L Trevor Young

University of Toronto, Toronto, Ontario, Canada

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Publications (161)839.33 Total impact

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    ABSTRACT: Bipolar I disorder (BD) is associated with increased inflammation, which is believed to be central to disease etiology and progression. However, BD patients also have high rates of obesity, itself an inflammatory condition, and the relative contributions of mood illness and obesity to inflammation are unknown. Moreover, the impact of inflammation on clinical illness course has not been well studied. The objectives of this analysis were therefore: (1) to determine if inflammation in BD is mood illness-related or secondary to elevated body mass index (BMI), and (2) to investigate the impact of inflammation on prospectively-ascertained relapse into depression and mania. We measured the serum levels of 7 inflammatory cytokines (TNF-α, γ-interferon, monocyte chemoattractant protein-1 [MCP-1], IL-1α, IL-2, IL-6, and IL-8) and 2 anti-inflammatory cytokines (IL-4 and IL-10) in 52 early-stage BD patients and 22 healthy subjects. In patients, a multivariate multiple regression model that controlled for psychotropic medications found that higher BMI, but not recent (past-6-month) mood episodes, predicted greater inflammatory cytokines (p=.05). Healthy subjects also had a BMI-related increase in inflammatory cytokines (p<.01), but it was counter-balanced by a compensatory increase in anti-inflammatory cytokines (p=.02), reducing their total inflammatory burden from higher BMI. In patients, linear regression showed that two inflammatory cytokines predicted depressive relapse in the 12 months after cytokine measurement: IL-1α (p<.01) and MCP-1 (p<.01). These results suggest that elevated BMI is a significant contributor to inflammation in BD, more so even than recent mood illness severity. They also point to inflammation as an important predictor of illness course, particularly depressive relapse.
    No preview · Article · Mar 2016 · Psychoneuroendocrinology
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    Liping Hou · Urs Heilbronner · Franziska Degenhardt · Mazda Adli · Kazufumi Akiyama · Nirmala Akula · Raffaella Ardau · Bárbara Arias · Lena Backlund · Claudio E.M. Banzato · [...] · Andreas Reif · Maria Del Zompo · Frank Bellivier · Martin Schalling · Naomi R. Wray · John R Kelsoe · Martin Alda · Marcella Rietschel · Francis J. McMahon · Thomas G. Schulze ·
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    ABSTRACT: Background Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. Methods Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. Findings A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10−8; rs78015114, p=1·31 × 10−8; rs74795342, p=3·31 × 10−9; and rs75222709, p=3·50 × 10−9). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1–13·0). Interpretation The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. Funding Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.
    Full-text · Article · Jan 2016 · The Lancet
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    ABSTRACT: Major depression (MDD) is a chronic psychiatric condition in which patients often show increasing cognitive impairment with recurring episodes. Neurodegeneration may play an important component in the pathogenesis of MDD associated with cognitive complaints. In agreement with this, patients with MDD show decreased brain volumes in areas implicated in emotional regulation and cognition, neuronal and glial cell death as well as activation of various pathways that can contribute to cell death. Therefore, the aim of this review is to provide an integrative overview of potential contributing factors to neurodegeneration in MDD. Studies have reported increased neuronal and glial cell death in the frontal cortex, amygdala, and hippocampus of patients with MDD. This may be due to decreased neurogenesis from lower levels of brain-derived neurotrophic factor (BDNF), excitotoxicity from increased glutamate signaling, and lower levels of gamma-aminobutyric acid (GABA) signaling. In addition, mitochondrial dysfunction and oxidative stress are found in similar brain areas where evidence of excitotoxicity has been reported. Also, levels of antioxidant enzymes were reported to be increased in patients with MDD. Inflammation may also be a contributing factor, as levels of inflammatory cytokines were reported to be increased in the prefrontal cortex of patients with MDD. While preliminary, studies have also reported neuropathological alterations in patients with MDD. Together, these studies suggest that lower BDNF levels, mitochondrial dysfunction, oxidative stress, inflammation and excitotoxicity may be contributing to neuronal and glial cell death in MDD, leading to decreased brain volume and cognitive dysfunction with multiple recurrent episodes. This highlights the need to identify specific pathways involved in neurodegeneration in MDD, which may elucidate targets that can be treated to ameliorate the effects of disease progression in this disorder.
