Publications by authors named "Mehala Subramaniapillai"

94 Publications

Ketamine monotherapy versus adjunctive ketamine in adults with treatment-resistant depression: Results from the Canadian Rapid Treatment Centre of Excellence.

J Psychiatr Res 2021 Sep 3;143:209-214. Epub 2021 Sep 3.

Mood Disorder Psychopharmacology Unit, University Health Network, University of Toronto, Toronto, ON, Canada; Canadian Rapid Treatment Center of Excellence, Mississauga, ON, Canada; Brain and Cognition Discovery Foundation, Canada, University of Toronto, Toronto, ON, Canada.

A proportion of individuals with major depressive disorder (MDD) do not receive adequate therapeutic benefit from conventional monoaminergic antidepressant drugs, leading to treatment-resistant depression (TRD). Ketamine has been shown to provide rapid and significant efficacy in treating patients with TRD. The majority of published studies have investigated the adjunctive efficacy of ketamine with one or more monoaminergic antidepressants. There remains a clinical need to ascertain the relative effectiveness of ketamine monotherapy versus adjunctive ketamine treatment in adults with TRD. In this retrospective study, we investigate multidimensional, self-reported outcomes (i.e., antidepressant, anti-suicidality, antianxiety, and anti-functional impairment) of 220 patients to compare monotherapy (n = 39) and adjunctive (n = 181) ketamine treatment for TRD at a community-based clinic. Both groups had clinically and statistically significant antidepressant effects (p < 0.05). Individuals receiving ketamine monotherapy exhibited a significantly greater reduction on the suicidal ideation (SI) item of the Quick Inventory for Depressive Symptomatology-Self Report 16-Item (QIDS-SR) than the adjunctive group, with a small effect size [F (1, 265) = 4.73; p = 0.03*; partial η = 0.02], and a significantly higher proportion of partial responders at post-infusion 4 (p = 0.034*). No other between-group differences were significant. Limitations include the small sample, single-centred, open-label, non-randomized, uncontrolled, retrospective nature of this study and indication bias. Our real-world evidence suggests that ketamine may be effective as monotherapy or adjunct to monoamine-based treatments. A priority research and clinical vista is to identify subsets of individuals with TRD who are most likely to have a desired therapeutic outcome with monotherapy versus adjunctive ketamine treatment.
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http://dx.doi.org/10.1016/j.jpsychires.2021.09.002DOI Listing
September 2021

Correction: Efficacy of omega-3 PUFAs in depression: A meta-analysis.

Transl Psychiatry 2021 Sep 7;11(1):465. Epub 2021 Sep 7.

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

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http://dx.doi.org/10.1038/s41398-021-01582-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423804PMC
September 2021

Correction: Efficacy of omega-3 PUFAs in depression: A meta-analysis.

Transl Psychiatry 2021 Sep 7;11(1):465. Epub 2021 Sep 7.

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

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http://dx.doi.org/10.1038/s41398-021-01582-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423804PMC
September 2021

The meaningful change threshold as measured by the 16-item quick inventory of depressive symptomatology in adults with treatment-resistant major depressive and bipolar disorder receiving intravenous ketamine.

J Affect Disord 2021 Nov 20;294:592-596. Epub 2021 Jul 20.

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

Objective: .To identify a meaningful change threshold (MCT) in depression outcomes in adults with treatment-resistant major depressive disorder (MDD) or bipolar disorder (BD) receiving intravenous ketamine treatment at a community-based mood disorders center.

Method: .A triangular approach integrating both anchor-based and distributive methods was used to identify meaningful change on the patient-reported Quick Inventory for Depressive Symptoms Self-Report 16-Item (QIDS-SR16) as associated with the Patient Global Impression - Severity (PGI-S). Both the QIDS-SR16 and the PGI-S are self-report measures, and were collected at five timepoints (timepoints were approximately 2-7 days apart).

Results: .A total of 297 adults with treatment-resistant depression (TRD) as part of either DSM-5-defined MDD or BD were included. The MCT for the QIDS-SR16 revealed that a mean improvement of 3.38 points from baseline was comparable to a 1-point improvement on the PGI-S. Together with an examination of the probability density function, a 3.5-point change is a reasonable MCT (i.e., 1-point PGI-S improvement) for the QIDS-SR16. A 2-point symptomatic improvement on the QIDS-SR16 was associated with no change on the PGI-S.

