Publications by authors named "Jane Foster"

84 Publications

The effect of early life immune challenge on adult forced swim test performance and hippocampal neurogenesis.

J Neuroimmunol 2021 Feb 27;354:577530. Epub 2021 Feb 27.

Psychiatry and Behavioural Neuroscience, McMaster University, Hamilton, Ontario, Canada.

Many psychiatric diseases can be considered neurodevelopmental in nature and accumulating evidence links immune system dysfunction to disease etiology. Yet, it is currently unknown how the immune system alters brain function through development to increase susceptibility to psychiatric illness. Neonatal immune challenge in rodents is a neurodevelopmental model that has been associated with long-term molecular and behavioural changes in stress-reactivity. As enhanced stress-reactivity is associated with the emergence of depressive-like behaviours concurrent with hippocampal pathology, we measured depressive-like behaviour in the forced swim test and hippocampal neurogenesis in adult mice neonatally exposed to lipopolysaccharide LPS; 0.05 mg/kg, i.p. on postnatal days 3 and 5. As there are important functional differences along the ventral-dorsal hippocampus axis, ventral and dorsal hippocampal neurogenesis were measured separately. Our findings reveal a sexually-dimorphic response to early-life LPS challenge. Male LPS-mice spent less time immobile in the forced swim test, suggesting altered reactivity to swim stress. This was accompanied by an increase in doublecortin-positive cells in the dorsal hippocampus of female mice. These findings demonstrate that exposure to an immune challenge during critical developmental time periods leads to long-term sexually-dimorphic alterations in stress-reactivity that are accompanied by changes to adult hippocampal neurogenesis.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577530DOI Listing
February 2021

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

Transl Psychiatry 2021 Feb 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

THE DEPRESSION INVENTORY DEVELOPMENT SCALE: Assessment of Psychometric Properties Using Classical and Modern Measurement Theory in a CAN-BIND Trial.

Innov Clin Neurosci 2020 Jul;17(7-9):30-40

Drs. Vaccarino, Evans and Gilbert Evans are with Indoc Research in Toronto, Ontario, Canada.

The goal of the Depression Inventory Development (DID) project is to develop a comprehensive and psychometrically sound rating scale for major depressive disorder (MDD) that reflects current diagnostic criteria and conceptualizations of depression. We report here the evaluation of the current DID item bank using Classical Test Theory (CTT), Item Response Theory (IRT) and Rasch Measurement Theory (RMT). The present study was part of a larger multisite, open-label study conducted by the Canadian Biomarker Integration Network in Depression (ClinicalTrials.gov: NCT01655706). Trained raters administered the 32 DID items at each of two visits (MDD: baseline, n=211 and Week 8, n=177; healthy participants: baseline, n=112 and Week 8, n=104). The DID's "grid" structure operationalizes intensity and frequency of each item, with clear symptom definitions and a structured interview guide, with the current iteration assessing symptoms related to and . Participants were also administered the Montgomery- Åsberg Depression Rating Scale (MADRS) and Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) that allowed DID items to be evaluated against existing "benchmark" items. CTT was used to assess data quality/reliability (i.e., missing data, skewness, scoring frequency, internal consistency), IRT to assess individual item performance by modelling an item's ability to discriminate levels of depressive severity (as assessed by the MADRS), and RMT to assess how the items perform together as a scale to capture a range of depressive severity (item targeting). These analyses together provided empirical evidence to base decisions on which DID items to remove, modify, or advance. Of the 32 DID items evaluated, eight items were identified by CTT as problematic, displaying low variability in the range of responses, floor effects, and/or skewness; and four items were identified by IRT to show poor discriminative properties that would limit their clinical utility. Five additional items were deemed to be redundant. The remaining 15 DID items all fit the Rasch model, with person and item difficulty estimates indicating satisfactory item targeting, with lower precision in participants with mild levels of depression. These 15 DID items also showed good internal consistency (alpha=0.95 and inter-item correlations ranging from r=0.49 to r=0.84) and all items were sensitive to change following antidepressant treatment (baseline vs. Week 8). RMT revealed problematic item targeting for the MADRS and QIDSSR, including an absence of MADRS items targeting participants with mild/moderate depression and an absence of QIDS-SR items targeting participants with mild or severe depression. The present study applied CTT, IRT, and RMT to assess the measurement properties of the DID items and identify those that should be advanced, modified, or removed. Of the 32 items evaluated, 15 items showed good measurement properties. These items (along with previously evaluated items) will provide the basis for validation of a penultimate DID scale assessing and . The strategies adopted by the DID process provide a framework for rating scale development and validation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839654PMC
July 2020

Microbiota-immune alterations in adolescents following early life adversity: A proof of concept study.

Dev Psychobiol 2020 Nov 29. Epub 2020 Nov 29.

Institute of Child Development, University of Minnesota-Twin Cities, Minneapolis, MN, USA.

Early adverse care has long-term impacts on physical and mental health. The influence of rearing conditions on the infant's gut microbiota and its relationship with developmental health has become more evident. The microbiome is essential for normal growth and metabolism, and the signaling from the gut to the brain may underlie individual differences in resilience later in life. Microbial diversity and composition were determined using 16S rRNA gene amplicon sequencing in fecal samples from 17 adolescents adopted internationally from orphanages into the United States and 18 adolescents reared in birth families who had similar educational and income levels. Analyses focused on diversity of the microbial community structure and differences in the abundance of specific bacterial taxa. Blood samples were used to immunophenotype the numbers of several T-cell subsets and cytomegalovirus (CMV) seropositivity. Negative binomial regression analysis revealed several operational taxonomic units that were significantly different based on early rearing conditions and CMV seropositivity. There were significant associations between the relative abundance of certain taxa, the percentages of T-cell subsets in circulation, and CMV seropositivity. These findings demonstrate a possible link between the gut microbiota and associations with immune alterations initiated by early life adversity.
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http://dx.doi.org/10.1002/dev.22061DOI Listing
November 2020

Diet and depression: exploring the biological mechanisms of action.

Mol Psychiatry 2021 01 3;26(1):134-150. Epub 2020 Nov 3.

Deakin University, IMPACT (the Institute for Mental and Physical Health and Clinical Translation), Food & Mood Centre, Geelong, VIC, Australia.

