Mood Stabilizers in Psychiatric Disorders and Mechanisms Learnt from In Vitro Model Systems

Abstract

Bipolar disorder (BD) and schizophrenia are psychiatric disorders that manifest unusual mental, behavioral, and emotional patterns leading to suffering and disability. These disorders span heterogeneous conditions with variable heredity and elusive pathophysiology. Mood stabilizers such as lithium and valproic acid (VPA) have been shown to be effective in BD and, to some extent in schizophrenia. This review highlights the efficacy of lithium and VPA treatment in several randomized, controlled human trials conducted in patients suffering from BD and schizophrenia. Furthermore, we also address the importance of using induced pluripotent stem cells (iPSCs) as a disease model for mirroring the disease’s phenotypes. In BD, iPSC-derived neurons enabled finding an endophenotype of hyperexcitability with increased hyperpolarizations. Some of the disease phenotypes were significantly alleviated by lithium treatment. VPA studies have also reported rescuing the Wnt/β-catenin pathway and reducing activity. Another significant contribution of iPSC models can be attributed to studying the molecular etiologies of schizophrenia such as abnormal differentiation of patient-derived neural stem cells, decreased neuronal connectivity and neurite number, impaired synaptic function, and altered gene expression patterns. Overall, despite significant advances using these novel models, much more work remains to fully understand the mechanisms by which these disorders affect the patients’ brains.

Current progress in understanding Schizophrenia using genomics and pluripotent stem cells: A Meta-analytical overview

“…Genome editing tools are still technically challenging for large genomic deletions and allow currently for the editing of small genomic regions that are relevant for SCZ; some of these small genomic regions mutations have already been modeled but much more work remains. 2D cultures derived from iPSCs can be used for differentiating into SCZ patient-specific neuronal subtypes but the lack of coherence between the different methods of iPSC reprogramming and differentiation can add confounding factors to the conclusions (Nayak et al 2021). In addition, further methodological advancements in iPSC disease modeling are required to fully recapitulate the in vivo brain development system (Noh et al 2017;Balan, Toyoshima, and Yoshikawa 2019).…”

“…Because of the interactions of multiple genetic and environmental risk factors, neuropsychiatric diseases such as SCZ, Bipolar disorder (BD), and Autism spectrum disorders (ASD) are difficult to study entirely in an animal model system (Nestler and Hyman 2010). At the cellular and molecular level, the use of iPSC technology in neuropsychiatric diseases has provided an alternative strategy to understand the complexity of patient-specific cell lines albeit with limitations as reviewed previously (Soliman et al 2017;De Los Angeles et al 2021;Nayak et al 2021).…”

Immunoglobulin genes expressed in lymphoblast cell lines discern and predict lithium response in bipolar disorder patients

“…Genome-wide association studies (GWAS) in BD patients have identi ed genomic loci associated with BD but, in the absence of functional validation, the causative genes are obscure [11][12][13][14][15] .…”

“…Animal models for BD are imperfect mainly due to its unknown genetic component and inability to mimic the extreme mood shifts observed in patients 16 . Disease modeling via induced pluripotent stem cell (iPSC) technology has opened a new possibility for studying psychiatric diseases by allowing researchers to investigate patient-speci c neural cells in vitro in 2D and 3D culture systems 14 . Recently, researchers have employed iPSC technology to study BD patient-speci c neurons to understand the cellular pathophysiology and mechanisms underlying BD [17][18][19][20] .…”

Information theory characteristics improve the prediction of lithium response in bipolar disorder patients using an SVM classifier

“…However, these have been limited in their influence on the patients 5 . The popular mood stabilizer lithium (Li) has shown a therapeutic effect in about one-third of BD patients with prophylactic treatment [6][7][8] ((these patients will be abbreviated as Li Responsive (LR) patients throughout the text). The remaining patients either respond partially or do not respond at all 9,10 .…”