Conclusion: .A 3.5-point reduction in the QIDS-SR16 represents a MCT based on the PGI-S for adults with treatment-resistant MDD or BD receiving intravenous ketamine treatment at a community-based mood disorders center. These findings are limited by the post-hoc nature of this analysis and open-label case-series design. Measurement-based care decisions by patients, providers and clinicians, as well as cost/reimbursement decisions should include consideration of meaningful change along with conventional objective outcomes.
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http://dx.doi.org/10.1016/j.jad.2021.07.035DOI Listing
November 2021

Added burden of major depressive disorder on cardiovascular morbidity and mortality among patients with cardiovascular disease and the modifying effects of antidepressants: A national retrospective cohort study.

J Affect Disord 2021 Nov 22;294:580-585. Epub 2021 Jul 22.

Department of Healthcare Administration, Asia University, Taiwan; Department of Psychology, Asia University, Taiwan. Electronic address:

Background: To evaluate the likelihood of a future cardiovascular event (i.e., in-hospital mortality or cardiovascular disease [CVD] complications/interventions) among patients with CVD and major depressive disorder (MDD) compared to those without MDD, and the antidepressant use on future cardiovascular events between the two groups.

Methods: This is a retrospective cohort with propensity score matching with 8941 patients with CVD and MDD, and 8941 non-MDD patients using data from the Longitudinal Health Insurance Database from 1999 to 2013 in Taiwan. The outcome was in-hospital mortality and the incidence of revascularization (i.e., percutaneous transluminal coronary angioplasty [PTCA] and coronary artery bypass graft surgery [CABG]).

Results: Patients with CVD and MDD were more likely to need revascularization (an adjusted hazard ratio [aHR]: 1.26 and 95% CI: 1.12-1.43) than those without MDD, regardless of whether PTCA (aHR: 1.23 and 95% CI: 1.07-1.40) or CABG (aHR: 1.60 and 95% CI: 1.16-2.21) had occurred. Antidepressant use was associated with a tendency of reduced risk of mortality (aHR: 0.92 and 95% CI: 0.84-1.00). Although the magnitude of aHR ranged from 0.92 to 0.95 with revascularization, they did not reach significant levels.

Limitations: Some covariates could not be controlled because they were not included in the national register dataset, and the causality is limited in an observational study.

Conclusions: Patients with CVD with MDD are more likely to experience a cardiovascular complication requiring intervention than CVD patients without MDD. Antidepressant use is associated with reduced in-hospital mortality.
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http://dx.doi.org/10.1016/j.jad.2021.07.082DOI Listing
November 2021

Association Between Mood Disorders and Risk of COVID-19 Infection, Hospitalization, and Death: A Systematic Review and Meta-analysis.

JAMA Psychiatry 2021 Jul 28. Epub 2021 Jul 28.

Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network, Toronto, Ontario, Canada.

Importance: Preexisting noncommunicable diseases (eg, diabetes) increase the risk of COVID-19 infection, hospitalization, and death. Mood disorders are associated with impaired immune function and social determinants that increase the risk of COVID-19. Determining whether preexisting mood disorders represent a risk of COVID-19 would inform public health priorities.

Objective: To assess whether preexisting mood disorders are associated with a higher risk of COVID-19 susceptibility, hospitalization, severe complications, and death.

Data Sources: Systematic searches were conducted for studies reporting data on COVID-19 outcomes in populations with and without mood disorders on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, LitCovid, and select reference lists. The search timeline was from database inception to February 1, 2021.

Study Selection: Primary research articles that reported quantitative COVID-19 outcome data in persons with mood disorders vs persons without mood disorders of any age, sex, and nationality were selected. Of 1950 articles identified through this search strategy, 21 studies were included in the analysis.

Data Extraction And Synthesis: The modified Newcastle-Ottawa Scale was used to assess methodological quality and risk of bias of component studies. Reported adjusted odds ratios (ORs) were pooled with unadjusted ORs calculated from summary data to generate 4 random-effects summary ORs, each corresponding to a primary outcome.

Main Outcomes And Measures: The 4 a priori primary outcomes were COVID-19 susceptibility, COVID-19 hospitalization, COVID-19 severe events, and COVID-19 death. The hypothesis was formulated before study search. Outcome measures between individuals with and without mood disorders were compared.

