Publications by authors named "Benoit Mulsant"

448 Publications

Assessing the Longitudinal Relationship between Theta-Gamma Coupling and Working Memory Performance in Older Adults.

Cereb Cortex 2021 Sep 14. Epub 2021 Sep 14.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto M6J 1H4, Canada.

Theta-gamma coupling (TGC) is a neurophysiologic mechanism that supports working memory (WM). TGC is associated with N-back performance, a WM task. Similar to TGC, theta and alpha event-related synchronization (ERS) and desynchronization (ERD) are also associated with WM. Few studies have examined the longitudinal relationship between WM performance and TGC, ERS, or ERD. This study aimed to determine if changes in WM performance are associated with changes in TGC (primary aim), as well as theta and alpha ERS or ERD over 6 to 12 weeks. Participants included 62 individuals aged 60 and older with no neuropsychiatric conditions or with remitted Major Depressive Disorder (MDD) and no cognitive disorders. TGC, ERS, and ERD were assessed using electroencephalography (EEG) during the N-back task (3-back condition). There was an association between changes in 3-back performance and changes in TGC, alpha ERD and ERS, and theta ERS in the control group. In contrast, there was only a significant association between changes in 3-back performance and changes in TGC in the subgroup with remitted MDD. Our results suggest that the relationship between WM performance and TGC is stable over time, while this is not the case for changes in theta and alpha ERS and ERD.
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http://dx.doi.org/10.1093/cercor/bhab295DOI Listing
September 2021

Efficacy and acceptability of pharmacotherapy for comorbid anxiety symptoms in bipolar disorder: A systematic review and meta-analysis.

Bipolar Disord 2021 Sep 10. Epub 2021 Sep 10.

Centre for Addiction and Mental Health, Toronto, ON, Canada.

Objective: Anxiety symptoms are highly prevalent among individuals with bipolar disorder (BD) but there is little guidance on pharmacotherapy for these symptoms. The objective of this systematic review and meta-analysis was to evaluate the available evidence for pharmacotherapy of comorbid anxiety symptoms in BD.

Methods: Completed randomized clinical trials (RCTs) of medications for BD published prior to December 2020 were identified through a systematic search of MEDLINE, Embase, PsycInfo, Web of Science, clinicaltrials.gov, and the ISRCTN. Data from RCTs measuring anxiety symptoms at baseline and endpoint and all-cause discontinuation were pooled to compare the efficacy and acceptability of medications with control conditions.

Results: Thirty-seven RCTs met our inclusion criteria; 13 placebo-controlled RCTs with 2175 participants had sufficient data to be included in the meta-analysis assessing anxiety symptoms. Compared with placebo, the overall effect size of medications (primarily atypical antipsychotics) on anxiety symptoms was small with a standardized mean difference (SMD) = -0.22 (95% CI: -0.34 to -0.11). Study heterogeneity was low (I  = 26%). The acceptability of these medications was comparable with placebo with odds ratio of discontinuation from all causes = 0.98 (95% CI: 0.91-1.06).

Conclusion: There is limited evidence for a small anxiolytic effect and good acceptability of pharmacotherapy (primarily atypical antipsychotics) in the treatment of comorbid anxiety symptoms in BD. These results highlight the need for further research on medications other than atypical antipsychotics.
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http://dx.doi.org/10.1111/bdi.13125DOI Listing
September 2021

Dorsolateral prefrontal cortex excitability abnormalities in Alzheimer's Dementia: Findings from transcranial magnetic stimulation and electroencephalography study.

Int J Psychophysiol 2021 Sep 6. Epub 2021 Sep 6.

Centre for Addiction and Mental Health, Toronto, Canada; Temerty Faculty of Medicine, University of Toronto, Toronto, Canada; Toronto Dementia Research Alliance, Toronto, Canada. Electronic address:

There is some evidence of cortical hyper-excitability in Alzheimer's Dementia (AD) but its relationship with cognition is not clear. In this study, we assessed dorsolateral prefrontal cortex (DLPFC) excitability and its relationship with cognition in AD. Twenty-four participants with AD (mean [SD] age = 74.1 [7.2] years) and eleven elderly healthy controls (HC) (mean [SD] age = 68.8 [7.3] years) were recruited. Transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) was used to assess cortical excitability. Cortical evoked activity (CEA) between 25 and 80 ms post-TMS stimulus was calculated as the primary measure of cortical excitability. TMS-evoked potential peak (TEP) amplitudes (P30, N45 and P60) were also calculated. Cognition was assessed using Montreal Cognitive Assessment (MoCA), Executive Interview (EXIT) and Cambridge Neuropsychological Test Automated Battery Stockings of Cambridge (SOC). There was no difference in TMS stimulus intensity between the groups. DLPFC-CEA was higher in the AD (mean [SD] = 134.64 [90.22] μV) than the HC group (mean [SD] = 82.65 [40.28] μV; t = 2.357, p = 0.025). There were no differences in TEP peak amplitudes between the groups. Further, DLPFC-CEA was inversely associated with MoCA and SOC, and positively associated with EXIT scores in AD. These results suggest increased DLPFC excitability in AD, and its inverse associations with global cognition and executive function. Future studies should examine these findings in larger samples and longitudinally, and could also assess these markers of cortical excitability in relation to other established markers of AD and in response to interventions.
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http://dx.doi.org/10.1016/j.ijpsycho.2021.08.008DOI Listing
September 2021

Antidepressant treatment outcomes in patients with and without comorbid physical or psychiatric disorders: A systematic review and meta-analysis.

J Affect Disord 2021 Aug 26;295:225-234. Epub 2021 Aug 26.

Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of California San Diego School of Medicine, Biomedical Sciences Building, School of Medicine 9500 Gilman Drive, San Diego, California 92093-0603, United States. Electronic address:

Background: Many patients with major depressive disorder (MDD) experience substantial impairment despite the availability of efficacious treatments. We performed a systematic review and meta-analysis to compare antidepressant outcomes in MDD with or without physical or psychiatric comorbidities.

