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.

Despite a prevailing paradigm that emphasizes an interaction of vulnerability and stress to account for the etiology of schizophrenia, diathesis—stress models of subsequent course and outcome of this disorder are rare. Even the simpler stress— process model, where the influence of stressors is mediated by supportive social relationships, has received little attention in studies of the course of schizophrenia. The objective of this study was to assess the following components of a diathesis—stress model as they predict the five-year outcome of first-episode schizophrenia: (1) stressful life events; (2) supportive social relationships; (3) brain lateral ventricle size; and (4) smooth pursuit eye movements. As part of the Greater Vancouver M.A.P. Project, we recruited first-episode DSM-III schizophrenia and affective psychosis patients. At intake to the study, their social relationships, smooth pursuit eye movement function, and brain ventricle size were assessed. Life events in the previous year were measured at intake; events over the following 18 months were assessed in two later interviews. Five years later we assessed outcome, using a global rating of social and occupational functioning. Descriptive results showed substantial variability within the schizophrenia group at intake and outcome. The trajectory of adaptive functioning over time was remarkably similar for the schizophrenic and affective psychosis groups. Of the four hypothesized predictors, only social relationships were associated (p=.O3) with five—year outcome. The number of life events was not associated with five—year outcome, nor was either of the biological risk factors. As a result, the predictor variables could not be combined in either a stress—process model or a vulnerability—stress model of the course of schizophrenia. That social relationship variables are associated with five-year outcome supports earlier findings regarding 18-month outcome, including the differing predictive roles for family and nonfamily relationships. The absence of hypothesized results for the life events data probably indicates that too much time had passed between outcome and the events as measured. Finally, that brain ventricle size and eye-movement dysfunction predict 18-month but not five—year outcome may indicate that impairment due to biological factors is expressed only in the early stages of schizophrenia.

The etiology and pathophysiology of schizophrenia are poorly understood, although increasing evidence suggests an important role for altered GABA neurotransmission. Animal models of schizophrenic symptoms include administration of noncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonists, such as dizocilpine (MK-801), and post-weaning social isolation. The present study tested the hypothesis that a “double-hit” model, in which subchronic MK-801 administration and post-weaning social isolation are combined, produces greater behavioural and neurochemical effects than either insult alone. As a secondary objective, the present study also assessed whether the timing of the subchronic MK-801 injections (early adolescence vs. early adulthood) influences these measures. Male Sprague-Dawley rats (N = 74) were obtained at weaning (P21) and were either socially isolated (n = 42) or group housed (n = 32) for the duration of the experiment. Subgroups received subchronic treatment with MK-801 (0.5 mg/kg ip) or saline injections (1.0 ml/kg ip) twice daily for seven days either during early adolescence (P25-P32) or early adulthood (P56-63). At P70, all groups were tested for locomotor activity and subsequently sacrificed to assess the function of the GABA membrane transport protein, GAT-1, and GABAA receptor expression in the frontal cortex and hippocampus. For animals treated in early adulthood, post-weaning social isolation, in comparison to group housing, resulted in an increase in (1) locomotor activity (2) GAT-1 activity in frontal cortex and hippocampus and (3) GABAA receptor expression in the frontal cortex. MK-801 treatment in early adulthood increased GABAA receptor expression in the hippocampus, whereas post-weaning social isolation had no effect on GABAA receptor expression in the hippocampus. Previous studies have demonstrated that increased GAT-1 activity is associated with suppression of GABA-mediated inhibitory synaptic transmission. Furthermore, increased GABAA receptor expression may be a compensatory response to decreased availability of GABA. These data indicated that combined post-weaning social isolation and subchronic MK-801 treatment do not produce additive or synergistic effects on locomotor behaviour or GABA signalling, but rather induced differential effects on GABAA receptor binding. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2010-09-01 15:21:58.474

Comorbid substance use disorders are quite common among patients with schizophrenia. Such individuals' substance use has been associated with psychiatric instability, psychosocial problems and an increased use of health care services. / An existing data set encompassing a range of health care services was analysed, along with patient demographics such as age, living arrangements and education. The subjects were 444 patients with a lifetime diagnosis of schizophrenia, with and without a secondary substance use disorder. / It was found that 32.4% of the male patients and 14.7% of the female patients in this study had a concurrent disorder. The substance abusers tended to be younger than the non-abusers. Male patients who lived in group homes were less likely to have a substance use disorder than male patients in other living situations. Patients with a substance use disorder were more intensive users of hospital services. / The need for the development of integrated services and role of the social worker was discussed.

