Abstract
Bipolar disorder (BD) is a mood disorder that affects millions worldwide and is associated with severe mood swings between mania and depression. The mood stabilizers valproate (VPA) and lithium (Li) are among the main drugs that are used to treat BD patients. However, these drugs are not effective for all patients and cause serious side effects. Therefore, better drugs are needed to treat BD patients. The main barrier to developing new drugs is the lack of knowledge about the therapeutic mechanism of currently available drugs. Several hypotheses have been proposed for the mechanism of action of mood stabilizers. However, it is still not known how they act to alleviate both mania and depression. The pathology of BD is characterized by mitochondrial dysfunction, oxidative stress, and abnormalities in calcium signaling. A deficiency in the unfolded protein response (UPR) pathway may be a shared mechanism that leads to these cellular dysfunctions. This is supported by reported abnormalities in the UPR pathway in lymphoblasts from BD patients. Additionally, studies have demonstrated that mood stabilizers alter the expression of several UPR target genes in mouse and human neuronal cells. In this review, we outline a new perspective wherein mood stabilizers exert their therapeutic mechanism by activating the UPR. Furthermore, we discuss UPR abnormalities in BD patients and suggest future research directions to resolve discrepancies in the literature.
Highlights
Bipolar disorder (BD) is a mood disorder that is characterized by moods alternating between mania and depression (Baldessarini et al, 2020)
Additional work demonstrated that deficient unfolded protein response (UPR) activation is caused by reduced transcription of the UPR target genes XBP1, glucose-regulated protein 94 (GRP94), and CCAAT/enhancer-binding protein homologous protein (CHOP) in lymphoblast cells from BD patients after treatment with the ER stressors thapsigargin (TG) and tunicamycin (Tun) (So et al, 2007; Hayashi et al, 2009; Bengesser et al, 2018)
The UPR pathway may play a significant role in the pathology and treatment of BD, a severe mood disorder that disrupts the lives of patients and their families (Gonda et al, 2012; Baldessarini et al, 2020)
Summary
Bipolar disorder (BD) is a mood disorder that is characterized by moods alternating between mania and depression (Baldessarini et al, 2020). Studies have suggested that the unfolded protein response (UPR) pathway may be part of the pathophysiology of BD and that mood stabilizers could exert their therapeutic mechanism by activating the UPR (Wang et al, 1999; Bown et al, 2000; Chen et al, 2000; Kakiuchi et al, 2003; Shao et al, 2006; Kim et al, 2009; Pfaffenseller et al, 2014; Bengesser et al, 2016).
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