Methods: Pubmed, EMBASE, and PsycInfo were searched up to May 14th, 2020 using keywords including MDD, antidepressant, medication, and comorbid. 1915 studies were reviewed. Studies that performed a direct and quantitative comparison of antidepressant effect in patients with MDD with or without comorbidities were included. Study characteristics and primary outcomes were extracted. Continuous and dichotomous variables were considered using standardized mean difference (SMD). Heterogeneity was measured using χ and I tests. Risk of bias was assessed using Cochrane Risk of Bias tool and NIH Quality Assessment Tool.

Results: 26 studies met selection criteria. Studies of physical (6 studies; I = 57.69%, p = 0.04) and psychiatric comorbidities (20 studies; I = 75.75%, p < 0.001) were heterogeneous. When compared to patients with MDD without comorbidities, those with physical (SMD = -0.19, 95% CI: -0.30 to -0.08, p = 0.001; 1910 and 2905 patients with or without comorbidities) or psychiatric comorbidities (SMD = -0.20, 95% CI: -0.31 to -0.095, p < 0.001; 4308 and 6867 patients with or without comorbidities) had worse antidepressant outcomes.

Limitations: Our limitations included aggregating the comorbidities into physical and psychiatric comorbidities and the high heterogeneity of the studies.

Conclusions: Our review provides updated evidence demonstrating that patients with MDD and physical or psychiatric comorbidities experience worse antidepressant outcomes.
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http://dx.doi.org/10.1016/j.jad.2021.08.046DOI Listing
August 2021

Targeting Metabolic Dysfunction for the Treatment of Mood Disorders: Review of the Evidence.

Life (Basel) 2021 Aug 11;11(8). Epub 2021 Aug 11.

Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada.

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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http://dx.doi.org/10.3390/life11080819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401631PMC
August 2021

Bipolar symptoms, somatic burden, and functioning in older-age bipolar disorder: Analyses from the Global Aging & Geriatric Experiments in Bipolar Disorder Database project.

Bipolar Disord 2021 Jul 27. Epub 2021 Jul 27.

Department of Psychiatry, University of California San Diego, San Diego, CA, USA.

Objective: Literature on older-age bipolar disorder (OABD) is limited. This first-ever analysis of the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) investigated associations among age, BD symptoms, comorbidity, and functioning.

Methods: This analysis used harmonized, baseline, cross-sectional data from 19 international studies (N = 1377). Standardized measures included the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), and Global Assessment of Functioning (GAF).

Results: Mean sample age was 60.8 years (standard deviation [SD] 12.2 years), 55% female, 72% BD I. Mood symptom severity was low: mean total YMRS score of 4.3 (SD 5.4) and moderate-to-severe depression in only 22%. Controlled for sample effects, both manic and depressive symptom severity appeared lower among older individuals (p's < 0.0001). The negative relationship between older age and symptom severity was similar across sexes, but was stronger among those with lower education levels. GAF was mildly impaired (mean =62.0, SD = 13.3) and somatic burden was high (mean =2.42, SD = 1.97). Comorbidity burden was not associated with GAF. However, higher depressive (p < 0.0001) and manic (p < 0.0001) symptoms were associated with lower GAF, most strongly among older individuals.

Conclusions: Findings suggest an attenuation of BD symptoms in OABD, despite extensive somatic burden. Depressive symptom severity was strongly associated with worse functioning in older individuals, underscoring the need for effective treatments of BD depression in older people. This international collaboration lays a path for the development of a better understanding of aging in BD.
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http://dx.doi.org/10.1111/bdi.13119DOI Listing
July 2021

Transcranial magnetic stimulation indices of cortical excitability enhance the prediction of response to pharmacotherapy in late-life depression.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Jul 23. Epub 2021 Jul 23.

Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Ontario, M6J 1H4, Canada;; Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, M5T 1R8, Canada;; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8, Canada;. Electronic address:

Background: Older adults with late-life depression (LLD) often experience incomplete or lack of response to first-line pharmacotherapy. The treatment of LLD could be improved using objective biological measures to predict response. Transcranial magnetic stimulation (TMS) can be used to measure cortical excitability, inhibition, and plasticity, which have been implicated in LLD pathophysiology, and associated with brain stimulation treatment outcomes in younger adults with depression. TMS measures have not yet been investigated as predictors of treatment outcomes in LLD, or pharmacotherapy outcomes in adults of any age with depression.

Methods: We assessed whether pre-treatment single-pulse and paired-pulse TMS measures, combined with clinical and demographic measures, predict venlafaxine treatment response in 76 outpatients with LLD. We compared the predictive performance of machine learning models including or excluding TMS predictors.

Results: Two single-pulse TMS measures predicted venlafaxine response: cortical excitability (neuronal membrane excitability), and the variability of cortical excitability (dynamic fluctuations in excitability levels). In cross-validation, models using a combination of these TMS predictors, clinical markers of treatment resistance, and age, classified patients with 73±11% balanced accuracy (average correct classification rate of responders and non-responders; permutation testing, p<0.005); these models significantly outperformed (corrected t-test, p=0.025) models using clinical and demographic predictors alone (60±10% balanced accuracy).

Conclusions: These preliminary findings suggest that single-pulse TMS measures of cortical excitability may be useful predictors of response to pharmacotherapy in LLD. Future studies are needed to confirm these findings and determine whether combining TMS predictors with other biomarkers further improves the accuracy of predicting LLD treatment outcome.
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http://dx.doi.org/10.1016/j.bpsc.2021.07.005DOI Listing
July 2021

Relationship between childhood trauma, personality, social support and depression in women attending general medical clinics in a low and middle-income country.

J Affect Disord 2021 09 11;292:526-533. Epub 2021 Jun 11.

University of Manchester, Manchester, UK.

Background: Associations between childhood trauma, personality, and Major Depressive Disorder (MDD) have been well established in studies conducted in high-income countries. However, there are limited studies on these associations in low and middle-income countries (LMICs), where MDD is highly prevalent. We assessed the relationships between childhood trauma, personality, and MDD in women in Karachi, Pakistan.

Method: In this cross-sectional study of 455 female patients attending general medical outpatient clinics, a diagnosis of MDD was confirmed using the Structured Clinical Interview for DSM-IV (SCID); retrospective reports of childhood trauma were collected using the childhood trauma questionnaire (CTQ); and Big Five personality traits were assessed using the NEO Personality Inventory Revised (NEO PI-R). Other measures included the Life Events Questionnaire (LEQ) and the Multidimensional Scale of Perceived Social Support (MSPSS). Factors independently associated with MDD were determined using logistic regression analyses.

