L Trevor Young

University of Toronto, Toronto, Ontario, Canada

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Publications (154)784.57 Total impact

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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.
    Journal of Psychiatric Research 10/2015; 72. DOI:10.1016/j.jpsychires.2015.10.015 · 3.96 Impact Factor
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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.
    Neuroscience & Biobehavioral Reviews 05/2015; 55. DOI:10.1016/j.neubiorev.2015.04.022 · 8.80 Impact Factor
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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.
    Nature Reviews Drug Discovery 03/2015; 14(3):149-50. DOI:10.1038/nrd4565 · 41.91 Impact Factor
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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.
    Neurochemistry International 10/2014; 79. DOI:10.1016/j.neuint.2014.10.002 · 3.09 Impact Factor
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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.
    Journal of Neural Transmission 09/2014; 122(6). DOI:10.1007/s00702-014-1318-8 · 2.40 Impact Factor
  • 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.
    08/2014; 218(1-2). DOI:10.1016/j.psychres.2014.04.005
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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.
    Bipolar Disorders 07/2014; 17(1). DOI:10.1111/bdi.12233 · 4.97 Impact Factor
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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.
    The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 05/2014; 23(3). DOI:10.1016/j.jagp.2014.05.008 · 4.24 Impact Factor
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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.
    Psychopharmacology 04/2014; 231(21). DOI:10.1007/s00213-014-3565-7 · 3.88 Impact Factor
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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.
    03/2014; 2(1):4. DOI:10.1186/2194-7511-2-4

  • American Journal of Geriatric Psychiatry 03/2014; 22(3):S109. DOI:10.1016/j.jagp.2013.12.125 · 4.24 Impact Factor
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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.
    Journal of psychiatry & neuroscience: JPN 02/2014; 39(1):130155. DOI:10.1503/jpn.130155 · 5.86 Impact Factor
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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.
    The International Journal of Neuropsychopharmacology 12/2013; 17(04):1-9. DOI:10.1017/S1461145713001569 · 4.01 Impact Factor
  • 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.
    Current Psychiatry Reports 12/2013; 15(12):425. DOI:10.1007/s11920-013-0425-9 · 3.24 Impact Factor
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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.
    Bipolar Disorders 11/2013; 15(8). DOI:10.1111/bdi.12131 · 4.97 Impact Factor
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    ABSTRACT: Objective: To investigate changes in the use of coping styles in response to early symptoms of mania in cognitive-behavioural therapy (CBT), compared with psychoeducation, for bipolar disorder. Method: Data were drawn from a randomized controlled trial comparing CBT and psychoeducation. A subsample of 119 participants completed the Coping Inventory for the Prodromes of Mania and symptom assessments before treatment and 72 weeks later. Results: Both CBT and psychoeducation were associated with similar improvements in symptom burden. Both treatments also produced equivalent improvements in stimulation reduction and problem-directed coping styles, but no statistically significant change on the endorsement of help-seeking behaviours. A treatment interaction showed that a reduction in denial and blame was present only in the CBT treatment condition. Conclusions: CBT and psychoeducation have similar impacts on coping styles for the prodromes of mania. The exception to this is denial and blame, which is positively impacted only by CBT but which does not translate into improved outcome. Given the similar change in coping styles and mood burden, teaching patients about how to cope in adaptive ways with the symptoms of mania may be a shared mechanism of change for CBT and psychoeducation. Clinical Trial Registration Number: NCT00188838.
    Canadian journal of psychiatry. Revue canadienne de psychiatrie 08/2013; 58(8):482-6. · 2.55 Impact Factor
  • Ana C Andreazza · Jun-Feng Wang · Faraz Salmasi · Li Shao · L Trevor Young ·
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    ABSTRACT: Previously, we found decreased mitochondrial complex I subunits levels and increased protein oxidation and nitration in postmortem prefrontal cortex (PFC) from patients with bipolar disorder (BD) and schizophrenia (SCZ). The objectives of this study were to replicate our findings in an independent sample of subjects with BD, and to examine more specifically oxidative and nitrosative damage to mitochondrial and synaptosomal proteins and lipid peroxidation in myelin. We isolated mitochondria, synaptosomes and myelin using a percoll gradient from postmortem PFC from patients with BD, SCZ, and healthy controls. Levels of mitochondrial complex I and III proteins, protein oxidation (carbonylation), and nitration (3-nitrotyrosine) were assessed using immunobloting analysis. Lipid peroxidation (lipid hydroperoxides, LPH, 8-isoprostane, 8-Iso, 4-hydroxy-2-nonenal, 4-HNE) were measured using colorimetric or ELISA assays. We found decreased complex I subunits levels in BD subjects compared to control (CTL), but no difference in complex III subunits. Carbonylation was increased in synaptosomes from BD group while 3-nitrotyrosine was increased in mitochondria from BD and SCZ groups. 8-Iso was found increased in the BD group while 4-HNE was increased in both SCZ and BD when compared to controls with no differences in LPH. Our results suggest that in BD mitochondrial proteins are more susceptible to potentially reversible nitrosative damage while more longstanding oxidative damage occurs to synaptic proteins. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 05/2013; 127(4). DOI:10.1111/jnc.12316 · 4.28 Impact Factor
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    Bipolar Disorders 03/2013; 15(3). DOI:10.1111/bdi.12055 · 4.97 Impact Factor
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    Ana C Andreazza · L Trevor Young ·
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    ABSTRACT: Bipolar disorder (BD) is a chronic psychiatric illness described by severe changes in mood. Extensive research has been carried out to understand the aetiology and pathophysiology of BD. Several hypotheses have been postulated, including alteration in genetic factors, protein expression, calcium signalling, neuropathological alteration, mitochondrial dysfunction and oxidative stress in BD. In the following paper, we will attempt to integrate these data in a manner which is to understand targets of treatment and how they may be, in particular, relevant to combination treatment. In summary, the data suggested that BD might be associated with neuronal and glial cellular impairment in specific brain areas, including the prefrontal cortex. From molecular and genetics: (1) alterations in dopaminergic system, through catechol-O-aminotransferase; (2) decreased expression and polymorphism on brain-derived neurotrophic factor; (3) alterations cyclic-AMP responsive element binding; (4) dysregulation of calcium signalling, including genome-wide finding for voltage-dependent calcium channel α-1 subunit are relevant findings in BD. Future studies are now necessary to understand how these molecular pathways interact and their connection to the complex clinical manifestations observed in BD.
    The International Journal of Neuropsychopharmacology 03/2013; 17(07):1-14. DOI:10.1017/S1461145713000096 · 4.01 Impact Factor

Publication Stats

8k Citations
784.57 Total Impact Points


  • 1988-2015
    • 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
  • 2000-2001
    • Forensic Psychiatric Hospital
      Coquitlam, British Columbia, Canada
    • Hamilton University
      Ontario, California, United States