Publications by authors named "James L Kennedy"

456 Publications

Barriers to clinical adoption of pharmacogenomic testing in psychiatry: a critical analysis.

Transl Psychiatry 2021 10 6;11(1):509. Epub 2021 Oct 6.

Tanenbaum Centre for Pharmacogenetics, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Pharmacogenomics (PGx) is the study of genetic influences on an individual's response to medications. Improvements in the quality and quantity of PGx research over the past two decades have enabled the establishment of commercial markets for PGx tests. Nevertheless, PGx testing has yet to be adopted as a routine practice in clinical care. Accordingly, policy regulating the commercialization and reimbursement of PGx testing is in its infancy. Several papers have been published on the topic of challenges, or 'barriers' to clinical adoption of this healthcare innovation. However, many do not include recent evidence from randomized controlled trials, economic utility studies, and qualitative assessments of stakeholder opinions. The present paper revisits the most cited barriers to adoption of PGx testing: evidence for clinical utility, evidence for economic effectiveness, and stakeholder awareness. We consider these barriers in the context of reviewing PGx literature published over the past two decades and emphasize data from commercial PGx testing companies, since they have published the largest datasets. We conclude with a discussion of existing limitations to PGx testing and recommendations for progress.
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http://dx.doi.org/10.1038/s41398-021-01600-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492820PMC
October 2021

Melatonin as an Add-On Treatment of COVID-19 Infection: Current Status.

Diseases 2021 Sep 20;9(3). Epub 2021 Sep 20.

Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires 1007, Argentina.

This brief review was written to provide a perspective on the flurry of reports suggesting that melatonin can be an important add-on therapy for COVID-19. Despite the passage of more than 60 years since its discovery and much evidence representing the contrary, there has been great reluctance to conceive melatonin as anything other than a hormone. Many other body chemicals are known to have multiple roles. Melatonin was first shown to be a hormone derived from the pineal gland, to be actively synthesized there only at night, and to act on targets directly or via the G-protein-coupled receptors (GPCRs) superfamily. It is of note that over 40 years ago, it was also established that melatonin is present, synthesized locally, and acts within the gastrointestinal tract. A wider distribution was then found, including the retina and multiple body tissues. In addition, melatonin is now known to have non-hormonal actions, acting as a free radical scavenger, an antioxidant, and as modulating immunity, dampening down innate tissue responses to invaders while boosting the production of antibodies against them. These actions make it a potentially excellent weapon against infection by the SARS-CoV-2 virus. Early published results support that thesis. Recently, a randomized controlled study reported that low doses of melatonin significantly improved symptoms in hospitalized COVID-19 patients, leading to more rapid discharge with no side effects, while significantly decreasing levels of CRP, proinflammatory cytokines, and modulating dysregulated genes governing cellular and humoral immunity. It is now critical that these trials be repeated, with dose-response studies conducted and safety proven. Numerous randomized controlled trials are ongoing, which should complete those objectives while also allowing for a more thorough evaluation of the mechanisms of action and possible applications to other severe diseases.
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http://dx.doi.org/10.3390/diseases9030064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482145PMC
September 2021

Genetically Predicted Brain C4A Expression Is Associated With TSPO and Hippocampal Morphology.

Biol Psychiatry 2021 Nov 7;90(9):652-660. Epub 2021 Jul 7.

Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada; Department of Psychiatry, McGill University, Montreal, Quebec, Canada. Electronic address:

Background: Alterations in the immune system, particularly C4A, have been implicated in the pathophysiology of schizophrenia. C4A promotes synapse elimination by microglia in preclinical models; however, it is unknown whether this process is also present in living humans and how it affects brain morphology.

Methods: Participants (N = 111; 33 patients with psychosis, 37 individuals at clinical high risk, and 41 healthy control subjects) underwent a TSPO [F]FEPPA positron emission tomography scan and a magnetic resonance imaging scan. Brain C4A expression was genetically predicted as a function of the dosage of each of 4 structural elements (C4AL, C4BL, C4AS, C4BS).

Results: Higher genetically predicted brain C4A expression was associated with higher brain microglial marker (TSPO) and altered hippocampal morphology, including reduced surface area and medial displacement in the CA1 area. This study is the first to quantify genetically predicted brain C4A expression in individuals at clinical high risk, showing significantly lower C4A in individuals at clinical high risk compared with healthy control subjects. We also showed a robust effect of sex on genetically predicted brain C4A expression and effects of both sex and cannabis use on brain TSPO.

Conclusions: This study shows for the first time complement system (C4A) coupling with a microglial marker (TSPO) and hippocampal morphology in living human brain. These findings pave the way for future research on the interaction between C4A and glial cell function, which has the potential to inform the disease mechanism underlying psychosis and schizophrenia.
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http://dx.doi.org/10.1016/j.biopsych.2021.06.021DOI Listing
November 2021

The Interplay Between Prenatal Adversity, Offspring Dopaminergic Genes, and Early Parenting on Toddler Attentional Function.

Front Behav Neurosci 2021 29;15:701971. Epub 2021 Jul 29.

Department of Psychiatry, McGill University Faculty of Medicine, Montreal, QC, Canada.

: Few studies have explored the complex gene-by-prenatal environment-by-early postnatal environment interactions that underlie the development of attentional competence. Here, we examined if variation in dopamine-related genes interacts with prenatal adversity to influence toddler attentional competence and whether this influence is buffered by early positive maternal behavior. : From the Maternal Adversity, Vulnerability and Neurodevelopment cohort, 134 participants (197 when imputing missing data) had information on prenatal adversity (prenatal stressful life events, prenatal maternal depressive symptoms, and birth weight), five dopamine-related genes (), observed maternal parenting behavior at 6 months and parent-rated toddler attentional competence at 18 and 24 months. The Latent Environmental and Genetic Interaction (LEGIT) approach was used to examine genes-by-prenatal environment-by-postnatal environment interactions while controlling for sociodemographic factors and postnatal depression. : Our hypothesis of a three-way interaction between prenatal adversity, dopamine-related genes, and early maternal parenting behavior was not confirmed. However, consistent two-way interactions emerged between prenatal adversity and dopamine-related genes; prenatal adversity and maternal parenting behavior, and dopamine-related genes and maternal parenting behavior in relation to toddler attentional competence. Significant interaction effects were driven by the , and genotypes; prenatal stressful life events; maternal sensitivity, tactile stimulation, vocalization, and infant-related activities. : Multiple dopamine-related genes affected toddler attentional competence and they did so in interaction with prenatal adversity and the early rearing environment, separately. Effects were already visible in young children. Several aspects of early maternal parenting have been identified as potential targets for intervention.
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http://dx.doi.org/10.3389/fnbeh.2021.701971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370126PMC
July 2021

Antioxidative Defense Genes and Brain Structure in Youth Bipolar Disorder.

