Publications by authors named "Elisa Brietzke"

259 Publications

Why do medications with little or no efficacy continue to be prescribed in the management of patients with bipolar disorder?

Bipolar Disord 2021 Jul 23. Epub 2021 Jul 23.

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

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http://dx.doi.org/10.1111/bdi.13114DOI Listing
July 2021

The importance of countertransference in the clinical care of individuals during acute phases of bipolar disorder.

Bipolar Disord 2021 Jul 3. Epub 2021 Jul 3.

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

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http://dx.doi.org/10.1111/bdi.13111DOI Listing
July 2021

Consensus on nomenclature for clinical staging models in bipolar disorder: A narrative review from the International Society for Bipolar Disorders (ISBD) Staging Task Force.

Bipolar Disord 2021 Jun 26. Epub 2021 Jun 26.

St. Joseph's Healthcare Hamilton McMaster University, Hamilton, ON, Canada.

Objectives: Clinical staging is widely used in medicine to map disease progression, inform prognosis, and guide treatment decisions; in psychiatry, however, staging remains a hypothetical construct. To facilitate future research in bipolar disorders (BD), a well-defined nomenclature is needed, especially since diagnosis is often imprecise with blurred boundaries, and a full understanding of pathophysiology is lacking.

Methods: Under the auspices of the International Society of Bipolar Disorders, a Task Force of international experts was convened to review, discuss, and integrate findings from the scientific literature relevant to the development of a consensus staging model and standardize a terminology that could be used to advance future research including staging of BD and related disorders.

Results: Consensus opinion and areas of uncertainty or difference were identified in regard to terms referring to staging as it may apply to BD, to at-risk status and subthreshold stages, and to various clinical stages of BD as it is currently diagnosed.

Conclusion: The use of a standardized nomenclature about the clinical stages of BD will facilitate communication about research on clinical and pathological components of this heterogeneous group of disorders. The concepts presented are based on current evidence, but the template provided allows for further refinements as etiological advances come to light.
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http://dx.doi.org/10.1111/bdi.13105DOI Listing
June 2021

Telomere shortening in late-life depression: A potential marker of depression severity.

Brain Behav 2021 Aug 21;11(8):e2255. Epub 2021 Jun 21.

Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada.

Objectives: Telomeres are structures at the extremity of chromosomes that prevents genomic instability, and its shortening seems to be a hallmark of cellular aging. Past studies have shown contradictory results of telomere length (TL) in major depression, and are a few studies in late-life depression (LLD). This explores the association between TL as a molecular marker of aging and diagnosis of LLD, the severity of depressive symptoms, and cognitive performance in older adults.

Methods/design: We included 78 older adults (45 with LLD and 33 nondepressed controls, according to DSM-V criteria), aged 60-90 years. TL was measured in leukocytes by a quantitative polymerase chain reaction, determining the relative ratio (T/S) between the telomere region copy number (T) and a single copy gene (S), using a relative standard curve.

Results: TL was significantly shorter in the LLD compared with control participants (p = .039). Comparing groups through the severity of depressive symptoms, we found a negative correlation with the severity of depressive symptoms (Hamilton Depression Rating Scale-21, r = -0.325, p = .004) and medical burden (r = -0.271, p = .038). There was no significant correlation between TL and cognitive performance (Mattis Dementia Rating Scale, r = 0.152, p = .21).

Conclusions: We found that older adults with LLD have shorter telomere than healthy controls, especially those with a more severe depressive episode. Our findings suggest that shorter TL can be a marker of the severity of depressive episodes in older adults and indicate that these individuals may be at higher risk of age-associated adverse outcomes linked to depression.
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http://dx.doi.org/10.1002/brb3.2255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413729PMC
August 2021

Telomere shortening in late-life depression: A potential marker of depression severity.

Brain Behav 2021 Aug 21;11(8):e2255. Epub 2021 Jun 21.

Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada.

Objectives: Telomeres are structures at the extremity of chromosomes that prevents genomic instability, and its shortening seems to be a hallmark of cellular aging. Past studies have shown contradictory results of telomere length (TL) in major depression, and are a few studies in late-life depression (LLD). This explores the association between TL as a molecular marker of aging and diagnosis of LLD, the severity of depressive symptoms, and cognitive performance in older adults.

Methods/design: We included 78 older adults (45 with LLD and 33 nondepressed controls, according to DSM-V criteria), aged 60-90 years. TL was measured in leukocytes by a quantitative polymerase chain reaction, determining the relative ratio (T/S) between the telomere region copy number (T) and a single copy gene (S), using a relative standard curve.

Results: TL was significantly shorter in the LLD compared with control participants (p = .039). Comparing groups through the severity of depressive symptoms, we found a negative correlation with the severity of depressive symptoms (Hamilton Depression Rating Scale-21, r = -0.325, p = .004) and medical burden (r = -0.271, p = .038). There was no significant correlation between TL and cognitive performance (Mattis Dementia Rating Scale, r = 0.152, p = .21).

Conclusions: We found that older adults with LLD have shorter telomere than healthy controls, especially those with a more severe depressive episode. Our findings suggest that shorter TL can be a marker of the severity of depressive episodes in older adults and indicate that these individuals may be at higher risk of age-associated adverse outcomes linked to depression.
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http://dx.doi.org/10.1002/brb3.2255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413729PMC
August 2021

Government response moderates the mental health impact of COVID-19: A systematic review and meta-analysis of depression outcomes across countries.

J Affect Disord 2021 07 27;290:364-377. Epub 2021 May 27.

Mood Disorders Psychopharmacology Unit, Toronto Western Hospital, University Health Network, Toronto, ON, Canada M5T 2S8; Institute of Medical Science, University of Toronto, Toronto, ON, Canada M5S 1A8; Department of Psychiatry, University of Toronto, Toronto, ON, Canada M5S 1A8; Department of Pharmacology, University of Toronto, Toronto, ON, Canada M5S 1A8.

Background: The COVID-19 pandemic represents a public health, economic and mental health crisis. We hypothesized that timely government implementation of stringent measures to reduce viral transmission would benefit mental health, as evidenced by reduced rates of depressive symptoms (i.e., Patient Health Questionnaire [PHQ]-9≥10, PHQ-2≥3).

Methods: The systematic review herein (PROSPERO CRD42020200647) evaluated to what extent differences in government-imposed stringency and timeliness of response to COVID-19 moderate the prevalence of depressive symptoms across 33 countries (k=114, N=640,037). We included data from six lower-middle-income countries, nine upper-middle-income countries, and 18 higher-income countries. Government-imposed stringency and timeliness in response were operationalized using the Oxford COVID-19 Government Response ("Stringency") Index.

