Understanding the Mechanism of Action of Lithium and the Pathophysiology of Bipolar Disorder with Molecular Imaging of the Serotonin System

Bipolar disorder is a chronic, disabling psychiatric disorder with a lifetime mortality rate from suicide between 10-20%. Despite its heavy toll, little progress has been made in the development of novel or improved therapeutics for this common condition affecting over 2% of the population. In fact, lithium treatment, discovered to have anti-mania properties decades ago, remains as one of the few effective treatments in bipolar disorder, with evidence of mood stabilizing, antidepressant, antisuicidal, and even neuroprotective qualities. Yet many with bipolar disorder do not tolerate its heavy side effect burden. Also, lithium can harm kidney function, thyroid function, cardiac conduction, and needs careful blood level monitoring because of high toxicity at levels not far above those required for its therapeutic benefits. Some of the more compelling evidence for disordered neurobiology in bipolar disorder implicates the brain's serotonin system, and actions of lithium specifically on the serotonin 1A receptor may be central to its antidepressive and antisuicidal properties. Characterizing the mechanisms by which lithium works in bipolar disorder promises to provide direct molecular targets for treatments that act similarly, but without the level of intolerability and risk of toxicity. In the last decade we have developed the ability to quantify with a great deal of precision the number and distribution of serotonin system proteins in patients suffering the effects of bipolar disorder using in vivo positron emission tomography (PET) and magnetic resonance imaging (MRI). With this emerging technology, our group has been able to demonstrate striking abnormalities in two serotonergic proteins implicated in bipolar depression, the serotonin 1A receptor (5-HT1A) and the serotonin transporter (5-HTT). We now are in a position to test whether lithium has its most clinically significant actions through changes it causes in the serotonin system. We plan to examine this in bipolar depression, the phase of bipolar disorder that dominates the condition and is associated with most of the disorder's morbidity and mortality. Based on findings from animal models, we hypothesize that lithium downregulates the presynaptic 5-HT1A receptor, upregulates the postsynaptic 5-HT1A receptor, and upregulates 5-HTT. We obtained pilot funding to perform PET scanning of the 5-HT1A and 5-HTT systems in bipolar depressed subjects before and after a therapeutic course of lithium monotherapy. In this small sample the brain proteins were altered as hypothesized. We are seeking additional funding to verify these preliminary findings in a larger sample and to assess whether lithium-induced changes in serotonergic proteins specifically correlate with improvements on clinical measures of bipolar depression and suicidality, hypothesizing that the extent of lithium-induced alterations will correlate with clinical efficacy. Elucidating the mechanism of one of the most effective pharmacological treatments in bipolar disorder promises to directly aid in the development of therapeutic agents that are more broadly tolerable and don't have a high potential of organ toxicities of lithium. 5-HT1A binding potential (BPF = Bmax/KD where Bmax = number of receptors and KD = 1/affinity to receptor) will be determined using the positron emission tomography (PET) radiotracer [11C]WAY 100635 and 5-HTT binding potential will be determined using [11C]DASB in 14 medication free bipolar subjects during a major depressive episode before and after lithium treatment. Our group has over eight years of doing dual injection brain PET imaging studies in mood disorders, and we have successfully recruited and acquired PET scans in over 40 patients with bipolar depression.