Int J Neuropsychopharmacol 2021 Aug 13. Epub 2021 Aug 13.

Department of Pharmacology, University of Toronto, Toronto, ON, Canada.

Background: Oxidative stress is implicated in the neuropathology of bipolar disorder (BD). We investigated the association of single-nucleotide polymorphisms (SNPs) in the antioxidative genes superoxide dismutase 2 (SOD2) and glutathione peroxidase 3 (GPX3) with structural neuroimaging phenotypes in youth BD.

Methods: SOD2 rs4880 and GPX3 rs3792797 SNP genotypes, along with structural magnetic resonance imaging, were obtained from 147 youth (BD=75; healthy controls (HC)=72). Images were processed using FreeSurfer, yielding surface area, volume, and thickness values for regions of interest (ROI; prefrontal cortex (PFC), caudal anterior cingulate cortex (cACC), hippocampus) and for vertex-wise whole brain analysis. Analyses controlled for age, sex, race, and intracranial volume for volume area, and thickness analyses.

Result: ROI analyses revealed diagnosis-by-SOD2 rs4880 interaction effects for cACC volume and surface area, and PFC volume; in each case, there was lower volume/area in the BD GG genotype group vs. the HC GG genotype group. There was a significant BD diagnosis x GPX3 rs3793797 interaction effect for PFC surface area, where area was lower in the BD A-allele carrier group vs. the other genotype groups. Vertex-wise analyses revealed significant interaction effects in frontal, temporal, and parietal regions, related to smaller brain structure in the BD SOD2 rs4880 GG group and BD GPX3 rs3793797 A-allele carrier group.

Conclusion: We found preliminary evidence that SOD2 rs4880 and GPX3 rs3792797 are differentially associated with brain structure in youth with BD, in regions that are relevant to BD. Further studies incorporating additional neuroimaging phenotypes and blood levels of oxidative stress markers are warranted.
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http://dx.doi.org/10.1093/ijnp/pyab056DOI Listing
August 2021

Neurostructural correlates of BDNF rs6265 genotype in youth bipolar disorder.

Bipolar Disord 2021 Jul 15. Epub 2021 Jul 15.

Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Objective: Brain-derived neurotrophic factor (BDNF) rs6265 single-nucleotide polymorphism has been associated with bipolar disorder (BD), and with brain structure among adults with BD. We set out to investigate the association of the BDNF rs6265 Met allele with neurostructural phenotypes in youth BD.

Methods: Caucasian youth (N = 99; 13-20 years; n = 56 BD, n = 43 age and sex-matched healthy controls) underwent 3-Tesla Magnetic Resonance Imaging and genotyping for BDNF rs6265. Region of interest (ROI) analyses of the ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), and hippocampus were complemented by vertex-wise analyses examining cortical thickness, surface area (SA) and volume. Multivariable models included the main effects of diagnosis and gene, and a diagnosis-by-genotype interaction term, controlling for age, sex, and intracranial volume.

Results: There were no significant gene main effects or diagnosis-by-gene interaction effects in ROI analyses. The vertex-wise analysis yielded a significant gene main effect whereby Met allele carriers had greater middle temporal gyrus SA (p = 0.001) and supramarginal gyrus volume (p = 0.03) than Val/Val individuals. Significant interaction effects were found on lateral occipital lobe SA (p = 0.03), whereby the Met allele was associated with increased SA in BD only. Interaction effects were also found on postcentral gyrus SA (p = 0.049) and supramarginal gyrus SA (p = 0.04), with smaller SA in BD Met carriers versus healthy control Met carriers.

Conclusion: These findings suggest that BDNF rs6265 is differentially associated with regional SA in youth BD. Further investigation is warranted to evaluate whether BDNF protein levels mediate the observed effects, and to evaluate rs6265-related developmental changes.
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http://dx.doi.org/10.1111/bdi.13116DOI Listing
July 2021

Evidence for association of vasopressin receptor 1A promoter region repeat with childhood onset aggression.

J Psychiatr Res 2021 08 27;140:522-528. Epub 2021 May 27.

Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Institute of Medical Science & Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.

Objective: Childhood onset aggression can cause major suffering to affected families and is associated with many negative outcomes in the child's later life, including poor academic performance, adolescent delinquency, drug abuse, depression and antisocial personality disorder. Currently available prevention and intervention strategies have limited efficacy, but a better understanding of underlying genetic and neurobiological factors can lead to more effective prevention and treatment strategies, through genetic screening programs and novel therapies.

Method: This study examined the RS1 (n = 299 aggression, n = 192 controls) and RS3 (n = 291 aggression, n = 189 controls) microsatellite repeats within the promoter region of the vasopressin receptor 1A gene (AVPR1A) and their association with extreme childhood aggression, as assessed by the Child Behavior Checklist (CBCL), as well as the Teacher Report Form (TRF) and Youth Self Report (YSR). Binary logistic regression was used to model the relationship between microsatellite length and childhood aggression. Age and sex were used as covariates.

Results: Logistic regression revealed a nominally significant association between one specific RS3 repeat and non-aggressive status. No association was found for any of the RS1 repeats. In a separate model, grouping repeats into short and long, carriers of long RS3 repeats were nominally significantly associated with non-aggressive status.

