Bipolar Lithium Imaging Structure and Spectroscopy

Bipolar disorder is a common psychiatric illness characterized by periods of depression (low mood, loss of enjoyment, reduced energy) and mania (elevated mood, racing thoughts, disturbed behaviour). Relapses can occur frequently and many patients do not fully recover between episodes, struggling with mood fluctuations and poor concentration. Bipolar disorder is highly disabling, seriously disrupting health, family relationships, social circumstances and occupational status. Lifespan is reduced on average by 9 years and one third of patients attempt suicide. Stability in life is undermined by the threat of relapse, the risk of which increases with each episode of illness.

Numerous medications are effective in acute episodes but in patients with a recurrent illness, maintenance treatment is advisable. A goal of maintenance treatment is the prevention of relapse and drugs which are capable of this are called mood stabilisers. Lithium is a unique mood stabiliser, treating and preventing mania and depression whilst reducing suicidal behaviour. To be effective against relapse, patients must take lithium for a long time at an adequate dose. The dose is determined by the lithium level in the blood, aiming for a level which is known to be effective but lower than that at which toxicity occurs.

Whilst a substantial proportion of patients have a good response to lithium, the rest experience a partial or limited response, or are unable to tolerate the side effects, despite having blood levels within the therapeutic range. Potential responders may be identified clinically, having a higher age of onset and a pattern of illness in which mania is followed by depression. Those in whom depression precedes mania do poorly with lithium, as do patients with constant cycling or numerous hospital admissions. However, the ability of these observations to predict response to lithium is fairly poor. Further, they are of limited value for patients early in the course of their illness in whom a pattern of illness has not yet emerged. Reliance on such predictors could mean that lithium initiation is delayed well past the point at which it was first indicated.

Understanding the mechanism of action of lithium might lead to a better way of determining which patients would be most likely to benefit from taking it. Whilst much is known about what effects lithium has, we lack a satisfactory account of its mode of action in bipolar disorder. It regulates the transmission of signals in the mood circuits of the brain, altering the concentration of key chemicals and the tendency for nerve cells to respond to a stimuli. It has been shown that lithium protects the brain from the damaging effects of psychiatric illness, stimulating the regeneration of damaged nerve cells and possibly even the growth of new brain tissue. Recent advances in brain imaging techniques mean that many of these effects can be safely and non-invasively detected using a magnetic resonance scanner.

My research will explore the relationship between the clinical effects of lithium and magnetic resonance estimates of its actions on the brain. Using advanced scanning techniques I will examine brain structure and composition in a group of patients with bipolar disorder taking lithium and compare the results against a group of patients with bipolar disorder taking other long term medications (and naive to lithium). Having thus identified potential markers of the effects of lithium, I will explore the extent to which each magnetic resonance measure accounts for the degree of response to lithium or the severity of its side effects. I will also determine the distribution of lithium in the brain using a novel adaptation of our magnetic resonance scanner - currently only available in our University. I expect that direct measures of brain lithium concentration will inform our understanding of its actions and improve the prediction of response compared to routine blood monitoring.

AIM: To better understand lithium response in bipolar disorder (BD).

OBJECTIVES:
1. Comprehensively evaluate the effects of lithium on the brain in BD.
2. Optimise and advance lithium multinuclear magnetic resonance (MR) techniques.
3. Characterise lithium response using clinical and biological data.

METHODS:
Euthymic adults with BD (type I or II) recruited from NE of England healthcare services, excluding patients with contraindications to MR scanning, current/recent harmful drug or alcohol use, comorbid diagnosis, impairment of capacity or current detention. Cross-sectional study of two groups: i) BD patients taking lithium for up to 5 years (n=80); ii) matched BD patients taking other mood stabilisers but naive to lithium (n=40). In a structured interview, diagnosis will be confirmed and a thorough clinical and archival assessment of each patient's BD undertaken. Blood samples will be taken for medication levels. Patients will complete tests of psychomotor processing speed and attention. MR sequences will include anatomical, quantitative relaxometry, diffusion tensor imaging, proton and phosphorous spectroscopy plus quantitative lithium spectroscopy and novel whole brain lithium imaging.

ANALYSIS
Complementary MR analyses to explore the influence of lithium within the frameworks of its actions on neuroprotection, cellular hydration and biophysical changes to the MR signal. With respect to lithium response, a new rating system will be developed; comparative and correlative analysis of MR, cognitive and clinical data will be performed; patients will also be clustered purely on the basis of their MR data before back-referencing to clinical characteristics.

NOVEL OUTPUT
1. A new clinical tool for rating lithium response, suitable for future prospective investigation of predictive factors.
2. High resolution 3D Li7 imaging.
3. Robust MR measures of lithium's effects (accounting for its actions on hydration and signal generation)

As with all high quality clinical translational research, my work will impact positively on patients, clinicians and health service providers, and advance the global scientific knowledge base whilst simultaneously equipping the future generation of academics with the skills and tools necessary to investigate and address a breadth of health disorders.

The academic beneficiaries of this research have been outlined, but it is important to reiterate that the innovative methodologies and techniques that will arise from this project hold great potential to advance our capability to investigate the basis and treatment of many psychiatric and neurological conditions. The health of psychiatric and imaging disciplines will be enhanced and highly skilled researchers delivered into the field.

Research validating the biological basis of mental illness and its treatment reduces the stigma associated with these conditions. Evidenced by the keen support offered from BipolarUK, research leading to the ability to establish effective treatment at an early stage in bipolar disorder is highly desirable. A greater understanding of the effects of lithium on the brain, in particular its concentration and distribution with respect to response, will directly influence practice. The capacity to titrate lithium dose according to brain concentration may lead to better outcomes and fewer side effects compared to traditional serum monitoring. Unlike other mood stabilisers, lithium reduces suicidal behaviour - research raising the profile and guiding the effective use of lithium will improve health outcomes globally.

This research will have an economic impact directly on the NHS and in a wider sense for the UK. Bipolar disorder is a highly disabling condition associated with substantial direct and indirect socioeconomic costs, many of which are related to the duration of time spent unwell and the delay between presentation, diagnosis and the initiation of effective treatment regimes. Early intervention by specialist services improves outcomes and the ability to predict treatment response with confidence at, or near first presentation would substantially reduce the burden of bipolar disorder across all measures. Compared to lithium, prescription costs for atypical antipsychotics (commonly used in maintenance treatment) are an order of magnitude greater.

The UK is the only country in Europe, and one of a handful worldwide, actively researching multinuclear lithium magnetic resonance spectroscopy. Not only will this research ensure that we remain competitive, but in advancing from spectroscopic detection to true lithium imaging, the UK will be established as the leader in the field. The competitive advantage of my research has been embraced by colleagues in industry. In advertising the advanced capabilities of their magnetic resonance scanner systems at scientific and industry meetings, Philips (Best, The Netherlands) actively promote my methods and results. This mutually advantageous relationship will be developed and formalised during my proposed research.