Results: The overall proportion of study participants with clinically significant depressive symptoms was 21.39% (95% CI 19.37-23.47). The prevalence of clinically significant depressive symptoms was significantly lower in countries wherein governments implemented stringent policies promptly. The moderating effect of government response remained significant after including the national frequency of COVID cases at the time of study commencement, Healthcare Access and Quality index, and the inclusion of COVID patients in the study.

Limitations: Factors that may have confounded our results include, for example, differences in lockdown duration, lack of study participant and outcome assessor blinding, and retrospective assessment of depressive symptom severity.

Conclusions: Governments that enacted stringent measures to contain the spread of COVID-19 benefited not only the physical, but also the mental health of their population.
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http://dx.doi.org/10.1016/j.jad.2021.04.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159271PMC
July 2021

Government response moderates the mental health impact of COVID-19: A systematic review and meta-analysis of depression outcomes across countries.

J Affect Disord 2021 07 27;290:364-377. Epub 2021 May 27.

Mood Disorders Psychopharmacology Unit, Toronto Western Hospital, University Health Network, Toronto, ON, Canada M5T 2S8; Institute of Medical Science, University of Toronto, Toronto, ON, Canada M5S 1A8; Department of Psychiatry, University of Toronto, Toronto, ON, Canada M5S 1A8; Department of Pharmacology, University of Toronto, Toronto, ON, Canada M5S 1A8.

Background: The COVID-19 pandemic represents a public health, economic and mental health crisis. We hypothesized that timely government implementation of stringent measures to reduce viral transmission would benefit mental health, as evidenced by reduced rates of depressive symptoms (i.e., Patient Health Questionnaire [PHQ]-9≥10, PHQ-2≥3).

Methods: The systematic review herein (PROSPERO CRD42020200647) evaluated to what extent differences in government-imposed stringency and timeliness of response to COVID-19 moderate the prevalence of depressive symptoms across 33 countries (k=114, N=640,037). We included data from six lower-middle-income countries, nine upper-middle-income countries, and 18 higher-income countries. Government-imposed stringency and timeliness in response were operationalized using the Oxford COVID-19 Government Response ("Stringency") Index.

Results: The overall proportion of study participants with clinically significant depressive symptoms was 21.39% (95% CI 19.37-23.47). The prevalence of clinically significant depressive symptoms was significantly lower in countries wherein governments implemented stringent policies promptly. The moderating effect of government response remained significant after including the national frequency of COVID cases at the time of study commencement, Healthcare Access and Quality index, and the inclusion of COVID patients in the study.

Limitations: Factors that may have confounded our results include, for example, differences in lockdown duration, lack of study participant and outcome assessor blinding, and retrospective assessment of depressive symptom severity.

Conclusions: Governments that enacted stringent measures to contain the spread of COVID-19 benefited not only the physical, but also the mental health of their population.
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http://dx.doi.org/10.1016/j.jad.2021.04.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159271PMC
July 2021

Is Obesity A Determinant Of Success With Pharmacological Treatment For Depression? A Systematic Review, Meta-Analysis And Meta-Regression.

J Affect Disord 2021 05 15;287:54-68. Epub 2021 Mar 15.

Mood Disorders Psychopharmacology Unit (MDPU), Toronto Western Hospital, University Health Network, Toronto, ON, Canada.

Background: The bidirectional association between Major Depressive Disorder (MDD) and obesity suggests that body mass index (BMI) at the baseline could influence remission rates (RR) with pharmacological treatment. We evaluated the influence of baseline BMI on the chances of remission among patients with MDD administered antidepressants.

Methods: Based on the guidelines of the PRISMA statement, we conducted a systematic review on PubMed, Cochrane and Embase databases with subsequent meta-analysis and meta-regression. We included only randomized controlled trials evaluating the efficacy of antidepressants of different classes (monotherapy and combined therapies) that evidenced baseline BMI assessment. We created a model to describe the linear relationship between baseline BMI and RR.

Results: Our systematic review yielded 70 studies with a total of 9,779 patients in the active group and 7,136 patients in the placebo group. In placebo controlled studies, BMI influenced the RR of patients randomized to active treatment. The RR for antidepressants in monotherapy was higher in normal weight to overweight patients rather than obese patients (33% vs 12%, respectively). Also in monotherapy, the RR is higher when the study is conducted on patients with a lower baseline BMI (p=0.029). For combined therapies, the pooled RR was higher in obese patients rather than in normal weight to overweight patients (75% vs 17%, respectively).

Limitations: BMI provides no information about body composition and obesity can be related to several potential confounders that potentially influence RR.

Conclusion: The RR with antidepressant therapy seems to be associated with baseline BMI in patients with MDD, although this simple variable was insufficiently explored so far.
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http://dx.doi.org/10.1016/j.jad.2021.03.032DOI Listing
May 2021

Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation.

Am J Psychiatry 2021 05 17;178(5):383-399. Epub 2021 Mar 17.

Mood Disorders Psychopharmacology Unit, University Health Network, Toronto (McIntyre, Rosenblat, Y. Lee, Lui, Mansur); Department of Psychiatry, University of Toronto, Toronto (McIntyre, Rosenblat, Mansur); Department of Pharmacology, University of Toronto, Toronto (McIntyre); Brain and Cognition Discovery Foundation, Toronto (McIntyre, Subramaniapillai); Canadian Rapid Treatment Center of Excellence, Mississauga, Ontario (Rosenblat, Kratiuk); Department of Psychiatry and Behavioral Sciences, Austin Dell Medical School, University of Texas, Austin (Nemeroff); Department of Psychiatry, Yale University School of Medicine, New Haven, Conn. (Sanacora); Depression and Anxiety Center for Discovery and Treatment, Department of Psychiatry, and Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York (Murrough); Deakin University, Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia (Berk, Dodd); Orygen, National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, University of Melbourne, Melbourne, Australia (Berk); Department of Psychiatry, Queen's University School of Medicine, and Centre for Neuroscience Studies, Queen's University, Kingston, Ontario (Brietzke); Centre for Youth Mental Health and Department of Psychiatry, University of Melbourne, Melbourne, Australia (Dodd); Université de Paris, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, and GHU Paris Psychiatrie et Neurosciences, CMME, Hôpital Sainte-Anne, Paris (Gorwood); Department of Psychological Medicine, Yong Loo Lin School of Medicine, and Institute of Health Innovation and Technology, National University of Singapore, Singapore (Ho); Department of Psychiatry, NYU School of Medicine, and Clinical Research Division, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York (Iosifescu); Department of Psychiatry, Universidad de Antioquia, Medellin, Colombia (Lopez Jaramillo); Center for Brain Research, Medical University of Vienna, Vienna (Kasper); Department of Clinical Immunology, Poznan University of Medical Sciences, Poznan, Poland (Kratiuk); Department of Psychiatry, College of Medicine, Haeundae Paik Hospital, Paik Institute for Clinical Research, and Department of Health Science and Technology, Graduate School, Inje University, Busan, Republic of Korea (J.G. Lee); Institute of Medical Science, University of Toronto, Toronto (Y. Lee); Clinical Trials Network and Institute, Massachusetts General Hospital, Boston (Papakostas); Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, and Corporal Michael J. Crescenz VA Medical Center, Philadelphia (Thase); Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona (Vieta); Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London and South London, and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Beckenham, Kent (Young); Experimental Therapeutics and Pathophysiology Branch and Section on the Neurobiology and Treatment of Mood Disorders, Division of Intramural Research Program, NIMH, Bethesda, Md. (Zarate); Department of Psychiatry and Neuroscience, University of California, Riverside, and University of California, San Diego (Stahl).

Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.
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http://dx.doi.org/10.1176/appi.ajp.2020.20081251DOI Listing
May 2021

Peripheral inflammatory biomarkers define biotypes of bipolar depression.

Mol Psychiatry 2021 Mar 3. Epub 2021 Mar 3.

Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada.

We identified biologically relevant moderators of response to tumor necrosis factor (TNF)-α inhibitor, infliximab, among 60 individuals with bipolar depression. Data were derived from a 12-week, randomized, placebo-controlled clinical trial secondarily evaluating the efficacy of infliximab on a measure of anhedonia (i.e., Snaith-Hamilton Pleasure Scale). Three inflammatory biotypes were derived from peripheral cytokine measurements using an iterative, machine learning-based approach. Infliximab-randomized participants classified as biotype 3 exhibited lower baseline concentrations of pro- and anti-inflammatory cytokines and soluble TNF receptor-1 and reported greater pro-hedonic improvements, relative to those classified as biotype 1 or 2. Pretreatment biotypes also moderated changes in neuroinflammatory substrates relevant to infliximab's hypothesized mechanism of action. Neuronal origin-enriched extracellular vesicle (NEV) protein concentrations were reduced to two factors using principal axis factoring: phosphorylated nuclear factorκB (p-NFκB), Fas-associated death domain (p-FADD), and IκB kinase (p-IKKα/β) and TNF receptor-1 (TNFR1) comprised factor "NEV1," whereas phosphorylated insulin receptor substrate-1 (p-IRS1), p38 mitogen-activated protein kinase (p-p38), and c-Jun N-terminal kinase (p-JNK) constituted "NEV2". Among infliximab-randomized subjects classified as biotype 3, NEV1 scores were decreased at weeks 2 and 6 and increased at week 12, relative to baseline, and NEV2 scores increased over time. Decreases in NEV1 scores and increases in NEV2 scores were associated with greater reductions in anhedonic symptoms in our classification and regression tree model (r = 0.22, RMSE = 0.08). Our findings provide preliminary evidence supporting the hypothesis that the pro-hedonic effects of infliximab require modulation of multiple TNF-α signaling pathways, including NF-κB, IRS1, and MAPK.
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http://dx.doi.org/10.1038/s41380-021-01051-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413393PMC
March 2021

Clinical effectiveness of non-TMS neurostimulation in depression: Clinical trials from 2010 to 2020.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Aug 19;110:110287. Epub 2021 Feb 19.

Department of Psychiatry and Centre for Neuroscience Studies, Queen's University, Kingston, Canada.

Objective: Treatment for major depressive disorder (MDD) have evolved, although there is still a strong unmet need for more effective and tolerable options. The present study summarizes and discusses recent evidence regarding the non-transcranial magnetic stimulation (non-TMS) neurostimulation treatment for MDD.

Methods: The authors reviewed non-TMS neurostimulation clinical trials for MDD between 2010 and 2020. Electroconvulsive therapy was not included in this review. A systematic review was performed in MEDLINE database through PubMed, the Cochrane Collaboration's Clinical Trials Register (CENTRAL), PsycINFO and Thomson Reuters's Web of Science.

Results: Only 20 articles met the inclusion criteria. Randomized controlled trials demonstrated efficacy of transcranial direct current stimulation (tDCS) in five of seven trials. tDCS augmented with sertraline, fluoxetine, citalopram and escitalopram was superior to placebo and to tDCS only. A comparative trial demonstrated that the duration of tDCS sessions can modulate the effectiveness of this treatment. Open trials indicated that deep brain stimulation, epidural cortical stimulation, trigeminal nerve stimulation, magnetic seizure therapy and vagus nerve stimulation may be effective in treatment-resistant depression.

Conclusion: This review confirmed the efficacy of tDCS in MDD. Despite new evidence showing effectiveness for other non-TMS neurostimulation, their effectiveness is still unclear. Non-TMS neurostimulation RCTs with large samples and head-to-head studies comparing non-TMS neurostimulation and gold standard pharmacological treatments are still lacking.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110287DOI Listing
August 2021

Ecological momentary assessment of depressive symptoms using the mind.me application: Convergence with the Patient Health Questionnaire-9 (PHQ-9).

J Psychiatr Res 2021 03 11;135:311-317. Epub 2021 Jan 11.

Mind Mental Health Technologies Inc., Montreal, QC, Canada.

Ecological momentary assessment (EMA) for mental disorders, using application-based (app) technology capable of passive and ambient data collection, has been insufficiently evaluated and validated with rigorous, adequately-powered, high-quality studies. Herein, we sought to validate the mind.me application for the assessment of depressive symptoms in adults. Adults (ages 18-65) who self-identified as having clinically significant depressive symptoms [i.e. Patient Health Questionnaire 9 (PHQ-9) ≥ 5] utilized the mind.me app-a mobile phone technology that collects data passively and continuously, and is capable of integrating broad multimodal data [e.g., location variance (e.g. GPS), behavioural (e.g. social network activity), and communication data (e.g. SMS texting, phone calls)]. The primary outcome was predictive accuracy (i.e. convergent validity with depressive symptom measurement, as captured by the PHQ-9). 200 subjects were enrolled in the study (mean age 46 ± 12.71). The average PHQ-9 score was 12.8 ± 6.9. The predictive accuracy of the mind.me app was 0.91 ± 0.06. The sensitivity was 0.98 and the specificity was 0.93. The mind.me app was rated by 200 users as highly usable and informative to their illness. The mind.me app exhibits robust predictive accuracy in detecting depressive symptoms in adults with clinically relevant depressive symptoms. The mind.me app more specifically demonstrates convergence with the PHQ-9.
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http://dx.doi.org/10.1016/j.jpsychires.2021.01.012DOI Listing
March 2021

Exploring brain insulin resistance in adults with bipolar depression using extracellular vesicles of neuronal origin.

J Psychiatr Res 2021 01 4;133:82-92. Epub 2020 Dec 4.

Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

Accumulating evidence suggests that disrupted insulin signaling is involved in bipolar disorder (BD) pathogenesis. Herein, we aimed to directly explore the potential role of neuronal insulin signaling using an innovative technique based on biomarkers derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We leveraged plasma samples from a randomized, double-blind, placebo-controlled, 12-week clinical trial evaluating infliximab as a treatment of bipolar depression. We isolated NEVs using immunoprecipitation against neuronal marker L1CAM from samples collected at baseline and weeks 2, 6 and 12 (endpoint) and measured NEV biomarkers using immunoassays. We assessed neuronal insulin signaling at its first node (IRS-1) and along the canonical (Akt, GSK-3β, p70S6K) and alternative (ERK1/2, JNK and p38-MAPK) pathways. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging (MRI) at baseline and endpoint. Pre-treatment, NEV biomarkers of insulin signaling were independently associated with cognitive function and MRI measures (i.e. hippocampal and ventromedial prefrontal cortex [vmPFC] volumes). In fact, the association between IRS-1 phosphorylation at serine site 312 (pS312-IRS-1), an indicator of insulin resistance, and cognitive dysfunction was mediated by vmPFC volume. In the longitudinal analysis, patients treated with infliximab, a tumor necrosis factor-alpha antagonist with known insulin sensitizing properties, compared to those treated with placebo, had augmented phosphorylation of proteins from the alternative pathway. Infliximab responders had significant increases in phosphorylated JNK levels, relative to infliximab non-responders and placebo responders. In addition, treatment with infliximab resulted in increase in MRI measures of brain volume; treatment-related changes in the dorsolateral prefrontal cortex volume were mediated by changes in biomarkers from the insulin alternative pathway. In conclusion, our findings support the idea that brain insulin signaling is a target for further mechanistic and therapeutic investigations.
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http://dx.doi.org/10.1016/j.jpsychires.2020.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855678PMC
January 2021

Effects of infliximab on brain neurochemistry of adults with bipolar depression.

J Affect Disord 2021 02 3;281:61-66. Epub 2020 Dec 3.

Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

Objectives: To explore the relationship between inflammation and neuronal metabolism in bipolar disorder (BD) by evaluating the neurochemical effects of the tumor necrosis factor-α (TNF-α) antagonist infliximab among individuals with bipolar depression METHODS: This is a post-hoc, exploratory analysis from a 12-week, randomized, double-blind, placebo-controlled trial with infliximab for adults with bipolar depression. We assessed the effects of infliximab on concentration of metabolites in the prefrontal cortex, using proton-magnetic resonance spectroscopy (H-MRS), as well as its association with clinical outcomes (i.e. depressive symptom severity and cognitive function).

Results: Eighteen participants in the placebo and 15 in the infliximab group were included in this analysis. In the pre-specified primary outcome, there were no significant effects of treatment on prefrontal concentrations of N-acetylaspartate (NAA; p = 0.712). In the secondary analyses, there was a significant treatment by time interaction for glutamate (Glx; p = 0.018), indicating that Glx levels decreased in infliximab-treated patients, relative to placebo. Treatment group significantly moderated the association between changes in Glx levels and changes in a neurocognitive test (i.e. Digit Symbol Substitution Test; p = 0.014), indicating that in infliximab-treated participants reductions in Glx were associated with cognitive improvement.

Conclusions: Treatment with infliximab did not affect prefrontal NAA concentration in adults with BD. Exploratory analysis suggested a potential effect of treatment on the glutamate system, a finding that should be confirmed and validated by additional studies.
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http://dx.doi.org/10.1016/j.jad.2020.11.128DOI Listing
February 2021

Using the Online Psychotherapy Tool to Address Mental Health Problems in the Context of the COVID-19 Pandemic: Protocol for an Electronically Delivered Cognitive Behavioral Therapy Program.

JMIR Res Protoc 2020 Dec 18;9(12):e24913. Epub 2020 Dec 18.

Department of Psychiatry, Faculty of Health Sciences, Queen's University, Kingston, ON, Canada.

Background: The considerable rise of mental health challenges during the COVID-19 pandemic has had detrimental effects on the public health sector and economy. To meet the overwhelming and growing demand for mental health care, innovative approaches must be employed to significantly expand mental health care delivery capacity. Although it is not feasible to increase the number of mental health care providers or hours they work in the short term, improving their time efficiency may be a viable solution. Virtually and digitally delivering psychotherapy, which has been shown to be efficient and clinically effective, might be a good method for addressing this growing demand.

Objective: This research protocol aims to evaluate the feasibility and efficacy of using an online, digital, asynchronous care model to treat mental health issues that are started or aggravated by stressors associated with the COVID-19 pandemic.

Methods: This nonrandomized controlled trial intervention will be delivered through the Online Psychotherapy Tool, a secure, cloud-based, digital mental health platform. Participants will be offered a 9-week electronically delivered cognitive behavioral therapy program that is tailored to address mental health problems in the context of the COVID-19 pandemic. This program will involve weekly self-guided educational material that provides an overview of behavioral skills and weekly homework. Participants (N=80) will receive personalized feedback from and weekly interaction with a therapist throughout the course of the program. The efficacy of the program will be evaluated using clinically validated symptomology questionnaires, which are to be completed by participants at baseline, week 5, and posttreatment. Inclusion criteria includes the capacity to consent; a primary diagnosis of generalized anxiety disorder or major depressive disorder, with symptoms that started or worsened during the COVID-19 pandemic; the ability to speak and read English; and consistent and reliable access to the internet. Exclusion criteria includes active psychosis, acute mania, severe alcohol or substance use disorder, and active suicidal or homicidal ideation.

Results: This study received funding in May 2020. Ethics approval was received in June 2020. The recruitment of participants began in June 2020. Participant recruitment is being conducted via social media, web-based communities, and physician referrals. To date, 58 participants have been recruited (intervention group: n=35; control group: n=23). Data collection is expected to conclude by the end of 2020. Analyses (ie, linear regression analysis for continuous outcomes and binomial regression analysis for categorical outcomes) are expected to be completed by February 2021.

Conclusions: If proven feasible, this care delivery method could increase care capacity by up to fourfold. The findings from this study can potentially influence clinical practices and policies and increase accessibility to care during the COVID-19 pandemic, without sacrificing the quality of care.

Trial Registration: ClinicalTrials.gov NCT04476667; https://clinicaltrials.gov/ct2/show/NCT04476667.

International Registered Report Identifier (irrid): DERR1-10.2196/24913.
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http://dx.doi.org/10.2196/24913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752186PMC
December 2020

Using the Online Psychotherapy Tool to Address Mental Health Problems in the Context of the COVID-19 Pandemic: Protocol for an Electronically Delivered Cognitive Behavioral Therapy Program.

JMIR Res Protoc 2020 Dec 18;9(12):e24913. Epub 2020 Dec 18.

Department of Psychiatry, Faculty of Health Sciences, Queen's University, Kingston, ON, Canada.