Conclusions: These findings suggest a role for AVPR1A and its RS3 microsatellite in extreme childhood aggression and could lead to a better understanding of the biological pathways of aggressive behavior. However, independent replication and further research into the functionality of studied genetic variants is required.
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http://dx.doi.org/10.1016/j.jpsychires.2021.05.062DOI Listing
August 2021

Melatonin's neuroprotective role in mitochondria and its potential as a biomarker in aging, cognition and psychiatric disorders.

Transl Psychiatry 2021 06 2;11(1):339. Epub 2021 Jun 2.

Molecular Brain Science Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Melatonin is an ancient molecule that is evident in high concentrations in various tissues throughout the body. It can be separated into two pools; one of which is synthesized by the pineal and can be found in blood, and the second by various tissues and is present in these tissues. Pineal melatonin levels display a circadian rhythm while tissue melatonin does not. For decades now, melatonin has been implicated in promoting and maintaining sleep. More recently, evidence indicates that it also plays an important role in neuroprotection. The beginning of our review will summarize this literature. As an amphiphilic, pleiotropic indoleamine, melatonin has both direct actions and receptor-mediated effects. For example, melatonin has established effects as an antioxidant and free radical scavenger both in vitro and in animal models. This is also evident in melatonin's prominent role in mitochondria, which is reviewed in the next section. Melatonin is synthesized in, taken up by, and concentrated in mitochondria, the powerhouse of the cell. Mitochondria are also the major source of reactive oxygen species as a byproduct of mitochondrial oxidative metabolism. The final section of our review summarizes melatonin's potential role in aging and psychiatric disorders. Pineal and tissue melatonin levels both decline with age. Pineal melatonin declines in individuals suffering from psychiatric disorders. Melatonin's ability to act as a neuroprotectant opens new avenues of exploration for the molecule as it may be a potential treatment for cases with neurodegenerative disease.
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http://dx.doi.org/10.1038/s41398-021-01464-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172874PMC
June 2021

Toward personalized medicine in schizophrenia: Genetics and epigenetics of antipsychotic treatment.

Schizophr Res 2021 06 25;232:112-124. Epub 2021 May 25.

Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Canada; Department of Psychiatry, University of Toronto, Canada. Electronic address:

Schizophrenia is a complex psychiatric disorder where genetic, epigenetic, and environmental factors play a role in disease onset, course of illness, and treatment outcome. Pharmaco(epi)genetic research presents an important opportunity to improve patient care through prediction of medication side effects and response. In this narrative review, we discuss the current state of research and important progress of both genetic and epigenetic factors involved in antipsychotic response, over the past five years. The review is largely focused on the following frequently prescribed antipsychotics: olanzapine, risperidone, aripiprazole, and clozapine. Several consistent pharmacogenetic findings have emerged, in particular pharmacokinetic genes (primarily cytochrome P450 enzymes) and pharmacodynamic genes involving dopamine, serotonin, and glutamate neurotransmission. In addition to studies analysing DNA sequence variants, there are also several pharmacoepigenetic studies of antipsychotic response that have focused on the measurement of DNA methylation. Although pharmacoepigenetics is still in its infancy, consideration of both genetic and epigenetic factors contributing to antipsychotic response and side effects no doubt will be increasingly important in personalized medicine. We provide recommendations for next steps in research and clinical evaluation.
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http://dx.doi.org/10.1016/j.schres.2021.05.010DOI Listing
June 2021

Diagnostic Precision in the Detection of Mild Cognitive Impairment: A Comparison of Two Approaches.

Am J Geriatr Psychiatry 2021 Apr 14. Epub 2021 Apr 14.

Department of Psychiatry (AJF, JLK, LM, BGP, TKR, BH, University of Toronto, Toronto, Ontario, Canada; Centre for Addiction and Mental Health (CRB, JLK, SO, BGP, TKR, BHM), Toronto, Ontario, Canada.

Objective: This study compared diagnostic rates and clinical predictors of discrepancies between diagnoses conferred via: 1) a comprehensive neuropsychological evaluation and National Institute on Aging-Alzheimer's Association (NIA-AA) criteria versus 2) a cognitive screener and Diagnostic Statistical Manual of Mental Disorders (DSM-5) criteria.

Design: Cross-sectional examination of baseline data from the Prevention of Alzheimer's dementia (AD) using Cognitive remediation and transcranial direct current stimulation in Mild Cognitive Impairment (MCI) and Depression (PACt-MD; ClinicalTrials.gov Identifier: NCT02386670) trial.

Setting: Five geriatric psychiatry and memory clinics located at academic hospitals affiliated with the Department of Psychiatry, University of Toronto.

Participants: Older adults (N = 431) with a history of major depressive disorder (MDD) in remission, MCI, or both.

Measurements: Main outcome was a comparison of NIA-AA diagnostic rates of MCI or dementia versus DSM-5 rates of mild or major neurocognitive disorder. Secondary analyses examined demographic, race, gender, premorbid intellectual ability, psychosocial, health-related, and genetic predictors of discrepancy between DSM-5 and NIA-AA diagnoses.

Results: There were 103 (23.8%) discrepant cases, with most (91; 88.3%) of these discrepant cases reflecting more impairment with the detailed neuropsychological testing and NIA-AA criteria. Discrepancies were more likely in individuals with a history of MDD or who had at least one ApoE4 allele.

Conclusion: The NIA-AA criteria, in conjunction with comprehensive neuropsychological testing, identified a greater prevalence of cognitive impairment than DSM-5 criteria, in conjunction with the Montreal Cognitive Assessment. Detailed neuropsychological evaluations are recommended for older adults who have a history of MDD or a genetic vulnerability to dementia.
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http://dx.doi.org/10.1016/j.jagp.2021.04.004DOI Listing
April 2021

Increased levels of circulating cell-free mtDNA in plasma of late life depression subjects.

J Psychiatr Res 2021 07 8;139:25-29. Epub 2021 May 8.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Adult Neurodevelopment and Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Background: Oxidative stress (OS) has been implicated in the pathophysiology of late-life depression (LLD). Mitochondria are the primary source of oxidative stress and can be significantly damaged with increased OS. Circulating cell-free mtDNA (ccf-mtDNA) is a marker of cellular stress and mitochondria damage triggered by oxidative stress.

