801 results on '"Benoit H. Mulsant"'
Search Results
2. Multidimensional analysis of heart rate variability and burden of illness in bipolar disorder
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Abigail Ortiz, Milos Milic, Marcos Sanches, M. Ishrat Husain, Benoit H. Mulsant, and Daniel Felsky
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Heart rate variability ,Burden of illness ,Bipolar disorder ,Canonical correlation ,Psychiatry ,RC435-571 - Abstract
Introduction: Patients with bipolar disorder (BD) face disproportionate rates of cardiovascular disease. While several mechanisms have been proposed for this association, both are multifactorial and heterogeneous illnesses, and it is unlikely that any individual factor can account for a significant portion of their association. Potential mediators have been mostly studied in isolation even though they are interrelated. Furthermore, few studies have accounted for baseline cardiovascular functioning or burden of illness. Methods: We sought to analyze the association between burden of illness, phase of the illness (e.g., depressive) and heart rate variability (HRV) in 48 patients diagnosed with BD using canonical correlation analysis. We hypothesized that the association between burden of illness and HRV measures would be different depending on the clinical phase (i.e., euthymia, depression or (hypo)mania). Results: A longer duration of (hypo)manic episodes was associated with higher rates of hypertension and increased sympathetic activation, along with lower rates of migraine and family history of suicide. In the second canonical variable, a later age at onset of (hypo)manic episodes was associated with higher parasympathetic activity. Limitations: Small sample size; while the magnitudes of correlations for these top functions were large, none of the models were statistically significant. Conclusions: There are different dimensions to the association between burden of illness and HRV in BD. The first dimension could comprise higher sympathetic activation in the context of longer (hypo)manic episodes, with lower rates for clinical variables that have been associated with a predominant depressive polarity (e.g., family history of suicide and migraine).
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- 2024
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3. Cognitive function based on theta-gamma coupling vs. clinical diagnosis in older adults with mild cognitive impairment with or without major depressive disorder
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Heather Brooks, Wei Wang, Reza Zomorrodi, Daniel M. Blumberger, Christopher R. Bowie, Zafiris J. Daskalakis, Corinne E. Fischer, Alastair J. Flint, Nathan Herrmann, Sanjeev Kumar, Krista L. Lanctôt, Linda Mah, Benoit H. Mulsant, Bruce G. Pollock, Aristotle N. Voineskos, Tarek K. Rajji, and the PACt-MD Study Group
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract Whether individuals with mild cognitive impairment (MCI) and a history of major depressive disorder (MDD) are at a higher risk for cognitive decline than those with MCI alone is still not clear. Previous work suggests that a reduction in prefrontal cortical theta phase-gamma amplitude coupling (TGC) is an early marker of cognitive impairment. This study aimed to determine whether using a TGC cutoff is better at separating individuals with MCI or MCI with remitted MDD (MCI+rMDD) on cognitive performance than their clinical diagnosis. Our hypothesis was that global cognition would differ more between TGC-based groups than diagnostic groups. We analyzed data from 128 MCI (mean age: 71.8, SD: 7.3) and 85 MCI+rMDD (mean age: 70.9, SD: 4.7) participants. Participants completed a comprehensive neuropsychological battery; TGC was measured during the N-back task. An optimal TGC cutoff was determined during the performance of the 2-back. This TGC cutoff was used to classify participants into low vs. high-TGC groups. We then compared Cohen’s d of the difference in global cognition between the high and low TGC groups to Cohen’s d between the MCI and MCI+rMDD groups. We used bootstrapping to determine 95% confidence intervals for Cohen’s d values using the whole sample. As hypothesized, Cohen’s d for the difference in global cognition between the TGC groups was larger (0.64 [0.32, 0.88]) than between the diagnostic groups (0.10 [0.004, 0.37]) with a difference between these two Cohen’s d’s of 0.54 [0.10, 0.80]. Our findings suggest that TGC is a useful marker to identify individuals at high risk for cognitive decline, beyond clinical diagnosis. This could be due to TGC being a sensitive marker of prefrontal cortical dysfunction that would lead to an accelerated cognitive decline.
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- 2024
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4. Protocol for an economic evaluation of scalable strategies to improve mental health among perinatal women: non-specialist care delivered via telemedicine vs. specialist care delivered in-person
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Daisy R. Singla, Claire de Oliveira, Sean M. Murphy, Vikram Patel, Jaime Charlebois, Wendy N. Davis, Cindy-Lee Dennis, J. Jo Kim, Paul Kurdyak, Andrea Lawson, Samantha Meltzer-Brody, Benoit H. Mulsant, Nour Schoueri-Mychasiw, Richard K. Silver, Dana Tschritter, Simone N. Vigod, and Sarah Byford
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Economic evaluation ,Protocol ,Perinatal mental health ,Randomized controlled trial ,Psychiatry ,RC435-571 - Abstract
Abstract Background Perinatal depression affects an estimated 1 in 5 women in North America during the perinatal period, with annualized lifetime costs estimated at $20.6 billion CAD in Canada and over $45.9 billion USD in the US. Access to psychological treatments remains limited for most perinatal women suffering from depression and anxiety. Some barriers to effective care can be addressed through task-sharing to non-specialist providers and through telemedicine platforms. The cost-effectiveness of these strategies compared to traditional specialist and in-person models remains unknown. This protocol describes an economic evaluation of non-specialist providers and telemedicine, in comparison to specialist providers and in-person sessions within the ongoing Scaling Up Maternal Mental healthcare by Increasing access to Treatment (SUMMIT) trial. Methods The economic evaluation will be undertaken alongside the SUMMIT trial. SUMMIT is a pragmatic, randomized, non-inferiority trial across five North American study sites (N = 1,226) of the comparable effectiveness of two types of providers (specialist vs. non-specialist) and delivery modes (telemedicine vs. in-person) of a behavioural activation treatment for perinatal depressive and anxiety symptoms. The primary economic evaluation will be a cost-utility analysis. The outcome will be the incremental cost-effectiveness ratio, which will be expressed as the additional cost required to achieve an additional quality-adjusted life-year, as assessed by the EuroQol 5-Dimension 5-Level instrument. A secondary cost-effectiveness analysis will use participants’ depressive symptom scores. A micro-costing analysis will be conducted to estimate the resources/costs required to implement and sustain the interventions; healthcare resource utilization will be captured via self-report. Data will be pooled and analysed using uniform price and utility weights to determine cost-utility across all trial sites. Secondary country-specific cost-utility and cost-effectiveness analyses will also be completed. Sensitivity analyses will be conducted, and cost-effectiveness acceptability-curves will be generated, in all instances. Discussion Results of this study are expected to inform key decisions related to dissemination and scale up of evidence-based psychological interventions in Canada, the US, and possibly worldwide. There is potential impact on real-world practice by informing decision makers of the long-term savings to the larger healthcare setting in services to support perinatal women with common mental health conditions.
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- 2023
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5. Brain-cognition relationships in late-life depression: a systematic review of structural magnetic resonance imaging studies
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Tulip Marawi, Nicholas J. Ainsworth, Peter Zhukovsky, Neda Rashidi-Ranjbar, Tarek K. Rajji, Maria Carmela Tartaglia, Aristotle N. Voineskos, and Benoit H. Mulsant
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract Background Most patients with late-life depression (LLD) have cognitive impairment, and at least one-third meet diagnostic criteria for mild cognitive impairment (MCI), a prodrome to Alzheimer’s dementia (AD) and other neurodegenerative diseases. However, the mechanisms linking LLD and MCI, and brain alterations underlying impaired cognition in LLD and LLD + MCI remain poorly understood. Methods To address this knowledge gap, we conducted a systematic review of studies of brain-cognition relationships in LLD or LLD + MCI to identify circuits underlying impaired cognition in LLD or LLD + MCI. We searched MEDLINE, PsycINFO, EMBASE, and Web of Science databases from inception through February 13, 2023. We included studies that assessed cognition in patients with LLD or LLD + MCI and acquired: (1) T1-weighted imaging (T1) measuring gray matter volumes or thickness; or (2) diffusion-weighted imaging (DWI) assessing white matter integrity. Due to the heterogeneity in studies, we only conducted a descriptive synthesis. Results Our search identified 51 articles, resulting in 33 T1 studies, 17 DWI studies, and 1 study analyzing both T1 and DWI. Despite limitations, reviewed studies suggest that lower thickness or volume in the frontal and temporal regions and widespread lower white matter integrity are associated with impaired cognition in LLD. Lower white matter integrity in the posterior cingulate region (precuneus and corpus callosum sub-regions) was more associated with impairment executive function and processing speed than with memory. Conclusion Future studies should analyze larger samples of participants with various degrees of cognitive impairment and go beyond univariate statistical models to assess reliable brain-cognition relationships in LLD.
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- 2023
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6. Beta to theta power ratio in EEG periodic components as a potential biomarker in mild cognitive impairment and Alzheimer’s dementia
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Hamed Azami, Christoph Zrenner, Heather Brooks, Reza Zomorrodi, Daniel M. Blumberger, Corinne E. Fischer, Alastair Flint, Nathan Herrmann, Sanjeev Kumar, Krista Lanctôt, Linda Mah, Benoit H. Mulsant, Bruce G. Pollock, Tarek K. Rajji, and on behalf of the PACt-MD Study Group
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Alzheimer’s dementia ,Mild cognitive impairment ,EEG ,Periodic EEG power components ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Alzheimer’s dementia (AD) is associated with electroencephalography (EEG) abnormalities including in the power ratio of beta to theta frequencies. EEG studies in mild cognitive impairment (MCI) have been less consistent in identifying such abnormalities. One potential reason is not excluding the EEG aperiodic components, which are less associated with cognition than the periodic components. Here, we investigate whether aperiodic and periodic EEG components are disrupted differently in AD or MCI vs. healthy control (HC) individuals and whether a periodic based beta/theta ratio differentiates better MCI from AD and HC groups than a ratio based on the full spectrum. Methods Data were collected from 44 HC (mean age (SD) = 69.1 (5.3)), 114 MCI (mean age (SD) = 72.2 (7.5)), and 41 AD (mean age (SD) = 75.7 (6.5)) participants. Aperiodic and periodic components and full spectrum EEG were compared among the three groups. Receiver operating characteristic curves obtained via logistic regression classifications were used to distinguish the groups. Last, we explored the relationships between cognitive performance and the beta/theta ratios based on the full or periodic spectrum. Results Aperiodic EEG components did not differ among the three groups. In contrast, AD participants showed an increase in full spectrum and periodic relative powers for delta, theta, and gamma and a decrease for beta when compared to HC or MCI participants. As predicted, MCI group differed from HC participants on the periodic based beta/theta ratio (Bonferroni corrected p-value = 0.036) measured over the occipital region. Classifiers based on beta/theta power ratio in EEG periodic components distinguished AD from HC and MCI participants, and outperformed classifiers based on beta/theta power ratio in full spectrum EEG. Beta/theta ratios were comparable in their association with cognition. Conclusions In contrast to a full spectrum EEG analysis, a periodic-based analysis shows that MCI individuals are different on beta/theta ratio when compared to healthy individuals. Focusing on periodic components in EEG studies with or without other biological markers of neurodegenerative diseases could result in more reliable findings to separate MCI from healthy aging, which would be valuable for designing preventative interventions.
