Bipolar disorder has been associated with blunted activity in regions associated with emotional processing, such as striatal activity during reward anticipation as well as prefrontal activity during reappraisal. Lithium is the most effective treatment in bipolar disorder. Neurochemical and molecular basis of lithium is well known, but how this translates to mood stabilisation is not understood. This study is designed to address how lithium influences reward and emotion regulation processes in humans.

Background:

Bipolar disorder is a relatively common psychiatric disorder for which treatment options are limited. The so-called mood stabiliser, lithium (usually in the form of lithium carbonate) is one of the most commonly used treatments for the disorder, and is effective in treating both acute mania and as a long term maintenance treatment. The investigator's understanding of the pharmacological mechanisms by which lithium exerts its actions is fairly well developed, however there is a lack of understanding of the psychological mechanisms. Within this study the investigators will look at two different types of emotional processing, namely reward anticipation/feedback and emotion regulation, to gain more understanding on how lithium exerts its mood stabilising effects.

Reward processing:

The neural correlates underlying reward anticipation and feedback can be measured with the Monetary Incentive Delay (MID) task, a widely used task for different disorders. Reward anticipation during the MID task has been associated among others, with ventral and dorsal striatum activity. Most critically, bipolar disorder has been associated with blunted reward function of the medial caudate. Reward feedback has been associated with ventral striatum and OFC/vmPFC activity.

Emotion regulation:

One of the most prominent approaches of emotion regulation is reappraisal . Reappraisal has been shown to consistently activate cognitive control regions and to modulate the bilateral amygdala. Insufficient prefrontal control and reduced downregulation of those prefrontal regions of the amygdala while reappraising negative stimuli has been consistently found in bipolar disorder.

Methods:

Using a double-blind, parallel-group design, 37 healthy volunteers (male and female) are randomly allocated to a 11 (+/- 1) day lithium administration or a placebo condition. After the intervention period, all participants undergo fMRI testing with the MID task and the emotional suppression task to assess reward processing and reappraisal of negative stimuli. The participants also complete a visual control task (checkerboard task) and several behavioural tasks and questionnaires. Lithium levels are measured at the end of the intervention period.

Hypothesis:

Based on the literature on bipolar disorder and the mood stabilising effects of Lithium, the investigators expect lithium administration in healthy participants to:

• Increase caudate activity during reward anticipation
• Increase activation of prefrontal control regions as well as increase negative connectivity between those regions and the amygdala during reappraisal

Fidelity check: significant increases in lithium levels in the lithium intervention group compared to the placebo group.

Inclusion Criteria:

• Subject is willing and able to give informed consent for participation in the study.
• Subject is between 18 and 55 years of age
• Subject has a body mass index (BMI) in the range of 19-30
• Subjects will be physically fit, as assessed by a physical examination by a medical doctor.
• if female and of child bearing age must have a negative pregnancy test for inclusion and must be using two forms of effective contraception.
• Subjects will be fluent English speakers
• Thyroid stimulating hormone and creatinine will be assessed pre-treatment to ensure that these are within healthy range
• non or light smoker < 5 cigarettes per day
• right handed

Exclusion Criteria:

• taking psychotropic medication
• any past or current axis 1 psychiatric disorder on DSM-IV
• Any medical contra-indication (for example, conditions that might alter absorption of lithium or which could impact on the safety of the druk for the volunteer, for example impaired renal function as assessed by creatinine levels or impaired thyroid function as assessed by thyroid stimulating hormone levels)
• Current pregnancy or breastfeeding
• Current or past history of drug or alcohol dependency
• Participant in a psychological or medical study involving the medication within the last 3 months
• Smoker > 5 cigarettes per day
• Dyslexia
• Any contra-indication to MRI scanning, for example chance of metal in the body
• Left-handed

When data was collected, no approval was acquired to share individual participant data. The investigators will make the summary statistics and analyses scripts available.

The randomisation schedule was drawn up by an experimenter in the lab who is not involved in the study, and all information was kept in a locked cabinet in the Neurosciences building at the Department of Psychiatry, University of Oxford.