illustrated-rendering-twin-avatar

Credit:www.freepik.com

Lithium (Li) has been the gold standard treatment for bipolar disorder (BD) for over seven decades, yet its precise mechanism of action remains elusive, and predicting treatment outcomes remains challenging. While Li is effective for ~30% of patients, over 40% demonstrate no significant clinical improvement. This variability in response necessitates a deeper understanding of the underlying biological mechanisms and the identification of predictors for treatment success. This review will explore recent findings from multi-omics studies and patient-derived models that shed light on the complex relationship between Li and BD, focusing on the potential role of focal adhesion, extracellular matrix (ECM), PI3K-Akt signaling, cholinergic, and glutamatergic pathways.

Multi-omics studies, combining transcriptomic and genomic data, have provided valuable insights into the molecular underpinnings of Li response in BD. One study identified focal adhesion, ECM, and PI3K-Akt signaling networks as being associated with Li response in the Pharmacogenomics of Bipolar Disorder (PGBD) sample (Ou et al., 2024). The replication of these findings in an independent sample of 2039 BD patients from the ConLiGen study confirmed the enrichment of focal adhesion and PI3K-Akt pathways, but not ECM, in Li responders (Ou et al., 2024). This suggested that deficits in neuronal growth cone and PI3K-Akt signaling, rather than ECM proteins, might influence Li response in BD.

41380_2023_2149_Fig1_HTML

ConLiGen = The International Consortium on Lithium Genetics, ALDA = Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder scale, HRC = Haplotype Reference Consortium, SNPs = Single Nucleotide Polymorphisms, MAF=Minor Allele Frequency, GWAS = Genome Wide Association analysis, Li++PGS = Polygenic score for lithium treatment response, LOG = Leave-one-group out procedure; PsyCourse = Pathomechanisms and Signature in the Longitudinal Course of Psychosis study and BipoLife = German research consortium for the study of bipolar disorder.

Credit:Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder

Another study developed a polygenic score (PGS) for Li treatment response (Li+PGS) and conducted gene-based pathway analyses (Amare et al., 2023). The Li+PGS demonstrated a positive association with Li treatment response in the ConLi+Gen cohort, with the highest odds of response observed in individuals with the highest Li+PGS. Gene-based analyses revealed 36 candidate genes enriched in pathways controlled by glutamate and acetylcholine, suggesting a potential role for these neurotransmitters in Li's therapeutic effects (Amare et al., 2023).

Patient-derived induced pluripotent stem cell (iPSC) models offer a powerful tool for studying disease mechanisms and drug responses in BD. One study compared iPSC-derived human cortical spheroids (hCS) from healthy controls and BD patients treated with Li (Osete et al., 2023). BD hCS showed smaller size, reduced neuronal proportion, decreased neuronal excitability, and lower neural network activity compared to controls. However, Li treatment rescued excitability and promoted growth in BD hCS, suggesting a neuroprotective role of Li (Osete et al., 2023). Besides, an earlier study conducted by Mertens et al. investigated the differential responses to Li in iPSC neurons derived from BD patients who were Li responders or non-responders. Only neurons from Li responders showed reversed hyperexcitability after Li treatment, highlighting the heterogeneity in Li response within BD patients.

Several pathways have emerged as potential targets for Li's therapeutic effects in BD. First, focal adhesion and PI3K-Akt signaling are crucial for neuronal development and axon growth. Deficits in these pathways may contribute to BD susceptibility and influence Li response by affecting neuronal growth cone morphology and function. Second, while not significantly enriched in Li responders, ECM proteins and interactions may play a role in modulating cell adhesion and signaling, potentially influencing Li's effects on neuronal development and function. Third, the cholinergic system, involving muscarinic acetylcholine receptors, is involved in mood regulation and neuroprotection. The association of Li response with genes enriched in cholinergic pathways suggests a potential role for this system in Li's therapeutic effects. Finally, the glutamatergic system, involving metabotropic glutamate receptors, is crucial for synaptic transmission and neuronal excitability. Dysregulation of this system is associated with BD and other psychiatric disorders. The enrichment of Li response-related genes in glutamatergic pathways suggests a potential role for modulating this system in Li's therapeutic effects.

Further research is needed to fully understand the complex interplay between Li and BD, and to develop more effective and personalized treatment strategies. Integrating additional omics data, such as proteomics and metabolomics, may provide a more comprehensive picture of the molecular changes induced by Li in BD. Epigenetic modifications, such as DNA methylation and histone modifications, may play a role in regulating gene expression and influencing Li response in BD. Targeting pathways identified as being associated with Li response in BD, such as focal adhesion, PI3K-Akt signaling, cholinergic, and glutamatergic pathways, may lead to the development of new treatments for BD. Further research is needed to validate the utility of PGSs and other biomarkers for predicting Li response in BD, and to explore their clinical applicability. By unraveling the complex molecular mechanisms of Li response in BD and identifying reliable predictors of treatment success, we can pave the way for more effective and personalized treatment approaches, ultimately improving the lives of individuals with BD.

Reference:

  1. Ou AH, Rosenthal SB, Adli M, et al. Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study. Transl Psychiatry. 2024 Feb 23;14(1):109.

  2. Amare AT, Thalamuthu A, Schubert KO, et al. Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder. Mol Psychiatry. 2023 Dec;28(12):5251-5261.

  3. Osete JR, Akkouh IA, Ievglevskyi O, et al. Transcriptional and functional effects of lithium in bipolar disorder iPSC-derived cortical spheroids. Mol Psychiatry. 2023 Jul;28(7):3033-3043.