Measures

The primary outcome will be mood severity and stability over the 6-week randomised period as measured using a quick inventory of depressive symptoms (16-item Quick Inventory of Depressive Symptoms–Self-Rated), the Altman Self-Rating Mania Scale and daily mood measures recorded using the short form of the Positive and Negative Affect Schedule (PANAS).

Cognitive task performance and neural dynamics will be measured to identify the effects of lithium on physiological variability and to explore the relationship between this variability and the experience of mood instability. The outcome measures will be (1) cognitive task performance for decision making, implicit and explicit reinforcement learning (completed daily using a smart device) in relation to variability in daily measures of mood (PANAS), and (2) the results of two brain scans, one using MEG and the other fMRI. Both will include scans during resting state and whilst performing a decision-making task similar to one of the daily outcomes. Scans will be performed between 3 and 4 weeks post-randomisation when the lithium level has reached a steady state.

Participants will wear an ActiGraph monitor (ActiGraph, Pensacola, FL, USA) for the duration of the study. This will allow us to monitor daytime activity and sleep patterns.

We will monitor circadian gene expression (including BMALL , PER 1 and PER 2) and genes targeted by lithium (e.g., GSK3, IMP and GAD L1) collected from the cheek. Circadian controlled hormones (cortisol and melatonin) will also be collected from saliva to explore the relationship between the circadian system, mood stability and lithium. Gene expression, melatonin and cortisol levels will all be measured every 4 h over two separate 32-h periods, one prior to randomisation and the other between weeks 3 and 4 post-randomisation.

Blood samples will be collected pre-randomisation and at the end of the randomised phase to explore changes in a number of known biomarkers related to thyroid (thyroid-stimulating hormone, thyroid antibodies, triiodothyronine and free thyroxine), parathyroid (parathyroid hormone, calcium and vitamin D) and renal function (urea, creatinine, potassium, glomerular filtration rate, neutrophil gelatinase-associated lipocalin and cystatin C). Blood samples will also be used to explore lithium-associated changes in intracellular protein composition and structure.