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Pouget J.G.,Campbell Family Research Institute | Pouget J.G.,University of Toronto | Shams T.A.,Campbell Family Research Institute | Shams T.A.,Ryerson University | And 3 more authors.
Dialogues in Clinical Neuroscience | Year: 2014

Antipsychotic medications are the gold-standard treatment for schizophrenia, and are often prescribed for other mental conditions. However, the efficacy and side-effect profiles of these drugs are heterogeneous, with large interindividual variability. As a result, treatment selection remains a largely trial-and-error process, with many failed treatment regimens endured before finding a tolerable balance between symptom management and side effects. Much of the interindividual variability in response and side effects is due to genetic factors (heritability, h2~ 0.60 - 0.80). Pharmacogenetics is an emerging field that holds the potential to facilitate the selection of the best medication for a particular patient, based on his or her genetic information. In this review we discuss the most promising genetic markers of antipsychotic treatment outcomes, and present current translational research efforts that aim to bring these pharmacogenetic findings to the clinic in the near future. © 2014 AICH - Servier Research Group. Source

Vigod S.N.,University of Toronto | Vigod S.N.,Womens College Hospital | Strasburg K.,University of Toronto | Daskalakis Z.J.,University of Toronto | And 3 more authors.
Archives of Women's Mental Health | Year: 2014

Deficiencies in the inhibitory functioning of gamma-aminobutyric acid (GABA) have been implicated in the pathophysiology of depressive disorders. Reproductive life cycle events, including menstruation, pregnancy, and menopause, are consistently associated with increased psychopathology, in particular mood disorders. Given that GABA-inhibitory activity may be modulated directly or indirectly by estrogen, progesterone, and their metabolites receptors, it has been hypothesized that GABA deficits may be evident during these reproductive periods. We aimed to compare GABA function among women during these "high-risk" reproductive periods to GABA function among women at other time periods. We conducted a systematic review of studies comparing women during reproductive life stages associated with depressive disorder risk (luteal phase of the menstrual cycle, perinatal period, and menopausal transition) to women at other time periods. The study outcome was GABA function. The review included 11 studies, 9 focused on the menstrual cycle, and 2 focused on the perinatal period. GABA-inhibitory function fluctuated across the menstrual cycle, with differing patterns in women with and without depressive disorders. GABA-inhibitory function was reduced in pregnancy and early postpartum compared to the nonpregnant state. Key limitations were the absence of studies evaluating the menopausal transition, and the heterogeneity of GABA outcome measures. GABA-inhibitory function fluctuates across the menstrual cycle and is reduced perinatally. This has potential implications for a role of GABAergically mediated interventions in the prevention and treatment of menstrual cycle-related and perinatal depressive disorders. © 2014 Springer-Verlag. Source

Huzayyin A.A.,Kings College | Andreazza A.C.,Kings College | Andreazza A.C.,University of Toronto | Andreazza A.C.,Campbell Family Research Institute | And 7 more authors.
International Journal of Neuropsychopharmacology | Year: 2014

Mitochondrial dysfunction, oxidative stress, and alterations in DNA methylation, are all associated with the pathophysiology of bipolar disorder (BD). We therefore studied the relationship between oxidative stress and DNA methylation in patients with BD with an excellent response to lithium treatment, their affected and unaffected relatives and healthy controls. Transformed lymphoblasts were cultured in the presence or absence of lithium chloride (0.75 mm). DNA and proteins were extracted from the cells to determine levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), 5-methylcytosine (5-mc), mitochondrial complex I and glutathione peroxidase (GPx) activities. Methylation was decreased in BD subjects and their relatives compared to controls and remained so after lithium treatment in BD subjects but not in their relatives. 8-OHdG levels and complex I activity did not differ between groups before and after lithium treatment. Finally, relatives of patients showed increased GPx activity before and after lithium treatment, which negatively correlated with 5-mc levels. Changes in global methylation may be specific for BD and lithium may be involved in glutathione regulation. The present study supports the importance of DNA methylation to the pathophysiology of BD and the therapeutic potential of antioxidants in this illness. © CINP 2013. Source

Wheeler A.L.,Research Imaging Center | Wheeler A.L.,Center for Addiction and Mental Health | Wheeler A.L.,University of Toronto | Wessa M.,Johannes Gutenberg University Mainz | And 22 more authors.
JAMA Psychiatry | Year: 2015

