It has been six decades since the discovery of lithium for the treatment of bipolar disorder. There is, as yet, no conclusive evidence as to how lithium produces this therapeutic effect, since it is known to interact with multiple cellular targets. One of the most credible targets is the enzyme, inositol monophosphatase (lMPase), which plays a crucial role in cell signalling. My aim was to find a novel IMPase inhibitor and evaluate it as a possible lithium-like mood stabiliser by using enzyme, cell and whole animal experiments. To achieve this, I created recombinant human and mouse IMPase enzymes and then used these for screening and crystallisation. I used two different approaches for the small-molecule screening: substrate-based virtual screening and drug repositioning using a library of compounds with clinically proven safety. I identified ebselen as a novel IMPase inhibitor suitable for drug repositioning. I determined thatebselen inhibited IMPase noncompetitively, likely through a covalent modification on a cysteine. In cell cultures, ebselen was found to inhibit not just IMPase but other steps that resulted in accumulation of higher inositol phosphates. When injected intraperitoneally into mice, ebselen crossed the blood- brain barrier and exhibited inhibition of IMPase ex vivo. Moreover, in mice, ebselen simulates some, but not all, of the behavioural effects of lithium. I have determined that ebselen inhibits IMPase and acts as a partial lithium mimetic. Given that ebselen is safe in man, it warrants clinical testing for the treatment of bipolar disorder.

Common medications utilized in the treatment of psychosis include lithium carbonate and the major tranquilizers. The efficacy of lithium is well established in the treatment of manic-depressive patients exhibiting symptoms of mania. The major tranquilizers treat a broader range of psychotic disorders including schizophrenia. In the treatment of manic-depressive illness, lithium produces normalization of affect with few side effects. However, since the interval between therapeutic and toxic dosages is narrow, lithium treatment must be closely monitored to avoid severe physical problems and even death. When a schizophrenic is incorrectly diagnosed as manic-depressive, and is treated with lithium, the patient does not benefit from treatment; this also constitutes an inappropriate risk for lithium toxicity. Conversely, when a manic-depressive is incorrectly diagnosed as schizophrenic and treated with major tranquilizers, the patient benefits only from the sedative effects of these drugs while risking the often debilitating side effects associated with them. Due to the similarity of their associated symptoms, the diagnostic discrimination of mania and schizophrenia is often difficult. This presents a problem, as diagnoses play an important role in the determination of the treatment of functional psychosis. The difficulty in achieving satisfactory levels of accuracy in diagnosis and subsequent choices of treatment for these two conditions may be due to the subjective nature of behavioral observations and clinical judgments in diagnostic interviews. The hazards of clinical judgment can be reduced through the application of appropriate objective tests. This research developed a scale from the Minnesota Multiphasic Personality Inventory (MMPI) item pool which is associated with therapeutic response to lithium carbonate.

Indiana University-Purdue University Indianapolis (IUPUI) / The present study sought to identify the effects of chronic lithium administration on ethanol intakes in high alcohol-preferring (HAP) mice. Lithium is a well-established treatment for bipolar disorder and has demonstrated efficacy in reducing impulsivity, an endophenotype of the disease. Impulsivity is also a prominent trait of alcoholism. HAP mice display a preference for consuming substantial amounts of ethanol and exhibit abnormally high levels of impulsivity. Previous work has determined that chronic lithium exposure in HAP mice reduces their levels of impulsivity. The present study analyzed fluctuations in established intake patterns after lithium exposure and how pre-exposure to lithium would affect ethanol intake acquisition. The results showed an increase in ethanol intake and no change in preference for ethanol over water in lithium treated mice. There was an increase in overall total fluid consumption in these mice, likely resulting from polydipsic effects. There also appeared to be a potentiated lithium toxicity effect found in those mice pre-exposed to lithium. The conclusion was that lithium therapy does not decrease ethanol consumption in HAP mice.