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- 2023
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7. Exploratory genome-wide analyses of cortical inhibition, facilitation, and plasticity in late-life depression
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Rafae A. Wathra, Xiaoyu Men, Samar S. M. Elsheikh, Victoria S. Marshe, Tarek K. Rajji, Jennifer I. Lissemore, Benoit H. Mulsant, Jordan F. Karp, Charles F. Reynolds, Eric J. Lenze, Zafiris J. Daskalakis, Daniel J. Müller, and Daniel M. Blumberger
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract Late-life depression (LLD) is a heterogenous mood disorder influenced by genetic factors. Cortical physiological processes such as cortical inhibition, facilitation, and plasticity may be markers of illness that are more strongly associated with genetic factors than the clinical phenotype. Thus, exploring the relationship between genetic factors and these physiological processes may help to characterize the biological mechanisms underlying LLD and improve diagnosis and treatment selection. Transcranial magnetic stimulation (TMS) combined with electromyography was used to measure short interval intracortical inhibition (SICI), cortical silent period (CSP), intracortical facilitation (ICF), and paired associative stimulation (PAS) in 79 participants with LLD. We used exploratory genome-wide association and gene-based analyses to assess for genetic correlations of these TMS measures. MARK4 (which encodes microtubule affinity-regulating kinase 4) and PPP1R37 (which encodes protein phosphatase 1 regulatory subunit 37) showed genome-wide significant association with SICI. EGFLAM (which encodes EGF-like fibronectin type III and laminin G domain) showed genome-wide significant association with CSP. No genes met genome-wide significant association with ICF or PAS. We observed genetic influences on cortical inhibition in older adults with LLD. Replication with larger sample sizes, exploration of clinical phenotype subgroups, and functional analysis of relevant genotypes is warranted to better characterize genetic influences on cortical physiology in LLD. This work is needed to determine whether cortical inhibition may serve as a biomarker to improve diagnostic precision and guide treatment selection in LLD.
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- 2023
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8. Predictors of adherence to electronic self-monitoring in patients with bipolar disorder: a contactless study using Growth Mixture Models
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Abigail Ortiz, Yunkyung Park, Christina Gonzalez-Torres, Martin Alda, Daniel M. Blumberger, Rachael Burnett, M. Ishrat Husain, Marcos Sanches, and Benoit H. Mulsant
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Bipolar disorder ,Adherence ,Electronic monitoring ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurophysiology and neuropsychology ,QP351-495 - Abstract
Abstract Background Several studies have reported on the feasibility of electronic (e-)monitoring using computers or smartphones in patients with mental disorders, including bipolar disorder (BD). While studies on e-monitoring have examined the role of demographic factors, such as age, gender, or socioeconomic status and use of health apps, to our knowledge, no study has examined clinical characteristics that might impact adherence with e-monitoring in patients with BD. We analyzed adherence to e-monitoring in patients with BD who participated in an ongoing e-monitoring study and evaluated whether demographic and clinical factors would predict adherence. Methods Eighty-seven participants with BD in different phases of the illness were included. Patterns of adherence for wearable use, daily and weekly self-rating scales over 15 months were analyzed to identify adherence trajectories using growth mixture models (GMM). Multinomial logistic regression models were fitted to compute the effects of predictors on GMM classes. Results Overall adherence rates were 79.5% for the wearable; 78.5% for weekly self-ratings; and 74.6% for daily self-ratings. GMM identified three latent class subgroups: participants with (i) perfect; (ii) good; and (iii) poor adherence. On average, 34.4% of participants showed “perfect” adherence; 37.1% showed “good” adherence; and 28.2% showed poor adherence to all three measures. Women, participants with a history of suicide attempt, and those with a history of inpatient admission were more likely to belong to the group with perfect adherence. Conclusions Participants with higher illness burden (e.g., history of admission to hospital, history of suicide attempts) have higher adherence rates to e-monitoring. They might see e-monitoring as a tool for better documenting symptom change and better managing their illness, thus motivating their engagement.
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- 2023
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9. Manipulating facial musculature with functional electrical stimulation as an intervention for major depressive disorder: a focused search of literature for a proposal
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Ilya Demchenko, Naaz Desai, Stephanie N. Iwasa, Fatemeh Gholamali Nezhad, José Zariffa, Sidney H. Kennedy, Nicholas O. Rule, Jeffrey F. Cohn, Milos R. Popovic, Benoit H. Mulsant, and Venkat Bhat
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Depressive disorder ,Facial muscles ,Myofunctional therapy ,Functional electrical stimulation ,Facial expression ,Neuromodulation ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract Background Major Depressive Disorder (MDD) is associated with interoceptive deficits expressed throughout the body, particularly the facial musculature. According to the facial feedback hypothesis, afferent feedback from the facial muscles suffices to alter the emotional experience. Thus, manipulating the facial muscles could provide a new “mind-body” intervention for MDD. This article provides a conceptual overview of functional electrical stimulation (FES), a novel neuromodulation-based treatment modality that can be potentially used in the treatment of disorders of disrupted brain connectivity, such as MDD. Methods A focused literature search was performed for clinical studies of FES as a modulatory treatment for mood symptoms. The literature is reviewed in a narrative format, integrating theories of emotion, facial expression, and MDD. Results A rich body of literature on FES supports the notion that peripheral muscle manipulation in patients with stroke or spinal cord injury may enhance central neuroplasticity, restoring lost sensorimotor function. These neuroplastic effects suggest that FES may be a promising innovative intervention for psychiatric disorders of disrupted brain connectivity, such as MDD. Recent pilot data on repetitive FES applied to the facial muscles in healthy participants and patients with MDD show early promise, suggesting that FES may attenuate the negative interoceptive bias associated with MDD by enhancing positive facial feedback. Neurobiologically, the amygdala and nodes of the emotion-to-motor transformation loop may serve as potential neural targets for facial FES in MDD, as they integrate proprioceptive and interoceptive inputs from muscles of facial expression and fine-tune their motor output in line with socio-emotional context. Conclusions Manipulating facial muscles may represent a mechanistically novel treatment strategy for MDD and other disorders of disrupted brain connectivity that is worthy of investigation in phase II/III trials.
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- 2023
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10. Protocol for a systematic review and meta-analysis of coordinate-based network mapping of brain structure in bipolar disorder across the lifespan
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Brett D. M. Jones, Peter Zhukovsky, Colin Hawco, Abigail Ortiz, Andrea Cipriani, Aristotle N. Voineskos, Benoit H. Mulsant, and Muhammad Ishrat Husain
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Bipolar disorders ,other imaging ,depressive disorders ,review ,connectivity ,Psychiatry ,RC435-571 - Abstract
Background Studies about brain structure in bipolar disorder have reported conflicting findings. These findings may be explained by the high degree of heterogeneity within bipolar disorder, especially if structural differences are mapped to single brain regions rather than networks. Aims We aim to complete a systematic review and meta-analysis to identify brain networks underlying structural abnormalities observed on T1-weighted magnetic resonance imaging scans in bipolar disorder across the lifespan. We also aim to explore how these brain networks are affected by sociodemographic and clinical heterogeneity in bipolar disorder. Method We will include case–control studies that focus on whole-brain analyses of structural differences between participants of any age with a standardised diagnosis of bipolar disorder and controls. The electronic databases Medline, PsycINFO and Web of Science will be searched. We will complete an activation likelihood estimation analysis and a novel coordinate-based network mapping approach to identify specific brain regions and brain circuits affected in bipolar disorder or relevant subgroups. Meta-regressions will examine the effect of sociodemographic and clinical variables on identified brain circuits. Conclusions Findings from this systematic review and meta-analysis will enhance understanding of the pathophysiology of bipolar disorder. The results will identify brain circuitry implicated in bipolar disorder, and how they may relate to relevant sociodemographic and clinical variables across the lifespan.
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- 2023
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11. A systematic review on the effectiveness of dialectical behavior therapy for improving mood symptoms in bipolar disorders
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Brett D. M. Jones, Madeha Umer, Mary E. Kittur, Ofer Finkelstein, Siqi Xue, Mikaela K. Dimick, Abigail Ortiz, Benjamin I. Goldstein, Benoit H. Mulsant, and Muhammad I. Husain
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Bipolar disorder ,DBT ,Psychotherapy ,Depression ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurophysiology and neuropsychology ,QP351-495 - Abstract
Abstract Background Evidence-based psychotherapies available to treat patients with bipolar disorders (BD) are limited. Dialectical behavior therapy (DBT) may target several common symptoms of BD. We conducted a systematic review on the efficacy of DBT for mood symptoms in patients with BD. The systematic search used key words related to DBT and BD in Medline, Embase, PsycInfo, CINAHL, and Cochrane Library databases from 1980 to April 1st, 2022. We included studies that enrolled patients with a BD I or II diagnosis (DSM or ICD), age 12 and older who received a DBT-based intervention. Studies reviewed were clinical trials including observational studies that reported at least one outcome related to BD mood symptoms or severity. We did not exclude based upon psychiatric or physical co-morbidity. Results We screened 848 abstracts and reviewed 28 full texts; 10 publications with 11 studies met our pre-determined eligibility criteria. All but one were feasibility pilot studies and most included participants in all mood states except for mania. The studies provided preliminary evidence suggesting these interventions may be effective for improving several core symptoms of BD. Overall, all the studies consistently supported that DBT-based interventions are feasible and acceptable for patients with BD. Conclusion DBT may be an effective treatment for BD; however, the confidence in this conclusion is limited by the small sample sizes, heterogeneity, and high risk of bias in all published trials. Larger well-designed RCTs are now required to establish the effectiveness of DBT in BD.