    No preview · Article · Jan 2016 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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    ABSTRACT: Phenomenologically, bipolar disorder (BD) is characterized by biphasic increases and decreases in energy. As this is a state-related phenomenon, identifying regulators responsible for this phasic dysregulation has the potential to uncover key elements in the pathophysiology of BD. Given the evidence suggesting mitochondrial complex I dysfunction in BD, we aimed to identify the main regulators of complex I in BD by reviewing the literature and using the published microarray data to examine their gene expression profiles. We also validated protein expression levels of the main complex I regulators by immunohistochemistry. Upon reviewing the literature, we found PARK-7, STAT-3, SIRT-3 and IMP-2 play an important role in regulating complex I activity. Published microarray studies however revealed no significant direction of regulation of STAT-3, SIRT-3, and IMP-2, but a trend towards downregulation of PARK-7 was observed in BD. Immunocontent of DJ-1 (PARK-7-encoded protein) were not elevated in post mortem prefrontal cortex from patients with BD. We also found a trend towards upregulation of DJ-1 expression with age. Our results suggest that DJ-1 is not significantly altered in BD subjects, however further studies are needed to examine DJ-1 expression levels in a cohort of older patients with BD.
    No preview · Article · Dec 2015
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    ABSTRACT: Mitochondrial complex I dysfunction, oxidative stress and immune-activation are consistently reported in bipolar disorder (BD). Mitochondrial production of reactive oxygen species was recently linked to activation of an inflammatory redox sensor, the nod-like receptor family pyrin domain-containing 3 (NLRP3). Upon its activation, NLRP3 recruits apoptosis-associated speck-like protein (ASC) and caspase-1 to form the NLRP3-inflamamsome, activating IL-1β. This study aimed to examine if immune-activation may be a downstream target of complex I dysfunction through the NLRP3-inflamamsome in BD. Post-mortem frontal cortex from patients with BD (N = 9), schizophrenia (N = 10), and non-psychiatric controls (N = 9) were donated from the Harvard Brain Tissue Resource Center. Levels of NLRP3, ASC and caspase-1 were measured by western blotting, ELISA and Luminex. While we found no effects of age, sex or post-mortem delay, lower levels of complex I (F2,25 = 3.46, p < 0.05) and NDUFS7, a subunit of complex I (F2,25 = 4.13, p < 0.05), were found in patients with BD. Mitochondrial NLRP3 (F2,25 = 3.86, p < 0.05) and ASC (F2,25 = 4.61, p < 0.05) levels were higher in patients with BD. However, levels of caspase 1 (F2,25 = 4.13, p < 0.05 for both), IL-1β (F2,25 = 7.05, p < 0.01), IL-6 (F2,25 = 5.48, p < 0.05), TNFα (F2,25 = 7.14, p < 0.01) and IL-10 (F2,25 = 5.02, p < 0.05) were increased in both BD and schizophrenia. These findings suggest that immune-activation in the frontal cortex may occur both in patients with BD and schizophrenia, while complex I dysfunction and NLRP3-inflammasome activation may be more specific to BD.
    No preview · Article · Oct 2015 · Journal of Psychiatric Research
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    ABSTRACT: Recently, multiple genome-wide association studies have identified a genetic polymorphism (CACNA1C rs1006737) that appears to confer susceptibility for BD. This article aims to summarize the existing literature regarding the impact of rs1006737 on functional and structural neuroimaging intermediate phenotypes. Twenty-eight articles, representing 2486 healthy participants, 369 patients with BD and 104 healthy first-degree relatives of patients with BD, are incorporated. Multiple studies have demonstrated structural differences, functional differences associated with emotion-related and frontal-executive tasks, and/or differences in behavioral task performance in risk allele carriers (AA or AG). Results comparing participants with BD to healthy controls are generally less pronounced than within-group genetic comparisons. The review concludes with an integration of how cardiovascular comorbidity may be a relevant mediator of the observed findings, and proposes future directions toward optimized therapeutic use of calcium channel blockers in BD. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · May 2015 · Neuroscience & Biobehavioral Reviews
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    ABSTRACT: The Structural Genomics Consortium (SGC) and its clinical, industry and disease-foundation partners are launching open-source preclinical translational medicine studies.
    Full-text · Article · Mar 2015 · Nature Reviews Drug Discovery
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    ABSTRACT: VLE attenuates cell mortality induced by H2O2 treatment as compared to lithium.•Morphology alterations induced by H2O2 were prevented by VLE similar to lithium.•Activation of apoptotic and necrotic pathways induced by H2O2 was decreased by VLE.•VLE ameliorates fluctuations of intracellular calcium levels comparable to lithium.•VLE prevents changes in relative CACNA1c levels despite H2O2 treatment.