Background: The considerable rise of mental health challenges during the COVID-19 pandemic has had detrimental effects on the public health sector and economy. To meet the overwhelming and growing demand for mental health care, innovative approaches must be employed to significantly expand mental health care delivery capacity. Although it is not feasible to increase the number of mental health care providers or hours they work in the short term, improving their time efficiency may be a viable solution. Virtually and digitally delivering psychotherapy, which has been shown to be efficient and clinically effective, might be a good method for addressing this growing demand.

Objective: This research protocol aims to evaluate the feasibility and efficacy of using an online, digital, asynchronous care model to treat mental health issues that are started or aggravated by stressors associated with the COVID-19 pandemic.

Methods: This nonrandomized controlled trial intervention will be delivered through the Online Psychotherapy Tool, a secure, cloud-based, digital mental health platform. Participants will be offered a 9-week electronically delivered cognitive behavioral therapy program that is tailored to address mental health problems in the context of the COVID-19 pandemic. This program will involve weekly self-guided educational material that provides an overview of behavioral skills and weekly homework. Participants (N=80) will receive personalized feedback from and weekly interaction with a therapist throughout the course of the program. The efficacy of the program will be evaluated using clinically validated symptomology questionnaires, which are to be completed by participants at baseline, week 5, and posttreatment. Inclusion criteria includes the capacity to consent; a primary diagnosis of generalized anxiety disorder or major depressive disorder, with symptoms that started or worsened during the COVID-19 pandemic; the ability to speak and read English; and consistent and reliable access to the internet. Exclusion criteria includes active psychosis, acute mania, severe alcohol or substance use disorder, and active suicidal or homicidal ideation.

Results: This study received funding in May 2020. Ethics approval was received in June 2020. The recruitment of participants began in June 2020. Participant recruitment is being conducted via social media, web-based communities, and physician referrals. To date, 58 participants have been recruited (intervention group: n=35; control group: n=23). Data collection is expected to conclude by the end of 2020. Analyses (ie, linear regression analysis for continuous outcomes and binomial regression analysis for categorical outcomes) are expected to be completed by February 2021.

Conclusions: If proven feasible, this care delivery method could increase care capacity by up to fourfold. The findings from this study can potentially influence clinical practices and policies and increase accessibility to care during the COVID-19 pandemic, without sacrificing the quality of care.

Trial Registration: ClinicalTrials.gov NCT04476667; https://clinicaltrials.gov/ct2/show/NCT04476667.

International Registered Report Identifier (irrid): DERR1-10.2196/24913.
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http://dx.doi.org/10.2196/24913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752186PMC
December 2020

The effect of transcranial direct current stimulation along with a hypocaloric diet on weight loss in excessive weight people: A pilot randomized clinical trial.

Clin Nutr ESPEN 2020 12 22;40:68-76. Epub 2020 Oct 22.

Universidade Federal do Rio Grande do Sul, Faculty of Medicine, Graduate Program in Medical Sciences: Endocrinology, Porto Alegre, Brazil; Division of Endocrinology and Metabolism, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. Electronic address:

Background & Aims: The dorsolateral prefrontal cortex plays an important role in the desire to eat and food intake regulation and may be a target for transcranial direct current stimulation (tDCS) to promote weight loss. Our aim was to test the effect of repeated, active tDCS along with a hypocaloric diet (HD) on weight loss in overweight adults.

Methods: This was a randomized, placebo-controlled, double-blind pilot study conducted in Porto Alegre, Brazil. Twenty-eight overweight adults were selected to receive 4-week (20 sessions, t0 to t20; 5 weekdays) fixed-dose tDCS along with an HD. Subjects were randomly assigned to active (AG) or sham (SG) tDCS groups. The primary outcome was weight loss as determined via body weight measurements at baseline (t0), weekly (t5, t10, t15, and t20), and after the intervention (tF). A visual analogue scale was used to assess desire to eat at t0 and at tF. Registered under ClinicalTrials.gov Identifier no. NCT02683902.

Results: Although there was a greater weight loss in the AG (mean -4.5 kg [95%CI: -9.4, 0.5]) than in the SG (-2.3 kg [-5.0, 0.3]), this difference was not statistically significant. However, the AG showed a significant reduction in the desire for sweet foods (P = 0.005).

Conclusions: Although this pilot study did not show that repeated tDCS is able to optimize weight loss, it was able to reduce the desire to eat sweet foods. These findings suggest that a protocol with a larger sample size could determine whether tDCS may be an adjunctive treatment of obesity.
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http://dx.doi.org/10.1016/j.clnesp.2020.10.005DOI Listing
December 2020

Development and implementation of guidelines for the management of depression: a systematic review.

Bull World Health Organ 2020 Oct 27;98(10):683-697H. Epub 2020 Aug 27.

School of Clinical Medicine, The University of Queensland, Brisbane, Australia.

Objective: To evaluate the development and implementation of clinical practice guidelines for the management of depression globally.

Methods: We conducted a systematic review of existing guidelines for the management of depression in adults with major depressive or bipolar disorder. For each identified guideline, we assessed compliance with measures of guideline development quality (such as transparency in guideline development processes and funding, multidisciplinary author group composition, systematic review of comparative efficacy research) and implementation (such as quality indicators). We compared guidelines from low- and middle-income countries with those from high-income countries.

Findings: We identified 82 national and 13 international clinical practice guidelines from 83 countries in 27 languages. Guideline development processes and funding sources were explicitly specified in a smaller proportion of guidelines from low- and middle-income countries (8/29; 28%) relative to high-income countries (35/58; 60%). Fewer guidelines (2/29; 7%) from low- and middle-income countries, relative to high-income countries (22/58; 38%), were authored by a multidisciplinary development group. A systematic review of comparative effectiveness was conducted in 31% (9/29) of low- and middle-income country guidelines versus 71% (41/58) of high-income country guidelines. Only 10% (3/29) of low- and middle-income country and 19% (11/58) of high-income country guidelines described plans to assess quality indicators or recommendation adherence.

Conclusion: Globally, guideline implementation is inadequately planned, reported and measured. Narrowing disparities in the development and implementation of guidelines in low- and middle-income countries is a priority. Future guidelines should present strategies to implement recommendations and measure feasibility, cost-effectiveness and impact on health outcomes.
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http://dx.doi.org/10.2471/BLT.20.251405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652558PMC
October 2020

The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder: Recommandations Du Groupe De Travail Du Réseau Canadien Pour Les Traitements De L'humeur Et De L'anxiété (Canmat) Concernant L'utilisation De La Kétamine Racémique Chez Les Adultes Souffrant De Trouble Dépressif Majeur.

Can J Psychiatry 2021 02 11;66(2):113-125. Epub 2020 Nov 11.

Department of Psychiatry, 8166University of British Columbia, Vancouver, British Columbia, Canada.