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- 2023
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12. Psilocybin for treatment-resistant depression without psychedelic effects: study protocol for a 4-week, double-blind, proof-of-concept randomised controlled trial
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Muhammad Ishrat Husain, Daniel M. Blumberger, David J. Castle, Nicole Ledwos, Elise Fellows, Brett D. M. Jones, Abigail Ortiz, Stefan Kloiber, Wei Wang, Joshua D. Rosenblat, and Benoit H. Mulsant
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Treatment-resistant depression ,major depressive disorder ,psilocybin ,randomised controlled trial ,psychedelic-assisted psychotherapy ,Psychiatry ,RC435-571 - Abstract
Background Randomised controlled trials (RCTs) of psilocybin have reported large antidepressant effects in adults with major depressive disorder and treatment-resistant depression (TRD). Given psilocybin's psychedelic effects, all published studies have included psychological support. These effects depend on serotonin 2A (5-HT2A) receptor activation, which can be blocked by 5-HT2A receptor antagonists like ketanserin or risperidone. In an animal model of depression, ketanserin followed by psilocybin had similar symptomatic effects as psilocybin alone. Aims To conduct a proof-of-concept RCT to (a) establish feasibility and tolerability of combining psilocybin and risperidone in adults with TRD, (b) show that this combination blocks the psychedelic effects of psilocybin and (c) provide pilot data on the antidepressant effect of this combination (compared with psilocybin alone). Method In a 4-week, three-arm, ‘double dummy’ trial, 60 adults with TRD will be randomised to psilocybin 25 mg plus risperidone 1 mg, psilocybin 25 mg plus placebo, or placebo plus risperidone 1 mg. All participants will receive 12 h of manualised psychotherapy. Measures of feasibility will include recruitment and retention rates; tolerability and safety will be assessed by rates of drop-out attributed to adverse events and rates of serious adverse events. The 5-Dimensional Altered States of Consciousness Rating Scale will be a secondary outcome measure. Results This trial will advance the understanding of psilocybin's mechanism of antidepressant action. Conclusions This line of research could increase acceptability and access to psilocybin as a novel treatment for TRD without the need for a psychedelic experience and continuous monitoring.
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- 2023
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13. Identifying patient-specific behaviors to understand illness trajectories and predict relapses in bipolar disorder using passive sensing and deep anomaly detection: protocol for a contactless cohort study
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Abigail Ortiz, Arend Hintze, Rachael Burnett, Christina Gonzalez-Torres, Samantha Unger, Dandan Yang, Jingshan Miao, Martin Alda, and Benoit H. Mulsant
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Bipolar disorder ,Episode prediction ,Wearable device ,Machine learning ,Psychiatry ,RC435-571 - Abstract
Abstract Background Predictive models for mental disorders or behaviors (e.g., suicide) have been successfully developed at the level of populations, yet current demographic and clinical variables are neither sensitive nor specific enough for making individual clinical predictions. Forecasting episodes of illness is particularly relevant in bipolar disorder (BD), a mood disorder with high recurrence, disability, and suicide rates. Thus, to understand the dynamic changes involved in episode generation in BD, we propose to extract and interpret individual illness trajectories and patterns suggestive of relapse using passive sensing, nonlinear techniques, and deep anomaly detection. Here we describe the study we have designed to test this hypothesis and the rationale for its design. Method This is a protocol for a contactless cohort study in 200 adult BD patients. Participants will be followed for up to 2 years during which they will be monitored continuously using passive sensing, a wearable that collects multimodal physiological (heart rate variability) and objective (sleep, activity) data. Participants will complete (i) a comprehensive baseline assessment; (ii) weekly assessments; (iii) daily assessments using electronic rating scales. Data will be analyzed using nonlinear techniques and deep anomaly detection to forecast episodes of illness. Discussion This proposed contactless, large cohort study aims to obtain and combine high-dimensional, multimodal physiological, objective, and subjective data. Our work, by conceptualizing mood as a dynamic property of biological systems, will demonstrate the feasibility of incorporating individual variability in a model informing clinical trajectories and predicting relapse in BD.
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- 2022
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14. Identifying the Common Genetic Basis of Antidepressant Response
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Oliver Pain, Karen Hodgson, Vassily Trubetskoy, Stephan Ripke, Victoria S. Marshe, Mark J. Adams, Enda M. Byrne, Adrian I. Campos, Tania Carrillo-Roa, Annamaria Cattaneo, Thomas D. Als, Daniel Souery, Mojca Z. Dernovsek, Chiara Fabbri, Caroline Hayward, Neven Henigsberg, Joanna Hauser, James L. Kennedy, Eric J. Lenze, Glyn Lewis, Daniel J. Müller, Nicholas G. Martin, Benoit H. Mulsant, Ole Mors, Nader Perroud, David J. Porteous, Miguel E. Rentería, Charles F. Reynolds, III, Marcella Rietschel, Rudolf Uher, Eleanor M. Wigmore, Wolfgang Maier, Naomi R. Wray, Katherine J. Aitchison, Volker Arolt, Bernhard T. Baune, Joanna M. Biernacka, Guido Bondolfi, Katharina Domschke, Masaki Kato, Qingqin S. Li, Yu-Li Liu, Alessandro Serretti, Shih-Jen Tsai, Gustavo Turecki, Richard Weinshilboum, Andrew M. McIntosh, Cathryn M. Lewis, Siegfried Kasper, Joseph Zohar, Stuart Montgomery, Diego Albani, Gianluigi Forloni, Panagiotis Ferentinos, Dan Rujescu, Julien Mendlewicz, Manuel Mattheisen, Maciej Trzaskowski, Abdel Abdellaoui, Esben Agerbo, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Tim B. Bigdeli, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Toni-Kim Clarke, Jonathan R.I. Coleman, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Ian J. Deary, Franziska Degenhardt, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Andreas J. Forstner, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Stefan Herms, Ian B. Hickie, Per Hoffmann, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Hougaard, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Peter McGuffin, Sarah E. Medland, Divya Mehta, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Hogni Oskarsson, Michael J. Owen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Danielle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Margarita Rivera, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Jianxin Shi, Stanley I. Shyn, Engilbert Sigurdsson, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Hreinn Stefansson, Stacy Steinberg, Fabian Streit, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, André G. Uitterlinden, Daniel Umbricht, Sandra Van der Auwera, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H. Witt, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Klaus Berger, Dorret I. Boomsma, Sven Cichon, Udo Dannlowski, E.J.C. de Geus, J. Raymond DePaulo, Enrico Domenici, Tõnu Esko, Hans J. Grabe, Steven P. Hamilton, Andrew C. Heath, Kenneth S. Kendler, Stefan Kloiber, Susanne Lucae, Pamela A.F. Madden, Patrik K. Magnusson, Andres Metspalu, Preben Bo Mortensen, Bertram Müller-Myhsok, Merete Nordentoft, Markus M. Nöthen, Michael C. O’Donovan, Sara A. Paciga, Nancy L. Pedersen, Brenda W.J.H. Penninx, Roy H. Perlis, James B. Potash, Martin Preisig, Catherine Schaefer, Thomas G. Schulze, Jordan W. Smoller, Kari Stefansson, Henning Tiemeier, Henry Völzke, Myrna M. Weissman, Thomas Werge, Douglas F. Levinson, Gerome Breen, Anders D. Børglum, and Patrick F. Sullivan
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Antidepressant response ,Depression ,Genetics ,GWAS ,MDD ,Polygenic score ,Psychiatry ,RC435-571 - Abstract
Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction. Methods: Genome-wide analysis of remission (nremit = 1852, nnonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism–based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA. Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism–based heritability was significantly different from zero for remission (h2 = 0.132, SE = 0.056) but not for percentage improvement (h2 = −0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response. Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.
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- 2022
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15. Low-Dose Augmentation With Buprenorphine for Treatment-Resistant Depression: A Multisite Randomized Controlled Trial With Multimodal Assessment of Target Engagement
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Hyewon H. Lee, Daniel M. Blumberger, Eric J. Lenze, Stewart J. Anderson, Deanna M. Barch, Kevin J. Black, Pilar Cristancho, Zafiris J. Daskalakis, Sarah A. Eisenstein, Yiyun Huang, Songye Li, Jennifer Lissemore, Jonathan McConathy, Benoit H. Mulsant, Tarek K. Rajji, Charles F. Reynolds, III, Yi Su, Zhude Tu, Daphne Voineskos, and Jordan F. Karp
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Antidepressants ,Buprenorphine ,Depression ,fMRI ,PET ,TMS ,Psychiatry ,RC435-571 - Abstract
Background: The experimental therapeutics approach that combines a placebo-controlled clinical trial with translational neuroscience methods can provide a better understanding of both the clinical and physiological effects of pharmacotherapy. We aimed to test the efficacy and tolerability of low-dose augmentation with buprenorphine (BPN) for treatment-resistant depression, combined with multimodal assessment of target engagement. Methods: In this multisite randomized clinical trial, 85 participants ≥50 years of age with a major depressive episode that had not responded to venlafaxine extended release were randomized to augmentation with BPN or placebo for 8 weeks. The primary outcome measure was the Montgomery–Åsberg Depression Rating Scale. In addition, three linked experiments were conducted to test target engagement: 1) functional magnetic resonance imaging using the monetary incentive delay task, 2) brain positron emission tomography of healthy participants using a novel kappa opioid receptor antagonist tracer [11C]LY2795050, and 3) transcranial magnetic stimulation measure of cortical transmission after daily BPN administration. Results: The mean ± SD dosage of BPN was 0.59 ± 0.33 mg/day. There were no significant differences between the BPN and placebo groups in Montgomery–Åsberg Depression Rating Scale changes over time or adverse effects. BPN administration had minimal effects on functional magnetic resonance imaging blood oxygen level–dependent responses in regions involved in reward anticipation and response, no significant displacement of kappa opioid receptor radioligand in positron emission tomography imaging, and no significant changes in transcranial magnetic stimulation measures of inhibitory and excitatory cortical transmission. Conclusions: Our findings suggest a lack of clinical effect of low-dose BPN augmentation and lack of target engagement with this dosage and physiological probes.
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- 2022
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16. Serotonergic psychedelics for depression: What do we know about neurobiological mechanisms of action?
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Muhammad Ishrat Husain, Nicole Ledwos, Elise Fellows, Jenna Baer, Joshua D. Rosenblat, Daniel M. Blumberger, Benoit H. Mulsant, and David J. Castle
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psychedelics ,hallucinogen ,depression ,psilocybin ,connectivity ,LSD ,Psychiatry ,RC435-571 - Abstract
IntroductionCurrent treatment options for major depressive disorder (MDD) have limited efficacy and are associated with adverse effects. Recent studies investigating the antidepressant effect of serotonergic psychedelics—also known as classic psychedelics—have promising preliminary results with large effect sizes. In this context, we conducted a review of the putative neurobiological underpinnings of the mechanism of antidepressant action of these drugs.MethodsA narrative review was conducted using PubMed to identify published articles evaluating the antidepressant mechanism of action of serotonergic psychedelics.ResultsSerotonergic psychedelics have serotonin (5HT)2A agonist or partial agonist effects. Their rapid antidepressant effects may be mediated—in part—by their potent 5HT2A agonism, leading to rapid receptor downregulation. In addition, these psychedelics impact brain derived neurotrophic factor and immunomodulatory responses, both of which may play a role in their antidepressant effect. Several neuroimaging and neurophysiology studies evaluating mechanistic change from a network perspective can help us to further understand their mechanism of action. Some, but not all, data suggest that psychedelics may exert their effects, in part, by disrupting the activity of the default mode network, which is involved in both introspection and self-referential thinking and is over-active in MDD.ConclusionThe mechanisms of action underlying the antidepressant effect of serotonergic psychedelics remains an active area of research. Several competing theories are being evaluated and more research is needed to determine which ones are supported by the most robust evidence.