    No preview · Article · Oct 2014 · Neurochemistry International
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    ABSTRACT: The aim of this study was to elucidate whether glutathione is involved in lithium's ability to decrease carbonylation and nitration produced by complex I inhibition, which is consistently found in BD. Neuroblastoma cells were treated with rotenone, a complex I inhibitor. Our results suggest that glutathione is essential for lithium's ability to ameliorate rotenone-induced protein carbonylation, but not nitration.
    No preview · Article · Sep 2014 · Journal of Neural Transmission
  • Nicole C. Brown · Ana C. Andreazza · L. Trevor Young
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    ABSTRACT: Despite its debilitating symptoms, the pathophysiology of bipolar disorder (BD) remains unclear. One consistently compelling finding, however, has been the presence of oxidative stress. In the present investigation, we conducted a meta-analysis of studies that measured oxidative stress markers in BD patients compared to healthy controls. Search terms and selection criteria were determined a priori to identify and include all studies that measured a marker of oxidative stress in BD compared to healthy controls. Eight markers were included: superoxide dismutase, catalase, protein carbonyl, glutathione peroxidase, 3-nitrotyrosine, lipid peroxidation, nitric oxide, and DNA/RNA damage. A meta-analysis of standardized means was conducted using a random-effects model with generic inverse weighting. Between-study heterogeneity, publication bias, and sensitivity analyses were also examined for each marker. Twenty-seven papers were included in the meta-analysis, which comprised a total of 971 unique patients with BD and 886 healthy controls. Lipid peroxidation, DNA/RNA damage, and nitric oxide were significantly increased in BD patients compared to healthy controls. Additionally, the effect size for lipid peroxidation was very high. Publication bias was not detected for any of the markers. The main limitations in this meta-analysis are the high degree of heterogeneity between studies and the small number of studies used in the analysis of some markers. Additionally, the sensitivity analysis indicated that some results are not very robust. The results from this meta-analysis support the role of oxidative stress in bipolar disorder, especially to DNA, RNA, and lipids.
    No preview · Article · Aug 2014
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    Full-text · Dataset · Jul 2014
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    ABSTRACT: Objectives The current study investigated the longitudinal course of symptoms in bipolar disorder among individuals receiving optimal treatment combining pharmacotherapy and psychotherapy, as well as predictors of the course of illness.MethodsA total of 160 participants with bipolar disorder (bipolar I disorder: n = 115; bipolar II disorder: n = 45) received regular pharmacological treatment, complemented by a manualized, evidence-based psychosocial treatment – that is, cognitive behavioral therapy or psychoeducation. Participants were assessed at baseline and prospectively for 72 weeks using the Longitudinal Interval Follow-up Evaluation (LIFE) scale scores for mania/hypomania and depression, as well as comparison measures (clinicaltrials.gov identifier: NCT00188838).ResultsOver a 72-week period, patients spent a clear majority (about 65%) of time euthymic. Symptoms were experienced more than 50% of the time by only a quarter of the sample. Depressive symptoms strongly dominated over (hypo)manic symptoms, while subsyndromal symptoms were more common than full diagnosable episodes for both polarities. Mixed symptoms were rare, but present for a minority of participants. Individuals experienced approximately six significant mood changes per year, with a full relapse on average every 7.5 months. Participants who had fewer depressive symptoms at intake, a later age at onset, and no history of psychotic symptoms spent more weeks well over the course of the study.Conclusions Combined pharmacological and adjunctive psychosocial treatments appeared to provide an improved course of illness compared to the results of previous studies. Efforts to further improve the course of illness beyond that provided by current optimal treatment regimens will require a substantial focus on both subsyndromal and syndromal depressive symptoms.
    Full-text · Article · Jul 2014 · Bipolar Disorders
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    ABSTRACT: Objective: Increases in oxidative stress have been consistently reported in younger patients with bipolar disorder (BD) in postmortem brain and blood samples studies. Changes in oxidative stress are also associated with the natural aging process. Thus, the investigation of oxidative stress across the life span of patients with BD is crucial. Methods: We compared the levels of oxidative damage to proteins and lipids in plasma from 110 euthymic older patients with BD I or II (mean±SD age: 63.9±9.7 years) and 75 older healthy individuals (66.0±9.6 years). To assess protein oxidation, we measured the plasma levels of protein carbonyl (PC) and 3-nitrotyrosine (3-NT) using the ELISA technique. To assess lipid peroxidation, we measured plasma levels of lipid hydroperoxide (LPH) and 4-hydroxynonenal (4-HNE) using spectrophotometric assays. Results: LPH levels were higher in patients than in the comparison healthy individuals, whereas there were no significant differences for PC, 3-NT, and 4-HNE between the two groups. Conclusions: The increased levels of an early component of the peroxidation chain (LPH) in euthymic older patients with BD support the hypothesis of a persistent effect of reactive species of oxygen in patients with BD into late life.