Results: This review included 21 studies that involved more than 91 million individuals. Significantly higher odds of COVID-19 hospitalization (OR, 1.31; 95% CI, 1.12-1.53; P = .001; n = 26 554 397) and death (OR, 1.51; 95% CI, 1.34-1.69; P < .001; n = 25 808 660) were found in persons with preexisting mood disorders compared with those without mood disorders. There was no association between mood disorders and COVID-19 susceptibility (OR, 1.27; 95% CI, 0.73-2.19; n = 65 514 469) or severe events (OR, 0.94; 95% CI, 0.87-1.03; n = 83 240). Visual inspection of the composite funnel plot for asymmetry indicated the presence of publication bias; however, the Egger regression intercept test result was not statistically significant.

Conclusions And Relevance: The results of this systematic review and meta-analysis examining the association between preexisting mood disorders and COVID-19 outcomes suggest that individuals with preexisting mood disorders are at higher risk of COVID-19 hospitalization and death and should be categorized as an at-risk group on the basis of a preexisting condition.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.1818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319830PMC
July 2021

Association Between Mood Disorders and Risk of COVID-19 Infection, Hospitalization, and Death: A Systematic Review and Meta-analysis.

JAMA Psychiatry 2021 Jul 28. Epub 2021 Jul 28.

Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network, Toronto, Ontario, Canada.

Importance: Preexisting noncommunicable diseases (eg, diabetes) increase the risk of COVID-19 infection, hospitalization, and death. Mood disorders are associated with impaired immune function and social determinants that increase the risk of COVID-19. Determining whether preexisting mood disorders represent a risk of COVID-19 would inform public health priorities.

Objective: To assess whether preexisting mood disorders are associated with a higher risk of COVID-19 susceptibility, hospitalization, severe complications, and death.

Data Sources: Systematic searches were conducted for studies reporting data on COVID-19 outcomes in populations with and without mood disorders on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, LitCovid, and select reference lists. The search timeline was from database inception to February 1, 2021.

Study Selection: Primary research articles that reported quantitative COVID-19 outcome data in persons with mood disorders vs persons without mood disorders of any age, sex, and nationality were selected. Of 1950 articles identified through this search strategy, 21 studies were included in the analysis.

Data Extraction And Synthesis: The modified Newcastle-Ottawa Scale was used to assess methodological quality and risk of bias of component studies. Reported adjusted odds ratios (ORs) were pooled with unadjusted ORs calculated from summary data to generate 4 random-effects summary ORs, each corresponding to a primary outcome.

Main Outcomes And Measures: The 4 a priori primary outcomes were COVID-19 susceptibility, COVID-19 hospitalization, COVID-19 severe events, and COVID-19 death. The hypothesis was formulated before study search. Outcome measures between individuals with and without mood disorders were compared.

Results: This review included 21 studies that involved more than 91 million individuals. Significantly higher odds of COVID-19 hospitalization (OR, 1.31; 95% CI, 1.12-1.53; P = .001; n = 26 554 397) and death (OR, 1.51; 95% CI, 1.34-1.69; P < .001; n = 25 808 660) were found in persons with preexisting mood disorders compared with those without mood disorders. There was no association between mood disorders and COVID-19 susceptibility (OR, 1.27; 95% CI, 0.73-2.19; n = 65 514 469) or severe events (OR, 0.94; 95% CI, 0.87-1.03; n = 83 240). Visual inspection of the composite funnel plot for asymmetry indicated the presence of publication bias; however, the Egger regression intercept test result was not statistically significant.

Conclusions And Relevance: The results of this systematic review and meta-analysis examining the association between preexisting mood disorders and COVID-19 outcomes suggest that individuals with preexisting mood disorders are at higher risk of COVID-19 hospitalization and death and should be categorized as an at-risk group on the basis of a preexisting condition.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.1818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319830PMC
July 2021

Efficacy of ketamine and esketamine on functional outcomes in treatment-resistant depression: A systematic review.

J Affect Disord 2021 10 24;293:285-294. Epub 2021 Jun 24.

Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Canadian Rapid Treatment Center of Excellence (CRTCE), Mississauga, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; Brain and Cognition Discovery Foundation, Canada; University of Toronto, Toronto, ON, Canada. Electronic address:

Background: In recent years, ketamine and esketamine treatment have demonstrated rapid antidepressant effects in adults with treatment-resistant depression (TRD). Hitherto, relatively few studies have reported the effect of ketamine/esketamine treatment on functional outcomes (e.g., psychosocial functioning, workplace functioning). Herein, we review and synthesize extant literature reporting functional outcomes with ketamine/esketamine treatment in adults with TRD.

