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.

Aim To determine the neural correlates of Bipolar Disorder (BD) using functional Magnetic Resonance Imaging (fMRI) in different phases of the illness. Methods Five fMRI studies were conducted in adult female BD patients and healthy matched comparison subjects. The first two studies examined patients with bipolar depression and hypomania using captioned-pictures to characterize mood-state related patterns of activation. The subsequent three studies investigated BD euthymia using emotional words and faces to identify a potential trait-marker. Results During depression, bipolar patients demonstrated additional subcortical activation in the thalamus, amygdala, hypothalamus and medial globus pallidus. In hypomania, patients again had additional subcortical activation involving the caudate and the thalamus. In both studies patients had prefrontal cortex activation, but the pattern differed from that in healthy subjects. These studies suggested a pattern of mood-state related subcortical recruitment for emotional processing in BD. The next set of studies examined euthymic BD patients to partition trait and state-markers. The first study used implicit positive and negative word-associated affect and found diminished responses to positive and negative affective words as compared to healthy subjects in both cortical and subcortical brain regions, in particular the cingulate, thalamus and caudate. The second study used the emotional Stroop task to elicit implicit affective processing and euthymic patients had less cortical and subcortical activation in response to affect, in particular decreased left ventral prefrontal cortex (BA47) activation. The final study used explicit emotional processing of fear and disgust to examine affective responses, and showed that patients were generally less responsive to disgust, but had comparatively greater activations to fear. Conclusions BD patients have a likely deficit in the ventral prefrontal cortex that is evident in euthymia. Prefrontal cognitive appraisal of emotions is constrained in euthymic, depressed and hypomanic phases, reflected in subcortical changes that suggest additional processing. The likely cause for this is a functional prefrontal cortex deficit that results in compensatory changes in emotional processing systems. Treatment probably stabilizes these systems without normalizing them. Our studies demonstrate the benefits of examining BD in its different phases, and future studies should attempt to emulate this in medication-free patients.

Previous event-related potential (ERP) studies have reported evidence of impaired auditory information processing in patients with schizophrenia. Some of these findings, such as the impaired P50 sensory gating, are consistent with a loss of inhibitory function. In auditory ERP studies using pairs of stimuli the size of the second response relative to the first response has been taken to indicate the extent to which responsiveness has recovered after a period of time. This variation of responsiveness has been termed the 'recovery cycle,' and is regarded as a measure of the time course of recovery of excitability of cortical neurons after stimulation. The recovery cycle of the auditory N1 ERP component was measured in 17 patients with schizophrenia and 17 age- and sexmatched healthy volunteers, and 12 patients with bipolar disorder and 12 age- and sex-matched healthy volunteers. Subjects performed a visual distraction task while listening to tone pairs, presented with intra-pair intervals of 1, 3, 5 or 7 s, with inter-pair intervals ranging between 9-13 s. Patients with schizophrenia had significantly reduced N1 amplitudes for S1 stimuli compared to healthy volunteers. For N1 amplitudes elicited by S2 stimuli there was a significant group effect whilst the main effect of intra-pair interval was not significant. A significant quadratic effect across ISI intervals was present in the healthy volunteer group, which was not significant in the schizophrenia group. Patients with bipolar disorder did not differ in N1 amplitudes elicited by S1 stimuli compared to healthy volunteers. There was no evidence of significant group differences in the recovery cycle effect between bipolar patients and matched healthy volunteers. The results provide evidence of inhibitory auditory processing deficits in schizophrenia, and further suggest that deficits in attention found in patients with schizophrenia, as indexed by reductions of auditory N1 amplitude, may be associated with impairments in inhibitory processes. In addition, different recovery cycle effects were found in patients with schizophrenia and those with bipolar disorder. Further study of the recovery cycle paradigm used in this study may lead to the development of an objective diagnostic tool.

Bipolar disorder is a psychiatric condition which affects up to 1% of the general population and results in episodes of mania and depression. Molecular biological studies have shown that several components of the signal transduction pathways are affected in bipolar illness. However, the precise systems and components involved in the disorder still remain unknown. Our goal was to identify some of the differences in signal transduction pathways of B-lymphocytes. Using cultured lymphocytes obtained from bipolar patients, we found that there exist no difference in the levels of protein kinase C, Galphas and Galphai proteins, and tubulin between control and bipolar cell lines following stimulation of the PI pathway with the 5-HT 2 receptor agonist, alpha-methyl serotonin. These data are not consistent with previous findings. The lack of a significant difference between control and bipolar with respect to PKC might be due to the fact that we studied a different cell type or to poor stimulation conditions, and/or possibly to a high PKC content in the membrane of these cells, thereby masking the effect of stimulation. The results obtained for the G proteins can be attributed to a lack of effect of the agonist on these proteins which are associated with the adenylate cyclase pathway.