Methods: We evaluated the plasma levels of ccf-mtDNA in between 32 LLD and 21 never-depressed participants. We also investigated the association between ccf-mtDNA and the severity of depressive episodes and cognition performance.

Results: We found a higher ccf-mtDNA level in LLD cases compared with controls (t = -2.91, p = 0.005). Also, ccf-mtDNA was significantly correlated with the severity of depression (r = 0.42, p = 0.001). There was no significant correlation between ccf-mtDNA and measures of cognitive decline.

Limitations: The small sample size and cross-sectional design were the main limitations of this study.

Conclusion: Our results suggest that LLD is associated with elevated mitochondrial damage and cellular stress. If validated, the measurement of ccf-mtDNA in LLD can guide the development of novel treatments focused on cytoprotection and reduction of mitochondrial dysfunction for this condition.
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http://dx.doi.org/10.1016/j.jpsychires.2021.05.015DOI Listing
July 2021

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Nat Genet 2021 06 17;53(6):817-829. Epub 2021 May 17.

Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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http://dx.doi.org/10.1038/s41588-021-00857-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192451PMC
June 2021

Structural neuroimaging phenotypes of a novel multi-gene risk score in youth bipolar disorder.

J Affect Disord 2021 06 28;289:135-143. Epub 2021 Apr 28.

University of Toronto, Toronto, ON, Canada; Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.

Background: Bipolar disorder (BD) is among the most heritable psychiatric disorders, particularly in early-onset cases, owing to multiple genes of small effect. Here we examine a multi-gene risk score (MGRS), to address the gap in multi-gene research in early-onset BD.

Methods: MGRS was derived from 34 genetic variants relevant to neuropsychiatric diseases and related systemic processes. Multiple MGRS were calculated across a spectrum of inclusion p-value thresholds, based on allelic associations with BD. Youth participants (123 BD, 103 healthy control [HC]) of European descent were included, of which 101 participants (58 BD, 43 HC) underwent MRI T1-weighted structural neuroimaging. Hierarchical regressions examined for main effects and MGRS-by-diagnosis interaction effects on 6 regions-of-interest (ROIs). Vertex-wise analysis also examined MGRS-by-diagnosis interactions.

Results: MGRS based on allelic association p≤0.60 was most robust, explaining 6.8% of variance (t(226)=3.46, p=.001). There was an MGRS-by-diagnosis interaction effect on ventrolateral prefrontal cortex surface area (vlPFC; β=.21, p=.0007). Higher MGRS was associated with larger vlPFC surface area in BD vs. HC. There were 8 significant clusters in vertex-wise analyses, primarily in fronto-temporal regions, including vlPFC.

Limitations: Cross-sectional design, modest sample size.

Conclusions: There was a diagnosis-by-MGRS interaction effect on vlPFC surface area, a region involved in emotional processing, emotional regulation, and reward response. Vertex-wise analysis also identified several clusters overlapping this region. This preliminary study provides an example of an approach to imaging-genetics that is intermediate between candidate gene and genome-wide association studies, enriched for genetic variants with established relevance to neuropsychiatric diseases.
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http://dx.doi.org/10.1016/j.jad.2021.04.040DOI Listing
June 2021

HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry.

Transl Psychiatry 2021 04 12;11(1):214. Epub 2021 Apr 12.

Department of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany.

The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm and 1500/mm were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E-06) and agranulocytosis (OR = 10.49, P = 1.83E-06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E-08; agranulocytosis: OR = 16.31, P = 1.39E-06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.
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http://dx.doi.org/10.1038/s41398-021-01322-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042025PMC
April 2021

Mitochondria's role in sleep: Novel insights from sleep deprivation and restriction studies.

World J Biol Psychiatry 2021 May 6:1-13. Epub 2021 May 6.

Department of Molecular Brain Science Research, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Objectives/methods: The biology underlying sleep is not yet fully elucidated, but it is known to be complex and largely influenced by circadian rhythms. Compelling evidence supports of a link among circadian rhythms, sleep and metabolism, which suggests a role for mitochondria. These organelles play a significant role in energy metabolism via oxidative phosphorylation (OXPHOS) and several mitochondrial enzymes display circadian oscillations. However, the interplay between mitochondria and sleep is not as well-known. This review summarises human and animal studies that have examined the role of mitochondria in sleep. Literature searches were conducted using PubMed and Google Scholar.

Results: Using various models of sleep deprivation, animal studies support the involvement of mitochondria in sleep via differential gene and protein expression patterns, OXPHOS enzyme activity, and morphology changes. Human studies are more limited but also show differences in OXPHOS enzyme activity and protein levels among individuals who have undergone sleep deprivation or suffer from different forms of insomnia.

Conclusions: Taken altogether, both types of study provide evidence for mitochondria's involvement in the sleep-wake cycle. We briefly discuss the potential clinical implications of these studies.
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http://dx.doi.org/10.1080/15622975.2021.1907723DOI Listing
May 2021

Supporting pharmacogenetic-guided opioid prescriptions for post-operative pain: The design, protocol and preliminary results of the OTP study.

J Psychiatr Res 2021 06 24;138:24-33. Epub 2021 Mar 24.

Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada; Institute of Medical Science, University of Toronto, 1 Kings College Circle, Toronto, ON, M5S 1A8, Canada; Department of Psychiatry, University of Toronto, 1 Kings College Circle, Toronto, ON, M5S 1A8, Canada.

