2026 ECNP Congress

PS02-2052

Paroxetine-associated weight gain: role of the 5-HT2C receptor

Gülsüm Irem Kılınç — B. ozbay, E. akdogan bulut, M. ak, T. yanık · necmettin erbakan medical faculty, psychiatry, konya, Türkiye

2026 ECNP Congress

Introduction

Obesity is one of the most threatening disorders to public health worldwide, and the risks it creates may give rise to many other health problems. Depressive disorders are one of the other consequences that concern public health, and especially after the 2019 SARS-CoV-2 pandemic, their prevalence has significantly increased. Medications classified as selective serotonin reuptake inhibitors (SSRIs) are the most prescribed medications for the treatment of depressive disorders. Paroxetine, one of the most prescribed SSRI group medications, is known for its weight-gaining properties, and it constitutes a risk of inducing the onset of obesity. However, the molecular mechanisms underlying paroxetine-induced weight gain remain poorly understood. The hypothalamus mainly regulates energy metabolism and weight gain. In this process, the orexigenic neuropeptide Y (NPY) and the anorexigenic proopiomelanocortin (POMC) play a key role. While the initial activation of 5-HT2C receptors in POMC neurons results in appetite suppression, chronic stimulation can lead to receptor desensitization and downregulation, potentially contributing to weight gain. [1]

Objective

The primary objective of this study is to investigate the mechanisms underlying paroxetine-associated weight gain. In this context, the focus is on the neuropeptides NPY and POMC, which are highly expressed in the hypothalamus and are associated with energy balance, and the 5-HT2C receptor. Furthermore, the behavioral effects and the modulatory potential of co-administering SB 242084, a neutral and selective 5-HT2C receptor antagonist, with paroxetine on weight gain have been evaluated. [2]

Methods

Four-week-old male C57BL/6 mice (n = 10 per group; total n = 40) were randomized into four groups: control (CON), SB242084-treated (SB), paroxetine-treated (PAR), and paroxetine + SB242084-treated (PARSB). Paroxetine (5 mg/kg/day) was administered via drinking water, whilst SB242084 (1 mg/kg) was administered by intraperitoneal injection for 60 days.

The Novelty-Suppressed Feeding Test (NSF) and the Forced Swimming Test (FST) were used for behavioral assessment. [5] RT-qPCR was used to analyze the expression of hypothalamic neuropeptides and the levels of 5-HT2C receptors. [3] The data were evaluated using one-way ANOVA and the Kruskal-Wallis test, following the Shapiro-Wilk normality test.

Results

An increase in NPY expression and a decrease in POMC and 5-HT2C receptor expression were observed in the PAR group. The concomitant administration of SB 242084 and paroxetine exhibited a propensity to modulate these alterations, concomitantly manifesting a partial attenuating effect on weight gain.

In behavioral assessments, an increase in FST mobility time was observed in the PARSB group; however, this effect was not statistically significant compared with the paroxetine group.

Conclusion

The hypothesis that paroxetine treatment may lead to weight gain, associated with increased NPY and reduced POMC and 5-HT2C receptor expression in the hypothalamus, is supported by the evidence. The results imply that co-administration of SB 242084 may partially modulate the aforementioned effects.

These findings suggest that 5-HT2C receptor modulation may exert non-linear, circuit-level complex effects on metabolic and behavioral processes. Consequently, further translational and clinical studies are required to evaluate the clinical application potential of 5-HT2C-targeted approaches.

References

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  2. Andrade AL, Abrahao KP, Goeldner FO, Souza-Formigoni mL. Administration of the 5-HT2C receptor antagonist SB-242084 into the nucleus accumbens blocks the expression of ethanol-induced behavioral sensitization in Albino Swiss mice. Neuroscience. 2011 Aug 25;189:178-86. doi: 10.1016/j.neuroscience.2011.05.028. Epub 2011 May 27. PMID: 21658435.
  3. Bong D, Sohn J, Lee SV. Brief guide to RT-qPCR. Mol Cells. 2024 Dec;47(12):100141. doi: 10.1016/j.mocell.2024.100141. Epub 2024 Oct 28. PMID: 39476972; PMCID: PMC11612376.
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