The field of nutritional psychiatry has generated observational and efficacy data supporting a role for healthy dietary patterns in depression onset and symptom management. To guide future clinical trials and targeted dietary therapies, this review provides an overview of what is currently known regarding underlying mechanisms of action by which diet may influence mental and brain health. The mechanisms of action associating diet with health outcomes are complex, multifaceted, interacting, and not restricted to any one biological pathway. Numerous pathways were identified through which diet could plausibly affect mental health. These include modulation of pathways involved in inflammation, oxidative stress, epigenetics, mitochondrial dysfunction, the gut microbiota, tryptophan-kynurenine metabolism, the HPA axis, neurogenesis and BDNF, epigenetics, and obesity. However, the nascent nature of the nutritional psychiatry field to date means that the existing literature identified in this review is largely comprised of preclinical animal studies. To fully identify and elucidate complex mechanisms of action, intervention studies that assess markers related to these pathways within clinically diagnosed human populations are needed.
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http://dx.doi.org/10.1038/s41380-020-00925-xDOI Listing
January 2021

Symptom Dimension of Interest-Activity Indicates Need for Aripiprazole Augmentation of Escitalopram in Major Depressive Disorder: A CAN-BIND-1 Report.

J Clin Psychiatry 2020 06 16;81(4). Epub 2020 Jun 16.

Members of the CAN-BIND Investigator Team are listed at www.canbind.ca/about-can-bind/our-team/.

Objective: Differential predictors of response to alternative treatment options are needed to improve the outcomes in major depressive disorder. The symptom dimension comprising loss of interest and reduced activity has been reported as a predictor of poor outcome of treatment with antidepressants. We hypothesized that augmentation with partial dopamine agonist aripiprazole will be effective for individuals with pronounced interest-activity symptoms.

Methods: We tested the hypothesis in the 2-phase Canadian Biomarker Integration Network in Depression trial 1 (CAN-BIND-1). All participants had a primary diagnosis of major depressive disorder confirmed with the Mini-International Neuropsychiatric Interview. In phase 1, 188 individuals received escitalopram monotherapy 10-20 mg daily for 8 weeks. In phase 2, nonresponders received augmentation with aripiprazole 2-10 mg daily while responders continued escitalopram monotherapy for another 8 weeks. Outcomes were measured with the Montgomery-Åsberg Depression Rating Scale (MADRS) every 2 weeks. Effects of baseline interest-activity symptoms on outcomes were tested in repeated-measures mixed-effects models.

Results: Higher baseline interest-activity score (indicative of more severe loss of interest and reduction in activity) predicted worse outcome of escitalopram monotherapy in phase 1 (b = 1.75; 95% CI, 0.45 to 3.05; P = .009), but the association disappeared with the augmentation option in phase 2 (b = -0.19; 95% CI, -1.30 to 0.92; P = .739). A significant interaction between the baseline interest-activity score and aripiprazole reflected the opposite direction of the relationship between baseline interest-activity score and degree of improvement with escitalopram monotherapy versus aripiprazole augmentation (b = -1.60; 95% CI, -2.35 to -0.84; P < .001).

Conclusions: Individuals with prominent loss of interest and reduction in activity benefit less from escitalopram monotherapy and more from aripiprazole augmentation. Future trials may test the benefits of early prodopaminergic augmentation guided by interest-activity symptoms.

Trial Registration: ClinicalTrials.gov identifier: NCT01655706.
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http://dx.doi.org/10.4088/JCP.20m13229DOI Listing
June 2020

Microbes and mental health: Can the microbiome help explain clinical heterogeneity in psychiatry?

Front Neuroendocrinol 2020 07 1;58:100849. Epub 2020 Jun 1.

Department of Psychiatry & Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada. Electronic address:

Trillions of microbes cover the surfaces of our bodies and inhabit our gastrointestinal tract. In the past decade, research efforts examining the role of the microbiome in mental health have moved to the forefront of neuroscience and psychiatry. Based on a foundation of animal studies demonstrating the vital role for microbiota-brain communication in brain development, behavior, and brain function over the life span, clinical studies have started to consider the microbiome in psychiatric disorders. The composition, diversity and function of commensal microbes is influenced by genetic, lifestyle, and environmental factors. This review provides an overview of the factors contributing to individual differences in the microbiome, reviews recent work in psychiatric disorders, and considers what is needed to advance a better understanding of how the microbiome impacts mental health which may help us understand the heterogeneity observed in clinical psychiatric populations.
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http://dx.doi.org/10.1016/j.yfrne.2020.100849DOI Listing
July 2020

A randomized, crossover comparison of ketamine and electroconvulsive therapy for treatment of major depressive episodes: a Canadian biomarker integration network in depression (CAN-BIND) study protocol.

BMC Psychiatry 2020 06 2;20(1):268. Epub 2020 Jun 2.

The Royal's Institute of Mental Health Research, 1145 Carling Avenue, Ottawa, ON, K1Z 7K4, Canada.

Background: Recent evidence underscores the utility of rapid-acting antidepressant interventions, such as ketamine, in alleviating symptoms of major depressive episodes (MDE). However, to date, there have been limited head-to-head comparisons of intravenous (IV) ketamine infusions with other antidepressant treatment strategies in large randomized trials. This study protocol describes an ongoing multi-centre, prospective, randomized, crossover, non-inferiority trial comparing acute treatment of individuals meeting diagnostic criteria for a major depressive episode (MDE) with ketamine and electroconvulsive therapy (ECT) on efficacy, speed of therapeutic effects, side effects, and health care resource utilization. A secondary aim is to compare a 6-month maintenance strategy for ketamine responders to standard of care ECT maintenance. Finally, through the measurement of clinical, cognitive, neuroimaging, and molecular markers we aim to establish predictors and moderators of treatment response as well as treatment-elicited effects on these outcomes.

Methods: Across four participating Canadian institutions, 240 patients with major depressive disorder or bipolar disorder experiencing a MDE are randomized (1:1) to a course of ECT or racemic IV ketamine (0.5 mg/kg) administered 3 times/week for 3 or 4 weeks. Non-responders (< 50% improvement in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) crossover to receive the alternate treatment. Responders during the randomization or crossover phases then enter the 6-month maintenance phase during which time they receive clinical assessments at identical intervals regardless of treatment arm. ECT maintenance follows standard of care while ketamine maintenance involves: weekly infusions for 1 month, then bi-weekly infusions for 2 months, and finally monthly infusions for 3 months (returning to bi-weekly in case of relapse). The primary outcome measure is change in MADRS scores after randomized treatment as assessed by raters blind to treatment modality.