Objective: Patients with major depressive disorder often have limited response to first-line and second-line medications; hence, novel pharmacological treatments are needed for treatment-resistant depression (TRD). Ketamine, an -methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated rapid antidepressant effects in patients with TRD. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence for efficacy and safety of racemic ketamine and to provide recommendations for its use in clinical practice.

Methods: A systematic review was conducted with computerized search of electronic databases up to January 31, 2020 using combinations of search terms, inspection of bibliographies, and review of other ketamine guidelines and consensus statements. The level of evidence and lines of treatment were assigned according to CANMAT criteria. Recommendations were given in question-answer format.

Results: Intravenous (IV) racemic ketamine given as a single infusion has Level 1 evidence for efficacy in adults with TRD. The evidence for multiple infusions, given as an acute series or as ongoing maintenance treatment, is limited to Level 3. Adverse events associated with ketamine infusions include behavioral (e.g., dissociative symptoms) and physiological (e.g., hypertension) events. There is only Level 3 or 4 evidence for non-IV formulations of racemic ketamine. Consensus recommendations are given for clinical administration of IV ketamine including patient selection, facility and personnel issues, monitoring, and maintaining response.

Conclusions: Single-dose IV racemic ketamine is a third-line recommendation for adults with TRD. The need for repeated and maintenance ketamine infusions should be carefully assessed on a case-by-case basis with consideration of potential risks and benefits. Because of limited evidence for efficacy and risk for misuse and diversion, the use of oral and other formulations of racemic ketamine should be limited to specialists with ketamine-prescribing expertise and affiliations with tertiary or specialized centers.
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http://dx.doi.org/10.1177/0706743720970860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918868PMC
February 2021

Early symptomatic improvements as a predictor of response to repeated-dose intravenous ketamine: Results from the Canadian Rapid Treatment Center of Excellence.

Prog Neuropsychopharmacol Biol Psychiatry 2021 03 5;105:110126. Epub 2020 Oct 5.

Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network, Toronto, ON, Canada; Canadian Rapid Treatment Center of Excellence, Mississauga, ON, Canada; Brain and Cognition Discovery Foundation, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

Background: Early symptomatic improvement with monoamine-based antidepressants is predictive of treatment response. The objective of this study was to determine if early symptomatic improvements with intravenous (IV) ketamine predicted treatment response to an acute course of four infusions.

Method: 134 adults with treatment resistant depression (TRD) received four ketamine infusions over one to two weeks. Depressive symptoms were measured using the Quick Inventory for Depressive Symptomatology Self-Report (QIDS-SR) at baseline and post-infusions 1, 2, 3, and 4. Early improvement was defined as ≥20% reduction in QIDS-SR scores after the first or second infusion. Linear models were used to determine whether early improvement was associated with post-infusion 4 QIDS-SR scores after controlling for baseline characteristics.

Results: Early improvement post-infusion 1 (β = -3.52, 95% BCa CI [-5.40, -1.78]) and 2 (β = -3.16, 95% BCa CI [-5.75, -1.59]) both significantly predicted QIDS-SR scores post-infusion 4. Early improvers had significantly lower QIDS-SR scores at post-infusion 4 (post-infusion 1 improvers: M = 9.8, SD = 4.5; post-infusion 2 improvers: M = 10.6, SD = 5.7) compared to non-early improvers (post-infusion 1 non-improvers: M = 13.7, SD = 5.8; post-infusion 2 non-improvers: M = 14.1, SD = 5.3) when controlling for baseline characteristics. The majority (58%) of individuals who did not improve post-infusions 1 or 2 still experienced an antidepressant response or partial response (≥20% reduction in QIDS-SR) post-infusion 4.

Limitations: This is a post-hoc analysis of an open-label study.

Conclusion: Early improvement was associated with greater antidepressant effects following a course of four ketamine infusions. However, individuals who did not show early improvements still had a high likelihood of experiencing clinically significant symptom reduction after the fourth infusion, suggesting that completing four infusions, regardless of early symptom changes, is appropriate and merited.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110126DOI Listing
March 2021

Impairments in Peripheral Blood T Effector and T Regulatory Lymphocytes in Bipolar Disorder Are Associated with Staging of Illness and Anti-cytomegalovirus IgG Levels.

Mol Neurobiol 2021 Jan 11;58(1):229-242. Epub 2020 Sep 11.

Department of Psychiatry, Queen's University School of Medicine, 752 King Street West, Postal Bag 603, Kingston, ON, K7L7X3, Canada.

There is now evidence that, based on cytokine profiles, bipolar disorder (BD) is accompanied by simultaneous activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS), and that both components may be associated with the staging of illness. Nevertheless, no BD studies have evaluated the IRS/CIRS ratio using CD (cluster of differentiation) molecules expressed by peripheral blood activated T effector (Teff) and T regulatory (Treg) subpopulations. This study examined Teff/Treg subsets both before and after ex vivo anti-CD3/CD28 stimulation using flow cytometric immunophenotyping in 25 symptomatic remitted BD patients and 21 healthy controls and assessed human cytomegalovirus (HCMV)-specific IgG antibodies. BD is associated with a significantly lowered frequency of unstimulated CD3 + CD8 + CD71+ and CD4 + CD25 + FOXP3 and increased CD4 + CD25 + FOXP3 + CD152+ frequencies and with lowered stimulated frequencies of CD3 + CD8 + CD71+, CD4 + CD25 + FOXP3 + CD152+, and CD4 + CD25 + FOXP3 + GARP cells and, consequently, by an increased stimulated Teff/Treg ratio. Moreover, the number of manic, but not hypomanic or depressive episodes, is significantly and negatively associated with the stimulated proportions of CD3 + CD4 + CD154+, and CD69+ and CD71+ expression on CD4+ and CD8+ cells, while duration of illness (≥ 10 years) is accompanied by a depleted frequency of stimulated CD152+ Treg, and CD154+ and CD71+ CD4+ T cells. BD and anti-human cytomegalovirus (HCMV) IgG levels significantly interact to decrease the expression of CD4 + CD25 + FOXP+GARP T phenotypes. In conclusion, in BD patients, immune injuries, staging, and HCMV seropositivity interact and cause CIRS dysfunctions and exaggerated IRS responses, which play a key role in parainflammation and neuroaffective toxicity. HCMV seropositivity contributes to an immune-risk phenotype in BD.
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http://dx.doi.org/10.1007/s12035-020-02110-1DOI Listing
January 2021

Cannabis and Inflammatory Mediators.

Eur Addict Res 2021 29;27(1):16-24. Epub 2020 Jul 29.

Department of Psychiatry, Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil.

Introduction: Although the recreational cannabis use is expressive worldwide, the literature about medical potential of cannabis extracts, including its anti-inflammatory properties, remains inconclusive.

