27th National Clinical Education Symposium Presentation Abstracts

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30 APRIL 2025, WEDNESDAY
13:00-14:00 ORAL PRESENTATION SESSION - 13

Neurobiological Evidence Of Lithium Response And Non-Response: A Resting-State Functional Magnetic Resonance Imaging Study With Bipolar Disorder Patients

Elif Sen1, Mehmet Cagdas Eker1, Ali Saffet Gonul1, Ömer Kitiş2, Seda Eroglu3

1. SoCAT Lab, Department of Psychiatry, School of Medicine, Ege University, İzmir, Türkiye
2. SoCAT Lab, Department of Psychiatry, School of Medicine, Ege University, Türkiye
3. SoCAT Lab, Department of Psychiatry, School of Medicine, Ege University, Department of Psychology,Izmir, Türkiye

DOI: 10.5080/kes27.abs149 Page 4-5

BACKGROUND AND AIM: In the treatment of bipolar disorder (BD), lithium has long been the primary option for managing acute episodes, preventing recurrences, and reducing suicide risk. However, while approximately one-third of BD patients respond to lithium, others exhibit partial response or non-response. These differences in response highlight the heterogeneity of the neurobiological underpinnings of BD and emphasize the necessity of identifying reliable biomarkers at an early stage. Neuroimaging techniques, particularly resting-state functional magnetic resonance imaging (rs-fMRI) and structural MRI-based cortical thickness analyses, provide valuable insights into biomarkers that could predict lithium response. The primary objective of this study is to investigate the neurobiological differences associated with lithium response in BD patients through rs-fMRI and structural MRI data obtained in resting-state conditions.
METHODS: All participants were aged between 18 and 50 years, and their diagnoses were confirmed using the Structured Clinical Interview for DSM-5 (SCID-5). A total of 50 BD patients were included. Patients were categorized based on the Alda Scale into lithium responders (BDLR, Alda score ≥7, n=27) and non-responders (BDLNR, Alda score ≤4, n=23). Among the lithium-responsive group, imaging was performed on 23 patients, but MRI data from 21 were included in the analysis due to structural pathology (n=1) and an incomplete scan (n=1). In the lithium-nonresponsive group, imaging was performed on 20 patients, with MRI data from 17 included due to similar exclusions (n=1 structural pathology, n=1 incomplete scan, n=1 image distortion). Additionally, MRI data from 21 healthy controls were included for comparison. All BD patients had been in remission for at least one month prior to participation, as determined by 17-item Hamilton Depression Rating Scale (HAMD-17) and the Young Mania Rating Scale (YMRS) scores within the euthymic range. Medication adherence was assessed using the Medication Adherence Rating Scale (MARS). For the lithium-responsive patients, therapeutic serum lithium levels were confirmed with at least two measurements within the past year. Imaging was performed using a Siemens 3.0 Tesla MRI scanner. High-resolution T1-weighted 3D MPRAGE sequences were used to obtain structural data, while resting-state fMRI scans were acquired using T2-weighted EPI sequences, with participants instructed to remain still, keep their eyes closed, and refrain from focusing on specific thoughts. Structural MRI data were processed using BrainSuite software, which involved removing non-brain tissues, segmenting gray and white matter, and generating cortical surfaces for cortical thickness measurements. Rs-fMRI data were preprocessed using MATLAB-based SPM and CONN toolbox, following standard procedures. Between-group differences were assessed using a general linear model (GLM), incorporating age, sex, and total hemisphere volume as covariates. Pairwise comparisons were conducted with multiple comparison corrections applied using Monte Carlo simulations and false discovery rate (FDR) adjustments. Statistical analyses were performed using IBM SPSS Statistics, with demographic and clinical data analyzed using parametric or non-parametric tests as appropriate. Ethical approval was obtained from the Ege University Faculty of Medicine Clinical Research Ethics Committee under approval number 23-5/68, dated May 9, 2023.
