Integrative analysis of lithium treatment associated effects on brain structure and peripheral gene expression reveals novel molecular insights into mechanism of action

Abstract

Lithium is a highly effective medication for bipolar disorder, but its mechanism of action remains unknown. In this study, brain MRI scans and blood samples for gene expression (total of 110 scans and 109 blood samples) were collected from 21 bipolar subjects before and after 2 and 8 weeks of lithium monotherapy and at the same timepoints from untreated 16 healthy controls. We used linear mixed-effects models to identify brain structural features and genes with expression changed after lithium treatment, with correction for multiple testing, and correlated their concurrent changes to identify molecular pathways associated with lithium effects. There are significant increases in gray matter fraction, global cortical thickness, and the frontal and parietal cortices after 8 weeks of lithium treatment (corrected p < 0.05). Volume increases were also seen for putamen, hippocampus, thalamic nuclei, and thalamic substructures. Several genes showed significant expression changes, and 14 gene pathways were identified for the present integration analysis. Of these, nine pathways had significant correlations with structural changes (FDR < 0.05). Three neurotrophy-related pathways (GDNF family of ligands, NFAT immune-response, and p53-signaling pathway) correlated with structural changes in multiple regions. Mediation analysis showed that the sphingomyelin metabolism pathway is associated with HAM-D change (p < 0.01), and this effect is mediated via the volume of mediodorsal thalamus (p < 0.03). In summary, the integration of lithium effects on brain structural and peripheral gene expression changes revealed effects on several neurotrophic molecular pathways, which provides further insights into the mechanism of lithium action. :,; 1234567890():,; 1234567890():,; 1234567890():,; This project was funded by the NIMH to A.A. (R01 MH075025-03S2).

The association between lithium in drinking water and neuropsychiatric outcomes: A systematic review and meta-analysis from across 2678 regions containing 113 million people

“…Lithium appears to modulate genes involved in neuroprotection, neuronal plasticity and other neuronal functions including neurotrophy (Malhi et al, 2012). This was further shown in a recent study where magnetic resonance imaging (MRI) scans showed increased grey matter, putamen, hippocampal and thalamic volumes in patients taking lithium as a consequence of lithium-induced gene expression (Anand et al, 2020). Further neuroprotection is evidenced as lithium prevents stress-induced dendritic damage (Wood et al, 2004) and shows anti-apoptotic activity (Bachmann et al, 2009; Chen and Chuang, 1999).…”

Hallmarks of Health

“…Prolonged stress causes atrophy of brain structures, loss of glial cells, and extensive shrinkage of the apical dendritic tree, hampering adaptive plasticity and compromising resilience. Of note, administration of serotonin reuptake inhibitors increases hippocampus volume (Maller et al, 2018), whereas lithium treatment increases the volume of gray matter (Anand et al, 2020). Mechanistically, transcription factors, epigenetic modulators, and chaperones are fundamental mediators of the adaptive responses in brain circuits.…”

Chronic lithium treatment alters the excitatory/inhibitory balance of synaptic networks and reduces mGluR5–PKC signalling in mouse cortical neurons

“…7 Despite its widespread use for more than 60 years as a treatment for bipolar disorder, lithium's mode of action needs to be better understood, as does the reason why it is effective in only about 30% of people with bipolar disorder. 11,12 Studies aimed at elucidating lithium's mode of action have found macroscopic changes in brain structure 13 and alterations at the cellular level. 14 For the latter, acute lithium administration has been shown to increase glutamate signalling.…”