El trastorn bipolar és una malaltia altament discapacitant i que té un gran impacte en la vida dels pacients. L’any 2007, el Programa de Trastorn Bipolar de l’Hospital Clínic juntament amb la col•laboració d’altres centres internacionals, va crear una escala anomenada Functioning Assessment Short Test (FAST). Aquest instrument va surgir com a resposta a la necessitat que existia, tant en la pràctica clínica com en la recerca, d’una escala clínica que avalués el funcionament psicosocial dels pacients amb trastorn bipolar. Existeixen moltes escales per mesurar el funcionament psicosocial en les poblacions psiquiàtriques però cap d’elles és específica pel trastorn bipolar. A més la utilització de diferents instruments de mesura i paràmetres de discapacitat al llarg de la literatura fan difícil la comparació entre estudis. A més, la FAST com a escala de mesura quantitativa del funcionament psicosocial té molts avantatges respecte les que s’han utilitzat fins al moment: a) està dissenyada per experts en trastorn bipolar; per tant, els ítems que s’exploren reflecteixen realment les àrees on els pacients presenten més dificultats; b) l’avaluació és clínica, per tant no només es basa en les respostes del pacient sinó també es complementa la información amb altres fonts (curs clínic, avaluació del psiquiatre, informació dels familiars...). D’aquesta manera es superen moltes fonts de biaix típiques dels instruments d’autoavaluació, com per exemple l’estat d’ànim concomitant a l’avaluació que pot afectar positiva o negativament les respostes que dóna el pacient; c) finalment, una altra avantatge és la facilitat i rapidesa en la seva aplicació que la fa idònia per ser utilitzada tant en context de recerca com en la pràctica clínica diària. Amb la validació de la FAST, l’any 2007 , coincidint amb la meva incorporació a l’equip, es va obrir un nou horitzó per explorar el funcionament en el trastorn bipolar amb aquesta nova escala i respondre preguntes que fins ara no quedaven clares en la literatura. Així doncs, el primer pas va ser vincular-me en un estudi que ja estava iniciat, on s’avaluava el funcionament dels pacients amb trastorn bipolar en els tres estats diferents de la malaltia: eutímia, depressió i (hipo)mania en comparació amb un grup de controls sans. En aquest estudi, es va comprovar que la simptomatologia depressiva era més discapacitant que la maníaca però també es va observar que els pacients eutímics presentaven dificultats en el funcionament psicosocial. Amb el segon estudi (es va comparar una mostra de pacients eutímics dividits en funció de la tipologia diagnòstica (subtipus I vs. subtipus II) ja que revisant la literatura no quedava clar fins a quin punt aquest factor podria influenciar el funcionament psicosocial dels pacients eutímics. Finalment i aprofitant que l’escala FAST permet avaluar tant el funcionament global com també l’estudi de dominis específics del funcionament psicosocial, es va portar a terme un tercer estudi per tal d’analitzar quines variables clíniques i neurocognitives podrien ser les que impacten en el funcionament psicosocial dels pacients amb trastorn bipolar. Aquest estudi, respecte als dos anteriors introdueix com a novetat les variables neurocognitives així com també un disseny longitudinal amb un seguiment als Quatre anys.

Previous event-related potential (ERP) studies have reported evidence of impaired auditory information processing in patients with schizophrenia. Some of these findings, such as the impaired P50 sensory gating, are consistent with a loss of inhibitory function. In auditory ERP studies using pairs of stimuli the size of the second response relative to the first response has been taken to indicate the extent to which responsiveness has recovered after a period of time. This variation of responsiveness has been termed the 'recovery cycle,' and is regarded as a measure of the time course of recovery of excitability of cortical neurons after stimulation. The recovery cycle of the auditory N1 ERP component was measured in 17 patients with schizophrenia and 17 age- and sexmatched healthy volunteers, and 12 patients with bipolar disorder and 12 age- and sex-matched healthy volunteers. Subjects performed a visual distraction task while listening to tone pairs, presented with intra-pair intervals of 1, 3, 5 or 7 s, with inter-pair intervals ranging between 9-13 s. Patients with schizophrenia had significantly reduced N1 amplitudes for S1 stimuli compared to healthy volunteers. For N1 amplitudes elicited by S2 stimuli there was a significant group effect whilst the main effect of intra-pair interval was not significant. A significant quadratic effect across ISI intervals was present in the healthy volunteer group, which was not significant in the schizophrenia group. Patients with bipolar disorder did not differ in N1 amplitudes elicited by S1 stimuli compared to healthy volunteers. There was no evidence of significant group differences in the recovery cycle effect between bipolar patients and matched healthy volunteers. The results provide evidence of inhibitory auditory processing deficits in schizophrenia, and further suggest that deficits in attention found in patients with schizophrenia, as indexed by reductions of auditory N1 amplitude, may be associated with impairments in inhibitory processes. In addition, different recovery cycle effects were found in patients with schizophrenia and those with bipolar disorder. Further study of the recovery cycle paradigm used in this study may lead to the development of an objective diagnostic tool.

Thesis (Ph.D.)--University of Melbourne, The Mental Health Research Institute of Victoria and the Dept. of Psychiatry, 2010. / Typescript. Includes bibliographical references (p. 193-229)

Thesis (M.A.)--The University of North Carolina at Greensboro, 2010. / Directed by Thomas Kwapil; submitted to the Dept. of Psychology. Title from PDF t.p. (viewed Jul. 7, 2010). Includes bibliographical references (p. 61-70).

Thesis (Ph.D.)--Duquesne University, 2006. / Title from document title page. Abstract included in electronic submission form. Includes bibliographical references (p.137-152) and index.

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