    No preview · Article · May 2014 · The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry
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    ABSTRACT: Mitochondrial complex I dysfunction and alterations in DNA methylation levels are consistently reported in bipolar disorder (BD) and are regulated by lithium. One of the mechanisms by which lithium may exert its effects in BD is by improving mitochondrial complex I function. Therefore, we examined whether complex I dysfunction induces methylation and hydroxymethylation of DNA and whether lithium alters these effects in rat primary cortical neurons. Rotenone was used to induce mitochondrial complex I dysfunction. Cell viability was measured by MTT assay, and ATP levels were assessed by Cell-Titer-Glo®. Complex I activity was measured using an ELISA-based assay. Apoptosis, DNA methylation, and hydroxymethylation levels were measured by immunocytochemistry. Rotenone decreased complex I activity and ATP production, but increased cell death and apoptosis. Rotenone treatment increased levels of 5-methylcytosine (5mc) and hydroxymethylcytosine (5hmc), suggesting a possible association between complex I dysfunction and DNA alterations. Lithium prevented rotenone-induced changes in mitochondrial complex I function, cell death and changes to DNA methylation and hydroxymethylation. These findings suggest that decreased mitochondrial complex I activity may increase DNA methylation and hydroxymethylation in rat primary cortical neurons and that lithium may prevent these effects.
    No preview · Article · Apr 2014 · Psychopharmacology
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    ABSTRACT: Bipolar disorder is a highly heritable illness that onsets in adolescence and young adulthood. We examined gene expression (mRNA) and protein levels of candidate immune and neurotrophic markers in well-characterized offspring of bipolar parents in order to identify reliable indicators of illness risk status and the early clinical stages of illness development. We measured mRNA expression and protein levels in candidate immune (TNF-α, IL-1β, IL-10, IFN-δ) and neurotrophic (brain-derived neurotrophic factor (BDNF)) markers from plasma. High-risk offspring were identified from families in which one parent had confirmed bipolar disorder. Control offspring were identified from families in which neither parent met lifetime criteria for a major psychiatric disorder. All parental Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnoses were based on Schedule for Affective Disorders - Lifetime Version (SADS-L) interviews and blind consensus review. As part of an ongoing study, all offspring were prospectively assessed using KSADS-PL format interviews and diagnoses confirmed on blind consensus review. High-risk offspring had significantly increased IL-6 (p = 0.050) and BDNF (p = 0.006) protein levels compared to controls. Those high-risk offspring in earlier compared to later clinical stages of illness development had higher IL-6 (p = 0.050) and BDNF (p = 0.045) protein levels. After adjustments, only differences in BDNF protein levels remained significant. There was a moderating effect of the BDNF genotype on both gene expression and protein levels in high-risk compared to control offspring. The BDNF genotype also moderated the association between clinical stage and gene expression levels in high-risk offspring. These findings provide support for detectable differences in candidate immune and neurotrophic markers in individuals at high risk of developing bipolar disorder and for detectable changes over the clinical stages of illness development. These associations appear to be moderated by genetic variants. Electronic supplementary material The online version of this article (doi:10.1186/2194-7511-2-4) contains supplementary material, which is available to authorized users.