Discussion: This multi-centre study will help identify molecular, imaging, and clinical characteristics of patients with treatment-resistant and/or severe MDEs who would benefit most from either type of therapeutic strategy. In addition to informing clinical practice and influencing health care delivery, this trial will add to the robust platform and database of CAN-BIND studies for future research and biomarker discovery.

Trial Registration: ClinicalTrials.gov identifier NCT03674671. Registered September 17, 2018.
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http://dx.doi.org/10.1186/s12888-020-02672-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265624PMC
June 2020

Clinical, behavioral, and neural measures of reward processing correlate with escitalopram response in depression: a Canadian Biomarker Integration Network in Depression (CAN-BIND-1) Report.

Neuropsychopharmacology 2020 07;45(8):1390-1397

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

Anhedonia is thought to reflect deficits in reward processing that are associated with abnormal activity in mesocorticolimbic brain regions. It is expressed clinically as a deficit in the interest or pleasure in daily activities. More severe anhedonia in major depressive disorder (MDD) is a negative predictor of antidepressant response. It is unknown, however, whether the pathophysiology of anhedonia represents a viable avenue for identifying biological markers of antidepressant treatment response. Therefore, this study aimed to examine the relationships between reward processing and response to antidepressant treatment using clinical, behavioral, and functional neuroimaging measures. Eighty-seven participants in the first Canadian Biomarker Integration Network in Depression (CAN-BIND-1) protocol received 8 weeks of open-label escitalopram. Clinical correlates of reward processing were assessed at baseline using validated scales to measure anhedonia, and a monetary incentive delay (MID) task during functional neuroimaging was completed at baseline and after 2 weeks of treatment. Response to escitalopram was associated with significantly lower self-reported deficits in reward processing at baseline. Activity during the reward anticipation, but not the reward consumption, phase of the MID task was correlated with clinical response to escitalopram at week 8. Early (baseline to week 2) increases in frontostriatal connectivity during reward anticipation significantly correlated with reduction in depressive symptoms after 8 weeks of treatment. Escitalopram response is associated with clinical and neuroimaging correlates of reward processing. These results represent an important contribution towards identifying and integrating biological, behavioral, and clinical correlates of treatment response. ClinicalTrials.gov: NCT01655706.
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http://dx.doi.org/10.1038/s41386-020-0688-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297974PMC
July 2020

Loss of T cells influences sex differences in stress-related gene expression.

J Neuroimmunol 2020 06 7;343:577213. Epub 2020 Mar 7.

Department of Psychiatry and Behavioural Neuroscience, McMaster University, Hamilton, ON, Canada. Electronic address:

Deficiencies in the adaptive immune system have been linked to anxiety-like behaviours and stress reactivity. Mice lacking T lymphocytes through knockout of the T cell receptor (TCR) β and δ chains were compared to wild type C57Bl/6 mice. Central stress circuitry gene expression was assessed following repeated restraint stress. TCRβ-/-δ-/- mice showed an increased baseline plasma corticosterone and exaggerated changes in stress-related gene expression after repeated restraint stress. Sexual dimorphic stress responses were observed in wild-type C57Bl/6 mice but not in TCRβ-/-δ-/- mice. These data suggest that T cell-brain interactions influence sex-differences in CNS stress circuitry and stress reactivity.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577213DOI Listing
June 2020

Loss of T cells influences sex differences in stress-related gene expression.

J Neuroimmunol 2020 06 7;343:577213. Epub 2020 Mar 7.

Department of Psychiatry and Behavioural Neuroscience, McMaster University, Hamilton, ON, Canada. Electronic address:

Deficiencies in the adaptive immune system have been linked to anxiety-like behaviours and stress reactivity. Mice lacking T lymphocytes through knockout of the T cell receptor (TCR) β and δ chains were compared to wild type C57Bl/6 mice. Central stress circuitry gene expression was assessed following repeated restraint stress. TCRβ-/-δ-/- mice showed an increased baseline plasma corticosterone and exaggerated changes in stress-related gene expression after repeated restraint stress. Sexual dimorphic stress responses were observed in wild-type C57Bl/6 mice but not in TCRβ-/-δ-/- mice. These data suggest that T cell-brain interactions influence sex-differences in CNS stress circuitry and stress reactivity.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577213DOI Listing
June 2020

Validation study of microRNAs previously associated with antidepressant response in older adults treated for late-life depression with venlafaxine.

Prog Neuropsychopharmacol Biol Psychiatry 2020 06 16;100:109867. Epub 2020 Jan 16.

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

Background: MicroRNAs (miRNAs) are small 22 nucleotides long, non-coding RNAs that are potential biomarkers for antidepressant treatment response. We aimed to replicate previous associations of miRNAs with antidepressant treatment response in a sample of older adults diagnosed with late-life depression.

Methods: Our sample included 184 older adults diagnosed with moderately severe depression that received open-label venlafaxine (up to 300 mg/day) for approximately 12 weeks. We quantified miRNA expression levels at baseline and week 12 for miRNAs miR-1202, miR-135a-5p, miR-16-5p, miR-146a-5p, miR-146b-5p, miR-425-3p, and miR-24-3p to explore their association with remission status, response trajectories, and time-to-remission.

Results: At T0 and T12, there were no differences in miRNA expression levels between remitters and non-remitters. However, remitters showed a trend toward higher baseline miR-135a-5p (Median = 11.3 [9.9, 15.7], p = .083). Prior to correction, baseline miR-135a-5p expression levels showed an association with remission status (OR = 1.8 [1.0, 3.3], p = .037). Individuals with higher baseline miR-135a-5p showed better response trajectories (F = 4.5, FDR-corrected p = 4.4 × 10), particularly at weeks 10 and 12 (p < .05). In addition, individuals with higher miR-135a-5p expression reached remission faster than those with lower expression (HR = 0.6 [0.4, 0.9], FDR-corrected p = .055).

Limitations: Although the sample size was relatively modest, our findings are consistent with the literature suggesting that higher miR-135a-5p levels may be associated with better antidepressant treatment response.

Conclusions: However, the miRNA signature of antidepressant response in older adults may be different as compared to younger adults.
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http://dx.doi.org/10.1016/j.pnpbp.2020.109867DOI Listing
June 2020

Use of Machine Learning for Predicting Escitalopram Treatment Outcome From Electroencephalography Recordings in Adult Patients With Depression.

JAMA Netw Open 2020 01 3;3(1):e1918377. Epub 2020 Jan 3.