Results: Of the 455 women recruited between August 1, 2011 and July 31, 2013, 242 (53%) had a diagnosis of MDD. Women with MDD were significantly more likely to be separated, had more stressful life events and higher CTQ scores. Higher perceived social support, conscientiousness and extraversion were independently associated with significantly reduced odds of MDD. There were no significant associations between CTQ scores and any of the NEO PI-R subscales.

Limitations: Ratings of childhood trauma were based on retrospective recall.

Conclusion: MDD and a history of childhood trauma were highly prevalent in Pakistani women attending general medical clinics. Interventions to prevent childhood trauma and promote social support in women may improve public mental health in LMICs like Pakistan.
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http://dx.doi.org/10.1016/j.jad.2021.06.010DOI Listing
September 2021

Evolutionary theory and the treatment of depression: It is all about the squids and the sea bass.

Behav Res Ther 2021 08 27;143:103849. Epub 2021 Mar 27.

Centre for Addiction and Mental Health & Department of Psychiatry, University of Toronto, Canada.

According to the analytical rumination hypothesis, depression is an evolved adaptation (like pain or anxiety) that served in our ancestral past to keep people focused on complex interpersonal problems until they could arrive at a resolution (spontaneous remission). If this is true, then those clinical treatments that most facilitate the functions that depression evolved to serve are likely to be more advantageous in the long run than others that simply relieve distress. For example, antidepressant medications may be efficacious in the treatment of depression but only work for so long as they are taken. They may also have an iatrogenic effect that prolongs the duration of the underlying episode. Cognitive and behavioral interventions are as efficacious as medications in terms of reducing acute distress and also appear to have an enduring effect that protects against the return of subsequent symptoms. However, the bulk of the evidence for this effect comes from comparisons to prior medication treatment and it remains unclear whether these psychosocial interventions are truly preventative, or antidepressant medications iatrogenic. A study is described that could resolve this issue and test evolutionary theory with respect to the purported role of rumination in bringing about spontaneous remission.
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http://dx.doi.org/10.1016/j.brat.2021.103849DOI Listing
August 2021

Diagnostic Precision in the Detection of Mild Cognitive Impairment: A Comparison of Two Approaches.

Am J Geriatr Psychiatry 2021 Apr 14. Epub 2021 Apr 14.

Department of Psychiatry (AJF, JLK, LM, BGP, TKR, BH, University of Toronto, Toronto, Ontario, Canada; Centre for Addiction and Mental Health (CRB, JLK, SO, BGP, TKR, BHM), Toronto, Ontario, Canada.

Objective: This study compared diagnostic rates and clinical predictors of discrepancies between diagnoses conferred via: 1) a comprehensive neuropsychological evaluation and National Institute on Aging-Alzheimer's Association (NIA-AA) criteria versus 2) a cognitive screener and Diagnostic Statistical Manual of Mental Disorders (DSM-5) criteria.

Design: Cross-sectional examination of baseline data from the Prevention of Alzheimer's dementia (AD) using Cognitive remediation and transcranial direct current stimulation in Mild Cognitive Impairment (MCI) and Depression (PACt-MD; ClinicalTrials.gov Identifier: NCT02386670) trial.

Setting: Five geriatric psychiatry and memory clinics located at academic hospitals affiliated with the Department of Psychiatry, University of Toronto.

Participants: Older adults (N = 431) with a history of major depressive disorder (MDD) in remission, MCI, or both.

Measurements: Main outcome was a comparison of NIA-AA diagnostic rates of MCI or dementia versus DSM-5 rates of mild or major neurocognitive disorder. Secondary analyses examined demographic, race, gender, premorbid intellectual ability, psychosocial, health-related, and genetic predictors of discrepancy between DSM-5 and NIA-AA diagnoses.

Results: There were 103 (23.8%) discrepant cases, with most (91; 88.3%) of these discrepant cases reflecting more impairment with the detailed neuropsychological testing and NIA-AA criteria. Discrepancies were more likely in individuals with a history of MDD or who had at least one ApoE4 allele.

Conclusion: The NIA-AA criteria, in conjunction with comprehensive neuropsychological testing, identified a greater prevalence of cognitive impairment than DSM-5 criteria, in conjunction with the Montreal Cognitive Assessment. Detailed neuropsychological evaluations are recommended for older adults who have a history of MDD or a genetic vulnerability to dementia.
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http://dx.doi.org/10.1016/j.jagp.2021.04.004DOI Listing
April 2021

Impact of COVID-19 on motor vehicle injuries and fatalities in older adults in Ontario, Canada.

Accid Anal Prev 2021 Jul 18;157:106195. Epub 2021 May 18.

Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Canada; Centre for Addiction and Mental Health, Toronto, Canada.

Background: Older adults constitute the group most vulnerable to COVID-19 mortality. As a result, in North America and elsewhere, older adults have been strongly advised to shelter in place. Older adults also represent the fastest growing segment of licensed drivers.

Objective: We examined the change in injuries and fatalities sustained by younger and older drivers and pedestrians during the first month of the COVID-19 pandemic. We hypothesized that adults ages 80 years and over would have a proportionally larger reduction than the other drivers and pedestrians.

Methods: Using a cohort design, we compared the proportion of drivers and pedestrians involved in injuries and fatalities attributable to individuals aged 80 years and over, as recorded in the Ministry of Transportation of Ontario (Canada) database, between the 30 days prior to shelter-in-place related to the COVID-19 pandemic and the subsequent 30 days. By way of comparison, we conducted a similar comparison for younger age cohorts (16-24 years, 25-34 years, 35-54 years, 55-64 years, and 65-79 years).

Results: Drivers aged 80 years and over represented 21 per 1000 injuries and fatalities in the 30 days prior to March 17, 2020 (95 % CI: 15-29), and 8 per 1000 injuries and fatalities in the 30 days beginning on that date (95 % CI: 2-20), a 64.7 % reduction (exp (β) post 0.353, 95 % CI 0.105-0.892). Drivers in the 35-54 year age range underwent a significant but smaller reduction of 22.9 %; no significant changes were seen for drivers in other age groups, or for pedestrians of any age.

