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Article

Dynamic Model of Serotonin Presynapse and Its Application to Suicide Attempt in Patients with Bipolar Disorder

by
Lana Radenković
1,
Jelena Karanović
2,
Maja Pantović-Stefanović
3,4,
Dušan Lazić
1,
Goran Brajušković
1,
Maja Ivković
3,4,
Jovan Pešović
1 and
Dušanka Savić-Pavićević
1,*
1
University of Belgrade-Faculty of Biology, Centre for Human Molecular Genetics, Studentski trg 16, 11000 Belgrade, Serbia
2
Laboratory for Molecular Biology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444A, 11042 Belgrade, Serbia
3
Clinic for Psychiatry, University Clinical Centre of Serbia, Pasterova 2, 11000 Belgrade, Serbia
4
University of Belgrade-Faculty of Medicine, Doktora Subotića 8, 11000 Belgrade, Serbia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(9), 4085; https://doi.org/10.3390/ijms26094085
Submission received: 19 February 2025 / Revised: 21 March 2025 / Accepted: 19 April 2025 / Published: 25 April 2025
(This article belongs to the Section Molecular Informatics)
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Abstract

Suicide attempts are prevalent among patients with bipolar disorder (BD). Impaired serotonin (5-HT) system in the pathogenesis of suicide attempt is partially heritable. To quantify the combined effects of multiple genetic variants, we developed a dynamic model of the 5-HT presynapse with functionally integrated individual genetic variants. The model includes five genetic variants in 5-HT system genes (TPH2, SLC6A4, MAOA) and quantitatively assesses their influence on 5-HT synthesis, reuptake, and degradation. The model was validated on 140 unaffected individuals and tested on 101 BD patients. Predicted mean concentrations of 5-HT, 5-HT precursor, and degradation product were compared between BD patients with and without a history of attempted suicide, and unaffected individuals. The model consists of eight differential equations that describe the temporal concentration change of model outputs. Calculated concentrations in unaffected control individuals aligned with published experimentally measured values, validating our model. BD patients with a history of suicide attempt showed lower calculated concentrations of 5-HT degradation product 5-hydroxy-3-indolacetic acid (5-HIAA) compared to unaffected individuals (p = 0.044). Additionally, higher calculated concentrations of free cellular 5-HT (p = 0.048) and stored 5-HT (p = 0.047), with the effect size d = 0.35, were observed when comparing suicide attempters to non-attempters.. Our approach illuminated a complex interplay of genetic variants in 5-HT system genes that contributes to the risk of suicide attempt, with quantitative and personalized outputs unattainable through genetic association studies.
Keywords: suicide attempt; dynamic model; serotonin system; bipolar disorder; genetic variants suicide attempt; dynamic model; serotonin system; bipolar disorder; genetic variants

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MDPI and ACS Style

Radenković, L.; Karanović, J.; Pantović-Stefanović, M.; Lazić, D.; Brajušković, G.; Ivković, M.; Pešović, J.; Savić-Pavićević, D. Dynamic Model of Serotonin Presynapse and Its Application to Suicide Attempt in Patients with Bipolar Disorder. Int. J. Mol. Sci. 2025, 26, 4085. https://doi.org/10.3390/ijms26094085

AMA Style

Radenković L, Karanović J, Pantović-Stefanović M, Lazić D, Brajušković G, Ivković M, Pešović J, Savić-Pavićević D. Dynamic Model of Serotonin Presynapse and Its Application to Suicide Attempt in Patients with Bipolar Disorder. International Journal of Molecular Sciences. 2025; 26(9):4085. https://doi.org/10.3390/ijms26094085

Chicago/Turabian Style

Radenković, Lana, Jelena Karanović, Maja Pantović-Stefanović, Dušan Lazić, Goran Brajušković, Maja Ivković, Jovan Pešović, and Dušanka Savić-Pavićević. 2025. "Dynamic Model of Serotonin Presynapse and Its Application to Suicide Attempt in Patients with Bipolar Disorder" International Journal of Molecular Sciences 26, no. 9: 4085. https://doi.org/10.3390/ijms26094085

APA Style

Radenković, L., Karanović, J., Pantović-Stefanović, M., Lazić, D., Brajušković, G., Ivković, M., Pešović, J., & Savić-Pavićević, D. (2025). Dynamic Model of Serotonin Presynapse and Its Application to Suicide Attempt in Patients with Bipolar Disorder. International Journal of Molecular Sciences, 26(9), 4085. https://doi.org/10.3390/ijms26094085

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