School of Mechatronic Systems Engineering, Simon Fraser University, Surrey, British Columbia, Canada.

Importance: Social and economic costs of depression are exacerbated by prolonged periods spent identifying treatments that would be effective for a particular patient. Thus, a tool that reliably predicts an individual patient's response to treatment could significantly reduce the burden of depression.

Objective: To estimate how accurately an outcome of escitalopram treatment can be predicted from electroencephalographic (EEG) data on patients with depression.

Design, Setting, And Participants: This prognostic study used a support vector machine classifier to predict treatment outcome using data from the first Canadian Biomarker Integration Network in Depression (CAN-BIND-1) study. The CAN-BIND-1 study comprised 180 patients (aged 18-60 years) diagnosed with major depressive disorder who had completed 8 weeks of treatment. Of this group, 122 patients had EEG data recorded before the treatment; 115 also had EEG data recorded after the first 2 weeks of treatment.

Interventions: All participants completed 8 weeks of open-label escitalopram (10-20 mg) treatment.

Main Outcomes And Measures: The ability of EEG data to predict treatment outcome, measured as accuracy, specificity, and sensitivity of the classifier at baseline and after the first 2 weeks of treatment. The treatment outcome was defined in terms of change in symptom severity, measured by the Montgomery-Åsberg Depression Rating Scale, before and after 8 weeks of treatment. A patient was designated as a responder if the Montgomery-Åsberg Depression Rating Scale score decreased by at least 50% during the 8 weeks and as a nonresponder if the score decrease was less than 50%.

Results: Of the 122 participants who completed a baseline EEG recording (mean [SD] age, 36.3 [12.7] years; 76 [62.3%] female), the classifier was able to identify responders with an estimated accuracy of 79.2% (sensitivity, 67.3%; specificity, 91.0%) when using only the baseline EEG data. For a subset of 115 participants who had additional EEG data recorded after the first 2 weeks of treatment, use of these data increased the accuracy to 82.4% (sensitivity, 79.2%; specificity, 85.5%).

Conclusions And Relevance: These findings demonstrate the potential utility of EEG as a treatment planning tool for escitalopram therapy. Further development of the classification tools presented in this study holds the promise of expediting the search for optimal treatment for each patient.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.18377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991244PMC
January 2020

Association Between Side Effects and Blood microRNA Expression Levels and Their Targeted Pathways in Patients With Major Depressive Disorder Treated by a Selective Serotonin Reuptake Inhibitor, Escitalopram: A CAN-BIND-1 Report.

Int J Neuropsychopharmacol 2020 02;23(2):88-95

McGill Group for Suicide Studies, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada.

Introduction: Antidepressant drugs are effective therapies for major depressive disorder; however, they are frequently associated with side effects. Although there is some evidence for a relationship between genetic variation and side effects, little is known regarding the role of dynamic molecular factors as moderators of side effects. The aim of this study was to assess microRNA (miRNA) changes associated with side effects during escitalopram treatment and their downstream effects on target gene expression.

Methods: A total 160 patients with major depressive disorder from the CAN-BIND-1 cohort were included. Side effects were assessed with the Toronto Side Effect Scale after 2 weeks of treatment with escitalopram. We assessed the relationship between side effects and changes in peripheral expression of miRNAs between baseline and week 2. For miRNA whose expression changed, we used target prediction algorithms to identify putative messenger RNA (mRNA) targets and assessed their expression.

Results: Nausea was experienced by 42.5% of patients. We identified 45 miRNAs whose expression changed on initiation of escitalopram treatment, of which 10 displayed a negative association with intensity of nausea (miR15b-5p, miR17-5p, miR20a-5p, miR20b-5p, miR103a-3p, miR103b, miR106a-5p, miR182-5p, miR185-5p, and miR660-5p). Additionally, we found negative associations between 4 microRNAs (miR20a-5p, miR106a-5p, miR185-5p, miR660-5p) and mRNA targets. The expression of the miR185-5p target, CAMK2δ was significantly decreased [log 2 mean = -0.048 (0.233)] between weeks 0 and 2 (P = .01)].

Conclusions: We identified an overexpression of miR185-5p during escitalopram treatment of major depressive disorder, which was negatively associated with intensity of nausea, and identified a potential mRNA target that may mediate this effect.
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http://dx.doi.org/10.1093/ijnp/pyz066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093997PMC
February 2020

Decoding Microbiome Research for Clinical Psychiatry.

Authors:
Jane A Foster

Can J Psychiatry 2020 01 28;65(1):19-20. Epub 2019 Nov 28.

Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada.

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http://dx.doi.org/10.1177/0706743719890725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966260PMC
January 2020

Gut microbial metabolites in depression: understanding the biochemical mechanisms.

Microb Cell 2019 Sep 27;6(10):454-481. Epub 2019 Sep 27.

Computational Systems Medicine, Department of Surgery and Cancer, Imperial College London, UK.

Gastrointestinal and central function are intrinsically connected by the gut microbiota, an ecosystem that has co-evolved with the host to expand its biotransformational capabilities and interact with host physiological processes by means of its metabolic products. Abnormalities in this microbiota-gut-brain axis have emerged as a key component in the pathophysiology of depression, leading to more research attempting to understand the neuroactive potential of the products of gut microbial metabolism. This review explores the potential for the gut microbiota to contribute to depression and focuses on the role that microbially-derived molecules - neurotransmitters, short-chain fatty acids, indoles, bile acids, choline metabolites, lactate and vitamins - play in the context of emotional behavior. The future of gut-brain axis research lies is moving away from association, towards the mechanisms underlying the relationship between the gut bacteria and depressive behavior. We propose that direct and indirect mechanisms exist through which gut microbial metabolites affect depressive behavior: these include (i) direct stimulation of central receptors, (ii) peripheral stimulation of neural, endocrine, and immune mediators, and (iii) epigenetic regulation of histone acetylation and DNA methylation. Elucidating these mechanisms is essential to expand our understanding of the etiology of depression, and to develop new strategies to harness the beneficial psychotropic effects of these molecules. Overall, the review highlights the potential for dietary interventions to represent such novel therapeutic strategies for major depressive disorder.
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http://dx.doi.org/10.15698/mic2019.10.693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780009PMC
September 2019

Integrated genome-wide methylation and expression analyses reveal functional predictors of response to antidepressants.

Transl Psychiatry 2019 10 8;9(1):254. Epub 2019 Oct 8.