RESULTS: Statistical analyses indicated that the groups were demographically comparable in terms of age, sex, and years of education. Euthymic status was confirmed in all groups based on HAMD and YMRS scores. As expected, the Alda Scale scores were higher in the lithium-responsive group. No significant differences were observed between groups regarding medication adherence, as measured by the MARS scale. The mean serum lithium level in the BDLR group was 0.70 ± 0.15 mmol/L. Resting-state functional connectivity analyses revealed no significant differences between lithium responders and healthy controls. However, lithium non-responders showed significantly altered connectivity relative to both lithium responders (F(2,55) = 9.58, p-unc = 0.00027, p-FDR = 0.046) and healthy controls (F(2,55) = 11.31, p-unc = 0.00008, p-FDR = 0.013). In the BDLNR, compared to the BDLR, decreased connectivity was observed between the right insular cortex and right paracingulate gyrus, the right planum polare and right superior frontal gyrus, and the right planum temporale and right paracingulate gyrus. Compared to healthy controls, the BDLNR exhibited increased connectivity between the right superior temporal gyrus and both the left caudate and left thalamus, as well as between the right superior temporal gyrus and both the right caudate and right thalamus. Additionally, increased connectivity was noted between the left superior temporal gyrus and left thalamus. Conversely, decreased connectivity was observed between the left Heschl’s gyrus and the right orbitofrontal cortex, as well as between the right supplementary motor area and the right orbitofrontal cortex. Moreover, reduced connectivity was found between the left superior temporal gyrus and the right temporal pole. Structural MRI-based cortical thickness analyses revealed significant differences between the BDLR and BDLNR groups. The BDLR group exhibited significantly greater cortical thickness in the right and left superior frontal gyrus, left pars opercularis, right precentral gyrus, right and left paracentral lobule, right postcentral gyrus, right superior temporal gyrus, and right transverse temporal gyrus. These differences remained significant after controlling for the number of past manic episodes and illness onset age. No significant differences in cortical thickness were observed between the lithium-responsive group and healthy controls. However, in comparison to healthy controls, the lithium-nonresponsive group demonstrated significant cortical thinning in the frontal and parietal regions.
CONCLUSIONS: The findings indicate that lithium-responsive patients exhibit brain connectivity and structural features comparable to those of healthy controls, whereas lithiumnonresponsive patients demonstrate distinct neurobiological differences. These results highlight the heterogeneity of bipolar disorder and suggest that neuroimaging biomarkers could aid in differentiating patient subgroups, reinforcing the need for personalized treatment strategies. Future research including healthy siblings, who share genetic risk factors but do not develop BD, could help differentiate neural alterations due to the disorder from those linked to genetic susceptibility without clinical manifestation. Overall, this study suggests that lithium may exert neuroprotective and regulatory effects; however, certain patient subgroups (non-responders) exhibit more persistent structural and functional brain alterations. Future large-scale, longitudinal studies integrating genetic and epigenetic data may enable the early identification of lithium responders and non-responders. Such advancements could optimize treatment decisions, minimize adverse effects, and reduce relapse risks, ultimately contributing to the development of more effective personalized therapeutic strategies for BD management. REFERENCES Gong JY, Chen G, Jia Y, Zhong S, Zhao L, Luo X ve ark. (2019) Disrupted functional connectivity within the default mode network and salience network in unmedicated bipolar II disorder. J Affect Disord 246: 183-9. Hajek T, Bauer M, Simhandl C, Rybakowski J, O’Donovan C, Pfennig A ve ark. (2014) Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response. Bipolar Disord 16: 418-29. Hibar DP, Westlye LT, van Erp TGM, Rasmussen J, Leonardo CD, Faskowitz J ve ark. (2018) Cortical abnormalities in bipolar disorder: An MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group. Mol Psychiatry 23: 932-42. Spielberg JM, Matyi MA, Karne H, Anand A. (2019) Lithium monotherapy associated longitudinal effects on resting state brain networks in clinical treatment of bipolar disorder. J Affect Disord 249: 301-8. Syan SK, Smith M, Frey BN, Remtulla R, Kapczinski F, Hall GBC ve ark. (2018) Resting-state functional connectivity in individuals with bipolar disorder during clinical remission: a systematic review. J Psychiatr Res 102: 1-13. Keywords: Bipolar Disorder, Cortical Thickness, Functional Connectivity, Functional Magnetic Resonance Imaging, Lithium Response, Neurobiological Marker