Methods: A systematic review of clinical studies reporting subjective or objective ratings of general functioning as primary or secondary outcomes was performed.

Results: Four randomized-controlled trials, one open-label clinical study and one case series reported on the efficacy of ketamine/esketamine on subjective measures of general functioning. Overall, mixed results were reported with respect to the effect across disparate functional measures (e.g., Sheehan Disability Scale [SDS]) using ketamine/esketamine. A single study demonstrated a significant decrease (i.e., improvement) in SDS total scores in TRD with esketamine treatment; most studies, however, did not report on functional outcomes and have functional outcomes as a (co)-primary outcome measure.

Limitations: Clinical studies that were included evaluated work- or social-related disability as a secondary outcome using subjective rating scales.

Conclusion: Functional outcomes in adults with TRD receiving ketamine/esketamine was insufficiently characterized. Available evidence indicates that improvements in general psychosocial functioning is apparent. The association, if any, between symptomatic improvement and functional improvement in TRD, as well as the temporality to improve functioning, are future research vistas.
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http://dx.doi.org/10.1016/j.jad.2021.06.032DOI Listing
October 2021

Repetitive transcranial magnetic stimulation for cognitive function in adults with bipolar disorder: A pilot study.

J Affect Disord 2021 10 16;293:73-77. Epub 2021 Jun 16.

Department of Affective Disorder, the Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou Medical University, Guangzhou, China. Electronic address:

Background: Cognitive deficits are prevalent in bipolar disorder and are a significant contributor to negative patient-reported outcomes. Herein we conducted a pilot study of repetitive transcranial magnetic stimulation (rTMS) to improve cognitive function in adults with bipolar disorder.

Methods: The study was a triple-blinded, randomized, placebo-control trial. Participants (aged 18 to 60) with a diagnosis of DSM-5-defined bipolar disorder (I or II) were recruited and randomized (N=36) to receive either a sham treatment (n=20) or an active rTMS treatment (n=16). Patients completed the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) at baseline and 1-2 weeks after the rTMS intervention.

Results: A significant group by time interaction was observed in the Hopkins Verbal Learning Test-Revised (HVLT-R), (F (1, 34) = 17.0, p < 0.001, partial η = 0.33). Post-hoc analysis revealed that although both groups did not significantly differ at baseline (p = 0.58), patients in the active rTMS group significantly improved following neurostimulation (p = 0.02) for HVLT-R. Moreover, within-subject analysis indicated that the active rTMS group significantly improved in score from pre-treatment to post-treatment (p < 0.001), while the sham group did not improve (p = 0.94) for HVLT-R. No significant differences were seen in the other cognitive measures.

Limitations: The study was conducted in a small sample .

Conclusion: This pilot study, which was intended to establish feasibility, suggests that rTMS may offer benefit in select domains of cognitive functioning in bipolar disorder. None of the measures across subdomains revealed a dyscognitive effect.
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http://dx.doi.org/10.1016/j.jad.2021.05.075DOI Listing
October 2021

Does pre-treatment functioning influence response to intravenous ketamine in adults with treatment-resistant depression?

J Affect Disord 2021 09 20;292:714-719. Epub 2021 Jun 20.

Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Canadian Rapid Treatment Center of Excellence, Mississauga, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

Background: The efficacy of monoamine-based antidepressants in adults with major depressive disorder (MDD) is attenuated in persons with greater pre-treatment functional impairment. Herein, we investigated whether pre-treatment functioning in outpatients with treatment-resistant depression (TRD) moderates response to intravenous (IV) ketamine.

Methods: Adults (N= 326; M = 45) with DSM-5-defined MDD or bipolar disorder and TRD received repeat-dose IV ketamine at a community-based clinic. Function was evaluated with the Sheehan Disability Scale (SDS), using total scores as well as scores on the subdomains of workplace/school, social life, and family life/home responsibilities. The primary dependent measure was change in depressive symptoms from pre-treatment to post-infusion 4, as measured by the Quick Inventory for Depressive Symptomatology-Self Report-16.

Results: Total functional disability, as well as the subdomains of social life and family life/home responsibilities, significantly moderated response to IV ketamine (p = .003; p = .008; p = .008). Follow-up simple slopes analyses indicated a significant improvement in depressive symptoms across the functional domain spectrum (ps < .001). Above average functional disability (i.e., 1 SD > mean functional impairment within the sample) was associated with a greater change in depressive symptoms. Workplace function did not significantly moderate response to IV ketamine (p = .307), suggesting that individuals with significantly impaired workplace functioning may expect a similar response to ketamine as those with less workplace impairment.