The interindividual variability in opioid response is an issue that contributes to the ongoing opioid crisis. Current evidence suggests this variability can be attributed to genetic factors. The pharmacogenetics of Opioid Treatment for acute post-operative Pain (OTP) project was a prospective study that aimed to identify genetic markers associated with opioid treatment outcomes. Healthy patients undergoing third-molar extractions were recruited from dental offices located within the Greater Toronto Area. Participants were evaluated using the Brief Pain Inventory Short Form, the Opioid Related Symptom Distress Scale, and the Leeds Dependence Questionnaire. Seventy-two participants had an active opioid prescription. Participants were prescribed one of the following opioids: codeine, morphine, hydromorphone, tramadol, or oxycodone. The majority of participants were female (57%), ranging from 16 to 44 years of age. Pain severity, pain interference, and side effects declined over the seven-day post-operative period. Additionally, 4% of participants displayed medium to high risk of dependence. It is anticipated that OTP will enable the development of a genetic test for opioid use and facilitate the introduction of this test into routine healthcare practice. The OTP study represents a novel approach to opioid treatment and has significant implications for future interventions targeting the ongoing opioid crisis. Employing a pharmacogenomic-guided strategy for prescribing opioids may improve patients' response to this treatment and, in so doing, increase adherence to the target treatment plan. Optimized prescriptions may also provide public healthcare systems with beneficial savings and reduce the risks associated with opioid use.
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http://dx.doi.org/10.1016/j.jpsychires.2021.03.040DOI Listing
June 2021

Supporting pharmacogenetic-guided opioid prescriptions for post-operative pain: The design, protocol and preliminary results of the OTP study.

J Psychiatr Res 2021 06 24;138:24-33. Epub 2021 Mar 24.

Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada; Institute of Medical Science, University of Toronto, 1 Kings College Circle, Toronto, ON, M5S 1A8, Canada; Department of Psychiatry, University of Toronto, 1 Kings College Circle, Toronto, ON, M5S 1A8, Canada.

The interindividual variability in opioid response is an issue that contributes to the ongoing opioid crisis. Current evidence suggests this variability can be attributed to genetic factors. The pharmacogenetics of Opioid Treatment for acute post-operative Pain (OTP) project was a prospective study that aimed to identify genetic markers associated with opioid treatment outcomes. Healthy patients undergoing third-molar extractions were recruited from dental offices located within the Greater Toronto Area. Participants were evaluated using the Brief Pain Inventory Short Form, the Opioid Related Symptom Distress Scale, and the Leeds Dependence Questionnaire. Seventy-two participants had an active opioid prescription. Participants were prescribed one of the following opioids: codeine, morphine, hydromorphone, tramadol, or oxycodone. The majority of participants were female (57%), ranging from 16 to 44 years of age. Pain severity, pain interference, and side effects declined over the seven-day post-operative period. Additionally, 4% of participants displayed medium to high risk of dependence. It is anticipated that OTP will enable the development of a genetic test for opioid use and facilitate the introduction of this test into routine healthcare practice. The OTP study represents a novel approach to opioid treatment and has significant implications for future interventions targeting the ongoing opioid crisis. Employing a pharmacogenomic-guided strategy for prescribing opioids may improve patients' response to this treatment and, in so doing, increase adherence to the target treatment plan. Optimized prescriptions may also provide public healthcare systems with beneficial savings and reduce the risks associated with opioid use.
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http://dx.doi.org/10.1016/j.jpsychires.2021.03.040DOI Listing
June 2021

Genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response.

Transl Psychiatry 2021 02 15;11(1):127. Epub 2021 Feb 15.

Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

Antidepressant outcomes in older adults with depression is poor, possibly because of comorbidities such as cerebrovascular disease. Therefore, we leveraged multiple genome-wide approaches to understand the genetic architecture of antidepressant response. Our sample included 307 older adults (≥60 years) with current major depression, treated with venlafaxine extended-release for 12 weeks. A standard genome-wide association study (GWAS) was conducted for post-treatment remission status, followed by in silico biological characterization of associated genes, as well as polygenic risk scoring for depression, neurodegenerative and cerebrovascular disease. The top-associated variants for remission status and percentage symptom improvement were PIEZO1 rs12597726 (OR = 0.33 [0.21, 0.51], p = 1.42 × 10) and intergenic rs6916777 (Beta = 14.03 [8.47, 19.59], p = 1.25 × 10), respectively. Pathway analysis revealed significant contributions from genes involved in the ubiquitin-proteasome system, which regulates intracellular protein degradation with has implications for inflammation, as well as atherosclerotic cardiovascular disease (n = 25 of 190 genes, p = 8.03 × 10, FDR-corrected p = 0.01). Given the polygenicity of complex outcomes such as antidepressant response, we also explored 11 polygenic risk scores associated with risk for Alzheimer's disease and stroke. Of the 11 scores, risk for cardioembolic stroke was the second-best predictor of non-remission, after being male (Accuracy = 0.70 [0.59, 0.79], Sensitivity = 0.72, Specificity = 0.67; p = 2.45 × 10). Although our findings did not reach genome-wide significance, they point to previously-implicated mechanisms and provide support for the roles of vascular and inflammatory pathways in LLD. Overall, significant enrichment of genes involved in protein degradation pathways that may be impaired, as well as the predictive capacity of risk for cardioembolic stroke, support a link between late-life depression remission and risk for vascular dysfunction.
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http://dx.doi.org/10.1038/s41398-021-01248-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884410PMC
February 2021

Dopamine D4 receptor gene polymorphism (DRD4 VNTR) moderates real-world behavioural response to the food retail environment in children.

BMC Public Health 2021 02 3;21(1):145. Epub 2021 Feb 3.

Desautels Faculty of Management, McGill Centre for the Convergence of Health and Economics, McGill University, Montreal, QC, Canada.

Background: Evidence for the impact of the food retailing environment on food-related and obesity outcomes remains equivocal, but only a few studies have attempted to identify sub-populations for whom this relationship might be stronger than others. Genetic polymorphisms related to dopamine signalling have been associated with differences in responses to rewards such as food and may be candidate markers to identify such sub-populations. This study sought to investigate whether genetic variation of the dopamine D4 receptor gene (DRD4 exon III 48 bp VNTR polymorphism) moderated the association between local exposure to food retailers on BMI and diet in a sample of 4 to12-year-old children.