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- 2023
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17. Culturally adapted psychoeducation for bipolar disorder in a low-resource setting: protocol for a multicentre randomised controlled trial – ERRATUM
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M. Ishrat Husain, Madeha Umer, Muqaddas Asif, Ameer B. Khoso, Tayyeba Kiran, Moin Ansari, Huma Aslam, Moti Ram Bhatia, Farasat A. Dogar, M. Omair Husain, Hazrat A. Khan, Ali A. Mufti, Benoit H. Mulsant, Farooq Naeem, Haider A. Naqvi, Claire de Oliveira, M. Sajjad Siddiqui, Asad Tamizuddin, Wei Wang, Juveria Zaheer, Nusrat Husain, Nasim Chaudhry, and Imran B. Chaudhry
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Psychiatry ,RC435-571 - Published
- 2023
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18. The futility of long-term predictions in bipolar disorder: mood fluctuations are the result of deterministic chaotic processes
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Abigail Ortiz, Kamil Bradler, Maxine Mowete, Stephane MacLean, Julie Garnham, Claire Slaney, Benoit H. Mulsant, and Martin Alda
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Bipolar disorder ,Mood fluctuations ,Nonlinear analyses ,Episode prediction ,Unaffected first-degree relatives ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurophysiology and neuropsychology ,QP351-495 - Abstract
Abstract Background Understanding the underlying architecture of mood regulation in bipolar disorder (BD) is important, as we are starting to conceptualize BD as a more complex disorder than one of recurring manic or depressive episodes. Nonlinear techniques are employed to understand and model the behavior of complex systems. Our aim was to assess the underlying nonlinear properties that account for mood and energy fluctuations in patients with BD; and to compare whether these processes were different in healthy controls (HC) and unaffected first-degree relatives (FDR). We used three different nonlinear techniques: Lyapunov exponent, detrended fluctuation analysis and fractal dimension to assess the underlying behavior of mood and energy fluctuations in all groups; and subsequently to assess whether these arise from different processes in each of these groups. Results There was a positive, short-term autocorrelation for both mood and energy series in all three groups. In the mood series, the largest Lyapunov exponent was found in HC (1.84), compared to BD (1.63) and FDR (1.71) groups [F (2, 87) = 8.42, p
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- 2021
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19. Culturally adapted psychoeducation for bipolar disorder in a low-resource setting: protocol for a multicentre randomised controlled trial
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M. Ishrat Husain, Madeha Umer, Muqaddas Asif, Ameer B. Khoso, Tayyeba Kiran, Moin Ansari, Huma Aslam, Moti Ram Bhatia, Farasat A. Dogar, M. Omair Husain, Hazrat A. Khan, Ali A. Mufti, Benoit H. Mulsant, Farooq Naeem, Haider A. Naqvi, Claire de Oliveira, M. Sajjad Siddiqui, Asad Tamizuddin, Wei Wang, Juveria Zaheer, Nusrat Husain, Nasim Chaudhry, and Imran B. Chaudhry
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Bipolar disorder ,psychoeducation ,clinical trial ,Pakistan ,psychosocial interventions ,Psychiatry ,RC435-571 - Abstract
Background Bipolar disorder is a source of marked disability, morbidity and premature death. There is a paucity of research on personalised psychosocial interventions for bipolar disorder, especially in low-resource settings. A pilot randomised controlled trial (RCT) of a culturally adapted psychoeducation intervention for bipolar disorder (CaPE) in Pakistan reported higher patient satisfaction, enhanced medication adherence, knowledge and attitudes regarding bipolar disorder, and improvement in mood symptom scores and health-related quality of life measures compared with treatment as usual (TAU). Aims The current protocol describes a larger multicentre RCT to confirm the clinical and cost-effectiveness of CaPE in Pakistan. Trial registration: NCT05223959. Method A multicentre individual, parallel-arm RCT of CaPE in 300 Pakistani adults with bipolar disorder. Participants over the age of 18, with a diagnosis of bipolar I or II disorder who are currently euthymic, will be recruited from seven sites: Karachi, Lahore, Multan, Rawalpindi, Peshawar, Hyderabad and Quetta. Time to recurrence will be the primary outcome assessed using the Longitudinal Interval Follow-up Evaluation (LIFE). Secondary measures will include mood symptoms, quality of life and functioning, adherence to psychotropic medications, and knowledge and attitudes regarding bipolar disorder. Results This trial will assess the effectiveness of the CaPE intervention compared with TAU in reducing the time to recurrence for people with bipolar disorder currently in remission in Pakistan and determine the effect on clinical outcomes, quality of life and functioning. Conclusions A successful trial might lead to rapid implementation of CaPE in clinical practice, not only in Pakistan, but also in other low-resource settings, including those in high-income countries, to improve clinical outcomes, social and occupational functioning, and quality of life in South Asian and other minority group patients with bipolar disorder.
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- 2022
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20. Genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response
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Victoria S. Marshe, Malgorzata Maciukiewicz, Anne-Christin Hauschild, Farhana Islam, Li Qin, Arun K. Tiwari, Etienne Sibille, Daniel M. Blumberger, Jordan F. Karp, Alastair J. Flint, Gustavo Turecki, Raymond W. Lam, Roumen V. Milev, Benicio N. Frey, Susan Rotzinger, Jane A. Foster, Sidney H. Kennedy, James L. Kennedy, Benoit H. Mulsant, Charles F. Reynolds, Eric J. Lenze, and Daniel J. Müller
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract 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 × 10−6) and intergenic rs6916777 (Beta = 14.03 [8.47, 19.59], p = 1.25 × 10−6), 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 × 10−6, 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 × 10−4). 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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- 2021
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21. The benefits and costs of changing treatment technique in electroconvulsive therapy due to insufficient improvement of a major depressive episode
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Harold A. Sackeim, Joan Prudic, D.P. Devanand, Mitchell S. Nobler, Roger F. Haskett, Benoit H. Mulsant, Peter B. Rosenquist, and William V. McCall
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Electroconvulsive therapy (ECT) ,Switching strategy ,Relapse ,Retrograde amnesia ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Background: Electroconvulsive therapy (ECT) technique is often changed after insufficient improvement, yet there has been little research on switching strategies. Objective: To document clinical outcome in ECT nonresponders who were received a second course using high dose, brief pulse, bifrontotemporal (HD BP BL) ECT, and compare relapse rates and cognitive effects relative to patients who received only one ECT course and as a function of the type of ECT first received. Methods: Patients were classified as receiving Weak, Strong, or HD BP BL ECT during three randomized trials at Columbia University. Nonresponders received HD BP BL ECT. In a separate multi-site trial, Optimization of ECT, patients were randomized to right unilateral or BL ECT and nonresponders also received further treatment with HD BP BL ECT. Results: Remission rates with a second course of HD BP BL ECT were high in ECT nonresponders, approximately 60% and 40% in the Columbia University and Optimization of ECT studies, respectively. Clinical outcome was independent of the type of ECT first received. A second course with HD BP BL ECT resulted in greater retrograde amnesia immediately, two months, and six months following ECT. Conclusions: In the largest samples of ECT nonresponders studied to date, a second course of ECT had marked antidepressant effects. Since the therapeutic effects were independent of the technique first administered, it is possible that many patients may benefit simply from longer courses of ECT. Randomized trials are needed to determine whether, when, and how to change treatment technique in ECT.
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- 2020
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22. Coping, fostering resilience, and driving care innovation for autistic people and their families during the COVID-19 pandemic and beyond
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Stephanie H. Ameis, Meng-Chuan Lai, Benoit H. Mulsant, and Peter Szatmari
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Autism ,SARS-CoV-2 virus ,COVID-19 ,Pandemic ,Resilience ,Telehealth ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract The new coronavirus disease (COVID-19) pandemic is changing how society operates. Environmental changes, disrupted routines, and reduced access to services and social networks will have a unique impact on autistic individuals and their families and will contribute to significant deterioration in some. Access to support is crucial to address vulnerability factors, guide adjustments in home environments, and apply mitigation strategies to improve coping. The current crisis highlights that our regular care systems are not sufficient to meet the needs of the autism communities. In many parts of the world, people have shifted to online school and increased use of remote delivery of healthcare and autism supports. Access to these services needs to be increased to mitigate the negative impact of COVID-19 and future epidemics/pandemics. The rapid expansion in the use of telehealth platforms can have a positive impact on both care and research. It can help to address key priorities for the autism communities including long waitlists for assessment and care, access to services in remote locations, and restricted hours of service. However, system-level changes are urgently needed to ensure equitable access and flexible care models, especially for families and individuals who are socioeconomically disadvantaged. COVID-19 mandates the use of technology to support a broader range of care options and better meet the diverse needs of autistic people and their families. It behooves us to use this crisis as an opportunity to foster resilience not only for a given individual or their family, but also the system: to drive enduring and autism-friendly changes in healthcare, social systems, and the broader socio-ecological contexts.
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- 2020
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23. Minocycline as adjunctive treatment for treatment-resistant depression: study protocol for a double blind, placebo-controlled, randomized trial (MINDEP2)
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Muhammad Ishrat Husain, Clare Cullen, Madeha Umer, Andre F. Carvalho, Stefan Kloiber, Jeffrey H. Meyer, Abigail Ortiz, Yuliya Knyahnytska, M. Omair Husain, Justine Giddens, Breno S. Diniz, Wei Wang, Allan H. Young, Benoit H. Mulsant, and Zafiris J. Daskalakis
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Depression ,Minocycline ,Inflammation ,Anti-inflammatory ,Clinical trial ,Psychiatry ,RC435-571 - Abstract
Abstract Background Available evidence suggests that adjunctive treatment with immunomodulatory medications may be effective in the treatment of major depressive disorder (MDD). A pilot trial of the tetracycline minocycline as adjunctive treatment in treatment-resistant depression (TRD), produced promising results, however, a larger scale trial is needed to confirm the antidepressant actions of this drug. Methods This is a 12-week double blind, placebo-controlled, randomized trial of minocycline as an add-on to standard antidepressants for adults (age > 18) with DSM-5 major depressive episode, who have failed to respond to at least two adequate trials of antidepressant treatment. It is a parallel-arm study with 50 participants in each group. The primary outcome measure is change in 17-item Hamilton Depression Rating Scale (HRSD-17) total scores from baseline to week 12. Secondary measures include the Clinical Global Impression (CGI) scale, World Health Organization Quality of Life Short Version (WHOQOL-BREF) and the Generalized Anxiety Disorder scale (GAD-7). Peripheral inflammatory biomarkers will be collected at baseline, week 6 and 12. Discussion If minocycline is well tolerated and effective in reducing depressive symptoms in patients with TRD, it would warrant genuine consideration as a treatment option for TRD. Additionally, if results demonstrate that minocycline has antidepressant properties, and that changes in inflammatory status are associated with its antidepressant action, it will inform the development of individualized treatment for a subset of patients with MDD. Trial registration Clinicaltrials.gov identifier: NCT03947827 . Registered 13th May, 2019.