Conclusions And Relevance: The physical distancing measures that aimed to reduce the spread of COVID-19 resulted in a marked reduction in driver injuries and fatalities in the oldest old, illustrating the impact of physical distancing recommendations in this population. The excess mortality burden faced by the oldest adults during the COVID-19 pandemic, by direct exposure to the virus, may be indirectly mitigated by the reduction in road-related deaths in this cohort.
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http://dx.doi.org/10.1016/j.aap.2021.106195DOI Listing
July 2021

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.

Front Psychiatry 2021 23;12:563906. Epub 2021 Apr 23.

Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

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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http://dx.doi.org/10.3389/fpsyt.2021.563906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102788PMC
April 2021

An update on antidepressant pharmacotherapy in late-life depression.

Expert Opin Pharmacother 2021 Jun 19:1-9. Epub 2021 Jun 19.

Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Canada.

: Clinically important depressive symptoms that occur in adults over age 60 are often termed late-life depression (LLD). LLD poses challenges for treating clinicians in both detection and treatment. Antidepressants are the most common first-line treatment approach. Older adults are at an increased risk of adverse effects because of polypharmacy.: This article summarizes the challenges and approaches when using pharmacotherapy in LLD with a focus on newer data that have become available during the last five years. While no new antidepressants have become available during this period, a review of the literature summarizes advances in the knowledge of the adverse effects associated with various antidepressants and on the potential contribution of pharmacogenetic tools when prescribing antidepressants to older patients.: During the past 5 years, most of the literature relevant to the pharmacotherapy of MDD in older patients has focused on adverse effects. In particular, the effects of antidepressants on cognition and bone are emerging as important areas for clinical attention and further investigation. There is also an emerging literature on the potential role of pharmacogenetic testing in patients with MDD, though recommendations for use in older adults await larger studies that demonstrate its efficacy and cost-effectiveness.
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http://dx.doi.org/10.1080/14656566.2021.1921736DOI Listing
June 2021

An update on antidepressant pharmacotherapy in late-life depression.

Expert Opin Pharmacother 2021 Jun 19:1-9. Epub 2021 Jun 19.

Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Canada.

: Clinically important depressive symptoms that occur in adults over age 60 are often termed late-life depression (LLD). LLD poses challenges for treating clinicians in both detection and treatment. Antidepressants are the most common first-line treatment approach. Older adults are at an increased risk of adverse effects because of polypharmacy.: This article summarizes the challenges and approaches when using pharmacotherapy in LLD with a focus on newer data that have become available during the last five years. While no new antidepressants have become available during this period, a review of the literature summarizes advances in the knowledge of the adverse effects associated with various antidepressants and on the potential contribution of pharmacogenetic tools when prescribing antidepressants to older patients.: During the past 5 years, most of the literature relevant to the pharmacotherapy of MDD in older patients has focused on adverse effects. In particular, the effects of antidepressants on cognition and bone are emerging as important areas for clinical attention and further investigation. There is also an emerging literature on the potential role of pharmacogenetic testing in patients with MDD, though recommendations for use in older adults await larger studies that demonstrate its efficacy and cost-effectiveness.
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http://dx.doi.org/10.1080/14656566.2021.1921736DOI Listing
June 2021

Relationships Between a New Cultured Cell-Based Serum Anticholinergic Activity Assay and Anticholinergic Burden Scales or Cognitive Performance in Older Adults.

Am J Geriatr Psychiatry 2021 Mar 18. Epub 2021 Mar 18.

Centre for Addiction and Mental Health (SC, NA, RR, JNN, WW, SK, BHM, BGP, TKR), Toronto, Canada; Department of Psychiatry (JNB, WW, CEF, AJF, NH, SK, KL, LM, BHM, BGP, TKR), University of Toronto, Toronto, Canada; Toronto Dementia Research Alliance (CEF, SK, KL, BHM, BGP, TKR), University of Toronto, Canada. Electronic address:

Objectives: Anticholinergic burden has been associated with deleterious effects on cognition particularly in those with an underlying brain disorder. We developed a new assay based on cultured cells to measure serum anticholinergic activity (cSAA). We report on its relationships with established anticholinergic burden rating scales and cognitive assessments in older patients with mild cognitive impairment (MCI) or major depressive disorder (MDD) in remission or both.

Design: The study was cross sectional in nature.

Setting: This was a five-centre study conducted in Toronto, Canada.

Participants: Serum samples were collected and cSAA levels were measured in 311 participants aged 60 years or older (154 with MCI, 57 with MDD, and 100 with MCI + MDD).

Measurements: The cSAA assay uses radio-ligand binding to cultured cells stably expressing the muscarinic M1 receptors, with an added procedure to remove potential confounds associated with serum proteins. Lists of medications were used to calculate Anticholinergic Burden and Anticholinergic Drug Scale total scores. Participants also completed a comprehensive cognitive battery.

Results: Higher cSAA levels were associated with higher anticholinergic burden and anticholinergic drug scale scores, and also with lower performance on executive function tests, after adjusting for age, gender, education, and diagnosis.

Conclusions: These results support the use of the cSAA assay as a laboratory measure of anticholinergic burden.
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http://dx.doi.org/10.1016/j.jagp.2021.03.002DOI Listing
March 2021

Reduced heart rate variability is associated with higher illness burden in bipolar disorder.

J Psychosom Res 2021 Jun 30;145:110478. Epub 2021 Mar 30.

Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health, Toronto, ON, Canada.

Background: Bipolar disorder (BD) is associated with premature death and ischemic heart disease is the main cause of excess mortality. Heart rate variability (HRV) predicts mortality in patients with or without cardiovascular disease. While several studies have analyzed the association between HRV and BD, none has analyzed the association of HRV with illness burden in BD.

Methods: 53 participants with BD I and II used a wearable device to assess the association between HRV and factors characterizing illness burden, including illness duration, number and type of previous episode(s), duration of the most severe episode, history of suicide attempts or psychotic symptoms during episodes, and co-morbid psychiatric disorders. We ran unadjusted models and models controlling statistically for age, sex, pharmacotherapy, baseline functional cardiovascular capacity, BMI, years of education, and marital status. We also explored the association between HRV and an overall illness burden index (IBI) integrating all these factors using a weighted geometric mean.