Methods: Data collected from a birth cohort and a community cross-sectional study conducted in Montreal, Canada, were combined to provide DRD4 VNTR polymorphism data in terms of presence of the 7-repeat allele (DRD4-7R) for 322 children aged between 4 and 12 (M (SD): 6.8(2.8) y). Outcomes were Body Mass Index (BMI) for age and energy density derived from a Food Frequency Questionnaire. Food environment was expressed as the proportion of local food retailers classified as healthful within 3 km of participants' residence. Linear regression models adjusted for age, sex, income, cohort, and geographic clustering were used to test gene*environment interactions.

Results: A significant gene*food environment interaction was found for energy density with results indicating that DRD4-7R carriers had more energy dense diets than non-carriers, with this effect being more pronounced in children living in areas with proportionally more unhealthy food retailers. No evidence of main or interactive effects of DRD4 VNTR and food environment was found for BMI.

Conclusions: Results of the present study suggest that a genetic marker related to dopamine pathways can identify children with potentially greater responsiveness to unhealthy local food environment. Future studies should investigate additional elements of the food environment and test whether results hold across different populations.
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http://dx.doi.org/10.1186/s12889-021-10160-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856809PMC
February 2021

An association of Myelin Oligodendrocyte Glycoprotein (MOG) gene variants with white matter volume in pediatric obsessive-compulsive disorder.

Psychiatry Res Neuroimaging 2021 01 21;307:111231. Epub 2020 Nov 21.

Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada; Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.

An increasing number of neuroimaging studies have implicated alterations of white matter in obsessive-compulsive disorder (OCD). The myelin oligodendrocyte glycoprotein (MOG) gene plays a major role in myelination, and has previously demonstrated significant association with this disorder, thus variations in this gene may contribute to observed white matter alterations. The purpose of this study is to examine the relationship between white matter volume in OCD and genetic variations in the MOG gene. Two polymorphisms in the MOG gene, MOG(C1334T) and MOG(C10991T), were investigated for association with total white matter volume as measured using volumetric magnetic resonance imaging in 37 pediatric OCD patients. We compared white matter volumes between allele and genotype groups for each polymorphism using ANCOVA. A significant relationship was detected between genotype C/C of MOG(C10991T) and decreased total white matter volume (P = 0.016). Our results showed an association between a MOG genetic variant and white matter volume. This finding is intriguing in light of the posited role of white matter alteration in the etiology of at least some cases of childhood-onset OCD. Further investigation with larger samples and sub-regional white matter volume phenotypes is warranted.
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http://dx.doi.org/10.1016/j.pscychresns.2020.111231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775903PMC
January 2021

Pharmacogenomic Studies in Intellectual Disabilities and Autism Spectrum Disorder: A Systematic Review: Études Pharmacogénomiques en Déficiences Intellectuelles et Trouble du Spectre de L'autisme: Une Revue Systématique.

Can J Psychiatry 2020 Nov 23:706743720971950. Epub 2020 Nov 23.

Tanenbaum Centre for Pharmacogenetics, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Background: Individuals with intellectual disability (ID) and autism spectrum disorder (ASD) often receive psychotropic medications such as antipsychotics and antidepressants to treat aberrant behaviors and mood symptoms, frequently resulting in polypharmacy and drug-related adverse effects. Pharmacogenomic (PGx) studies with ASD and/or ID (ASD/ID) have been scarce despite the promise of optimizing treatment outcomes. We reviewed the literature on PGx studies with antipsychotics and antidepressants (e.g., treatment response and adverse effects) in ASD/ID.

Methods: We performed a systematic review using MEDLINE, Embase, and PsycINFO, including peer-reviewed original articles in English referring to PGx in the treatment of ASD/ID in any age groups (e.g., treatment response and adverse effects).

Results: A total of 28 PGx studies using mostly candidate gene approaches were identified across age groups. Notably, only 3 studies included adults with ASD/ID while the other 25 studies focused specifically on children/adolescents with ASD/ID. Twelve studies primarily investigated treatment response, of which 5 and 6 studies included patients treated with antipsychotics and antidepressants, respectively. Most interesting results for response were reported for 2 sets of candidate gene studies, namely: (1) The (rs6280) polymorphism was examined in patients treated with risperidone in 3 studies, 2 of which reported an association with risperidone treatment response and (2) the 5-HTTLPR polymorphism and treatment response to antidepressants which was investigated in 4 studies, 3 of which reported significant associations. In regard to side effects, 9 of 15 studies focused on hyperprolactinemia in patients treated with risperidone. Among them, 7 and 5 studies examined the impact of and polymorphisms, respectively, yielding mostly negative study findings.

Conclusions: There is limited data available on PGx in individuals with ASD/ID and in particular in adults. Given the potential for PGx testing in improving treatment outcomes, additional PGx studies for psychotropic treatment in ASD/ID across age groups are warranted.
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http://dx.doi.org/10.1177/0706743720971950DOI Listing
November 2020

Review and Consensus on Pharmacogenomic Testing in Psychiatry.

Pharmacopsychiatry 2021 Jan 4;54(1):5-17. Epub 2020 Nov 4.

Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Kansas City, Kansas City and School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA.

The implementation of pharmacogenomic (PGx) testing in psychiatry remains modest, in part due to divergent perceptions of the quality and completeness of the evidence base and diverse perspectives on the clinical utility of PGx testing among psychiatrists and other healthcare providers. Recognizing the current lack of consensus within the field, the International Society of Psychiatric Genetics assembled a group of experts to conduct a narrative synthesis of the PGx literature, prescribing guidelines, and product labels related to psychotropic medications as well as the key considerations and limitations related to the use of PGx testing in psychiatry. The group concluded that to inform medication selection and dosing of several commonly-used antidepressant and antipsychotic medications, current published evidence, prescribing guidelines, and product labels support the use of PGx testing for 2 cytochrome P450 genes (). In addition, the evidence supports testing for human leukocyte antigen genes when using the mood stabilizers carbamazepine (), oxcarbazepine (), and phenytoin (CYP2C9, HLA-B). For valproate, screening for variants in certain genes () is recommended when a mitochondrial disorder or a urea cycle disorder is suspected. Although barriers to implementing PGx testing remain to be fully resolved, the current trajectory of discovery and innovation in the field suggests these barriers will be overcome and testing will become an important tool in psychiatry.
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http://dx.doi.org/10.1055/a-1288-1061DOI Listing
January 2021

Contributions of cholinergic receptor muscarinic 1 and CYP1A2 gene variants on the effects of plasma ratio of clozapine/N-desmethylclozapine on working memory in schizophrenia.