Department of Psychiatry, McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.

Major depressive disorder (MDD) is primarily treated with antidepressants, yet many patients fail to respond adequately, and identifying antidepressant response biomarkers is thus of clinical significance. Some hypothesis-driven investigations of epigenetic markers for treatment response have been previously made, but genome-wide approaches remain unexplored. Healthy participants (n = 112) and MDD patients (n = 211) between 18-60 years old were recruited for an 8-week trial of escitalopram treatment. Responders and non-responders were identified using differential Montgomery-Åsberg Depression Rating Scale scores before and after treatment. Genome-wide DNA methylation and gene expression analyses were assessed using the Infinium MethylationEPIC Beadchip and HumanHT-12 v4 Expression Beadchip, respectively, on pre-treatment peripheral blood DNA and RNA samples. Differentially methylated positions (DMPs) located in regions of differentially expressed genes between responders (n = 82) and non-responders (n = 95) were identified, and technically validated using a targeted sequencing approach. Three DMPs located in the genes CHN2 (cg23687322, p = 0.00043 and cg06926818, p = 0.0014) and JAK2 (cg08339825, p = 0.00021) were the most significantly associated with mRNA expression changes and subsequently validated. Replication was then conducted with non-responders (n = 76) and responders (n = 71) in an external cohort that underwent a similar antidepressant trial. One CHN2 site (cg06926818; p = 0.03) was successfully replicated. Our findings indicate that differential methylation at CpG sites upstream of the CHN2 and JAK2 TSS regions are possible peripheral predictors of antidepressant treatment response. Future studies can provide further insight on robustness of our candidate biomarkers, and greater characterization of functional components.
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http://dx.doi.org/10.1038/s41398-019-0589-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783543PMC
October 2019

Integrated genome-wide methylation and expression analyses reveal functional predictors of response to antidepressants.

Transl Psychiatry 2019 10 8;9(1):254. Epub 2019 Oct 8.

Department of Psychiatry, McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.

Major depressive disorder (MDD) is primarily treated with antidepressants, yet many patients fail to respond adequately, and identifying antidepressant response biomarkers is thus of clinical significance. Some hypothesis-driven investigations of epigenetic markers for treatment response have been previously made, but genome-wide approaches remain unexplored. Healthy participants (n = 112) and MDD patients (n = 211) between 18-60 years old were recruited for an 8-week trial of escitalopram treatment. Responders and non-responders were identified using differential Montgomery-Åsberg Depression Rating Scale scores before and after treatment. Genome-wide DNA methylation and gene expression analyses were assessed using the Infinium MethylationEPIC Beadchip and HumanHT-12 v4 Expression Beadchip, respectively, on pre-treatment peripheral blood DNA and RNA samples. Differentially methylated positions (DMPs) located in regions of differentially expressed genes between responders (n = 82) and non-responders (n = 95) were identified, and technically validated using a targeted sequencing approach. Three DMPs located in the genes CHN2 (cg23687322, p = 0.00043 and cg06926818, p = 0.0014) and JAK2 (cg08339825, p = 0.00021) were the most significantly associated with mRNA expression changes and subsequently validated. Replication was then conducted with non-responders (n = 76) and responders (n = 71) in an external cohort that underwent a similar antidepressant trial. One CHN2 site (cg06926818; p = 0.03) was successfully replicated. Our findings indicate that differential methylation at CpG sites upstream of the CHN2 and JAK2 TSS regions are possible peripheral predictors of antidepressant treatment response. Future studies can provide further insight on robustness of our candidate biomarkers, and greater characterization of functional components.
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http://dx.doi.org/10.1038/s41398-019-0589-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783543PMC
October 2019

Microbe and host interaction in gastrointestinal homeostasis.

Psychopharmacology (Berl) 2019 May 21;236(5):1623-1640. Epub 2019 Mar 21.

Department of Psychiatry and Behavioural Neurosciences, McMaster University, St. Joseph's Healthcare, 50 Charlton Ave. E, T3308, Hamilton, ON, L8N 4A6, Canada.

Rationale: Researchers in psychiatry and neuroscience are increasingly recognizing the importance of gut-brain communication in mental health. Both genetics and environmental factors influence gut microbiota composition and function. This study examines host-microbe signaling at the gastrointestinal barrier to identify bottom-up mechanisms of microbiota-brain communication.

Objectives: We examined differences in gut microbiota composition and fecal miRNA profiles in BALB/c and C57BL/6 mice, in relation to gastrointestinal homeostasis and evaluated the response to perturbation of the gut microbiota by broad-spectrum antibiotic treatment.

Methods And Results: Differences in the gut microbiota composition between BALB/c and C57BL/6 mice, evaluated by fecal 16S rRNA gene sequencing, included significant differences in genera Prevotella, Alistipes, Akkermansia, and Ruminococcus. Significant differences in fecal miRNA profiles were determined using the nCounter NanoString platform. A BLASTn analysis identified conserved fecal miRNA target regions in bacterial metagenomes with 14 significant correlations found between fecal miRNA and predicted taxa relative abundance in our dataset. Treatment with broad-spectrum antibiotics for 2 weeks resulted in a host-specific physiological response at the gastrointestinal barrier including a decrease in barrier permeability in BALB/c mice and alterations in the expression of barrier regulating genes in both strains. Genera Parabacteroides and Bacteroides were associated with changes in barrier function.

Conclusions: The results of this study provide insight into how specific taxa influence gut barrier integrity and function. More generally, these data in the context of recent published studies makes a significant contribution to our understanding of host-microbe interactions providing new knowledge that can be harnessed by us and others in future mechanistic studies.
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http://dx.doi.org/10.1007/s00213-019-05218-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599184PMC
May 2019

Symptomatic and Functional Outcomes and Early Prediction of Response to Escitalopram Monotherapy and Sequential Adjunctive Aripiprazole Therapy in Patients With Major Depressive Disorder: A CAN-BIND-1 Report.

J Clin Psychiatry 2019 02 5;80(2). Epub 2019 Feb 5.

Members of the CAN-BIND Investigator Team are listed at www.canbind.ca/our-team/..

Objective: To report the symptomatic and functional outcomes in patients with major depressive disorder (MDD) during a 2-phase treatment trial and to estimate the value of early improvement after 2 weeks in predicting clinical response to escitalopram and subsequently to adjunctive treatment with aripiprazole.