Results: Adjusted and unadjusted models had similar results. Longer illness duration, higher number of depressive episodes, longer duration of most severe manic/hypomanic episode, co-morbid anxiety disorders, and family history of suicide were associated with reduced HRV, as was bipolar depression severity in the participants experiencing a depressive episode. Finally, a higher IBI score was associated with lower HRV.

Conclusions: High illness burden is associated with reduced HRV in BD. While the IBI needs to be validated in a larger sample, it may provide an overall measure that captures illness burden in BD.
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http://dx.doi.org/10.1016/j.jpsychores.2021.110478DOI Listing
June 2021

Mild cognitive impairment and major depressive disorder are associated with molecular senescence abnormalities in older adults.

Alzheimers Dement (N Y) 2021 31;7(1):e12129. Epub 2021 Mar 31.

Adult Neurodevelopment and Geriatric Psychiatry Division Centre for Addiction and Mental Health (CAMH) Toronto Ontario Canada.

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 ( < .001). A higher SASP index was significantly associated with worse global cognitive performance, executive dysfunction, slower processing speed, and episodic memory deficits.

Discussion: Our study suggests that increased molecular changes are associated with cognitive impairment in older adults with MDD and indicate that accelerated biological aging is an underlying feature of MDD.
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http://dx.doi.org/10.1002/trc2.12129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012242PMC
March 2021

Comparing cardiovascular risk factors in older persons with mild cognitive impairment and lifetime history of major depressive disorder.

Int Psychogeriatr 2021 Mar 29:1-7. Epub 2021 Mar 29.

Department of Psychiatry, University of Toronto, Toronto, Canada.

Objectives: To compare the prevalence of select cardiovascular risk factors (CVRFs) in patients with mild cognitive impairment (MCI) versus lifetime history of major depression disorder (MDD) and a normal comparison group using baseline data from the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study.

Design: Baseline data from a multi-centered intervention study of older adults with MCI, history of MDD, or combined MCI and history of MDD (PACt-MD) were analyzed.

Setting: Community-based multi-centered study based in Toronto across 5 academic sites.

Participants: Older adults with MCI, history of MDD, or combined MCI and history of MDD and healthy controls.

Measurements: We examined the baseline distribution of smoking, hypertension and diabetes in three groups of participants aged 60+ years in the PACt-MD cohort study: MCI (n = 278), MDD (n = 95), and healthy older controls (n = 81). Generalized linear models were fitted to study the effect of CVRFs on MCI and MDD as well as neuropsychological composite scores.

Results: A higher odds of hypertension among the MCI cohort compared to healthy controls (p < .05) was noted in unadjusted analysis. Statistical significance level was lost on adjusting for age, sex and education (p > .05). A history of hypertension was associated with lower performance in composite executive function (p < .05) and overall composite neuropsychological test score (p < .05) among a pooled cohort with MCI or MDD.

Conclusions: This study reinforces the importance of treating modifiable CVRFs, specifically hypertension, as a means of mitigating cognitive decline in patients with at-risk cognitive conditions.
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http://dx.doi.org/10.1017/S1041610221000259DOI Listing
March 2021

Association between psychomotor disturbance and treatment outcome in psychotic depression: a STOP-PD II report.

Psychol Med 2021 Mar 26:1-7. Epub 2021 Mar 26.

Department of Psychiatry, Weill Cornell Medicine of Cornell University and New York Presbyterian Hospital, Westchester Division, New York, NY, USA.

Background: Little is known about the relationship between psychomotor disturbance (PMD) and treatment outcome of psychotic depression. This study examined the association between PMD and subsequent remission and relapse of treated psychotic depression.

Methods: Two hundred and sixty-nine men and women aged 18-85 years with an episode of psychotic depression were treated with open-label sertraline plus olanzapine for up to 12 weeks. Participants who remained in remission or near-remission following an 8-week stabilization phase were eligible to participate in a 36-week randomized controlled trial (RCT) that compared the efficacy and tolerability of sertraline plus olanzapine (n = 64) with sertraline plus placebo (n = 62). PMD was measured with the psychiatrist-rated sign-based CORE at acute phase baseline and at RCT baseline. Spearman's correlations and logistic regression analyses were used to analyze the association between CORE total score at acute phase baseline and remission/near-remission and CORE total score at RCT baseline and relapse.

Results: Higher CORE total score at acute phase baseline was associated with lower frequency of remission/near-remission. Higher CORE total score at RCT baseline was associated with higher frequency of relapse, in the RCT sample as a whole, as well as in each of the two randomized groups.

Conclusions: PMD is associated with poorer outcome of psychotic depression treated with sertraline plus olanzapine. Future research needs to examine the neurobiology of PMD in psychotic depression in relation to treatment outcome.
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http://dx.doi.org/10.1017/S0033291721000805DOI Listing
March 2021

The use of sequential pharmacotherapy for the treatment of acute major depression: a scoping review.

Expert Opin Pharmacother 2021 Jun 22;22(8):1005-1014. Epub 2021 Feb 22.

Department of Psychiatry, University of Toronto, Toronto, Canada.

Introduction: Major Depressive Disorder (MDD) is a chronic, relapsing, and remitting disorder affecting over 250 million persons each year worldwide. More than 50% of the patients do not respond to their initial antidepressant treatment and may benefit from sequential pharmacotherapy for the acute treatment of their MDD. Although guidelines outline options for next-step treatments, there is a paucity of evidence to select specific second- or third-step treatments.

Areas Covered: This scoping review synthesizes and discusses available evidence for sequential pharmacotherapy for MDD. MEDLINE was searched from inception to 7 July 2020; 4490 studies were identified. We selected meta-analyses and reports on clinical trials that were judged to inform the sequential selection of pharmacotherapy for MDD.

Expert Opinion: Most relevant published trials are focused on, and support, the use of augmentation pharmacotherapy. There is also some support for other strategies such as combining or switching antidepressants. In the future, more studies need to directly compare these sequential options. To provide more personalized treatment within the framework of precision psychiatry, these studies should include an assessment of moderators and mediators ('mechanism') of antidepressant response.
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http://dx.doi.org/10.1080/14656566.2021.1878144DOI Listing
June 2021

Individual Differences in Response to Antidepressants: A Meta-analysis of Placebo-Controlled Randomized Clinical Trials.