J Psychopharmacol 2021 01 4;35(1):31-39. Epub 2020 Nov 4.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada.

Background: Clozapine has heterogenous efficacy in enhancing working memory in schizophrenia. We have previously hypothesized that this is due to opposing effects of clozapine and its metabolite, N-desmethylclozapine, at the muscarinic M1 receptor and demonstrated that a lower clozapine/-desmethylclozapine ratio is associated with better working memory than clozapine or -desmethylclozapine levels alone.

Aims: In this study, we expanded the above hypothesis to explore whether genetic variation in the cholinergic receptor muscarinic 1 gene, encoding the M1 receptor, affects the relationship between clozapine/-desmethylclozapine and working memory. Further, we explored whether CYP1A2 gene variants affect the ratio of clozapine/-desmethylclozapine and by this, working memory performance.

Methods: We evaluated two functionally significant single nucleotide polymorphisms, rs1942499 and rs2075748, in cholinergic receptor muscarinic 1, with the haplotype T-A associated with lower transcriptional activity than the haplotype C-G. Further, we examined *1F, with *1F/*1F conferring high inducibility in the presence of smoking.

Results: In a sample of 30 patients with schizophrenia on clozapine monotherapy, clozapine/-desmethylclozapine was correlated with working memory only in non-carriers of the haplotype T-A of the gene. Interaction of genotype and smoking status significantly affected clozapine concentrations, but there were no significant effects of genotype and smoking status on the relationship between clozapine/-desmethylclozapine on working memory.

Conclusions: Our finding that the relationship between clozapine/-desmethylclozapine and working memory is specific to patients with potentially higher transcription of M1 receptor (i.e. non-carriers of the haplotype T-A of ) supports a cholinergic mechanism underlying this relationship.
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http://dx.doi.org/10.1177/0269881120946288DOI Listing
January 2021

Genetics of human startle reactivity: A systematic review to acquire targets for an anxiety endophenotype.

World J Biol Psychiatry 2021 07 12;22(6):399-427. Epub 2020 Nov 12.

Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Canada.

Objectives: Startle response is an objective physiological measure integral to the human defense system and a promising target for endophenotype investigations of anxiety. Given the alterations in startle reactivity observed among anxiety and related disorders, we searched for genetic variants associated with startle reactivity as they may be further involved in pathological anxiety risk.

Methods: A systematic literature review was performed to identify genetic variants associated with startle reactivity in humans, specifically baseline and fear- or anxiety-potentiated startle.

Results: The polymorphisms Val66Met (rs6265) from brain-derived neurotrophic factor (), Val158Met (rs4680) from catechol-O-methyltransferase (), and the serotonin transporter-linked polymorphic region (5-HTTLPR) from the serotonin transporter gene () were most commonly studied in human startle. In addition, several other genetic variants have also been identified as potential candidates that warrant further research, especially given their novelty in in the context of anxiety.

Conclusions: Similar to psychiatric genetic studies, the studies on startle reactivity primarily focus on candidate genes and are plagued by non-replication. Startle reactivity is a promising endophenotype that requires concerted efforts to collect uniformly assessed, large, well-powered samples and hypothesis-free genome-wide strategies. To further support startle as an endophenotype for anxiety, this review suggests advanced genetic strategies for startle research.
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http://dx.doi.org/10.1080/15622975.2020.1834619DOI Listing
July 2021

Liver enzyme gene and tardive dyskinesia.

Pharmacogenomics 2020 10 24;21(15):1065-1072. Epub 2020 Sep 24.

Tanenbaum Centre for Pharmacogenetics, Campbell Family Mental Health Research Institute, Centre for Addiction & Mental Health, Toronto, ON, M5T 1R8, Canada.

Tardive dyskinesia (TD) is an iatrogenic involuntary movement disorder occurring after extended antipsychotic use with unclear pathogenesis. is a liver enzyme involved in antipsychotic metabolism and a well-studied gene candidate for TD. We tested predicted CYP2D6 metabolizer phenotype with TD occurrence and severity in our two samples of European chronic schizophrenia patients (total n = 198, of which 82 had TD). TD occurrence were associated with extreme metabolizer phenotype, controlling for age and sex (p = 0.012). In other words, individuals with either increased and no CYP2D6 activity were at higher risk of having TD. Unlike most previous findings, TD occurrence may be associated with both extremes of CYP2D6 metabolic activity rather than solely for poor metabolizers.
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http://dx.doi.org/10.2217/pgs-2020-0065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586356PMC
October 2020

Neurostructural phenotypes of CACNA1C rs1006737 in adolescents with bipolar disorder and healthy controls.

Prog Neuropsychopharmacol Biol Psychiatry 2021 01 13;104:110071. Epub 2020 Aug 13.

Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Pharmacology, University of Toronto, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada. Electronic address:

Objective: Investigate the effects of CACNA1C rs1006737 on cortical and subcortical neurostructural phenotypes in Caucasian bipolar disorder (BD) and healthy control (HC) adolescents.

Methods: Seventy-one adolescents (14-20 years; 38BD, 33HC) underwent 3-Tesla Magnetic Resonance Imaging (MRI). Region of interest (ROI) and vertex-wise analyses examined cortical volume, surface area (SA), and thickness, as well as subcortical volume. ROIs included the ventromedial prefrontal cortex (vmPFC), ventrolateral prefrontal cortex (vlPFC), anterior cingulate cortex (ACC), putamen, and amygdala. General linear models included main effects of diagnosis and rs1006737, and an interaction term, controlling for age, sex, and total intracranial volume.