IMPORTANCE: The clinical heterogeneity of schizophrenia has hindered neurobiological investigations aimed at identifying neural correlates of the disorder. OBJECTIVE: To identify network-based biomarkers across the spectrum of impairment present in schizophrenia by separately evaluating individuals with deficit and nondeficit subtypes of this disorder. DESIGN, SETTING, AND PARTICIPANTS: A university hospital network-based neuroimaging study was conducted between February 1, 2007, and February 28, 2012. Participants included patients with schizophrenia (n = 128) and matched healthy controls (n = 130) from two academic centers and patients with bipolar I disorder (n = 39) and matched healthy controls (n = 43) from a third site. Patients with schizophrenia at each site in the top quartile on the proxy scale for the deficit syndrome were classified as having deficit schizophrenia and those in the bottom quartile were classified as having nondeficit schizophrenia. EXPOSURE: All participants underwent magnetic resonance brain imaging. MAIN OUTCOMES AND MEASURES: Network-level properties of cortical thickness were assessed in each group. Interregional cortexwide coupling was compared among the groups, and graph theoretical approaches were used to assess network density and node degree, betweenness, closeness, and eigenvector centrality. RESULTS: Stronger frontoparietal and frontotemporal coupling was found in patients with deficit schizophrenia compared with those with nondeficit schizophrenia (17 of 1326 pairwise relationships were significantly different, P < .05; 5% false discovery rate) and in patients with deficit schizophrenia compared with healthy controls (49 of 1326 pairwise relationships were significantly different, P < .05; 5% false discovery rate). Participants with nondeficit schizophrenia and bipolar I disorder did not show significant differences in coupling relative to those in the control groups (for both comparisons, 0 of 1326 pairwise relationships were significantly different, P > .05; 5% false discovery rate). The networks formed from patients with deficit schizophrenia demonstrated increased density of connections relative to controls and nondeficit patients (range, 0.07-0.45 in controls, 0.09-0.43 in the nondeficit group, and 0.18-0.67 in the deficit group). High centrality nodes were identified in the supramarginal, middle, and superior temporal and inferior frontal regions in deficit schizophrenia networks based on ranking of 4 centrality metrics. High centrality regions were identified as those that ranked in the top 10 in 50% or more of the thresholded networks in 3 or more of the centrality measures. Network properties were similar in patients with deficit schizophrenia from both study sites. CONCLUSIONS AND RELEVANCE: Patients with schizophrenia at one end of a spectrum show characteristic signatures of altered intracortical relationships compared with those at the other end of that spectrum, patients with bipolar I disorder, and healthy individuals. Cortical connectomic approaches can be used to reliably identify neural signatures in clinically heterogeneous groups of patients. Copyright 2015 American Medical Association. All rights reserved. Source

Sriretnakumar V.,Campbell Family Research Institute | Sriretnakumar V.,University of Toronto | Huang E.,Campbell Family Research Institute | Huang E.,University of Toronto | And 2 more authors.
Expert Opinion on Drug Metabolism and Toxicology | Year: 2015

Introduction: Clozapine (CLZ) is the most effective treatment for treatment-resistant schizophrenia (SCZ) patients, with potential added benefits of reduction in suicide risk and aggression. However, CLZ is also mainly underused due to its high risk for the potentially lethal side-effect of agranulocytosis as well as weight gain and related metabolic dysregulation. Pharmacogenetics promises to enable the prediction of patient treatment response and risk of adverse effects based on patients genetics, paving the way toward individualized treatment.Area covered: This article reviews pharmacogenetics studies of CLZ response and side-effects with a focus on articles from January 2012 to February 2015, as an update to the previous reviews. Pharmacokinetic genes explored primarily include CYP1A2, while pharmacodynamic genes consisted of traditional pharmacogenetic targets such as brain-derived neurotrophic factor as well novel mitochondrial genes, NDUFS-1 and translocator protein.Expert opinion: Pharmacogenetics is a promising avenue for individualized medication of CLZ in SCZ, with several consistently replicated gene variants predicting CLZ response and side-effects. However, a large proportion of studies have yielded mixed results. Large-scale Genome-wide association studies (e.g., CRESTAR) and targeted gene studies with standardized designs (response measurements, treatment durations, plasma level monitoring) are required for further progress toward clinical translation. Additionally, in order to improve study quality, we recommend accounting for important confounders, including polypharmacy, baseline measurements, treatment duration, gender, and age at onset. © 2015 Taylor & Francis. Source

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