JAMA Psychiatry 2021 May;78(5):490-497

Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Importance: Antidepressants are commonly used to treat major depressive disorder (MDD). Antidepressant outcomes can vary based on individual differences; however, it is unclear whether specific factors determine this variability or whether it is at random.

Objective: To investigate the assumption of systematic variability in symptomatic response to antidepressants and to assess whether variability is associated with MDD severity, antidepressant class, or study publication year.

Data Sources: Data used were updated from a network meta-analysis of treatment with licensed antidepressants in adults with MDD. The Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, and PsycInfo were searched from inception to March 21, 2019. Additional sources were international trial registries and sponsors, drug companies and regulatory agencies' websites, and reference lists of published articles. Data were analyzed between June 8, 2020, and June 13, 2020.

Study Selection: Analysis was restricted to double-blind, randomized placebo-controlled trials with depression scores available at the study's end point.

Data Extraction And Synthesis: Baseline means, number of participants, end point means and SDs of total depression scores, antidepressant type, and publication year were extracted.

Main Outcomes And Measures: Log SDs (bln σ̂) were derived for treatment groups (ie, antidepressant and placebo). A random-slope mixed-effects model was conducted to estimate the difference in bln σ̂ between treatment groups while controlling for end point mean. Secondary models determined whether differences in variability between groups were associated with baseline MDD severity; antidepressant class (selective serotonin reuptake inhibitors and other related drugs; serotonin and norepinephrine reuptake inhibitors; norepinephrine-dopamine reuptake inhibitors; noradrenergic agents; or other antidepressants); and publication year.

Results: In the 91 eligible trials (18 965 participants), variability in response did not differ significantly between antidepressants and placebo (bln σ̂, 1.02; 95% CI, 0.99-1.05; P = .19). This finding is consistent with a range of treatment effect SDs (up to 16.10), depending on the association between the antidepressant and placebo effects. Variability was not associated with baseline MDD severity or publication year. Responses to noradrenergic agents were 11% more variable than responses to selective serotonin reuptake inhibitors (bln σ̂, 1.11; 95% CI, 1.01-1.21; P = .02).

Conclusions And Relevance: Although this study cannot rule out the possibility of treatment effect heterogeneity, it does not provide empirical support for personalizing antidepressant treatment based solely on total depression scores. Future studies should explore whether individual symptom scores or biomarkers are associated with variability in response to antidepressants.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.4564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890446PMC
May 2021

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

Transl Psychiatry 2021 02 15;11(1):127. Epub 2021 Feb 15.

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

Antidepressant outcomes in older adults with depression is poor, possibly because of comorbidities such as cerebrovascular disease. Therefore, we leveraged multiple genome-wide approaches to understand the genetic architecture of antidepressant response. Our sample included 307 older adults (≥60 years) with current major depression, treated with venlafaxine extended-release for 12 weeks. A standard genome-wide association study (GWAS) was conducted for post-treatment remission status, followed by in silico biological characterization of associated genes, as well as polygenic risk scoring for depression, neurodegenerative and cerebrovascular disease. The top-associated variants for remission status and percentage symptom improvement were PIEZO1 rs12597726 (OR = 0.33 [0.21, 0.51], p = 1.42 × 10) and intergenic rs6916777 (Beta = 14.03 [8.47, 19.59], p = 1.25 × 10), respectively. Pathway analysis revealed significant contributions from genes involved in the ubiquitin-proteasome system, which regulates intracellular protein degradation with has implications for inflammation, as well as atherosclerotic cardiovascular disease (n = 25 of 190 genes, p = 8.03 × 10, FDR-corrected p = 0.01). Given the polygenicity of complex outcomes such as antidepressant response, we also explored 11 polygenic risk scores associated with risk for Alzheimer's disease and stroke. Of the 11 scores, risk for cardioembolic stroke was the second-best predictor of non-remission, after being male (Accuracy = 0.70 [0.59, 0.79], Sensitivity = 0.72, Specificity = 0.67; p = 2.45 × 10). Although our findings did not reach genome-wide significance, they point to previously-implicated mechanisms and provide support for the roles of vascular and inflammatory pathways in LLD. Overall, significant enrichment of genes involved in protein degradation pathways that may be impaired, as well as the predictive capacity of risk for cardioembolic stroke, support a link between late-life depression remission and risk for vascular dysfunction.
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http://dx.doi.org/10.1038/s41398-021-01248-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884410PMC
February 2021

Pharmacotherapy Prescriptions for Relapse Prevention of Psychotic Depression After Electroconvulsive Therapy.

J Clin Psychopharmacol 2021 Mar-Apr 01;41(2):196-199

From the Department of Psychiatry, Weill Medical College of Cornell University and New York Presbyterian Hospital, Westchester Division, White Plains, NY.

Purpose/background: Electroconvulsive therapy (ECT) is effective in the treatment of acute episodes of psychotic depression. However, no adequately powered studies have directly investigated the efficacy of antipsychotic pharmacotherapy in relapse prevention of psychotic depression after ECT. In the absence of such literature, we reviewed the clinical practice of 4 academic medical centers that have made research contributions in the treatment of psychotic depression over the past 20 years.

Methods/procedures: We reviewed medical records of patients with a diagnosis of psychotic depression who received 1 or more acute courses of ECT over the span of 3 years. Chi-square tests were used to compare pharmacotherapy prescribed at the time of completion of ECT.

Findings/results: A total of 163 patients received 176 courses of ECT for separate episodes of psychotic depression. The combination of an antidepressant plus an antipsychotic was the most common regimen, ranging from 61.9% to 85.5% of all prescriptions. One center added lithium in 45.5% of cases treated with the combination of an antidepressant plus an antipsychotic. An antipsychotic alone was prescribed in less than 10% of cases. An antidepressant alone or other drug combinations were rare.

