolic disorders. Olanzapine, for instance, triggers inflammatory responses in both peripheral tissues and the central nervous system, contributing to macrophage infiltration and increased proinflammatory cytokines. Moreover, individual responses to these drugs vary, with some individuals more susceptible to obesity.

Gene expression profiles reveal that inflammatory and immunomodulatory signaling nodes are elevated in those prone to obesity, suggesting a genetic predisposition. A potential breakthrough lies in the use of the second-generation tetracycline antibiotic minocycline, known for its anti-inflammatory effects, which has demonstrated effectiveness in mitigating weight gain and hyperglycemia associated with olanzapine treatment.

Leptin, a hormone known for its role in body fat regulation, has emerged as a significant player in the context of antipsychotic drug therapy. Studies indicate that circulating leptin levels increase before the onset of substantial weight gain in patients undergoing antipsychotic therapy. Clozapine, a specific antipsychotic drug, has been shown to directly regulate leptin gene expression.

Recent experiments using a mouse model replicated the spectrum of antipsychotic drug effects, demonstrating that hyperleptinemia precedes weight gain. Notably, suppressing leptin signaling through a monoclonal leptin-neutralizing antibody (LepAb) partially mitigates risperidone-induced obesity and prevents metabolic dysfunction.

However, the role of hyperleptinemia in body weight regulation remains debated, with conflicting results from studies involving leptin transgenic mice. The mouse model used in this study not only sheds light on the impact of antipsychotic drugs but also highlights enhanced mammary gland development, raising concerns about the use of these drugs in younger patients.

Despite the promising findings, the study acknowledges limitations, such as the need for clinical validation and the observed gender-specific response in mice. Future research aims to address these limitations and explore the potential addition of leptin-neutralizing antibodies to antipsychotic therapy, offering hope for improved management of metabolic side effects in patients with psychotic conditions.



Journal Reference

Zhao, S., Lin, Q., Xiong, W., Li, L., Straub, L., Zhang, D., … Scherer, P. E. (2023). Science Translational Medicine15(723). Doi:10.1126/Scitranslmed.Ade846

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