Methods: Participants with MDD (N = 211) identified with the Montgomery-Asberg Depression Rating Scale (MADRS) and confirmed with the Mini-International Neuropsychiatric Interview were recruited from 6 outpatient centers across Canada (August 2013 through December 2016) and treated with open-label escitalopram (10-20 mg) for 8 weeks (Phase 1). Clinical and functional outcomes were evaluated using the MADRS, Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), Sheehan Disability Scale (SDS), and Lam Employment Absence and Productivity Scale (LEAPS). Participants were evaluated at 8 and 16 weeks for clinical and functional response and remission. Phase 1 responders continued escitalopram while nonresponders received adjunctive aripiprazole (2-10 mg) for a further 8 weeks (Phase 2).

Results: After Phase 1, MADRS response (≥ 50% decrease from baseline) and remission (score ≤ 10) were, respectively, 47% and 31%, and SDS response (score ≤ 12) and remission (score ≤ 6) were, respectively, 53% and 24%. Response to escitalopram was maintained in 91% of participants at week 16, while 61% of the adjunctive aripiprazole group achieved MADRS response during Phase 2. Response and remission rates with the QIDS-SR were lower than with the MADRS. The LEAPS demonstrated significant occupational improvement (P < .05). Early symptomatic improvement predicted outcomes with modest accuracy.

Conclusions: This study demonstrates comparable symptomatic and functional outcomes to those of other large practical-design studies. There was a high response rate with the adjunctive use of aripiprazole in escitalopram nonresponders. Given the limited value of early clinical improvement to predict outcome, integration of clinical and biological markers deserves further exploration.

Trial Registration: ClinicalTrials.gov identifier: NCT01655706.
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http://dx.doi.org/10.4088/JCP.18m12202DOI Listing
February 2019

The Canadian Biomarker Integration Network in Depression (CAN-BIND): magnetic resonance imaging protocols

J Psychiatry Neurosci 2019 07;44(4):223-236

From the Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Alta., Canada (MacQueen, Hassel, Addington, Sharma); the Rotman Research Institute, Baycrest, and Department of Medical Biophysics, University of Toronto, Toronto, Ont., Canada (Arnott, Zamyadi, Strother); the Department of Psychology, Queen’s University, Kingston, Ont., Canada (Bowie, Harkness, Milev); the Department of Radiology, University of Calgary, Calgary, Alta., Canada (Bray, Lebel); the Alberta Children’s Hospital Research Institute, Calgary, Alta., Canada (Bray, Lebel); the Child and Adolescent Imaging Research (CAIR) Program, Calgary, Alta., Canada (Bray, Lebel); the Department of Psychology, Neuroscience and Behaviour, McMaster University, and St. Joseph’s Healthcare Hamilton, Hamilton, Ont., Canada (Hall); the Krembil Research Institute and Centre for Mental Health, University Health Network, Toronto, Ont., Canada (Downar); the Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ont., Canada (Downar); the Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ont., Canada (Downar, Müller, Rizvi, Rotzinger, Kennedy); the Department of Psychiatry, Krembil Research Centre, University Health Network, University of Toronto, Toronto, Ont., Canada (Foster, Rotzinger, Kennedy); the Department of Psychiatry and Behavioural Neurosciences, McMaster University, and St. Joseph’s Healthcare Hamilton, Hamilton, Ont., Canada (Foster, Frey); the Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, Ont., Canada (Goldstein); the Departments of Psychiatry and Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Ont., Canada (Goldstein); the Department of Computer Science, University of Alberta, Edmonton, Alta., Canada (Harris); the University of British Columbia and Vancouver Coastal Health Authority, Vancouver, B.C., Canada (Lam, Vila-Rodriguez); the Department of Psychiatry, Queen’s University and Providence Care Hospital, Kingston, Ont., Canada (Milev, Soares); the Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ont., Canada (Müller); the Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA (Parikh); the Arthur Sommer Rotenberg Suicide and Depression Studies Program, Li Ka Shing Knowledge Institute and St. Michael’s Hospital, Toronto, Ont., Canada (Rizvi); the Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ont., Canada (Rizvi); the Department of Psychiatry, St. Michael’s Hospital, University of Toronto, Toronto, Ont., Canada (Rotzinger, Soares, Yu); McGill University, Montréal, Que., Canada (Turecki); the Douglas Mental Health University Institute, Frank B. Common, Montréal, Que., Canada (Turecki); and the Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ont., Canada (Kennedy).

Studies of clinical populations that combine MRI data generated at multiple sites are increasingly common. The Canadian Biomarker Integration Network in Depression (CAN-BIND; www.canbind.ca) is a national depression research program that includes multimodal neuroimaging collected at several sites across Canada. The purpose of the current paper is to provide detailed information on the imaging protocols used in a number of CAN-BIND studies. The CAN-BIND program implemented a series of platform-specific MRI protocols, including a suite of prescribed structural and functional MRI sequences supported by real-time monitoring for adherence and quality control. The imaging data are retained in an established informatics and databasing platform. Approximately 1300 participants are being recruited, including almost 1000 with depression. These include participants treated with antidepressant medications, transcranial magnetic stimulation, cognitive behavioural therapy and cognitive remediation therapy. Our ability to analyze the large number of imaging variables available may be limited by the sample size of the substudies. The CAN-BIND program includes a multimodal imaging database supported by extensive clinical, demographic, neuropsychological and biological data from people with major depression. It is a resource for Canadian investigators who are interested in understanding whether aspects of neuroimaging — alone or in combination with other variables — can predict the outcomes of various treatment modalities.
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http://dx.doi.org/10.1503/jpn.180036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606427PMC
July 2019

The Effects of Probiotics on Symptoms of Depression: Protocol for a Double-Blind Randomized Placebo-Controlled Trial.

Neuropsychobiology 2020 13;79(1):108-116. Epub 2019 Feb 13.

Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.

Background: A growing body of evidence has linked mental health outcomes to the gut microbiome. This has led to the investigation of the GI tract as a target for novel treatments and interventions for depression, including probiotic supplementation. Our recent pilot study provided the first evidence of probiotics improving symptoms of depression in treatment-naive depressed patients. To further support and expand upon this evidence, data from the pilot study were used to plan a 16-week, double-blind, randomized, placebo-controlled trial to assess the effects of probiotics on depression. Here, we report the protocol for this trial.

