Cellular calcium in bipolar disorder: systematic review and meta-analysis

Abstract

Calcium signalling has long been implicated in bipolar disorder, especially by reports of altered intracellular calcium ion concentrations ([Ca 2+ ]). However, the evidence has not been appraised critically. We carried out a systematic review and metaanalysis of studies of cellular calcium indices in bipolar disorder. 2281 records were identified and 117 screened, of which 32 were eligible and 21 were suitable for meta-analyses. The latter each involved up to 642 patients and 404 control subjects. We found that basal free intracellular [Ca 2+ ] is increased in bipolar disorder, both in platelets and in lymphocytes. The effect size is 0.55, with an estimated elevation of 29%. It is observed in medication-free patients. It is present in mania and bipolar depression, but data are equivocal for euthymia. Cells from bipolar disorder individuals also show an enhanced [Ca 2+ ] response to stimulation with 5-HT or thrombin, by an estimated 25%, with an effect size of 0.63. In studies which included other diagnoses, intracellular basal [Ca 2+ ] was higher in bipolar disorder than in unipolar depression, but not significantly different from schizophrenia. Functional parameters of cellular Ca 2+ (e.g. calcium transients), and neuronal [Ca 2+ ], have been much less investigated, and no firm conclusions can be drawn. In summary, there is a robust, medium effect size elevation of basal and stimulated free intracellular [Ca 2+ ] in bipolar disorder. The results suggest altered calcium functioning in the disorder, and encourage further investigations into the underlying mechanisms, and the implications for pathophysiology and therapeutics.

Biological Pathways Associated with Neuroprogression in Bipolar Disorder

“…Among the molecular pathways related to BD, calcium signaling has been highlighted [62,63], supporting previous findings on aberrant calcium signaling in BD [64,65]. In addition, a recent meta-analysis showed that there is a robust increase of basal and stimulated free intracellular calcium in BD [66], reinforcing the role of impaired calcium signaling in this illness. A chronic accumulation of calcium could be associated with cellular dysfunctions and the aforementioned impaired cellular resilience in BD.…”

Chaperone Sigma1R and Antidepressant Effect

“…Calcium signaling is involved in neuroplasticity induced by BDNF and glutamatergic mechanisms [ 214 , 215 , 216 ]. The relationship between changes in the concentration of mitochondrial or intracellular calcium and the development of depressive disorders has been demonstrated [ 19 , 217 , 218 ].…”

“…The role of glutamatergic processes in the development of depressive disorders and rapid antidepressant action has been confirmed experimentally [ 15 , 16 , 17 ]. The importance of potassium channels, intracellular calcium, and post-receptor signaling pathways has been demonstrated [ 18 , 19 , 20 ]. In the 1990s, sigma-1 receptors (Sigma1R) were considered as a pharmacological target for antidepressants.…”

A new molecular risk pathway for postpartum mood disorders: clues from steroid sulfatase–deficient individuals

“…adenylate cyclase and phosphodiesterases (Lane Brown et al 2006), may also be involved in the pathogenesis of postpartum mood disorders. Abnormal calcium signalling, phosphodiesterase activity, and cyclic AMP/GMP signalling have been implicated in a variety of neurological and psychiatric (mood) conditions (Hebb and Robertson 2007;Harrison et al 2019), with much focus on phosphodiesterase 10A (PDE10A). PDE10A is highly expressed in the GABAergic neurons of the olfactory tubercle and the striatum (MacMullen et al 2017), is dysregulated in an animal model of postpartum depression (Yun et al 2019), and has been genetically associated with bipolar disorder, hypo-and hyperthyroidism, and blood pressure (GWAS Catalog 2020).…”