Schizophrenia is a common and serious mental disorder affecting approximately 1% of the population (WHO, 1973). That genetic and other developmental factors give rise to a predisposition or vulnerability to schizophrenia is well recognized. However, the role of the environment in conferring risk for the disorder is now indisputable. Psychosocial, economic and cultural factors all impact on risk as evidenced by recent epidemiological studies reporting variable incidence in relation to factors including unemployment, urbanicity, migration and trauma. Complex gene-gene and gene-environment (GxE) interactions lie at the origin of this common human disorder and account for the diversity of epidemiological findings and clinical presentations that we encounter in research and clinical practice. This thesis comprises of six research papers and includes data from two separate studies of first-episode psychosis (FEP) conducted in KwaZulu-Natal, South Africa. The first study (Chapter 2) explored the impact of income inequality and poverty on the incidence of FEP and the results provide the first evidence for an association between increasing income inequality and increased incidence of FEP. The second study (Chapter 3) investigated the impact of a number of psychosocial, economic and cultural factors on the clinical presentation of FEP. Previous experiences of trauma were associated with positive and affective symptoms at psychosis onset, while cannabis use was associated with clinical features of FEP that previously have been associated with better outcome. Cultural factors such as spiritual attributions of cause and previous consultation with traditional healers may delay entry to psychiatric care and thereby negatively impact on prognosis of FEP. Chapter 4 addresses the issue of how the environment acts through GxE interactions to modify risk and alter the clinical presentation and course of schizophrenia. In this paper, new epidemiological findings are integrated with an evolutionary genetic theory of schizophrenia. In Chapter 5, I present a human rights perspective on the inequities and inequalities that characterize the lives of those with serious mental disorders such as schizophrenia, resulting from psychosocial, political, economic and cultural forces in the environment. The concluding chapter draws all of the data together, highlights key findings and conclusions from the thesis, addresses weaknesses and limitations of these conclusions and identifies priority areas for future research in this field. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2010.

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Schizophrenia patients typically exhibit cognitive impairments that directly affect their daily functioning, but are not effectively treated by current antipsychotics. Maternal immune activation (MIA) during pregnancy, which can be triggered by a variety of infectious agents, has been associated with the development of schizophrenia in adult offspring. Epidemiological evidence indicates that elevated maternal levels of the chemokine interleukin- 8 (IL-8) during MIA contribute to the neurodevelopmental alterations underlying the disorder. The present experiments used an animal model of neurodevelopmental disorders to study the effects of MIA and chemokine receptor antagonism on the behavior of rat offspring, with behavioral tests chosen to examine cognitive functions that are typically impaired in human schizophrenia patients. The viral mimetic polyinosinic-polycytidylic acid (polyI:C) (4.0 mg/kg, i.v.) was injected into pregnant Long-Evans (LE) dams on gestational day (GD) 15. Dams were also treated with the three injections of CXCL8(3–72)K11R/G31P (G31P) (500 µg/kg, i.p.), a chemokine receptor antagonist that binds CXCR1 and CXCR2 with high affinity. PolyI:C treatment significantly increased maternal levels of the chemokine CXCL1, the rodent analogue of IL-8 that binds CXCR1 and CXCR2. The offspring of polyI:C-treated dams showed impaired associative recognition memory and multisensory integration, as well as subtle impairments in prepulse inhibition (PPI). G31P administration did not reverse any of the behavioral deficits caused by polyI:C, although G31P did alter PPI during adolescence. Although the present experiments included replications and novel findings for the polyI:C model, the effects of polyI:C were smaller than in other published research. Utilizing animal models that include both genetic and environmental components, as well as more widely targeted anti-inflammatory therapies will likely result in more promising findings in future research.