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- 2020
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24. Sahaj Samadhi Meditation versus a Health Enhancement Program for depression in chronic pain: protocol for a randomized controlled trial and implementation evaluation
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Abhimanyu Sud, Michelle L. A. Nelson, Darren K. Cheng, Alana Armas, Kirk Foat, Michelle Greiver, Fardous Hosseiny, Joel Katz, Rahim Moineddin, Benoit H. Mulsant, Ronnie I. Newman, Leon Rivlin, Akshya Vasudev, and Ross Upshur
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Chronic pain ,Depression ,Meditation ,Education ,Randomized controlled trial (RCT) ,Implementation ,Medicine (General) ,R5-920 - Abstract
Abstract Background Despite the high prevalence of comorbid chronic pain and depression, this comorbidity remains understudied. Meditation has demonstrated efficacy for both chronic pain and depression independently, yet there have been few studies examining its effectiveness when both conditions are present concurrently. Furthermore, while meditation is generally accepted as a safe and effective health intervention, little is known about how to implement meditation programs within or alongside the health care system. Methods We will conduct a hybrid type 1 effectiveness–implementation evaluation. To measure effectiveness, we will conduct a randomized controlled trial comparing Sahaj Samadhi Meditation and the Health Enhancement Program in 160 people living with chronic pain, clinically significant depressive symptoms, and on long-term opioid therapy. Changes in depressive symptoms will be our primary outcome; pain severity, pain-related function, opioid use, and quality of life will be the secondary outcomes. The primary end point will be at 12 weeks with a secondary end point at 24 weeks to measure the sustainability of acute effects. Patients will be recruited from a community-based chronic pain clinic in a large urban center in Mississauga, Canada. The meditation program will be delivered in the clinical environment where patients normally receive their chronic pain care by certified meditation teachers who are not regulated health care providers. We will use a mixed-methods design using the multi-level framework to understand the implementation of this particular co-location model. Discussion Results of this hybrid evaluation will add important knowledge about the effectiveness of meditation for managing depressive symptoms in people with chronic pain. The implementation evaluation will inform both effectiveness outcomes and future program development, scalability, and sustainability. Trial registration ClinicalTrials.gov: NCT04039568 . Registered on 31 July 2019.
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- 2020
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25. The Impact of COVID-19 on Psychiatric Emergency and Inpatient Services in the First Month of the Pandemic in a Large Urban Mental Health Hospital in Ontario, Canada
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Helena K. Kim, Andre F. Carvalho, David Gratzer, Albert H. C. Wong, Shayla Gutzin, M. Ishrat Husain, Benoit H. Mulsant, Vicky Stergiopoulos, and Zafiris J. Daskalakis
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COVID-19 ,psychiatry ,Canada ,pandemic ,emergency ,inpatient ,Psychiatry ,RC435-571 - Abstract
The World Health Organization characterized COVID-19 (coronavirus disease 2019) as a pandemic on March 11, 2020 (WHO). Within a couple of days, all Canadian provinces announced the implementation of social distancing measures. We evaluated the immediate effect of COVID-19 on psychiatric emergency and inpatient services in Canada's largest psychiatric hospital in the first month of the pandemic. We extracted data from the electronic medical records of the Center for Addiction and Mental Health in Toronto, Canada. We compared emergency department visits, inpatient occupancy rates, and length of stay in March 2019 and March 2020, and during the first and second half of March 2020. There was a decrease in the number of emergency department visits and inpatient occupancy rates in March 2020 compared to March 2019. There was also a significant decrease in the number of emergency department visits and inpatient occupancy rates in the second half of March 2020 compared to the first half. Our findings suggest that the pandemic was followed by a rapid decrease in the usage of psychiatric emergency and inpatient services in a large mental health hospital. Future studies will need to assess whether this decrease will be followed by a return to baseline or an increase in need for these services.
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- 2021
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26. Resting state functional connectivity in patients with remitted psychotic depression: A multi-centre STOP-PD studyResearch in context
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Nicholas H. Neufeld, Benoit H. Mulsant, Erin W. Dickie, Barnett S. Meyers, George S. Alexopoulos, Anthony J. Rothschild, Ellen M. Whyte, Matthew J. Hoptman, Arash Nazeri, Jonathan Downar, Alastair J. Flint, and Aristotle N. Voineskos
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Medicine ,Medicine (General) ,R5-920 - Abstract
Background: There is paucity of neurobiological knowledge about major depressive disorder with psychotic features (“psychotic depression”). This study addresses this knowledge gap by using resting state functional magnetic resonance imaging (R-fMRI) to compare functional connectivity in patients with psychotic depression and healthy controls. Methods: We scanned patients who participated in a randomized controlled trial as well as healthy controls. All patients achieved remission from depressive and psychotic symptoms with sertraline and olanzapine. We employed Independent Component Analysis in independent samples to isolate the default mode network (DMN) and compared patients and controls. Findings: The Toronto sample included 28 patients (mean [SD], age 56·2 [13·7]) and 39 controls (age 55·1 [13·5]). The Replication sample included 29 patients (age 56·1 [17·7]) and 36 controls (age 48·3 [17·9]). Patients in the Toronto sample demonstrated decreased between-network functional connectivity between the DMN and bilateral insular, somatosensory/motor, and auditory cortices with peak activity in the right planum polare (t = 4·831; p = 0·001, Family Wise Error (FWE) corrected). A similar pattern of between-network functional connectivity was present in our Replication sample with peak activity in the right precentral gyrus (t = 4·144; p = 0·003, FWE corrected). Interpretation: Remission from psychotic depression is consistently associated with an absence of increased DMN-related functional connectivity and presence of decreased between-network functional connectivity. Future research will evaluate this abnormal DMN-related functional connectivity as a potential biomarker for treatment trajectories. Funding: National Institute of Mental Health. Keywords: Default mode network, Functional connectivity, Biomarkers, Remission, Psychosis, Major depressive disorder
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- 2018
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27. Mild cognitive impairment and major depressive disorder are associated with molecular senescence abnormalities in older adults
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Breno S. Diniz, Erica M. Vieira, Ana Paula Mendes‐Silva, Christopher R. Bowie, Meryl A. Butters, Corinne E. Fischer, Alastair Flint, Nathan Herrmann, James Kennedy, Krista L. Lanctôt, Linda Mah, Bruce G. Pollock, Benoit H. Mulsant, Tarek K. Rajji, and on behalf of the PACt‐MD Study Group
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aging ,biomarkers ,cognitive impairment ,late‐life depression ,major depressive disorder ,SASP ,Neurology. Diseases of the nervous system ,RC346-429 ,Geriatrics ,RC952-954.6 - Abstract
Abstract Introduction The biological mechanisms linking mild cognitive impairment (MCI) and major depressive disorder are not well understood. We investigated whether molecular senescence changes in older adults are associated with a history of major depressive disorder (MDD) or MCI. Methods We included 371 participants: 167 with MCI; 62 cognitively normal with a history of MDD; 97 with MDD+MCI; and 45 cognitively unimpaired (CU) without a history of MDD. The candidate Senescence‐Associated Secretory Phenotype (SASP) biomarkers were measured in the plasma using a customized LUMINEX assay. Results The MDD+MCI group had a higher SASP index than the other groups (P
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- 2021
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28. Effectively Caring for Individuals With Behavioral and Psychological Symptoms of Dementia During the COVID-19 Pandemic
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Alvin Keng, Eric E. Brown, Aviva Rostas, Tarek K. Rajji, Bruce G. Pollock, Benoit H. Mulsant, and Sanjeev Kumar
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Alzheimer’s disease and related disorders ,behavioral and psychological symptoms of dementia ,COVID-19 ,pandemic ,coronavirus ,clinical care ,Psychiatry ,RC435-571 - Abstract
The COVID-19 pandemic has significantly affected the elderly and particularly individuals with Alzheimer’s disease and related disorders (ADRD). Behavioral and psychological symptoms of dementia (BPSD) are heterogeneous and common in individuals with ADRD and are associated with more severe illness. However, unlike the cognitive symptoms of ADRD that are usually progressive, BPSD may be treatable. Individuals with BPSD are facing unique challenges during the pandemic due to the inherent nature of the illness and the biological and psychosocial impacts of COVID-19. These challenges include a higher risk of severe COVID-19 infection in individuals with BPSD due to their frailty and medical vulnerability, difficulty participating in screening or testing, and adhering to infection control measures such as physical distancing. Further, biological effects of COVID-19 on the brain and its psychosocial impact such as isolation and disruption in mental health care are likely to worsen BPSD. In this paper, we discuss these challenges and strategies to manage the impact of COVID-19 and to effectively care for individuals with BPSD in community, long-term care, or hospital settings during the pandemic. Despite the ongoing uncertainty associated with this pandemic, we can reduce its impact on individuals with BPSD with a proactive approach.
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- 2020
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29. Evidence for Structural and Functional Alterations of Frontal-Executive and Corticolimbic Circuits in Late-Life Depression and Relationship to Mild Cognitive Impairment and Dementia: A Systematic Review
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Neda Rashidi-Ranjbar, Dayton Miranda, Meryl A. Butters, Benoit H. Mulsant, and Aristotle N. Voineskos
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late-life depression ,mild cognitive impairment ,Alzheimer's disease ,frontal-executive ,corticolimbic ,diffusion-tensor imaging ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Depression is a risk factor for developing Alzheimer's disease and Related Dementia (ADRD). We conducted a systematic review between 2008 and October 2018, to evaluate the evidence for a conceptual mechanistic model linking depression and ADRD, focusing on frontal-executive and corticolimbic circuits. We focused on two neuroimaging modalities: diffusion-weighted imaging measuring white matter tract disruptions and resting-state functional MRI measuring alterations in network dynamics in late-life depression (LLD), mild cognitive impairment (MCI), and LLD+MCI vs. healthy control (HC) individuals. Our data synthesis revealed that in some but not all studies, impairment of both frontal-executive and corticolimbic circuits, as well as impairment of global brain topology was present in LLD, MCI, and LLD+MCI vs. HC groups. Further, posterior midline regions (posterior cingulate cortex and precuneus) appeared to have the most structural and functional alterations in all patient groups. Future cohort and longitudinal studies are required to address the heterogeneity of findings, and to clarify which subgroups of people with LLD are at highest risk for developing MCI and ADRD.
