The schedule for the OxLith trial is displayed in Fig. 1.
Study objectives
The study objectives are as follows:
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1.
To compare the effects of lithium and placebo on mood instability
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2.
To measure the cognitive effects of lithium and to look for correlations with current mood state
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3.
To explore the effects of lithium on the variability in neural dynamics during magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) scans
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4.
To explore the effects of lithium on physical activity and sleep
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5.
To explore the short-term effects of lithium on gene expression; circadian hormones; and thyroid, parathyroid and renal function
Study design
The trial is designed as a single-centre, prospective, randomised, double-blind, placebo-controlled trial. Eligible participants will be randomised in a 1:1 allocation to lithium or placebo. The randomisation algorithm will minimise separately on two variables age (<25 and ≥25 years) and sex (male, female) which are related to prognosis. Routine psychiatric follow-up with be arranged outside the trial as required. Participants will be randomised following a 2-week run-in period and take the study drug for 6 weeks.
Ethics
Written consent will be obtained from all participants. The consent form will include agreement for the results of any blood tests performed before consent to be used as baseline measures for the trial, negating the need for additional venepuncture. The study protocol was approved on 14 April 2015 by the National Research Ethics Service Committee South Central – Oxford A (reference number 15/SC/0109) and on 10 July 2015 by Oxford Health NHS Foundation Trust.
Participants and recruitment
Participants will be recruited from the bipolar disorders research clinic in Oxford. All participants will have a diagnosis of bipolar disorder (I, II or not otherwise specified) based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria and will report clinically significant mood instability. In addition, they will be individuals for whom there is uncertainty about the benefits of lithium (for example, for an individual who has recently been diagnosed or has had relatively few major mood episodes). Participants will be aged 18 years or older; will have pre-treatment renal, cardiac, thyroid and parathyroid function acceptable for the initiation of lithium; and will be willing and able to consent to participate in the trial. Exclusion criteria include any contraindication to taking lithium, concomitant psychotropic medication which cannot be withdrawn, clinically significant substance abuse, the need for treatment of an acute mood episode where placebo would be unethical, pregnancy or being of childbearing age not using effective contraception, and current suicidal ideation.
Interventions
The interventions are placebo or lithium carbonate 200-mg prolonged release tablets are to be taken orally at night and titrated to target serum level of 0.7 mmol/L. This dosing is consistent with routine practice.
Measures
Primary outcome
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).
Secondary outcomes
Cognition and neural dynamics
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.
Sleep and motor activation
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.
Circadian system
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.
Physiological effects of lithium
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.
Power analysis and sample size
The target sample size is 40 participants (20 of whom will be allocated to treatment with lithium and 20 to placebo). This sample size will give more than 90 % power to detect differences between groups on the main mood outcomes at a significance level of 0.5 %. Pragmatically, this sample size is achievable.
Blinding
All trial psychiatrists and participants will be blinded. For those participants taking placebo, sham lithium level results will be presented to the trial psychiatrist by an unblinded researcher. The sham results will be based upon information about reported adherence, time since most recent dose, and adverse events. At or just before the 6-week visit, the unblinded researcher will reveal the participant’s allocated treatment to enable the participant and psychiatrist to discuss treatment options. In the event of a medical emergency, routine care for a patient who may have been taking lithium and has symptoms consistent with lithium toxicity would be to obtain a lithium level immediately, thus negating the need for the treating doctor to be informed about the trial allocation.
Statistical analysis plan
Multiple pre- and post-randomisation mood measurements will be used in an analysis of covariance model to compare lithium with placebo. Methods from the fMRIB Statistical Library (FSL) will be used to analyse fMRI data. The FSL is a software library containing image analysis and statistical tools for functional, structural and diffusion magnetic resonance imaging brain data. MEG data will be analysed using a generalised linear model (GLM) and analysis of variance. The GLM method is a standard non-linear beam former used to determine the time course of neuronal activation for each point in a predefined source space. Actigraphy data will be correlated with mood and cognitive data.
In addition to these more traditional approaches to analysis, we will apply linear and non-linear time series methods and other advanced mathematical approaches, including machine learning. These techniques can produce binary or multi-level classifications as well as point and density forecasts to quantify confidence intervals. We will also apply the mathematical theory of rough paths [21], providing a method to reduce datasets from complex non-linear systems subjected to rapidly fluctuating stimuli to their critical information, facilitating classification and prediction.
Dissemination
Regardless of the magnitude or direction of effect, the main findings of the trial will be compiled and published in an appropriate journal and made available to participants.