Conclusions: Symptomatic benefit with IV ketamine was observed in patients with TRD and significant pre-treatment functional impairment. The foregoing result has implications for mechanism of action, cost-effectiveness, and patient selection in adults with TRD receiving IV ketamine.
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http://dx.doi.org/10.1016/j.jad.2021.05.090DOI Listing
September 2021

Changes in the gut microbiome associated with infliximab in patients with bipolar disorder.

Brain Behav 2021 08 21;11(8):e2259. Epub 2021 Jun 21.

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

Objectives: Available information exists supporting the gut-brain axis, but additional information is needed to explore how the gut microbiome changes when exposed to mood disorder treatments. We sought to explore the effects of a novel treatment for bipolar disorder (BD), infliximab, on the gut microbiome.

Methods: Participants with a primary diagnosis of BD (n = 15) who participated in a 12-week, randomized placebo-controlled trial evaluating the efficacy of adjunctive infliximab in the treatment of BD were recruited and followed. Stool samples were collected prior to randomization and at 12 weeks. 16S rRNA sequencing was employed in order to analyze the gut microbial community profile.

Results: A total of 17 participants were randomized to infliximab (n = 9; mean [SD] age, 47.6 [10.3] years; 8 female) or to placebo (n = 8; mean [SD] age, 45.9 [10.7] years; 7 female) but two participants from the infliximab group were lost to follow-up post randomization. Across all time points, there were no differences in the diversity on either Shannon or Simpson's Diversity indices. Comparison of Aitchison distances revealed a lack of clustering of the microbiota by time point, but did reveal a small overall effect of treatment that was not significantly different at individual time points. There were also no effects of either time or treatment on differential abundance at either the amplicon sequence variant or genus level.

Conclusions: These observations indicate that no community-wide changes in the microbiota diversity and profile were detected after the use of infliximab treatment.
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http://dx.doi.org/10.1002/brb3.2259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413825PMC
August 2021

Changes in the gut microbiome associated with infliximab in patients with bipolar disorder.

Brain Behav 2021 08 21;11(8):e2259. Epub 2021 Jun 21.

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

Objectives: Available information exists supporting the gut-brain axis, but additional information is needed to explore how the gut microbiome changes when exposed to mood disorder treatments. We sought to explore the effects of a novel treatment for bipolar disorder (BD), infliximab, on the gut microbiome.

Methods: Participants with a primary diagnosis of BD (n = 15) who participated in a 12-week, randomized placebo-controlled trial evaluating the efficacy of adjunctive infliximab in the treatment of BD were recruited and followed. Stool samples were collected prior to randomization and at 12 weeks. 16S rRNA sequencing was employed in order to analyze the gut microbial community profile.

Results: A total of 17 participants were randomized to infliximab (n = 9; mean [SD] age, 47.6 [10.3] years; 8 female) or to placebo (n = 8; mean [SD] age, 45.9 [10.7] years; 7 female) but two participants from the infliximab group were lost to follow-up post randomization. Across all time points, there were no differences in the diversity on either Shannon or Simpson's Diversity indices. Comparison of Aitchison distances revealed a lack of clustering of the microbiota by time point, but did reveal a small overall effect of treatment that was not significantly different at individual time points. There were also no effects of either time or treatment on differential abundance at either the amplicon sequence variant or genus level.

Conclusions: These observations indicate that no community-wide changes in the microbiota diversity and profile were detected after the use of infliximab treatment.
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http://dx.doi.org/10.1002/brb3.2259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413825PMC
August 2021

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

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

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

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

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

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

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

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

The effect of intravenous ketamine on cognitive functions in adults with treatment-resistant major depressive or bipolar disorders: Results from the Canadian rapid treatment center of excellence (CRTCE).

Psychiatry Res 2021 Aug 13;302:113993. Epub 2021 May 13.

