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The aetiology of bipolar disorder remains unclear and investigation to date has focussed largely on bipolar patients. Whilst ultimately of huge value, such studies may also be confounded by current mood or experience of repeated illness episodes or current or past medication; using at-risk samples may bypass some of these problems. The current research therefore assessed the efficacy of the Mood Disorder Questionnaire (MDQ) as a screening tool for vulnerability to bipolar disorder. The MDQ was used with two sets of criteria to identify two sub-groups of medication-naïve young bipolar phenotype subjects who were at risk for bipolar disorder by virtue of experience of mood elevation. Analysis of data from the Student Stress Survey was carried out to characterise the bipolar phenotype. Compared to a control group with no experience of mood elevation, the two bipolar phenotype sub-groups showed a gradient of prevalence of bipolar diagnosis and associated co-morbidity. Behavioural and functional magnetic resonance imaging (fMRI) techniques were employed to investigate emotional processing, decision-making, and sleep and circadian rhythmicity in bipolar phenotype students. Analyses revealed that positive emotional processing biases, disrupted decision-making, and increased activity during sleep were associated with the bipolar phenotype and, therefore, may represent vulnerability markers for bipolar disorder. Finally, a psychopharmacological investigation of quetiapine, which stabilises mood, was carried out in healthy volunteers. One-week quetiapine administration resulted in biases away from both positive and negative emotional stimuli (i.e. a mood-stabilising effect), reduced discrimination between different magnitudes of gains and losses during risky decision-making (consistent with an antidepressant effect), and increased sleep duration. In sum, this research has developed our understanding of vulnerability markers associated with the bipolar phenotype and provided a first step towards uncovering the psychological mechanisms through which quetiapine’s clinical effects may be mediated.

The discriminative stimulus properties of the 'psychotomimetic' MK-801 and the novel, often termed 'atypical', antipsychotics clozapine and quetiapine are investigated using an operant fixed-ratio drug discrimination assay. The use of MK801 discrimination to detect novel antipsychotics is assessed in view of a study by Corbett (1995) reporting that clozapine, but not the typical antipsychotic haloperidol, fully antagonises an MK-801 cue. Clozapine only partially antagonises the MK-801 cue (max 47%), but haloperidol produces 75% antagonism. These results are in complete contrast to Corbett's findings. Some selective ligands are also tested (the 5- HT», antagonist ketanserin and the a adrenoceptor antagonist prazosin), as they have been shown to block some MK-801-induced effects in other paradigms. These compounds produce minimal antagonism of the MK-801 cue (max 17% and 36% respectively). These results indicate that the MK-801 discriminative cue may not in fact be 'psychotomimetic'. It is possible that MK-801 discrimination can only be a useful screen for novel antipsychotics under restricted experimental procedures (e.g. shock avoidance paradigms as used by Corbett). The discriminative stimulus properties of antipsychotics are investigated using a range of novel and typical antipsychotics and specific ligands in rats trained to discriminate clozapine and quetiapine. Generalisation tests with antipsychotics show that drugs with affinity for multiple receptors generalise fully to clozapine (zotepine and PNU 96415) and to quetiapine (clozapine, olanzapine and risperidone). The novel antipsychotic amisulpride (D2/D3; antagonist) and the typical antipsychotics haloperidol, chlorpromazine and loxapine fail to generalise more than partially to quetiapine. These data support the hypothesis that both the clozapine and quetiapine cues may be compound cues, as drugs which only generalise partially have more restricted binding profiles than drugs which generalise fully. Tests with specific ligands produce very similar results in both discriminations: mepyramine (Hi antagonist) and L 745,870 (D4 antagonist) fail to generalise (max 22%); SCH 23390 (D; antagonist) generalises partially (38%-44%); PNU 99194A (D3 antagonist) and prazosin (a, adrenoceptor antagonist) generalise substantially (54%-80%); and scopolamine (muscarinic antagonist) generalises fully (87%-100%). SCH 23390, tested for antagonism of the clozapine cue, produces only minimal antagonism (max 20%). These results indicate that antagonism at H; and D, receptors plays little role in mediating the quetiapine or clozapine cues and that D; agonism has no significant role in mediating the clozapine cue. Antagonist actions at D), «; and D3 receptors may play a significant but limited role in mediating both cues, although the selectivity of PNU 99194A as a D3 antagonist is questionable in view of the failure of other D3 antagonists to generalise to clozapine and the failure of the D3 agonist 7-OH-DPAT to block clozapine- and PNU 99194A-induced drug lever selection. The full generalisation seen with scopolamine implies that muscarinic antagonism may be critical in mediating both cues. This is paradoxical, as some antipsychotics with negligible muscarinic affinity generalise fully to clozapine (e.g. PNU 96415) and to quetiapine (e.g. risperidone). Several explanations for this paradox are proposed and it is concluded that muscarinic antagonism may be sufficient but not necessary for full generalisation. The full generalisation of clozapine to quetiapine may indicate a clozapine-like action of quetiapine clinically, although as the mechanisms of action of these drugs remain unknown this is impossible to prove. Similarities between clozapine and quetiapine therapeutically but not in binding profiles indicate that drug discrimination measures common in vivo behavioural responses possibly related to antipsychotic effects, but not predictable from in vitro binding studies.