    Preview · Article · Mar 2014

  • No preview · Article · Mar 2014 · American Journal of Geriatric Psychiatry
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    ABSTRACT: Increased oxidative stress is strongly implicated in bipolar disorder (BD), where protein oxidation, lipid peroxidation and oxidative damage to DNA have been consistently reported. High levels of dopamine (DA) in mania are also well-recognized in patients with BD, and DA produces reactive oxygen species and electron-deficient quinones that can oxidize proteins when it is metabolized. Using immunohistochemistry and acceptor photobleaching Förster resonance energy transfer (FRET), we examined oxidation and nitration of areas immunoreactive for the DA transporter (DAT) and tyrosine hydroxylase (TH) in the postmortem prefrontal cortex from patients with BD, schizophrenia and major depression as well as nonpsychiatric controls. We found increased oxidation of DAT-immunoreactive regions in patients with BD (F3,48 = 6.76, p = 0.001; Dunnett post hoc test p = 0.001) and decreased nitration of TH-immunoreactive regions in both patients with BD (F3,45 = 3.10, p = 0.036; Dunnett post hoc test p = 0.011) and schizophrenia (p = 0.027). On the other hand, we found increased global levels of oxidation in patients with BD (F3,44 = 6.74, p = 0.001; Dunnett post hoc test p = 0.001) and schizophrenia (p = 0.020), although nitration levels did not differ between the groups (F3,46 = 1.75; p = 0.17). Limitations of this study include the use of postmortem brain sections, which may have been affected by factors such as postmortem interval and antemortem agonal states, although demographic factors and postmortem interval were accounted for in our statistical analysis. These findings suggest alterations in levels of protein oxidation and nitration in DA-rich regions of the prefrontal cortex in patients with BD and schizophrenia, but more markedly in those with BD.
    Full-text · Article · Feb 2014 · Journal of psychiatry & neuroscience: JPN
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    ABSTRACT: 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.
    Full-text · Article · Dec 2013 · The International Journal of Neuropsychopharmacology
  • Benjamin I Goldstein · L Trevor Young
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    ABSTRACT: The importance of biomarkers to many branches of medicine is illustrated by their utility in diagnosis and monitoring treatment response and outcome. There is much enthusiasm in the field of mood disorders on the emergence of clinically relevant biomarkers with several potential targets. While there are generally accepted criteria to establish a biomarker, such approaches are premature for our field as we acquire evidence on the most relevant candidates. A number of components of the inflammatory pathway are supported by published data together with an increasing focus on brain-derived neurotrophic factor. These markers may have measurable impacts on endothelial function, which may be particularly amenable to study in clinical samples. The adolescent population is a key focus as identifying biomarkers before the onset of comorbid medical conditions and which may help direct early intervention seem especially promising. A systematic approach to biomarker development in mood disorders is clearly warranted.
    No preview · Article · Dec 2013 · Current Psychiatry Reports
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    ABSTRACT: Abnormalities of signal transduction are considered among the susceptibility factors for bipolar disorder (BD). These include changes in G-protein-mediated signaling and subsequent modification of gene expression via transcription factors such as cAMP response element-binding protein (CREB). We investigated levels of CREB in lymphoblasts from patients with BD, all responders to lithium prophylaxis (n = 13), and healthy control subjects (n = 15). Phosphorylated CREB (pCREB) was measured by immunoblotting in subjects with BD (n = 15) as well as in their affected (n = 17) and unaffected (n = 18) relatives, and healthy controls (n = 16). Basal CREB levels were comparable in patients and control subjects and were not changed by lithium treatment. pCREB levels were increased in both patients and their relatives compared to controls (p = 0.003). Forskolin stimulation led to a 24% increase in pCREB levels in cells from healthy subjects (p = 0.002) but not in the other three groups. When using basal and stimulated pCREB levels as a biochemical phenotype in a preliminary linkage study, we found the strongest support for linkage in regions largely overlapping with those showing linkage with the clinical phenotype (3p, 6p, 16p, 17q, 19q, and 21q). Abnormal pCREB signaling could be considered a biochemical phenotype for lithium-responsive BD.
    Full-text · Article · Nov 2013 · Bipolar Disorders

Publication Stats

9k Citations
839.33 Total Impact Points

Institutions

  • 1988-2016
    • University of Toronto
      • • Department of Psychiatry
      • • Institute of Medical Sciences
      Toronto, Ontario, Canada
  • 2007-2013
    • University of British Columbia - Vancouver
      • Department of Psychiatry
      Vancouver, British Columbia, Canada
  • 1996-2008
    • McMaster University
      • Department of Psychiatry and Behavioural Neurosciences
      Hamilton, Ontario, Canada
  • 2006
    • Universitätsklinikum Dresden
      • Klinik und Poliklinik für Psychiatrie und Psychotherapie
      Dresden, Saxony, Germany
  • 2004
    • Centre for Addiction and Mental Health
      Toronto, Ontario, Canada
  • 2003
    • St. Joseph's Healthcare Hamilton
      Hamilton, Ontario, Canada
  • 2001
    • Nagoya City University
      • Medical School
      Nagoya, Aichi, Japan
  • 2000-2001
    • Forensic Psychiatric Hospital
      Coquitlam, British Columbia, Canada
    • Hamilton University
      Ontario, California, United States