Results: Vertex-wise analysis found significant BD-by-rs1006737 interactions for prefrontal and occipital regions such that BD A-carriers were found to have greater SA relative to BD non-carriers, while HC A-carriers had reduced SA relative to HC non-carriers. ROI analysis found an interaction in the ACC such that BD A-carriers were found to have greater SA relative to BD non-carriers, while no significant difference was found in HCs. Main effects of rs1006737 were also found on ACC SA from ROI analysis, and occipital SA from vertex-wise analysis, such that A-carriers had larger SA relative to non-carriers in both of these regions.

Conclusions: The current study identified neurostructural intermediate phenotypes relevant to the impact of CACNA1C rs1006737 on adolescent BD. Further investigation is warranted into the neurofunctional and neurocognitive relevance of rs1006737 associations with BD-specific elevations in regional SA.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110071DOI Listing
January 2021

The pharmacogenetics of opioid treatment for pain management.

J Psychopharmacol 2020 11 25;34(11):1200-1209. Epub 2020 Jul 25.

Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada.

Background: Opioids are widely used as an analgesic for the treatment of moderate to severe pain. However, there are interindividual variabilities in opioid response. Current evidence suggests that these variabilities can be attributed to single nucleotide polymorphisms in genes involved in opioid pharmacodynamics and pharmacokinetics. Knowledge of these genetic factors through pharamacogenetic (PGx) testing can help clinicians to more consistently prescribe opioids that can provide patients with maximal clinical benefit and minimal risk of adverse effects.

Aim: The research outlined in this literature review identifies variants involved in opioid PGx, which may be an important tool to achieving the goal of personalized pain management.

Results: Cytochrome P450 () , catechol-o-methyltransferase (), adenosine triphosphate binding cassette transporter B1 (), opioid receptor mu 1 (), and opioid receptor delta 1 () are all important genes involved in opioid drug response, side effect profile and risk of dependence; these are important genetic factors that should be included in potential opioid PGx tests for pain management.

Conclusions: Employing a PGx-guided strategy for prescribing opioids can improve response rate, reduce side effects and increase adherence to treatment plans for pain; more research is needed to explore opioid-related PGx factors for the development and validation of an opioid genetic panel. Optimal prescriptions could also provide healthcare payers with beneficial savings, while reducing the risk of propagating the current opioid crisis.
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http://dx.doi.org/10.1177/0269881120944162DOI Listing
November 2020

Regulation of melanocortin-4-receptor (MC4R) expression by SNP rs17066842 is dependent on glucose concentration.

Eur Neuropsychopharmacol 2020 08 16;37:39-48. Epub 2020 Jul 16.

Pharmacogenetics Research Clinic, Molecular Brain Science, Centre for Addiction and Mental Health, Toronto M5T 1R8, ON, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario M5T 1R8, Canada. Electronic address:

Melanocortin-4-receptor (MC4R) gene codes for a G-protein-coupled receptor that is highly expressed in the hypothalamus and involved in the regulation of appetite. Single-nucleotide polymorphisms (SNPs) in the MC4R gene region have been associated with obesity, type 2-diabetes (T2D) and with antipsychotic-induced weight gain. Of these, rs17066842 (G>A) in the MC4R promoter region is the top variant associated with obesity and diabetes. In this study, we investigated the effect of rs17066842 on MC4R expression at various glucose concentrations using reporter gene expression in the SH-SY5Y cell line and regulation of MC4R expression in human cerebral organoids. We observed that higher glucose concentrations significantly reduced MC4R mRNA expression in SH-SY5Y cells. In addition, at high glucose concentrations, the luciferase reporter plasmid containing the MC4R promoter insert with the G-allele of rs170066842 showed significantly reduced activity compared to the A-allele carrying plasmid. The immediate early gene product, early growth-response 1 (EGR-1), was identified to bind to the sequence containing the G-allele at rs17066842 but not to the A-allele-containing sequence. Interestingly, in human induced pluripotent stem cell (hiPSC)-derived cerebral organoids, we observed increased MC4R expression in response to high glucose exposure. These opposite observations might suggest that glucose regulation is complex and may be cell-specific. This study provides evidence that rs17066842 regulates MC4R gene expression through binding of EGR-1 and that this process is influenced by glucose concentration.
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http://dx.doi.org/10.1016/j.euroneuro.2020.05.008DOI Listing
August 2020

Older molecular brain age in severe mental illness.

Mol Psychiatry 2021 Jul 6;26(7):3646-3656. Epub 2020 Jul 6.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15312, USA.

Psychiatric disorders are associated with accelerated aging and enhanced risk for neurodegenerative disorders. Brain aging is associated with molecular, cellular, and structural changes that are robust on the group level, yet show substantial inter-individual variability. Here we assessed deviations in gene expression from normal age-dependent trajectories, and tested their validity as predictors of risk for major mental illnesses and neurodegenerative disorders. We performed large-scale gene expression and genotype analyses in postmortem samples of two frontal cortical brain regions from 214 control subjects aged 20-90 years. Individual estimates of "molecular age" were derived from age-dependent genes, identified by robust regression analysis. Deviation from chronological age was defined as "delta age". Genetic variants associated with deviations from normal gene expression patterns were identified by expression quantitative trait loci (cis-eQTL) of age-dependent genes or genome-wide association study (GWAS) on delta age, combined into distinct polygenic risk scores (PRS and PRS), and tested for predicting brain disorders or pathology in independent postmortem expression datasets and clinical cohorts. In these validation datasets, molecular ages, defined by 68 and 76 age-related genes for two brain regions respectively, were positively correlated with chronological ages (r = 0.88/0.91), elevated in bipolar disorder (BP) and schizophrenia (SCZ), and unchanged in major depressive disorder (MDD). Exploratory analyses in independent clinical datasets show that PRSs were associated with SCZ and MDD diagnostics, and with cognition in SCZ and pathology in Alzheimer's disease (AD). These results suggest that older molecular brain aging is a common feature of severe mental illnesses and neurodegeneration.
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http://dx.doi.org/10.1038/s41380-020-0834-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785531PMC
July 2021
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