Abstract: Myelin is an essential component of nervous system functioning: it supports axonal metabolism, enables saltatory conduction to allow for precise timing across cortical networks to regulate information processing and is increasingly recognized as an integral type of adult experience-dependent structural plasticity. As such, myelin’s role is aiding the neuroplastic reorganization of the brain after stroke has recently received considerable attention, but significant gaps in knowledge remain, chief amongst them the widely differing timecourse and spatial distribution of myelination changes reported across various studies. To help characterize these post-stroke changes in myelin, particularly in the immediate vicinity of the primary site of injury, we investigated the utility of a novel label-free in vivo imaging technique called Spectral Confocal Reflectance Microscopy (SCORE) capable of stably tracking individual superficial cortical myelinated fibers over a period of weeks. We concurrently tracked changes in the integrity and density of axons projecting to or passing through the same peri-lesional areas originating in the contralesional homotopic regions and simultaneously monitored meso-scale functional activation of the cortex in response to somatosensory stimuli of the fore- and hindlimb to gauge the extent of functional recovery occurring in somatosensory processing, given that the stroke model used specifically targeted the forelimb somatosensory representation. The pole test and the cylinder test were also utilized as an indices of behavioral recovery. Furthermore, we administered the atypical antipsychotic quetiapine - a known pro-myelinating agent - to see whether its myelin boosting effect was observable following an ischemic injury as well and to further help evaluate the functional significance of post-stroke myelin densities in aiding functional recovery. We showed longitudinal imaging of both GFP-expressing contralateral crossing fibers and SCORE-imaged myelinated fibers are stable and powerful techniques for evaluating the changing architecture of the post-stroke brain: though a severe deficit in both types of fiber densities are evident immediately in the days following stroke, robust recovery to baseline levels particularly in the density of contralaterally projecting crossing fibers was apparent within 2 weeks after the initial injury. Myelin density, however, particularly in regions close to the stroke core, remained persistently decreased even at 4 weeks post-stroke. Quetiapine treatment increased the density of intact contralateral crossing fibers, but more dramatically helped partially alleviate the chronic myelin deficit observed surrounding the infarct core. Despite these effects, however, quetiapine did not significantly boost the timecourse or extent of the functional recovery of somatosensory processing or behavioral recovery. Nevertheless, myelin density was still shown to be a significant predictor of the size of both forelimb and hindlimb stimulation activated cortical responses, indicating that though myelination appears to play some role in contributing to functional recovery, it does so in concert with other, potentially more influential mechanisms of recovery. Alternatively, functional patterns of cortical activity dictated by rehabilitative training may be necessary to induce more functional patterns of myelination across the recovering cortical networks than was observed in our model of quetiapine administration with no directed sensorimotor rehabilitation.

