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The marked heterogeneity between individuals diagnosed as experiencing schizophrenia has troubled nosologists since the very coining of the term. Catalysed by Crows (1980) hypothesis of independent positive, and negative syndromes, which led to substantial breakthroughs in our comprehension of schizophrenia, the last two decades have seen a resurgence of interest in the characterisation of symptom dimensions to resolve the issue of heterogeneity. A three dimensional model, comprising 'psychotic', 'negative', 'disorganised' syndromes has received considerable research attention and has been proposed for inclusion in the Diagnostic and Statistical Manual of Mental Disorders. Similarly, a five-dimensional model, adding syndromes of 'affective disturbance'and 'excitement', has also attracted an increasing profile of literature. Mounting evidence suggests, however, that these models do not adequately reflect the diversity of symptoms seen among those with a diagnosis of schizophrenia, and that they may emerge as an artefact of lossy factor-analytic techniques applied to measurement models biased or inadequate in their coverage of symptoms. To overcome such limitations, in the present study one hundred in- and out- patients diagnosed with schizophrenia were assessed for completed a battery of neuropsychological tests tapping five aspects of attention, and smooth pursuit eye tracking was also recorded. Using cluster analyses to examine correlations between symptoms, eleven groups of symptoms were identified: 'hostility', 'conceptual disorganisation', 'bizarre behaviour', 'grandiosity', 'auditory hallucinations', 'loss of boundary delusions', 'paranoia', 'anxious intropunitiveness', 'cognitive dysfunction', 'negative signs' and 'social dysfunctions'. All groupings were internally consistent, largely independent of others, and supported by other symptom models proposed in the literature. Several of the symptom groupings were validated by demonstration of independent relationships with neuropsychological variables or aspects of eye movements, and the more complex symptom model was equivalent or superior in the prediction of neuropsychological performance than the three- and five- factor symptom models. Implicit in dimensional approaches to conceptualising schizophrenia is the notion that the identified groupings may reflect the functioning of distinct brain systems. This thesis has demonstrated that the 'syndromes' defined by the three- and five- dimensional models of schizophrenia are actually heterogeneous groupings of poorly correlated symptoms. This, in turn, obscures the relationships between symptoms and underlying pathology. Dimensional approaches to psychopathology hold great promise for unravelling the nature of psychosis. However, the existing facile descriptions may actively constrain the potential for research progress. The rigorously developed description of symptomatology presented here represents a compact and useful representation of the spectrum of symptoms experienced in schizophrenia, and has demonstrated an advantage over existing conceptions that demands implementation and vigorous research attention.

Major depressive disorder (MDD) is a widespread psychiatric disorder that affects millions of people worldwide and is hypothesized to occur due to impairments in several neurotransmitter systems, including the monoaminergic and glutamatergic neurotransmitter systems. Antidepressant medications targeting multiple monoamine neurotransmitters have been shown to be effective for the treatment of depression. Racemic amisulpride is an atypical antipsychotic that has been used at low doses to treat dysthymia, a mild form of depression, and functions as an antagonist at DA2/3, 5-HT2B, and 5-HT7 receptors. Recent preclinical studies have suggested that the S(+) isomer may be more critical for amisulpride’s antidepressant-like effects; however, this interpretation has not been fully characterized in comparison to the R(-) isomer. The glutamatergic system also has been shown to play a critical role in alleviating depression. Several studies have demonstrated that the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine produces rapid and sustained antidepressant-like effects in clinical trials; however, few studies have examined the degree to which ketamine’s isomers contribute to antidepressant-like effects. Fully characterizing these differences in a preclinical model of depression may offer important insight into the role of these neurotransmitter systems on depression. The present study used a 72-sec differential-reinforcement-of-low-rate (DRL) task to assess the antidepressant-like effects of amisulpride, ketamine, and their isomers in mice. The DRL 72-sec task has shown to be a reliable and sensitive screen for drugs that possess antidepressant-like activity as reflected by an increase in the number of reinforcers, a decrease in the number of responses, and a right-ward shift in the interresponse time distributions (IRTs; i.e. the elapsed time between two successive responses). For comparison, the effects of the tricyclic antidepressant imipramine and the N-methyl-D-aspartate antagonist MK-801 as positive and negative controls, respectively, were determined. Consistent with previous findings, we hypothesized that amisulpride and S(-)-amisulpride, but not R(+)-amisulpride, would produce antidepressant-like effects, and all formulations of ketamine would produce antidepressant effects. Racemic amisulpride and S(-)-amisulpride, but not R(+)-amisulpride, produced an antidepressant-like effect, evidenced by a significant increase in the number of reinforcers and a significant decrease in the number of responses. Racemic ketamine and R(-)-ketamine significantly increased the number of reinforcers and decreased the number of responses, while S(+)-ketamine significantly increased the number of reinforcers, but did not decrease the number of responses (at the doses tested). Overall, these results indicate that the racemic formulations of amisulpride and ketamine, S(-)-amisulpride, and both ketamine isomers demonstrate antidepressant-like effects as assessed in the DRL task and may be useful in a clinical context. If either of the ketamine isomers can be shown to produce fewer psychotomimetic effects in humans, then the isomers may offer a significant clinical advantage over the parent compound ketamine. Regarding amisulpride, the present results demonstrate that the S(-) isomer, but not the R(+) isomer, possess antidepressant-like activity similar to racemic amisulpride.

Myocardial infarction (MI), often referred to as a heart attack, is a serious health issue in the United States. There is a well-documented link between MI and major depressive disorder (MDD), with a high incidence of MDD occurring after an MI. Overlapping pathologies have been observed within the hippocampus of the brain in animal models of MI and depression. These observations suggest that pathobiological cross-talk between the heart and brain could have a role in the etiology of MDD that occurs after an MI. Spinal cord stimulation (SCS) has previously been shown to have both cardioprotective and neuroprotective effects post-MI, and hence may protect individuals from developing depression post-MI. In this study, we examined the potential biochemical mechanisms that might underlie the neuroprotective actions of SCS following MI. Brain tissues were obtained from three groups of canines: sham-operated animals, animals subjected to experimental myocardial infarction/mitral regurgitation (MI/MR), and animals subjected to MI/MR that were simultaneously administered SCS. The whole hippocampus and hippocampal dentate gyrus were dissected from frozen brains. Quantitative endpoint-PCR and RT-qPCR techniques were employed to measure select biochemical mediators of neuroprotection, i.e. adenosine A2A receptor, ghrelin, and ghrelin receptor expression in hippocampal samples. SCS induced a significant decrease in A2A receptor expression and a dramatic increase in ghrelin expression in MI/MR canines as compared to the MI/MR group without SCS. These findings suggest that adenosine receptors and ghrelin may play a biochemical role in SCS-induced neuroprotection of the hippocampus. Understanding the neuroprotective actions of SCS has the potential to aid the development of new treatments or preventative measures for depression following a heart attack.

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