There is no abstract available for this thesis.

This thesis has investigated the nature of the family, so-called "schizophrenia", and society as viewed by the major anti-psychiatric theorists and radical psychologists/psychiatrists. Particular emphasis was placed on the works of R. D. Laing, D. G. Cooper, and M. Schatzman. The family was investigated as the primary tool of induction of the individual into socially "acceptable" (i.e. conformist) roles via abdication of self, as well as the basic context in which particular individuals are labeled as "mad". The diagnostic category of "schizophrenia" was studied as a false abstraction applied to some individuals by others in a particular social situation in which the diagnosed individual's behavior has been removed from its social context and viewed wrongly as the result of a pathological process. Society was investigated as the meta-context within which these phenomena occur and their appearance of irrationality is to be understood.

This study investigated the auditory and perceptual patterns of two schizophrenic groups. A paranoid group containing 10 males and 10 females was matched with a non-paranoid group and evaluated through the use of The Sound Test, an auditory projective test, and the Holtzman Inkblots, a visual projection technique. The results found no significant differences between groups on any variable. Trends were observed in the direction of the hypotheses when male response patterns were viewed separately. The results were discussed in terms of male and female response differences and chronicity as contaminating variables.

Interpatient variability in clinical response to antipsychotics (AP) is observed in the treatment of schizophrenia (SCZ) with evidence to support a genetic basis for this phenomenon. Dysfunction in the dopaminergic (DA) system as well as the glutamatergic (GLU) system have both been implicated in the formation of SCZ symptoms. Therefore, we explored the role of DA and GLU receptor variation on clinical response to CLZ, an AP of last resort. We focused on DA receptor genes DRD3, DRD4, and DRD5 having already previously published on DRD1 and DRD2 in this sample. N-methyl-D-aspartate receptor (NMDAR) subunit gene variants and epistatic effects between and among these variants and DA receptor gene variants were also studied. For DRD3, we extended a statistically significant meta-analysis on single nucleotide polymorphism (SNP) rs6280 (Ser9Gly) previously performed by Jonsson et al. (2003). We observed a consistent trend for the serine allele and poor CLZ response (six of seven studies with the same direction of effect). Eight other tagged DRD3 SNPs were also tested with two identified for future replication. For DRD4, associations were observed between the 4-repeat allele of the exon III variable number tandem repeat (VNTR) polymorphism and better CLZ response in Caucasians with a non-significant but same direction of effect in African-Americans; the 142/140-base pair (bp) genotype of the intron 1 guanine mononucleotide repeat ((G)n) polymorphism with poor CLZ response in the whole sample; and the 1-copy allele of the 5’-flanking region 120-bp tandem repeat polymorphism in African-Americans. Three other tagged SNPs across DRD4 and five across DRD5 were negative. Our investigation of GLU receptor gene variants focused on NMDAR subunit genes GRIN1, GRIN2A, and GRIN2B with negative findings. Examining gene-gene epistatic effects among and between NMDAR subunit and DA receptor gene polymorphisms identified several interactions with the strongest result being between the DRD1 rs686 G carrier/DRD3 Ser9Gly G non-carrier group with good response. Overall, our results suggest possible minor roles for DA receptor gene variants on CLZ response. Integrating this data with exciting new advances in technologies and bioinformatics will surely bring us closer to personalized medicine in psychiatry.

No description available.

Psychological stress increases dopamine release in the striatum and is thought toplay a role in susceptibility to psychotic illness. In schizophrenia, a prototypicalpsychotic illness, there is evidence of abnormal dopamine response to pharmacologicalchallenge or psychological stressors. Stress, like dopamine agonist drugs, can triggerrelapse in schizophrenic patients. It has been proposed that exaggerated responses tostress are key in the etiology of psychosis in vulnerable individuals. However, it is notknown whether differences in brain dopaminergic responsiveness precede psychosis ordevelop subsequent to illness onset. / Le stress psychologique augmente le niveau de dopamine dans le striatum, phenomene qui pourrait contribuer a la vulnerabilite aux maladies psychotiques. Dans la schizophrenie, une maladie psychotique prototypique, les etudes ont montre qu'il y a une liberation anormale de la dopamine en reponse aux drogues ou au stress psychologique. Le stress, comme les agonistes dopaminergiques, peut precipiter une rechute chez des patients schizophrenes. On avance Phypothese que les reponses excessives au stress sont primordiales dans l'etiologie de la psychose chez les individus vulnerables. Cependant, on ne sait pas si les anomalies de la reponse dopaminergique du cerveau precedent la psychose, ou se developpent apres le debut de la maladie.

Background: Cognitive impairment and cannabis use are common among patients with schizophrenia. However, the moderating role of cannabis on cognition remains unclear. Aim: We sought to examine cognition and symptomatology as a function of cannabis use patterns in schizophrenia. Methodology: Cognition was assessed in male outpatients with current cannabis dependence (n=18), historical cannabis dependence (n=21) and patients with no lifetime use (n=8). In addition, we explored the relationship between cumulative cannabis exposure and cognition among lifetime users. Results: Lifetime cannabis users demonstrated better processing speed than patients with no lifetime use. Notably, patients with current dependence exhibited robust relationships between cumulative cannabis exposure and cognition; associations were absent in former users. Conclusions: Cannabis status has minimal effects on cognition in schizophrenia. However, cumulative cannabis exposure significantly impairs cognition in current, but not former users, suggesting that the state dependent negative effects of cannabis may be reversed with sustained abstinence.