Background: The unique recovery process and treatment needs of persons with bipolar II disorder (BD II) has been subject of limited research. BD II is associated with high rates of disability worldwide and people with BD II are among the highest risk of suicide of all populations. Research of psychotherapy for bipolar disorders (BDs) in general has focused on clinical outcomes (i.e., reducing mood symptoms, remission of mood episodes) rather than functional outcomes, suicide risk, or co-occurring problems. This dissertation addresses these gaps in three quantitative studies, which investigate the recovery process of individuals with BDs and what treatment (i.e., psychotherapy alone or in combination with medication) works for whom (i.e., individuals with childhood trauma, anxiety, and various stages of illness progression) to improve symptoms, reduce suicidal thoughts, and restore functioning to all major life areas. The goal of these studies is to inform treatment considerations for BD II to decrease the high rates of mortality and disability associated with BD II. These studies are guided by kindling theory and social rhythms disruption therapy, which emphasize stressful life events and disruption of social and biological rhythms, in combination with genetic predisposition to explain the etiology and ongoing expression of BDs.Methods: Study design consisted of a randomized, double blind, controlled trial (ClinicalTrials.gov identifier: NCT01133821) testing the efficacy of interpersonal social rhythms therapy (IPSRT) plus placebo compared to IPSRT plus medication (i.e., quetiapine) for adults with BD II depression (n = 92). Study 1 used multilevel logistic regression with growth curve modeling to examine (1) the comparative effectiveness of IPSRT plus placebo compared to IPSRT plus medication on suicidal ideation outcomes, and (2) whether higher levels of childhood trauma and anxiety predicted change in suicidal ideation. Study 2 used multilevel modeling with growth curve modeling to examine (1) the comparative effectiveness of IPSRT plus placebo compared to IPSRT plus medication on specific domains of functioning, and (2) whether stage of illness progression predicted functional outcomes. Study 3 used Kaplan Meir survival analysis to calculate recovery rates (i.e., symptomatic, syndromal, and functional recovery) at 8, 12, and 20 weeks. Log rank tests examined effect between treatment groups and z-tests examined differences between the different types of recovery rates. Results: Study one’s results demonstrated a significant decrease in suicidal ideation with each additional week of treatment. There was no significant difference in the decrease in suicidal ideation over time between those receiving IPSRT alone v. IPSRT plus quetiapine. Childhood trauma and anxiety did not predict worse functional outcomes. Study two’s results demonstrated improvement in functioning in all areas (i.e., autonomy, occupational, cognitive, financial, interpersonal, and leisure) with no significant difference over time between those receiving IPSRT alone ad IPSRT + quetiapine. However, despite improvement the majority of participants remained impaired in all areas of functioning at the end of acute treatment other than leisure time. Stage of illness progression did not predict functional outcomes, except those with those most advanced stage of illness had the worst occupational functioning at baseline, but showed the most improvement over the course of the 20-week treatment period. Study three’s results demonstrated participants reached each type of recovery (i.e., symptomatic, syndromal, and functional) at comparable rates between the two treatment groups. Significantly more participants recovered syndromally than functionally or symptomatically.Conclusions: Results suggest individuals with BD II can improve in suicidal ideation, all areas of functioning, and achieve all forms recovery whether or not they receive medication in addition to psychotherapy. Functional recovery required longer time than reduction of active symptoms and half of participants did not reach remission, indicating longer, more intensive or combination treatments may be needed for half of individuals with BD II. However, psychotherapy independent of medication may be a reasonable treatment option for some individuals with BD II. Replication with larger sample size and additional comparator conditions is needed before forming treatment recommendations. Limitations include small sample size with limited racial diversity, high attrition, and lack of a standard of care psychotherapy group or medication only group.

An estimated 35 million diabetic patients worldwide take antipsychotic medications for a variety of co-morbid mental illnesses. Diabetic patients frequently experience hypoglycemic episodes ranging from mild to severe. Interestingly, the combination of antipsychotic medications and hypoglycemia has remained largely unstudied. Both antipsychotic medications and hypoglycemia modulate extracellular glutamate creating the potential for glutamate-mediated excitotoxicity. The typical antipsychotic medication, haloperidol, has been shown to elevate extracellular glutamate levels through its binding pharmacology at the D2 and 5HT1A receptors. Conversely, quetiapine, an atypical antipsychotic medication, is not predicted to elevate extracellular glutamate through its binding pharmacology at the D2, 5HT1A, and 5HT2A receptors and may be less likely to induce this toxicity when combined with hypoglycemia.We hypothesized that haloperidol and hypoglycemia, not quetiapine and hypoglycemia, would elevate neuronal death and microglial activation. We predicted that this would occur through glutamate-mediated excitotoxicity potentiated by activated microglia. We investigated this hypothesis by combining these medications with a range of different hypoglycemic episodes: acute, severe; single, moderate; and multiple, moderate. The combination of severe hypoglycemia with these antipsychotic medications showed that both medications elevated neuronal death as compared to hypoglycemia alone. This suggests that the predicted abilities of quetiapine to attenuate extracellular glutamate levels and prevent glutamate-mediated excitotoxicity of neurons are overshadowed in instances of severe hypoglycemia. However, when moderate hypoglycemic episodes were combined with antipsychotic medications, no changes in neuronal death or microglial activation were detected. Overall, these data suggest that severe hypoglycemia and antipsychotic medications induce neuronal death, but the effects of these medications and moderate hypoglycemia on microglial activation may be more subtle in nature. These studies are relevant to the treatment and safety of the millions of diabetic patients taking antipsychotic medications who may be at risk for serious side effects.