Implications/conclusions: The combination of an antidepressant plus an antipsychotic was the most commonly prescribed regimen at the completion of ECT for relapse prevention in patients with psychotic depression acutely treated with ECT. Although this report offers a view of the clinical practice of 4 academic medical centers, it also points to the need of randomized controlled trials on continuation pharmacotherapy after treatment of psychotic depression with ECT.
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http://dx.doi.org/10.1097/JCP.0000000000001354DOI Listing
February 2021

Effects of Repetitive Transcranial Magnetic Stimulation on Working Memory Performance and Brain Structure in People With Schizophrenia Spectrum Disorders: A Double-Blind, Randomized, Sham-Controlled Trial.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 04 28;6(4):449-458. Epub 2020 Nov 28.

Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of California San Diego School of Medicine, La Jolla, California.

Background: There are currently no approved treatments for working memory deficits in schizophrenia spectrum disorders (SSDs). The objective of the present study was to assess whether repetitive transcranial magnetic stimulation (rTMS) to the bilateral dorsolateral prefrontal cortex (DLPFC) in people with SSDs 1) improves working memory deficits and 2) changes brain structure.

Methods: We conducted a double-blind, parallel, randomized, sham-controlled study at the Centre for Addiction and Mental Health in Toronto, Canada. We randomized 83 participants with SSDs to receive either active 20 Hz rTMS applied to the bilateral DLPFC or sham rTMS for 4 weeks. The participants also completed pre/posttreatment magnetic resonance imaging. Clinical and cognitive assessments were performed at baseline, treatment end, and 1 month later. The primary outcome was change in verbal n-back working memory performance accuracy (d-prime). The secondary outcome measures were change in DLPFC thickness and fractional anisotropy of white matter tracts connecting to the DLPFC. Prespecified exploratory outcome measures were changes in general cognition; positive, negative, and depressive symptoms.

Results: Compared with sham treatment, active rTMS did not lead to significant change in working memory performance; it was associated with an increase in right DLPFC thickness but not fractional anisotropy. Prespecified exploratory analysis showed a significant decrease in depressive symptoms in the active group; the decrease in depressive symptoms was correlated with an increase in right DLPFC thickness.

Conclusions: Although rTMS applied to the bilateral DLPFC was not efficacious in treating working memory deficits in SSDs, it did increase right DLPFC thickness and decrease depressive symptoms. These findings deserve further study given the lack of efficacy of antidepressant medications in SSDs.
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http://dx.doi.org/10.1016/j.bpsc.2020.11.011DOI Listing
April 2021

Effects of Repetitive Transcranial Magnetic Stimulation on Working Memory Performance and Brain Structure in People With Schizophrenia Spectrum Disorders: A Double-Blind, Randomized, Sham-Controlled Trial.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 04 28;6(4):449-458. Epub 2020 Nov 28.

Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of California San Diego School of Medicine, La Jolla, California.

Background: There are currently no approved treatments for working memory deficits in schizophrenia spectrum disorders (SSDs). The objective of the present study was to assess whether repetitive transcranial magnetic stimulation (rTMS) to the bilateral dorsolateral prefrontal cortex (DLPFC) in people with SSDs 1) improves working memory deficits and 2) changes brain structure.

Methods: We conducted a double-blind, parallel, randomized, sham-controlled study at the Centre for Addiction and Mental Health in Toronto, Canada. We randomized 83 participants with SSDs to receive either active 20 Hz rTMS applied to the bilateral DLPFC or sham rTMS for 4 weeks. The participants also completed pre/posttreatment magnetic resonance imaging. Clinical and cognitive assessments were performed at baseline, treatment end, and 1 month later. The primary outcome was change in verbal n-back working memory performance accuracy (d-prime). The secondary outcome measures were change in DLPFC thickness and fractional anisotropy of white matter tracts connecting to the DLPFC. Prespecified exploratory outcome measures were changes in general cognition; positive, negative, and depressive symptoms.

Results: Compared with sham treatment, active rTMS did not lead to significant change in working memory performance; it was associated with an increase in right DLPFC thickness but not fractional anisotropy. Prespecified exploratory analysis showed a significant decrease in depressive symptoms in the active group; the decrease in depressive symptoms was correlated with an increase in right DLPFC thickness.

Conclusions: Although rTMS applied to the bilateral DLPFC was not efficacious in treating working memory deficits in SSDs, it did increase right DLPFC thickness and decrease depressive symptoms. These findings deserve further study given the lack of efficacy of antidepressant medications in SSDs.
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http://dx.doi.org/10.1016/j.bpsc.2020.11.011DOI Listing
April 2021

The primary care assessment and research of a telephone intervention for neuropsychiatric conditions with education and resources study: Design, rationale, and sample of the PARTNERs randomized controlled trial.

Contemp Clin Trials 2021 04 19;103:106284. Epub 2021 Jan 19.

Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. Electronic address:

While most patients with depression, anxiety, or at-risk drinking receive care exclusively in primary care settings, primary care providers experience challenges in diagnosing and treating these common problems. Over the past two decades, the collaborative care model has addressed these challenges. However, this model has been adopted very slowly due to the high costs of care managers; inability to sustain their role in small practices; and the perceived lack of relevance of interventions focused on a specific psychiatric diagnosis. Thus, we designed an innovative randomized clinical trial (RCT), the Primary Care Assessment and Research of a Telephone Intervention for Neuropsychiatric Conditions with Education and Resources study (PARTNERs). This RCT compared the outcomes of enhanced usual care and a novel model of collaborative care in primary care patients with depressive disorders, generalized anxiety, social phobia, panic disorder, at-risk drinking, or alcohol use disorders. These conditions were selected because they are present in almost a third of patients seen in primary care settings. Innovations included assigning the care manager role to trained lay providers supported by computer-based tools; providing all care management centrally by phone - i.e., the intervention was delivered without any face-to-face contact between the patient and the care team; and basing patient eligibility and treatment selection on a transdiagnostic approach using the same eligibility criteria and the same treatment algorithms regardless of the participants' specific psychiatric diagnosis. This paper describes the design of this RCT and discusses the rationale for its main design features.
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http://dx.doi.org/10.1016/j.cct.2021.106284DOI Listing
April 2021

Relationship of Hair Cortisol with History of Psychosis, Neuropsychological Performance and Functioning in Remitted Later-Life Major Depression.

Neuropsychobiology 2021 13;80(4):313-320. Epub 2021 Jan 13.

Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.