Background: Cognitive impairment and cannabis use are common among patients with schizophrenia. However, the moderating role of cannabis on cognition remains unclear. Aim: We sought to examine cognition and symptomatology as a function of cannabis use patterns in schizophrenia. Methodology: Cognition was assessed in male outpatients with current cannabis dependence (n=18), historical cannabis dependence (n=21) and patients with no lifetime use (n=8). In addition, we explored the relationship between cumulative cannabis exposure and cognition among lifetime users. Results: Lifetime cannabis users demonstrated better processing speed than patients with no lifetime use. Notably, patients with current dependence exhibited robust relationships between cumulative cannabis exposure and cognition; associations were absent in former users. Conclusions: Cannabis status has minimal effects on cognition in schizophrenia. However, cumulative cannabis exposure significantly impairs cognition in current, but not former users, suggesting that the state dependent negative effects of cannabis may be reversed with sustained abstinence.

Over the past decade, a combination of genetic, biological and imaging approaches have identified Disrupted-in-Schizophrenia-1 (DISC1) as a strong susceptibility gene for psychiatric illnesses including schizophrenia, bipolar disorder and major depression. DISC1 regulates various neurodevelopmental processes including neurogenesis, neuronal migration, neurite outgrowth, spine development and neurotransmitter signaling. Human post-mortem brain studies in schizophrenia have revealed some consistent neuropathological findings such as abnormal neuron morphology, reduced spine density, aberrant cytoarchitecture and interneuron deficits in the dorsolateral prefrontal cortex and hippocampus. However, the etiology and development of these histological abnormalities remain unclear. Therefore, we investigated brain histology of two independently-derived Disc1 mutant mice with point mutations (Disc1-Q31L and -L100P). Both mutants displayed reductions in cortical neuron density, decreased neurogenesis and altered cortical neuron distribution when compared to wild-type controls. Frontal cortical pyramidal neurons had shorter dendrites and reduced dendritic surface area. Spine density was also reduced on apical dendrites of both frontal cortical and hippocampal pyramidal neurons. In addition, we observed a pronounced defect in tangential migration of interneurons in the embryonic brains of Disc1-L100P mutants when compared to wild-type mice. Adult Disc1-L100P mutants also have selective alterations of calbindin- and parvalbumin-expressing interneurons in the cortex and hippocampus, decreased glutamate decarboxylase 67/parvalbumin co-localization and mis-positioned interneurons across the neocortex. Finally, we investigated the effects of GSK3α inactivation on frontal cortical neuron morphology in Disc1-L100P mutants. Disc1-L100P, GSK3α -/- and 100P/100P;GSK3α double mutants all exhibited significant reductions in dendritic length and surface area while spine density was significantly reduced only in Disc1-L100P and 100P/100P;GSK3α +/- mutants when compared to wild-type mice. Interestingly, spine density was rescued in 100P/100P;GSK3α -/- double mutants and comparable to wild-type mice. Overall, these findings are consistent with the anomalies seen in post-mortem schizophrenia studies and other Disc1 mutant mouse models, providing further evidence that DISC1 participates in neurodevelopment. GSK3 is only one of many pathways modulated by DISC1, so more research is required to fully understand how the network of DISC1-interacting proteins is involved in the pathophysiology of psychiatric disorders. Better understanding of these mechanisms could lead to the development of new treatments.

Over the past decade, a combination of genetic, biological and imaging approaches have identified Disrupted-in-Schizophrenia-1 (DISC1) as a strong susceptibility gene for psychiatric illnesses including schizophrenia, bipolar disorder and major depression. DISC1 regulates various neurodevelopmental processes including neurogenesis, neuronal migration, neurite outgrowth, spine development and neurotransmitter signaling. Human post-mortem brain studies in schizophrenia have revealed some consistent neuropathological findings such as abnormal neuron morphology, reduced spine density, aberrant cytoarchitecture and interneuron deficits in the dorsolateral prefrontal cortex and hippocampus. However, the etiology and development of these histological abnormalities remain unclear. Therefore, we investigated brain histology of two independently-derived Disc1 mutant mice with point mutations (Disc1-Q31L and -L100P). Both mutants displayed reductions in cortical neuron density, decreased neurogenesis and altered cortical neuron distribution when compared to wild-type controls. Frontal cortical pyramidal neurons had shorter dendrites and reduced dendritic surface area. Spine density was also reduced on apical dendrites of both frontal cortical and hippocampal pyramidal neurons. In addition, we observed a pronounced defect in tangential migration of interneurons in the embryonic brains of Disc1-L100P mutants when compared to wild-type mice. Adult Disc1-L100P mutants also have selective alterations of calbindin- and parvalbumin-expressing interneurons in the cortex and hippocampus, decreased glutamate decarboxylase 67/parvalbumin co-localization and mis-positioned interneurons across the neocortex. Finally, we investigated the effects of GSK3α inactivation on frontal cortical neuron morphology in Disc1-L100P mutants. Disc1-L100P, GSK3α -/- and 100P/100P;GSK3α double mutants all exhibited significant reductions in dendritic length and surface area while spine density was significantly reduced only in Disc1-L100P and 100P/100P;GSK3α +/- mutants when compared to wild-type mice. Interestingly, spine density was rescued in 100P/100P;GSK3α -/- double mutants and comparable to wild-type mice. Overall, these findings are consistent with the anomalies seen in post-mortem schizophrenia studies and other Disc1 mutant mouse models, providing further evidence that DISC1 participates in neurodevelopment. GSK3 is only one of many pathways modulated by DISC1, so more research is required to fully understand how the network of DISC1-interacting proteins is involved in the pathophysiology of psychiatric disorders. Better understanding of these mechanisms could lead to the development of new treatments.