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- 2020
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30. Atorvastatin in the treatment of Lithium-induced nephrogenic diabetes insipidus: the protocol of a randomized controlled trial
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Jocelyn Fotso Soh, Susana G. Torres-Platas, Serge Beaulieu, Outi Mantere, Robert Platt, Istvan Mucsi, Sybille Saury, Suzane Renaud, Andrea Levinson, Ana C. Andreazza, Benoit H. Mulsant, Daniel Müller, Ayal Schaffer, Annemiek Dols, Pablo Cervantes, Nancy CP Low, Nathan Herrmann, Birgitte M. Christensen, Francesco Trepiccione, Tarek Rajji, and Soham Rej
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Lithium ,Nephrogenic diabetes insipidus ,Kidney function ,Atorvastatin ,Placebo ,Urinary osmolality ,Psychiatry ,RC435-571 - Abstract
Abstract Background Lithium is the gold-standard treatment for bipolar disorder, is highly effective in treating major depressive disorder, and has anti-suicidal properties. However, clinicians are increasingly avoiding lithium largely due to fears of renal toxicity. Nephrogenic Diabetes Insipidus (NDI) occurs in 15–20% of lithium users and predicts a 2–3 times increased risk of chronic kidney disease (CKD). We recently found that use of statins is associated with lower NDI risk in a cross-sectional study. In this current paper, we describe the methodology of a randomized controlled trial (RCT) to treat lithium-induced NDI using atorvastatin. Methods We will conduct a 12-week, double-blind placebo-controlled RCT of atorvastatin for lithium-induced NDI at McGill University, Montreal, Canada. We will recruit 60 current lithium users, aged 18–85, who have indicators of NDI, which we defined as urine osmolality (UOsm)
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- 2018
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31. Clinical, Demographic, and Criminal Behavior Characteristics of Patients With Intellectual Disabilities in a Canadian Forensic Program
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Ipsita Ray, Alexander I. F. Simpson, Roland M. Jones, Kristina Shatokhina, Anupam Thakur, and Benoit H. Mulsant
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intellectual disability ,forensic mental health ,behavioral incidents ,risk assessment ,offending behaviour ,Psychiatry ,RC435-571 - Abstract
Background: People with intellectual disability (ID) and forensic issues constitute a challenging clinical group that has been understudied in forensic settings.Methods: We assessed the characteristics of patients with ID under the authority of the Ontario Review Board (ORB) in a large forensic program of a tertiary psychiatric hospital (excluding those with a cognitive disorder) and compared their characteristics with those of a non-ID control group.Results: Among 510 adult ORB patients, 47 had an ID diagnosis. ID patients were of younger age at index offense, with a lower level of education, and were less likely to have been married or employed, more likely to have committed a sexual offense, more likely to have a diagnosis of paraphilia, less likely to be “not criminally responsible,” and more likely to be “unfit to stand trial.” They were also more likely to have committed their index offenses against care professionals and be treated in a secure unit.Conclusion: Our findings have major implications for clinicians, clinical leaders, and policymakers about the specific needs of patients with ID presenting with forensic issues and differing needs in terms of treatment and risk management.
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- 2019
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32. Targeting Metabolic Dysfunction for the Treatment of Mood Disorders: Review of the Evidence
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Brett D. M. Jones, Salman Farooqui, Stefan Kloiber, Muhammad Omair Husain, Benoit H. Mulsant, and Muhammad Ishrat Husain
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major depressive disorder ,bipolar disorder ,metabolic function ,Science - Abstract
Major depressive disorder (MDD) and bipolar disorder (BD) are often chronic with many patients not responding to available treatments. As these mood disorders are frequently associated with metabolic dysfunction, there has been increased interest in novel treatments that would target metabolic pathways. The objectives of this scoping review were to synthesize evidence on the impact on mood symptoms of lipid lowering agents and anti-diabetics drugs, while also reviewing current knowledge on the association between mood disorders and dyslipidemia or hyperglycemia. We propose that metabolic dysfunction is prevalent in both MDD and BD and it may contribute to the development of these disorders through a variety of pathophysiological processes including inflammation, brain structural changes, hormonal alterations, neurotransmitter disruptions, alteration on brain cholesterol, central insulin resistance, and changes in gut microbiota. Current evidence is conflicting on the use of statins, polyunsaturated fatty acids, thiazolidinediones, glucagon-like peptide agonists, metformin, or insulin for the treatment of MDD and BD. Given the paucity of high-quality randomized controlled trials, additional studies are needed before any of these medications can be repurposed in routine clinical practice. Future trials need to enrich patient recruitment, include evaluations of mechanism of action, and explore differential effects on specific symptom domains such as anhedonia, suicidality, and cognition.
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- 2021
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33. Low-dose augmentation with buprenorphine increases emotional reactivity but not reward activity in treatment resistant mid- and late-life depression
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Chemin Lin, Helmet T. Karim, Marta Pecina, Howard J. Aizenstein, Eric J. Lenze, Daniel M. Blumberger, Benoit H. Mulsant, Evan D. Kharasch, Charles F. Reynolds III, and Jordan F. Karp
- Subjects
Computer applications to medicine. Medical informatics ,R858-859.7 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Buprenorphine is currently being studied for treatment-resistant depression because of its rapid effect, relative safety, and unique pharmacodynamics. To understand the neural impact of buprenorphine in depression, we examined acute limbic and reward circuit changes during an intervention with low-dose buprenorphine augmentation pharmacotherapy. Mid and late-life adults with major depression (N = 31) who did not completely respond to an adequate trial of venlafaxine were randomized to augmentation with low-dose buprenorphine or matching placebo. We investigated early neural changes using functional magnetic resonance imaging (fMRI) from pre-randomization to 3 weeks using both an emotional reactivity task and a gambling task. We tested if: 1) there were significant neural changes acutely per intervention group, and 2) if acute neural changes were associated with depressive symptom change over 8 weeks using both the total score and the dysphoria subscale of the Montgomery Asberg Depression Rating Scale. Participants in both the buprenorphine and placebo groups showed similar changes in depressive symptoms. Neither the emotional reactivity nor gambling task resulted in significant neural activation changes from pre-randomization to 3-weeks. In both groups, increases in rostral anterior cingulate (rACC) and ventromedial prefrontal cortex (vmPFC) activation during the emotional reactivity task were associated with overall symptom improvement. In the buprenorphine but not the placebo group, increased activation in left anterior insula (aINS) and bilateral middle frontal gyrus (MFG) was associated with improvement on the dysphoria subscale. Activation changes in the reward task were not associated with buprenorphine. This is the first study to show an association between acute neural changes during emotion reactivity and changes in depression severity with buprenorphine treatment. Keywords: Treatment-resistant depression, Geriatric, Buprenorphine, Placebo, fMRI, Clinical trial
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- 2019
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34. Theta-Gamma Coupling and Working Memory in Alzheimer’s Dementia and Mild Cognitive Impairment
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Michelle S. Goodman, Sanjeev Kumar, Reza Zomorrodi, Zaid Ghazala, Amay S. M. Cheam, Mera S. Barr, Zafiris J. Daskalakis, Daniel M. Blumberger, Corinne Fischer, Alastair Flint, Linda Mah, Nathan Herrmann, Christopher R. Bowie, Benoit H. Mulsant, and Tarek K. Rajji
- Subjects
mild cognitive impairment ,Alzheimer’s dementia ,electroencephalography ,neural oscillations ,theta-gamma coupling ,working memory ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Working memory deficits are common among individuals with Alzheimer’s dementia (AD) or mild cognitive impairment (MCI). Yet, little is known about the mechanisms underlying these deficits. Theta-gamma coupling—the modulation of high-frequency gamma oscillations by low-frequency theta oscillations—is a neurophysiologic process underlying working memory. We assessed the relationship between theta-gamma coupling and working memory deficits in AD and MCI. We hypothesized that: (1) individuals with AD would display the most significant working memory impairments followed by MCI and finally healthy control (HC) participants; and (2) there would be a significant association between working memory performance and theta-gamma coupling across all participants. Ninety-eight participants completed the N-back working memory task during an electroencephalography (EEG) recording: 33 with AD (mean ± SD age: 76.5 ± 6.2), 34 with MCI (mean ± SD age: 74.8 ± 5.9) and 31 HCs (mean ± SD age: 73.5 ± 5.2). AD participants performed significantly worse than control and MCI participants on the 1- and 2-back conditions. Regarding theta-gamma coupling, AD participants demonstrated the lowest level of coupling followed by the MCI and finally control participants on the 2-back condition. Finally, a linear regression analysis demonstrated that theta-gamma coupling (β = 0.69, p < 0.001) was the most significant predictor of 2-back performance. Our results provide evidence for a relationship between altered theta-gamma coupling and working memory deficits in individuals with AD and MCI. They also provide insight into a potential mechanism underlying working memory impairments in these individuals.
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- 2018
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35. A Novel Unsupervised Machine Learning Approach to Assess Postural Dynamics in Euthymic Bipolar Disorder.
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Ramzi Halabi, Christina Gonzalez-Torres, Stephane MacLean, M. Ishrat Husain, Abhishek Pratap, Martin Alda, Benoit H. Mulsant, and Abigail Ortiz
- Published
- 2024
- Full Text
- View/download PDF
36. Towards Outcome-Driven Patient Subgroups: A Machine Learning Analysis Across Six Depression Treatment Studies.
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David Benrimoh, Akiva Kleinerman, Toshi A. Furukawa, Charles F. Reynolds III, Eric Lenze, Jordan F. Karp, Benoit H. Mulsant, Caitrin Armstrong, Joseph Mehltretter, Robert Fratila, Kelly Perlman, Sonia Israel, Myriam Tanguay-Sela, Christina Popescu, Grace Golden, Sabrina Qassim, Alexandra Anacleto, Adam Kapelner, Ariel Rosenfeld, and Gustavo Turecki
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- 2023
- Full Text
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37. The relationship of white matter microstructure with psychomotor disturbance and relapse in remitted psychotic depression
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Kathleen S. Bingham, Navona Calarco, Erin W. Dickie, George S. Alexopoulos, Meryl A. Butters, Barnett S. Meyers, Patricia Marino, Nicholas H. Neufeld, Anthony J. Rothschild, Ellen M. Whyte, Benoit H. Mulsant, Alastair J. Flint, and Aristotle N. Voineskos
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Psychiatry and Mental health ,Clinical Psychology - Published
- 2023
38. Associations between peripheral inflammation and clinical phenotypes of bipolar depression in a lower-middle income country
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Brett D.M. Jones, Urbee Mahmood, John Hodsoll, Imran B. Chaudhry, Ameer B. Khoso, Mohammed O. Husain, Abigail Ortiz, Nusrat Husain, Benoit H. Mulsant, Allan H. Young, and Muhammad I. Husain
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Psychiatry and Mental health ,Neurology (clinical) - Abstract
Objective There has been increased interest in repurposing anti-inflammatories for the treatment of bipolar depression. Evidence from high-income countries suggests that these agents may work best for specific depressive symptoms in a subset of patients with biochemical evidence of inflammation but data from lower-middle income countries (LMICs) is scarce. This secondary analysis explored the relationship between pretreatment inflammatory markers and specific depressive symptoms, clinical measures, and demographic variables in participants with bipolar depression in Pakistan. Methods The current study is a cross-sectional secondary analysis of a randomized controlled trial of two anti-inflammatory medications (minocycline and celecoxib) for bipolar depression (n = 266). A series of logistic and linear regression models were completed to assess the relationship between C-reactive protein (CRP) (CRP > or Results The prevalence of low-grade inflammation (CRP > 3 mg/L) in the sample was 70.9%. After adjusting for baseline body mass index, socioeconomic status, age, gender, symptoms related to anhedonia, fatigue, and motor retardation were most associated with low-grade inflammation. Conclusions Bipolar disorder (BD) patients from LMICs may experience higher rates of peripheral inflammation than have been reported in Western populations with BD. Future trials of repurposed anti-inflammatory agents that enrich for participants with these symptom profiles may inform the development of personalized treatment for bipolar depression in LMICs.