Introduction: Major depressive disorder (MDD) is associated with hypothalamic-pituitary-adrenal axis dysfunction that may persist into remission. Preliminary evidence suggests that this dysfunction may be associated with impaired neuropsychological performance in remitted MDD. MDD with psychotic features ("psychotic depression") is associated with greater neuropsychological and functional impairment than nonpsychotic depression, including in remission. Therefore, the aim of this exploratory study was to examine the relationships among hair cortisol concentration (HCC) - a marker of longer term endogenous cortisol exposure - and history of psychotic features, neuropsychological performance, and functioning in remitted MDD.

Methods: This cross-sectional study compared the relationship between HCC and (i) history of psychosis, (ii) neuropsychological performance, and (iii) everyday functioning in a group of 60 participants with remitted later-life MDD using Pearson's correlation coefficients. This study also measured HCC in a group of 36 nonpsychiatric volunteers to examine the clinical significance of HCC in the patient group.

Results: There were no statistically significant correlations between HCC and history of psychotic features, neuropsychological performance, or functioning. Furthermore, there was no clinically meaningful difference in HCC between patients and nonpsychiatric volunteers.

Conclusion: This study is the first to examine HCC in psychotic depression. The results do not support the hypothesis that impaired neuropsychological performance, and everyday function in remitted psychotic depression is due to a sustained elevation of cortisol.
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http://dx.doi.org/10.1159/000512081DOI Listing
January 2021

COVID-19: Implications for bipolar disorder clinical care and research.

SAGE Open Med 2020 14;8:2050312120981178. Epub 2020 Dec 14.

Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

The COVID-19 pandemic has posed significant challenges to health care globally, and individuals with bipolar disorder are likely disproportionally affected. Based on review of literature and collective clinical experience, we discuss that without special intervention, individuals with bipolar disorder will experience poorer physical and mental health outcomes due to interplay of patient, provider and societal factors. Some risk factors associated with bipolar disorder, including irregular social rhythms, risk-taking behaviours, substantial medical comorbidities, and prevalent substance use, may be compounded by lockdowns, social isolation and decrease in preventive and maintenance care. We further discuss implications for clinical research of bipolar disorders during the pandemic. Finally, we propose mitigation strategies on working with individuals with bipolar disorder in a clinical and research context, focusing on digital medicine strategies to improve quality of and accessibility to service.
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http://dx.doi.org/10.1177/2050312120981178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739076PMC
December 2020

Prolactin and Estrogen Levels in Postmenopausal Women Receiving Aripiprazole Augmentation Treatment for Depression.

J Clin Psychopharmacol 2021 Jan/Feb 01;41(1):31-35

From the Department of Psychiatry, Washington University in St. Louis, School of Medicine, St Louis, MO.

Background: Antipsychotic drugs are well established to alter serum prolactin levels, often resulting in adverse effects including amenorrhea, galactorrhea, osteoporosis, and loss of libido. There is growing preclinical evidence that prolactin-elevating drugs can instigate the progression of precancerous lesions to breast cancer and that genes activated by prolactin are associated with the development and proliferation of breast cancer. Current guides advise a cautious approach (weighing risks and benefits) to the administration of prolactin-elevating antipsychotic drugs in women with a previously detected breast cancer. Aripiprazole is known to be a prolactin-sparing antipsychotic; however, data regarding its effects on prolactin and estrogens in postmenopausal women are lacking.

Methods: We examined serum hormone levels in n = 66 women who participated in a randomized, double-blind, placebo-controlled, multicenter trial of aripiprazole (high and low doses) added to an antidepressant in adults older than 60 years. Aripiprazole or placebo tablets were administered for 12 weeks as an augmentation strategy in venlafaxine-treated women. The primary outcomes were the difference in prolactin and estrogen levels.

Results: There was no significant effect of aripiprazole treatment on prolactin or estrogen levels, including in models that divided groups into low and high doses: prolactin (P = 0.075), estrone (P = 0.67), and estradiol (P = 0.96).

Conclusions: Aripiprazole addition to an antidepressant did not alter serum estrogens or prolactin. These findings may be relevant in the treatment of some postmenopausal women with depression.
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http://dx.doi.org/10.1097/JCP.0000000000001335DOI Listing
September 2021

Effect of Older vs Younger Age on Anthropometric and Metabolic Variables During Treatment of Psychotic Depression With Sertraline Plus Olanzapine: The STOP-PD II Study.

Am J Geriatr Psychiatry 2021 07 15;29(7):645-654. Epub 2020 Nov 15.

Department of Psychiatry (GSA, PM, CDP, BSM)), Weill Cornell Medicine of Cornell University and New York Presbyterian Hospital, Westchester Division, NY.

Objective: To examine the effect of older versus younger age on change in anthropometric and metabolic measures during extended treatment of psychotic depression with sertraline plus olanzapine.

Methods: Two hundred and sixty-nine men and women aged 18-85 years with an episode of psychotic depression were treated with open-label sertraline plus olanzapine for up to 12 weeks. Participants who remained in remission following an 8-week stabilization phase were eligible to participate in a 36-week randomized controlled trial (RCT) that compared the efficacy and tolerability of sertraline plus olanzapine with sertraline plus placebo. Weight, waist circumference and plasma lipids, glucose, HbA1c, and insulin were measured at regular intervals during the acute, stabilization and randomized phases of the study. Linear mixed models were used to analyze the trajectories of anthropometric and metabolic measures.

Results: Participants aged 60 years or older experienced less weight gain and less increase in cholesterol during the combined acute and stabilization phases of the study compared with those aged 18-59 years. At the acute-stabilization termination visit, mean weight in older participants was 6.5 lb. less than premorbid weight, whereas it was 17.9 lb. more than premorbid weight in younger participants. In the RCT, there was a significant interaction of treatment and age group for the trajectory of weight, but the post hoc tests that compared age groups within each treatment arm were not statistically significant. There were no clinically significant differences between younger and older participants in glycemic measures.

Conclusion: Older patients with psychotic depression experienced less increase in weight and total cholesterol than their younger counterparts during acute and stabilization treatment with sertraline plus olanzapine. In the older group, weight gained during the acute and stabilization phases appeared to be partial restoration of weight lost during the index episode of depression, whereas weight gain in younger participants was not.
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http://dx.doi.org/10.1016/j.jagp.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121896PMC
July 2021
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