Methods: We screened all articles, published on the PubMed database, on inflammatory mediators and any information about cannabis use from 1980 to March 2019.

Results: Six studies were included, and the main findings were as follows: (i) among healthy volunteers and cannabis users, cannabinoids seemed to decrease the inflammatory response, thus decreasing the immune response, which led to a higher risk of infections; (ii) among patients with multiple sclerosis, cannabinoids seemed to have little impact on the inflammatory markers' levels.

Discussion: Although cannabis use can produce immune inflammatory suppression in healthy people, this effect is not robust enough to change inflammatory mediators' levels in situations of highly dysfunctional inflammatory activation. Nevertheless, the impact of cannabinoids in clinical outcomes of these conditions remains to be determined.
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http://dx.doi.org/10.1159/000508840DOI Listing
September 2021

Cannabis and Inflammatory Mediators.

Eur Addict Res 2021 29;27(1):16-24. Epub 2020 Jul 29.

Department of Psychiatry, Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil.

Introduction: Although the recreational cannabis use is expressive worldwide, the literature about medical potential of cannabis extracts, including its anti-inflammatory properties, remains inconclusive.

Methods: We screened all articles, published on the PubMed database, on inflammatory mediators and any information about cannabis use from 1980 to March 2019.

Results: Six studies were included, and the main findings were as follows: (i) among healthy volunteers and cannabis users, cannabinoids seemed to decrease the inflammatory response, thus decreasing the immune response, which led to a higher risk of infections; (ii) among patients with multiple sclerosis, cannabinoids seemed to have little impact on the inflammatory markers' levels.

Discussion: Although cannabis use can produce immune inflammatory suppression in healthy people, this effect is not robust enough to change inflammatory mediators' levels in situations of highly dysfunctional inflammatory activation. Nevertheless, the impact of cannabinoids in clinical outcomes of these conditions remains to be determined.
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http://dx.doi.org/10.1159/000508840DOI Listing
September 2021

Corrigendum to "Applications of machine learning algorithms to predict therapeutic outcomes in depression: A meta-analysis and systematic review." J Affect Disord. 241 (2018) 519-532.

J Affect Disord 2020 Sep 30;274:1211-1215. Epub 2020 Apr 30.

Institute of Medical Science, University of Toronto, Toronto, Canada; Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Canada; Brain and Cognition Discovery Foundation, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada; Department of Pharmacology, University of Toronto, Toronto, Canada. Electronic address:

The authors regret an error in one of the extracted data points in the meta-analysis. The classification accuracy for Serretti et al. (2007) was corrected to 64% (Table 3b). The overall results before and after this correction remain directionally consistent and are summarized below (Figures 2 and 3; Table 2; results subsection 3.6). The authors apologise for any inconvenience caused.
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http://dx.doi.org/10.1016/j.jad.2020.02.037DOI Listing
September 2020

Leptin mediates improvements in cognitive function following treatment with infliximab in adults with bipolar depression.

Psychoneuroendocrinology 2020 10 20;120:104779. Epub 2020 Jun 20.

Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

A potential role for leptin in the pathophysiology of bipolar disorder (BD) has been proposed. We recently investigated the effects of the tumor necrosis factor-alpha (TNF-α) antagonist infliximab in individuals with bipolar depression. Leptin is known to interact with the TNF-α system. Herein, we aimed to explore infliximab's effects on leptin and its relationship with brain structure and function. Sixty adults with bipolar depression were enrolled in this randomized, double-blind, 12-week clinical trial of adjunctive infliximab (n = 29) and saline control (n = 31), which were administered intravenously at weeks 0, 2, and 6. Plasma concentrations of leptin, TNF-α and soluble TNF receptors (sTNFR) 1 and 2 were assessed at weeks 0, 2, 6, and 12. We observed a significant decrease in leptin levels in infliximab-treated patients, relative to placebo. Infliximab treatment also significantly reduced TNF-α and sTNFR2, but not sTNFR1 levels. Changes in sTNR2 levels at week 6 significantly determined changes in leptin at week 12 in infliximab-, but not placebo-treated participants. Improvements in verbal memory and increases in global cortical volume were associated with reduction in leptin levels in the treatment group. Mediation analysis indicated that cognitive improvement in infliximab-treated patients was mediated by reductions in leptin levels, which in its turn were determined by decreases in sTNR2 levels. In conclusion, infliximab treatment reduced plasma leptin levels in individuals with BD, through modulation of sTNFR2. Decreases in leptin signaling were associated with an increase in global cortical volume and better performance in a verbal memory task.
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http://dx.doi.org/10.1016/j.psyneuen.2020.104779DOI Listing
October 2020

The potential anti-depressant properties of dexmedetomidine infusion: a review of mechanistic, preclinical, and clinical evidence.

Rev Neurosci 2020 Aug;31(6):649-658

Department of Psychiatry, Queens University School of Medicine, 752 King Street West, Postal Bag 603, Kingston, ONK7L 7X3, Canada.

Major depressive disorder (MDD) is a highly prevalent and disabling condition for which the currently available treatments are not fully effective. Existing unmet needs include rapid onset of action and optimal management of concurrent agitation. Dexmedetomidine (DEX) is a selective and potent α2-adrenergic receptor (α2-AR) agonist, with unique pharmacokinetic and pharmacodynamic properties. In this review, we discuss pre-clinical and clinical studies which focused on DEX in the context of its putative antidepressant effects for the management of MDD. Preliminary data support DEX as an antidepressant with fast onset of action, which would be especially helpful for patients experiencing treatment resistant depression, and agitation. We further explore the mechanistic and clinical implications of considering DEX as a putative antidepressant agent, and the next steps to explore the efficacy of low dose DEX infusion among patients with treatment resistant depression.
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http://dx.doi.org/10.1515/revneuro-2020-0001DOI Listing
August 2020

Caloric restriction, resting metabolic rate and cognitive performance in Non-obese adults: A post-hoc analysis from CALERIE study.

J Psychiatr Res 2020 09 25;128:16-22. Epub 2020 May 25.

Mood Disorders Psychopharmacology Unit, Toronto Western Hospital, University Health Network, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada. Electronic address:

Physical activity (PA) has been proposed as a determinant of cognitive function and is one component of energy balance (EB). EB is the difference between energy intake (EI) and the total daily energy expenditure (TDEE). TDEE is a combination of resting metabolic rate (RMR), thermic effect of food and PA. The potential role of each of these components on cognitive function has not yet been systemically investigated. We aim to evaluate the association between each component of EB on cognition, using baseline and longitudinal data from a clinical trial of caloric restriction (CR). This is a parallel-group, randomized clinical trial comparing two years of 25% CR with two years of ad libitum diet (AL), with 220 healthy volunteers of both sex, aged between 21 and 50 years and initial BMI ≥ 22 kg/m2 and <28 kg/m2. Body weight, fat mass (FM), fat-free mass (FFM), and bone mineral content were evaluated, as well as RMR, TDEE, cognitive performance and baseline energy intake. A 30 min/day of a moderate level on a minimum of 5 days/week was advised as PA measure. Longitudinal analysis demonstrated that the influence of CR in the improvement of cognitive performance was moderated by changes in RMR, suggesting that in individuals submitted to CR, the cognitive performance and the RMR improved proportionally, independently of changes in EI and body mass. EB and homeostasis are crucial to modulate the RMR. Moreover, RMR presents an important influence on cognitive function in individuals submitted to CR in a long term.
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http://dx.doi.org/10.1016/j.jpsychires.2020.05.018DOI Listing
September 2020

Allostatic load, emotional hyper-reactivity, and functioning in individuals with bipolar disorder.