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- 2023
39. Recruiting for a Randomized Clinical Trial for Late-Life Depression During COVID-19: Outcomes of Provider Referrals Versus Facebook Self-Referrals
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Nicholas J. Ainsworth, Hailey Wright, Ksenya Tereshchenko, Daniel M. Blumberger, Alastair J. Flint, Eric J. Lenze, Athina Perivolaris, and Benoit H. Mulsant
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Psychiatry and Mental health ,Geriatrics and Gerontology - Published
- 2023
40. Genomic Investigation of Remission and Relapse of Psychotic Depression Treated with Sertraline plus Olanzapine: The STOP-PD II Study
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Xiaoyu Men, Victoria Marshe, Samar S. Elsheikh, George S. Alexopoulos, Patricia Marino, Barnett S. Meyers, Benoit H. Mulsant, Anthony J. Rothschild, Aristotle N. Voineskos, Ellen M. Whyte, James Lowery Kennedy, Alastair J. Flint, and Daniel J. Müller
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Psychiatry and Mental health ,Neuropsychology and Physiological Psychology ,Biological Psychiatry - Abstract
Introduction: Little is known regarding genetic factors associated with treatment outcome of psychotic depression. We explored genomic associations of remission and relapse of psychotic depression treated with pharmacotherapy. Methods: Genomic analyses were performed in 171 men and women aged 18–85 years with an episode of psychotic depression who participated in the Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II). Participants were treated with open-label sertraline plus olanzapine for up to 12 weeks; those who achieved remission or near-remission and maintained it following 8 weeks of stabilization were eligible to participate in a 36-week randomized controlled trial that compared sertraline plus olanzapine with sertraline plus placebo in preventing relapse. Results: There were no genome-wide significant associations with either remission or relapse. However, at a suggestive threshold, SNP rs1026501 (31 kb from SYNPO2) in the whole sample and rs6844137 (within the intronic region of SYNPO2) in the European ancestry subsample were associated with a decreased likelihood of remission. In polygenic risk analyses, participants who had greater improvement after antidepressant treatments showed a higher likelihood of reaching remission. Those who achieved remission and had a higher polygenic risk for Alzheimer’s disease had a significantly decreased likelihood of relapse. Conclusion: Our analyses provide preliminary insights into the genetic architecture of remission and relapse in a well-characterized group of patients with psychotic depression.
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- 2023
41. Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression
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Eric J. Lenze, Benoit H. Mulsant, Steven P. Roose, Helen Lavretsky, Charles F. Reynolds, Daniel M. Blumberger, Patrick J. Brown, Pilar Cristancho, Alastair J. Flint, Marie A. Gebara, Torie R. Gettinger, Emily Lenard, J. Philip Miller, Ginger E. Nicol, Hanadi A. Oughli, Vy T. Pham, Bruce L. Rollman, Lei Yang, and Jordan F. Karp
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General Medicine - Published
- 2023
42. Major depression, physical health and molecular senescence markers abnormalities
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Johanna Seitz-Holland, Benoit H. Mulsant, Charles F. Reynolds III, Daniel M. Blumberger, Jordan F. Karp, Meryl A. Butters, Ana Paula Mendes-Silva, Erica L. Vieira, George Tseng, Eric J. Lenze, and Breno S. Diniz
- Abstract
Previous studies suggested the role of cellular senescence in late-life depression (LLD). However, it is unclear how this finding relates to common features of LLD, such as medical and cognitive problems. We applied factor analyses to an extensive battery of clinical variables in 426 individuals with LLD. Here we tested the relationship between these factors, age and sex, with an index of cellular senescence based on 22 senescence-associated secretory phenotype proteins. We found four factors: ‘depression and anxiety severity’, ‘cognitive functioning’, ‘cardiovascular and cardiometabolic health’ and ‘blood pressure’. A higher senescence-associated secretory phenotype index was associated with poorer ‘cognitive functioning’ and ‘cardiovascular and cardiometabolic health’ but not with ‘depression and anxiety severity’. These findings highlight the role of cellular senescence in poorer physical and cognitive health in LLD. They are consonant with the viewpoint that co-occurring medical burdens and their associated disabilities are part of a phenotype of accelerated ageing in LLD.
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- 2023
43. Intravenous Ketamine for Late-Life Treatment-Resistant Depression: A Pilot Study of Tolerability, Safety, Clinical Benefits, and Effect on Cognition
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Hanadi Ajam, Oughli, Marie Anne, Gebara, Adam, Ciarleglio, Helen, Lavretsky, Patrick J, Brown, Alastair J, Flint, Nuri B, Farber, Jordan F, Karp, Benoit H, Mulsant, Charles F, Reynolds, Steven P, Roose, Lei, Yang, Meryl A, Butters, and Eric J, Lenze
- Subjects
Psychiatry and Mental health ,Geriatrics and Gerontology - Abstract
Evidence-based treatment options for late-life treatment-resistant depression (TRD) are limited. Ketamine is a promising treatment for TRD; however, there is a paucity of data on its safety and efficacy in older adults.In this pilot clinical trial, 25 adults aged ≥60 years with TRD received IV ketamine openly twice a week for 4 weeks; partial responders at the end of this acute phase were eligible to receive weekly infusions for 4 more weeks in a continuation phase. Acceptability, tolerability, and safety, including adverse and serious adverse events (AEs and SAEs), blood pressure changes, dissociation, craving, in addition to rates of depression response and remission were evaluated. The NIH Toolbox Cognitive Battery was used to assess specific measures of executive function (EF) and overall fluid cognition.Completion rates were 88% for the acute phase and 100% for the continuation phase. No AEs resulted in participant discontinuation, and there were no SAEs. Treatment-emergent elevation of blood pressure, dissociation, and craving were transient and did not result in any participant discontinuation. Depressive symptoms improved significantly and 48% of participants responded. During the acute phase, the EF measures and the fluid cognition composite score improved (Cohen's d = 0.61), and these improvements were sustained in the continuation phase.This pilot study suggests that repeated IV ketamine infusions are well-tolerated and are associated with improvement in depression and EF in older adults with TRD. These promising findings need to be confirmed and extended in a larger randomized controlled trial.
- Published
- 2023
44. Predictors of relapse of psychotic depression: Findings from the STOP-PD II randomized clinical trial
- Author
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Alastair J. Flint, Kathleen S. Bingham, George S. Alexopoulos, Patricia Marino, Benoit H. Mulsant, Nicholas H. Neufeld, Anthony J. Rothschild, Aristotle N. Voineskos, Ellen M. Whyte, and Barnett S. Meyers
- Subjects
Psychiatry and Mental health ,Biological Psychiatry - Abstract
Psychotic depression has a high rate of relapse. The study aims were to identify a prediction model of risk of relapse of psychotic depression and examine whether predictors moderated the effect of treatment on relapse. One hundred and twenty-six men and women aged 18-85 years, who experienced sustained remission or near-remission of psychotic depression with sertraline plus olanzapine, participated in a 36-week randomized controlled trial that compared sertraline plus olanzapine with sertraline plus placebo in preventing relapse (NCT01427608). Cox regression analyses were performed to identify significant predictors of relapse and to model the combined role of significant predictors. Concordance statistic was calculated to determine the accuracy of the best fit multivariable models in predicting relapse. Finally, interaction terms were tested for each significant predictor to examine whether they moderated the effect of treatment on risk of relapse. Lifetime number of depressive episodes, severity of residual depressive symptoms at the time of randomization, and psychomotor disturbance both at acute enrollment when participants were depressed and at the time of randomization predicted risk of relapse. Multivariable models had 69-70% accuracy in predicting relapse. Psychomotor disturbance was associated with increased risk of relapse in the sertraline plus olanzapine group compared with sertraline plus placebo, whereas the other predictors did not moderate the effect of treatment on relapse. Future research is needed to determine whether a combination of clinical and biological variables can further increase the accuracy of prediction of relapse of psychotic depression.
- Published
- 2023
45. Sex-specific associations between lifetime diagnosis of bipolar disorder and cardiovascular disease: A cross-sectional analysis of 257,673 participants from the UK Biobank
- Author
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Abigail Ortiz, Marcos Sanches, Mohamed Abdelhack, Tyler R. Schwaiger, Michael Wainberg, Shreejoy J. Tripathy, Daniel Felsky, Benoit H. Mulsant, and Jess G. Fiedorowicz
- Subjects
Male ,Heart Failure ,Bipolar Disorder ,Coronary Artery Disease ,United Kingdom ,Psychiatry and Mental health ,Clinical Psychology ,Cross-Sectional Studies ,Cardiovascular Diseases ,Risk Factors ,Humans ,Female ,Essential Hypertension ,Biomarkers ,Biological Specimen Banks - Abstract
Sex is seldom considered as a potential moderator of the impact of bipolar disorder (BD) on cardiovascular disease (CVD) risk. We aimed to characterize the sex-specific association of CVD and BD using data from the UK Biobank.In a cross-sectional analysis, we compared the odds ratio between women and men with BD for seven CVD diagnoses (coronary artery disease, myocardial infarction, angina, atrial fibrillation, heart failure, stroke, and essential hypertension) and four cardiovascular biomarkers (arterial stiffness index, low-density lipoprotein, C-reactive protein, and HbA1c) in 293 participants with BD and 257,380 psychiatrically healthy controls in the UK Biobank.After adjusting for age, we found a two- to three-fold stronger association among women than among men between BD and rates of coronary artery disease, heart failure, and essential hypertension, with a significant sex-by-diagnosis interactions. The association remained significant after controlling for self-reported race, education, income, and smoking status. After controlling for potential confounders, there was no significant association between sex and any cardiovascular biomarkers.These analyses could not disentangle effects of BD from its treatment.Our results underscore the importance of incorporating sex and mental illness in risk estimation tools for CVD, and improving screening for, and timely treatment of, CVD in those with BD. Future research is needed to better understand the contributors and mechanisms of sex differences related to CVD risk in BD.