Methods: Participants diagnosed with depression will orally consume a probiotic supplement containing Lactobacillus helveticus and Bifidobacterium longum or placebo once daily. Participants will undergo assessments measuring clinical outcomes using a battery of validated clinical scales and questionnaires. Sleep architecture and quality will be measured using polysomnography. Neuroimaging data will be collected using magnetic resonance imaging to examine functional and structural neurophysiological changes. Molecular data will be collected from blood, stool, and urine samples to examine cytokine levels and explore potential genes and proteins that may predict outcomes in depression.

Results: We expect results to replicate and expand on our pilot data demonstrating that probiotics may be effective in alleviating symptoms of depression, and to find biomarkers that will predict these outcomes.

Conclusions: The findings from this study will add to the growing body of research in this emerging field, which eventually may provide evidence for probiotics having a role in alleviating symptoms of depression.
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http://dx.doi.org/10.1159/000496406DOI Listing
November 2020

A pilot dose finding study of pioglitazone in autistic children.

Mol Autism 2018 26;9:59. Epub 2018 Nov 26.

1Holland Bloorview Kids Rehabilitation Hospital, University of Toronto, 150 Kilgour Road, Toronto, ON M4G 1R8 Canada.

Background: Pioglitazone is a promising compound for treatment of core autism spectrum disorder (ASD) symptoms as it targets multiple relevant pathways, including immune system alterations.

Objective: This pilot study aimed to elucidate the maximum tolerated dose, safety, preliminary evidence of efficacy, and appropriate outcome measures in autistic children ages 5-12 years old.

Methods: We conducted a 16-week prospective cohort, single blind, single arm, 2-week placebo run-in, dose-finding study of pioglitazone. Twenty-five participants completed treatment. A modified dose finding method was used to determine safety and dose response among three dose levels: 0.25 mg/kg, 0.5 mg/kg, and 0.75 mg/kg once daily.

Results: there were no serious adverse events (SAEs) and as such the maximum tolerated dose within the range tested was 0.75 mg/Kg once daily. overall, pioglitazone was well tolerated. Two participants discontinued intervention due to perceived non-efficacy and one due to the inability to tolerate interim blood work. Three participants experienced mild neutropenia. statistically significant improvement was observed in social withdrawal, repetitive behaviors, and externalizing behaviors as measured by the Aberrant Behavior Checklist (ABC), Child Yale-Brown Obsessive Compulsive Scale (CY-BOCS), and Repetitive Behavior Scale-Revised (RBS-R). Forty-six percent of those enrolled were deemed to be global responders.

Conclusions And Relevance: Pioglitazone is well-tolerated and shows a potential signal in measures of social withdrawal, repetitive, and externalizing behaviors. Randomized controlled trials using the confirmed dose are warranted.

Trial Registration: ClinicalTrials.gov, NCT01205282. Registration date: September 20, 2010.
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http://dx.doi.org/10.1186/s13229-018-0241-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258310PMC
January 2019

Metabolic and Microbiota Measures as Peripheral Biomarkers in Major Depressive Disorder.

Front Psychiatry 2018 22;9:513. Epub 2018 Oct 22.

Department of Psychiatry & Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.

Advances in understanding the role of the microbiome in physical and mental health are at the forefront of medical research and hold potential to have a direct impact on precision medicine approaches. In the past 7 years, we have studied the role of microbiota-brain communication on behavior in mouse models using germ-free mice, mice exposed to antibiotics, and healthy specific pathogen free mice. Through our work and that of others, we have seen an amazing increase in our knowledge of how bacteria signal to the brain and the implications this has for psychiatry. Gut microbiota composition and function are influenced both by genetics, age, sex, diet, life experiences, and many other factors of psychiatric and bodily disorders and thus may act as potential biomarkers of the gut-brain axis that could be used in psychiatry and co-morbid conditions. There is a particular need in major depressive disorder and other mental illness to identify biomarkers that can stratify patients into more homogeneous groups to provide better treatment and for development of new therapeutic approaches. Peripheral outcome measures of host-microbe bidirectional communication have significant translational value as biomarkers. Enabling stratification of clinical populations, based on individual biological differences, to predict treatment response to pharmacological and non-pharmacological interventions. Here we consider the links between co-morbid metabolic syndrome and depression, focusing on biomarkers including leptin and ghrelin in combination with assessing gut microbiota composition, as a potential tool to help identify individual differences in depressed population.
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http://dx.doi.org/10.3389/fpsyt.2018.00513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204462PMC
October 2018

Mouse MRI shows brain areas relatively larger in males emerge before those larger in females.

Nat Commun 2018 07 5;9(1):2615. Epub 2018 Jul 5.

Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, M5T 3H7, Canada.

Sex differences exist in behaviors, disease and neuropsychiatric disorders. Sexual dimorphisms however, have yet to be studied across the whole brain and across a comprehensive time course of postnatal development. Here, we use manganese-enhanced MRI (MEMRI) to longitudinally image male and female C57BL/6J mice across 9 time points, beginning at postnatal day 3. We recapitulate findings on canonically dimorphic areas, demonstrating MEMRI's ability to study neuroanatomical sex differences. We discover, upon whole-brain volume correction, that neuroanatomical regions larger in males develop earlier than those larger in females. Groups of areas with shared sexually dimorphic developmental trajectories reflect behavioral and functional networks, and expression of genes involved with sex processes. Also, post-pubertal neuroanatomy is highly individualized, and individualization occurs earlier in males. Our results demonstrate the ability of MEMRI to reveal comprehensive developmental differences between male and female brains, which will improve our understanding of sex-specific predispositions to various neuropsychiatric disorders.
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http://dx.doi.org/10.1038/s41467-018-04921-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033927PMC
July 2018

GWAS-based machine learning approach to predict duloxetine response in major depressive disorder.

J Psychiatr Res 2018 04 2;99:62-68. Epub 2018 Feb 2.

Department of Molecular Medicine, Queen's University, Kingston, ON, Canada.

Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders and is commonly treated with antidepressant drugs. However, large variability is observed in terms of response to antidepressants. Machine learning (ML) models may be useful to predict treatment outcomes. A sample of 186 MDD patients received treatment with duloxetine for up to 8 weeks were categorized as "responders" based on a MADRS change >50% from baseline; or "remitters" based on a MADRS score ≤10 at end point. The initial dataset (N = 186) was randomly divided into training and test sets in a nested 5-fold cross-validation, where 80% was used as a training set and 20% made up five independent test sets. We performed genome-wide logistic regression to identify potentially significant variants related to duloxetine response/remission and extracted the most promising predictors using LASSO regression. Subsequently, classification-regression trees (CRT) and support vector machines (SVM) were applied to construct models, using ten-fold cross-validation. With regards to response, none of the pairs performed significantly better than chance (accuracy p > .1). For remission, SVM achieved moderate performance with an accuracy = 0.52, a sensitivity = 0.58, and a specificity = 0.46, and 0.51 for all coefficients for CRT. The best performing SVM fold was characterized by an accuracy = 0.66 (p = .071), sensitivity = 0.70 and a sensitivity = 0.61. In this study, the potential of using GWAS data to predict duloxetine outcomes was examined using ML models. The models were characterized by a promising sensitivity, but specificity remained moderate at best. The inclusion of additional non-genetic variables to create integrated models may improve prediction.
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http://dx.doi.org/10.1016/j.jpsychires.2017.12.009DOI Listing
April 2018

Effects of exercise and enrichment on behaviour in CD-1 mice.

Behav Brain Res 2018 04 12;342:43-50. Epub 2018 Jan 12.

Psychiatry and Behavioural Neuroscience, McMaster University, Hamilton, Ontario, Canada; Department of Psychiatry, St. Michael's Hospital, Toronto, Ontario, Canada. Electronic address:

A host of scholarly work has characterized the positive effects of exercise and environmental enrichment on behaviour and cognition in animal studies. The purpose of this study was to investigate the uptake and longitudinal impact of exercise and enrichment on the behavioural phenotype of male and female CD-1 mice. CD-1 mice housed in standard (STD) or exercise and enrichment (EE) conditions post-weaning were tested in the 3-chamber sociability test, open field, and elevated plus maze and exercise activity was monitored throughout the enrichment protocol. Male and female EE mice both showed reduced anxiety and activity in the open field and elevated plus maze relative to sex-matched STD mice. EE altered social behaviours in a sex-specific fashion, with only female EE mice showing increased social preference relative to female STD mice and a preference for social novelty only present in male EE mice. This sexual dimorphism was not observed to be a product of exercise uptake, as CD-1 mice of both sexes demonstrated a consistent trend of wheel rotation frequencies. These findings suggest the importance of considering variables such as sex and strain on experimental design variables in future work on environmental enrichment.
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http://dx.doi.org/10.1016/j.bbr.2018.01.007DOI Listing
April 2018

Stress & the gut-brain axis: Regulation by the microbiome.

Neurobiol Stress 2017 Dec 19;7:124-136. Epub 2017 Mar 19.

APC Microbiome Institute, University College Cork, Cork, Ireland.

The importance of the gut-brain axis in regulating stress-related responses has long been appreciated. More recently, the microbiota has emerged as a key player in the control of this axis, especially during conditions of stress provoked by real or perceived homeostatic challenge. Diet is one of the most important modifying factors of the microbiota-gut-brain axis. The routes of communication between the microbiota and brain are slowly being unravelled, and include the vagus nerve, gut hormone signaling, the immune system, tryptophan metabolism, and microbial metabolites such as short chain fatty acids. The importance of the early life gut microbiota in shaping later health outcomes also is emerging. Results from preclinical studies indicate that alterations of the early microbial composition by way of antibiotic exposure, lack of breastfeeding, birth by Caesarean section, infection, stress exposure, and other environmental influences - coupled with the influence of host genetics - can result in long-term modulation of stress-related physiology and behaviour. The gut microbiota has been implicated in a variety of stress-related conditions including anxiety, depression and irritable bowel syndrome, although this is largely based on animal studies or correlative analysis in patient populations. Additional research in humans is sorely needed to reveal the relative impact and causal contribution of the microbiome to stress-related disorders. In this regard, the concept of psychobiotics is being developed and refined to encompass methods of targeting the microbiota in order to positively impact mental health outcomes. At the 2016 Neurobiology of Stress Workshop in Newport Beach, CA, a group of experts presented the symposium "The Microbiome: Development, Stress, and Disease". This report summarizes and builds upon some of the key concepts in that symposium within the context of how microbiota might influence the neurobiology of stress.
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http://dx.doi.org/10.1016/j.ynstr.2017.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736941PMC
December 2017

The comparative effectiveness of electroencephalographic indices in predicting response to escitalopram therapy in depression: A pilot study.

J Affect Disord 2018 02 3;227:542-549. Epub 2017 Nov 3.

Department of Psychiatry, University of Toronto, Toronto, Canada; Department of Psychiatry, University Health Network, Toronto, Canada; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada.

Background: This study aims to compare the effectiveness of EEG frequency band activity including interhemispheric asymmetry and prefrontal theta cordance in predicting response to escitalopram therapy at 8-weeks post-treatment, in a multi-site initiative.

Methods: Resting state 64-channel EEG data were recorded from 44 patients with a diagnosis of major depressive disorder (MDD) as part of a larger, multisite discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). Clinical response was measured at 8-weeks post-treatment as change from baseline Montgomery-Asberg Depression Rating Scale (MADRS) score of 50% or more. EEG measures were analyzed at (1) pre-treatment baseline (2) 2 weeks post-treatment and (3) as an ''early change" variable defined as change in EEG from baseline to 2 weeks post-treatment.

Results: At baseline, treatment responders showed elevated absolute alpha power in the left hemisphere while non-responders showed the opposite. Responders further exhibited a cortical asymmetry in the parietal region. Groups also differed in pre-treatment relative delta power with responders showing greater power in the right hemisphere over the left while non-responders showed the opposite. At 2 weeks post-treatment, responders exhibited greater absolute beta power in the left hemisphere relative to the right and the opposite was noted for non-responders. A reverse pattern was noted for absolute and relative delta power at 2 weeks post-treatment. Responders exhibited early reductions in relative alpha power and early increments in relative theta power. Non-responders showed a significant early increase in prefrontal theta cordance.

Conclusions: Hemispheric asymmetries in the alpha and delta bands at baseline and at 2 weeks post-treatment have moderately strong predictive utility in predicting response to antidepressant treatment.
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http://dx.doi.org/10.1016/j.jad.2017.10.028DOI Listing
February 2018

Targeting the Microbiome for Mental Health: Hype or Hope?

Authors:
Jane A Foster

Biol Psychiatry 2017 10;82(7):456-457

Department of Psychiatry & Behavioural Neurosciences, St. Joseph's Healthcare, Hamilton, Ontario, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2017.08.002DOI Listing
October 2017