Bipolar Disord 2020 11 16;22(7):711-721. Epub 2020 May 16.

Institut Pasteur, Unité Perception et Mémoire, Paris, France.

Objectives: Diagnosis and management of bipolar disorder (BD) are limited by the absence of available biomarkers. Allostatic load (AL) represents the strain that stress, including the effects of acute phases and inter-episode chronic mood instability, exerts on interconnected biological systems. This study aimed to operationalize an AL index and explore whether it could be relevant to better characterize BD patients with and without emotional hyper-reactivity particularly those at higher risk of immune-cardiometabolic dysregulation and functional impairment.

Methods: Levels of biomarkers of chronic inflammation (hsCRP and albumin), cardiovascular (systolic/diastolic blood pressure) and metabolic functions (fasting glucose, glycosylated hemoglobin, total cholesterol, LDL, HDL, and triglycerides) were measured in 1072 adult BD outpatients. Patients were classified in two groups (with/without emotional hyper-reactivity) assessed by the Multidimensional Assessment of Thymic States scale. An Allostatic Load Index for BD (BALLI), comprising six biomarkers, was constructed using data-driven biomarker selection.

Results: BALLI showed 81.1% accuracy with good sensitivity (81%) and specificity (81.2%) for characterizing BD patients presenting emotional hyper-reactivity, elevated risk of inflammation (increased hsCRP, hypoalbuminemia) and cardiometabolic disturbances (hypertension, hyperglycemia, and hypertriglyceridemia). Patients classified by the BALLI as presenting emotional hyper-reactivity had significantly lower global and cognitive functioning than those without emotional hyper-reactivity (P < .0001).

Conclusions: A multidimensional approach based on a simple AL score (eg, BALLI) and dimensions of behavior (eg, emotional hyper-reactivity) alongside mood is clinically relevant. AL index could be a useful tool to detect multisystemic physiological dysregulations in BD patients with/without emotional hyper-reactivity particularly those at higher risk of immune-cardiometabolic disturbances and functional impairment.
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http://dx.doi.org/10.1111/bdi.12927DOI Listing
November 2020

Exploring the mechanisms of action of the antidepressant effect of the ketogenic diet.

Rev Neurosci 2020 08;31(6):637-648

Department of Psychiatry, Queen's University School of Medicine, 752 King Street West, K7L7X3, Kingston, ON, Canada.

The ketogenic diet (KD) is characterized by a diet ratio of 4:1 fat to non-fat energy sources. For decades KD has been successfully used to control seizures in epilepsy patients. Investigations into its mechanism of action suggest that it may have an effect on the metabolic, nervous, immune, and digestive systems. In this review, we postulate that KD may also improve depressive symptoms - for that, we highlight the similarities between depression and epilepsy, describe the extent to which body systems involved in both conditions are affected by the KD, and ultimately hypothesize how KD could improve MDD outcomes. Research into animal models and human patients have reported that KD can increase mitochondrial biogenesis and increase cellular resistance to oxidative stress both at the mitochondrial and genetic levels. Its effect on neurotransmitters alters cell-to-cell communication in the brain and may decrease hyperexcitability by increasing Gamma Aminobutyric Acid (GABA) and decreasing excitatory neurotransmitter levels. Its anti-inflammatory effects are mediated by decreasing chemo- and cytokine levels, including TNF-alpha and IL-1 levels. Finally, KD can alter gut microbiota (GM). Certain strains of microbiota predominate in major depressive disorder (MDD) when compared to healthy individuals. Recent evidence points to Bacteroidetes as a potential treatment predictor as it seems to increase in KD treatment responders for epilepsy. Each of these observations contributes to the presumed modulatory effects of KD on mood and supports its potential role as antidepressant.
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http://dx.doi.org/10.1515/revneuro-2019-0073DOI Listing
August 2020

Efficacy of adjunctive infliximab vs. placebo in the treatment of anhedonia in bipolar I/II depression.

Brain Behav Immun 2020 08 4;88:631-639. Epub 2020 May 4.

Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada. Electronic address:

We investigated the efficacy of tumour necrosis factor (TNF)-α antagonist infliximab on a measure of anhedonia amongst individuals with bipolar I/II depression (ClinicalTrials.gov identifier NCT02363738). Adults (ages 18-65) with bipolar I/II disorder currently experiencing a major depressive episode with a higher probability of inflammatory activity (i.e., meeting one or more of the following inflammatory/metabolic criteria: obesity and dyslipidemia/hypertension, daily cigarette smoking, diabetes mellitus, migraine, inflammatory bowel disease, and/or C-reactive protein level of ⩾5 mg/L) were enrolled in a double-blind, 12-week clinical trial of adjunctive infliximab (5 mg/kg) and saline control, which were administered at weeks 0, 2, and 6. The primary outcome measure for the present secondary analysis was change in the Snaith-Hamilton Pleasure Scale (SHAPS) total score between placebo- and infliximab-treated subjects from baseline to weeks 6 and 12. Plasma concentrations of TNF-α and soluble TNF receptors (sTNFR) 1 and 2 were assessed at weeks 0, 2, 6, and 12. Sixty eligible adults received treatment with infliximab (n=29) or placebo (n=31); 47 subjects completed the study (infliximab: n=21, placebo: n=26). Overall, infliximab-randomized subjects exhibited significantly larger increases in SHAPS total score, denoting greater reductions in anhedonic symptoms, when compared to placebo-randomized subjects (treatment × time interaction effect: χ=7.15,df=2,p=0.03). Anti-anhedonic efficacy was moderated by baseline plasma levels of TNF-α and sTNFR1, but not by changes in TNF-α or sTNFR1 concentrations. Baseline and changes in sTNFR2 concentrations did not moderate anti-anhedonic efficacy. Infliximab significantly improved a measure of anhedonia relative to placebo in adults with bipolar I/II depression at week 6; intervention efficacy was not sustained 6 weeks after the final infusion.
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http://dx.doi.org/10.1016/j.bbi.2020.04.063DOI Listing
August 2020
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