- Published
- 2022
46. A Qualitative Analysis of Suicide Notes to Understand Suicidality in Older Adults
- Author
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Ari B, Cuperfain, Zainab, Furqan, Mark, Sinyor, Benoit H, Mulsant, Kenneth, Shulman, Paul, Kurdyak, and Juveria, Zaheer
- Subjects
Aged, 80 and over ,Ontario ,Suicide ,Psychiatry and Mental health ,Risk Factors ,Mental Disorders ,Loneliness ,Humans ,Geriatrics and Gerontology ,Aged ,Suicidal Ideation - Abstract
Suicide is a complex multifactorial process influenced by a variety of biological, psychological, and social stressors. Many older adults face a characteristic set of challenges that predispose them to suicidal ideation, suicide-related behavior, and death by suicide. This study explored the subjective experience of suicidality through the analysis of suicide notes from older adults.Qualitative study analyzing written suicide notes.Written notes for suicide deaths in Toronto, Canada, between 2003 and 2009 were obtained from the Office of the Chief Coroner for Ontario.The analysis comprised 29 suicide notes (mean words per note: 221; range: 6-1095) written by individuals 65 years and older (mean ± SD age: 76.2 ± 8.3).We employed a constructivist grounded theory framework for the analysis, conducted through line-by-line open coding, axial coding, and theorizing of data to establish themes.Suicide notes elucidated the writers' conception of suicide and their emotional responses to stressors. Expressed narratives contributing to suicide centered on burdensomeness or guilt, experiences of mental illness, loneliness or isolation, and poor physical health or disability. Terms related to pain, poor sleep, apology, and inability to go on were recurrent.Suicide notes enrich our understanding of the thoughts and emotions of those at highest risk of suicide, and they inform potential interventions for reducing suicide risk in older adults.
- Published
- 2022
47. Bipolar I and bipolar <scp>II</scp> subtypes in older age: Results from the Global Aging and Geriatric Experiments in Bipolar Disorder ( <scp>GAGE‐BD</scp> ) project
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Alexandra J. M. Beunders, Federica Klaus, Almar A. L. Kok, Sigfried N. T. M. Schouws, Ralph W. Kupka, Hilary P. Blumberg, Farren Briggs, Lisa T. Eyler, Brent P. Forester, Orestes V. Forlenza, Ariel Gildengers, Esther Jimenez, Benoit H. Mulsant, Regan E. Patrick, Soham Rej, Martha Sajatovic, Kaylee Sarna, Ashley Sutherland, Joy Yala, Eduard Vieta, Luca M. Villa, Nicole C. M. Korten, Annemieke Dols, APH - Mental Health, Psychiatry, APH - Aging & Later Life, Neurology, and Amsterdam Neuroscience - Neurodegeneration
- Subjects
cognition ,Aging ,impairment ,Bipolar Disorder ,Clinical Sciences ,comorbidities ,elderly ,functioning ,Clinical Research ,Humans ,Cognitive Dysfunction ,Aetiology ,Biological Psychiatry ,Aged ,Psychiatry ,geriatrics ,Depression ,Neurosciences ,Serious Mental Illness ,older-age bipolar disorder ,Brain Disorders ,Psychiatry and Mental health ,Cross-Sectional Studies ,Mental Health ,diagnostic subtypes ,2.4 Surveillance and distribution - Abstract
ObjectivesThe distinction between bipolar I disorder (BD-I) and bipolar II disorder (BD-II) has been a topic of long-lasting debate. This study examined differences between BD-I and BD-II in a large, global sample of OABD, focusing on general functioning, cognition and somatic burden as these domains are often affected in OABD.MethodsCross-sectional analyses were conducted with data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database. The sample included 963 participants aged ≥50 years (714 BD-I, 249 BD-II). Sociodemographic and clinical factors were compared between BD subtypes including adjustment for study cohort. Multivariable analyses were conducted with generalized linear mixed models (GLMMs) and estimated associations between BD subtype and (1) general functioning (GAF), (2) cognitive performance (g-score) and (3) somatic burden, with study cohort as random intercept.ResultsAfter adjustment for study cohort, BD-II patients more often had a late onset ≥50 years (p=0.008) and more current severe depression (p=0.041). BD-I patients were more likely to have a history of psychiatric hospitalization (p
- Published
- 2022
48. Symptom Severity Mixity in Older-Age Bipolar Disorder: Analyses From the Global Aging and Geriatric Experiments in Bipolar Disorder Database (GAGE-BD)
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Lisa T. Eyler, Farren B.S. Briggs, Annemiek Dols, Soham Rej, Osvaldo P. Almeida, Alexandra J.M. Beunders, Hilary P. Blumberg, Brent P. Forester, Regan E. Patrick, Orestes V. Forlenza, Ariel Gildengers, Esther Jimenez, Eduard Vieta, Benoit H. Mulsant, Sigfried Schouws, Nadine P.G. Paans, Sergio Strejilevich, Ashley Sutherland, Shangying Tsai, Martha Sajatovic, Neurology, Psychiatry, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Mental Health
- Subjects
Cohort Studies ,Aging ,Mania ,Psychiatry and Mental health ,Bipolar Disorder ,Cross-Sectional Studies ,Humans ,Geriatrics and Gerontology ,Aged - Abstract
Objective: Some individuals with bipolar disorder (BD) experience manic and depressive symptoms concurrently, but data are limited on symptom mixity in older age bipolar disorder (OABD). Using the Global Aging & Geriatric Experiments in Bipolar Disorder Database, we characterized mixity in OABD and associations with everyday function. Methods: The sample (n = 805), from 12 international studies, included cases with both mania and depression severity ratings at a single timepoint. Four mixity groups were created: asymptomatic (A), mixed (Mix), depressed only (Dep), and manic only (Man). Generalized linear mixed models used mixity group as the predictor variable; cohort was included as a random intercept. Everyday function was assessed with the Global Assessment of Functioning score. Results: Group proportions were Mix (69.6%; n = 560), followed by Dep (18.4%; n = 148), then A (7.8%; n = 63), then Man (4.2%; n= 34); levels of depression and mania were similar in Mix compared to Dep and Man, respectively. Everyday function was lowest in Mix, highest in A, and intermediate in Man and Dep. Within Mix, severity of depression was the main driver of worse functioning. Groups differed in years of education, with A higher than all others, but did not differ by age, gender, employment status, BD subtype, or age of onset. Conclusions: Mixed features predominate in a cross-sectional, global OABD sample and are associated with worse everyday function. Among those with mixed symptoms, functional status relates strongly to current depression severity. Future studies should include cognitive and other biological variables as well as longitudinal designs to allow for evaluation of causal effects.
- Published
- 2022
49. Predicting Medication Nonadherence in Older Adults With Difficult-to-Treat Depression in the IRL-GRey Randomized Controlled Trial
- Author
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Helene M, Altmann, Joseph, Kazan, Marie Anne, Gebara, Daniel M, Blumberger, Jordan F, Karp, Eric J, Lenze, Benoit H, Mulsant, Charles F, Reynolds, and Sarah T, Stahl
- Subjects
Depressive Disorder, Major ,Psychiatry and Mental health ,Depression ,Venlafaxine Hydrochloride ,Humans ,Geriatrics and Gerontology ,Antidepressive Agents ,Aged ,Medication Adherence - Abstract
Nonadherence to antidepressants interferes with optimal treatment of late-life depression. This analysis examines clinical and treatment factors predicting medication nonadherence in difficult-to-treat late-life depression.Secondary analysis of data from a clinical trial of antidepressant pharmacotherapy for Major Depressive Disorder in 468 adults aged 60+ years. All participants received venlafaxine XR for 12 weeks. Nonremitters were randomized to augmentation with either aripiprazole or placebo for 12 additional weeks. Medication adherence was assessed 14 times over 24 weeks. The analyses examined sociodemographic, clinical, and treatment factors that may predict antidepressant nonadherence during early (weeks 1-6), late (weeks 7-12), and augmentation (weeks 13--24) treatment.Poor cognitive function and early response were predictive of early nonadherence. Poor cognitive function and prior nonadherence were predictive of late nonadherence. Living alone was associated with nonadherence both late and during augmentation treatment.Future studies should consider the role of early response and cognitive function to improve antidepressant adherence, particularly among older adults who live alone.
- Published
- 2022
50. Identification of Endocannabinoid Predictors of Treatment Outcomes in Major Depressive Disorder: A Secondary Analysis of the First Canadian Biomarker Integration Network in Depression (CAN-BIND 1) Study
- Author
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Helena K. Kim, Gwyneth Zai, Daniel J. Müller, Muhammad I. Husain, Raymond W. Lam, Benicio N. Frey, Claudio N. Soares, Sagar V. Parikh, Roumen Milev, Jane A. Foster, Gustavo Turecki, Faranak Farzan, Benoit H. Mulsant, Sidney H. Kennedy, Shreejoy J. Tripathy, and Stefan Kloiber
- Subjects
Canada ,Depressive Disorder, Major ,Aripiprazole ,General Medicine ,Psychiatry and Mental health ,Treatment Outcome ,Escitalopram ,Double-Blind Method ,Humans ,Pharmacology (medical) ,RNA, Messenger ,Biomarkers ,Endocannabinoids ,Genome-Wide Association Study - Abstract
Introduction An increasing number of studies are examining the link between the endocannabinoidome and major depressive disorder (MDD). We conducted an exploratory analysis of this system to identify potential markers of treatment outcomes. Methods The dataset of the Canadian Biomarker Integration Network in Depression-1 study, consisting of 180 patients with MDD treated for eight weeks with escitalopram followed by eight weeks with escitalopram alone or augmented with aripiprazole was analyzed. Association between response Montgomery-Asberg Depression Rating Scale (MADRS; score reduction≥50%) or remission (MADRS score≤10) at weeks 8 and 16 and single nucleotide polymorphisms (SNPs), methylation, and mRNA levels of 33 endocannabinoid markers were examined. A standard genome-wide association studies protocol was used for identifying SNPs, and logistic regression was used to assess methylation and mRNA levels. Results Lower methylation of CpG islands of the diacylglycerol lipase alpha gene (DAGLA) was associated with non-remission at week 16 (DAGLA; OR=0.337, p Discussion Methylation of DAGLA is a promising candidate as a marker of treatment outcomes for MDD and needs to be explored further.
- Published
- 2022
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