Canadian Rapid Treatment Center of Excellence, Mississauga, ON, Canada; Mood Disorders Psychopharmacology Unit, Poul Hansen Depression Centre, University Health Network, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

Ketamine may exert pro-cognitive effects on select measures of cognition in adults with mood disorders. We evaluated the effectiveness of intravenous (IV) ketamine on cognition in 68 adult outpatients with treatment-resistant depression (TRD) at the Canadian Rapid Treatment Center of Excellence between July 3, 2018 and April 16, 2020 (NCT04209296). Eligibility criteria for the present retrospective study included: primary diagnosis of major depressive or bipolar disorder; currently depressed; and insufficient response to two or more prior treatments. Participants received four infusions of ketamine hydrochloride (0.5-0.75 mg/kg) over 1-2 weeks. We assessed objective and subjective measures of cognition before and after two infusions, i.e., Digit Symbol Substitution Test (DSST), Trail Making Test-B (TMT-B), Patient Deficits Questionnaire, 5-item (PDQ-5-D). Ketamine significantly improved DSST (effect size [ES]=0.60), TMT-B (ES=0.84), as well as PDQ-5-D scores (ES=0.63), indicative of a moderate-to-large effect size. Improvements in DSST and PDQ-5-D with ketamine were mediated by reductions in depressive symptoms, whereas improvements in TMT-B were independent of changes in depressive symptoms. Our results support the independent, rapid-onset, pro-cognitive effects with IV ketamine in adults with TRD. Larger, randomized, controlled trials with ketamine wherein cognition is the primary outcome measure in mood and non-mood disorder samples are warranted.
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http://dx.doi.org/10.1016/j.psychres.2021.113993DOI Listing
August 2021

Validation of the McIntyre And Rosenblat Rapid Response Scale (MARRRS) in Adults with Treatment-Resistant Depression Receiving Intravenous Ketamine Treatment.

J Affect Disord 2021 06 26;288:210-216. Epub 2021 Mar 26.

Mood Disorders Psychopharmacology Unit, University Health Network; University of Toronto, Toronto, ON, Canada; Canadian Rapid Treatment Center of Excellence, Mississauga, ON, Canada; Brain and Cognition Discovery Foundation, Canada; University of Toronto, Toronto, ON, Canada.

Background: Depression severity and efficacy measurement scales employed for rapid-acting treatments (e.g., ketamine) were initially validated in adults receiving conventional monoamine-based antidepressants. The emergence of rapid-acting antidepressants in psychiatry provides the impetus for outcome measures that have been validated as sensitive to change with rapid-acting treatments. Herein, we provide results validating the McIntyre and Rosenblat Rapid Response Scale (MARRRS).

Methods: Adults with treatment-resistant depression (TRD) receiving intravenous (IV) ketamine had depressive symptoms measured with the 16-Item Quick Inventory Depressive Symptoms Self-Report (QIDS-SR-16) and MARRRS at baseline and as a repeated measure across an acute course of four infusions. The MARRRS is a self-report measure assessing depressive symptoms during the past 72 hours.

Results: Sixty-four patients (M = 45.4 ± 13.5) were included. The MARRRS had a high internal consistency across acute infusions as determined by Cronbach's alpha (0.84 to 0.94). There was significant convergent validity between the QIDS-SR-16 and MARRRS total scores across infusions (rs(292) = .87, p < .001); the MARRRS was also sensitive to change (rs(49) = .70, p < .001). Exploratory factor analysis revealed that MARRRS items loaded onto two factors (i.e., dysphoria and psychic anxiety) accounting for 63.4% of the total variance.

Limitations: Heterogenous sample of adults with TRD receiving open-label treatment without placebo comparison.

Conclusion: The MARRRS is a brief validated self-report metric of depression symptom severity that is sensitive to change with the rapid-acting antidepressant ketamine. Measuring outcomes with the MARRRS informs treatment progress and facilitates treatment decisions in persons receiving the rapid-acting antidepressant ketamine. Studies of other rapid-acting antidepressants should incorporate outcome measures that are validated as sensitive to change with rapid-acting antidepressants.
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http://dx.doi.org/10.1016/j.jad.2021.03.053DOI Listing
June 2021

Validation of the McIntyre And Rosenblat Rapid Response Scale (MARRRS) in Adults with Treatment-Resistant Depression Receiving Intravenous Ketamine Treatment.

J Affect Disord 2021 06 26;288:210-216. Epub 2021 Mar 26.

Mood Disorders Psychopharmacology Unit, University Health Network; University of Toronto, Toronto, ON, Canada; Canadian Rapid Treatment Center of Excellence, Mississauga, ON, Canada; Brain and Cognition Discovery Foundation, Canada; University of Toronto, Toronto, ON, Canada.

Background: Depression severity and efficacy measurement scales employed for rapid-acting treatments (e.g., ketamine) were initially validated in adults receiving conventional monoamine-based antidepressants. The emergence of rapid-acting antidepressants in psychiatry provides the impetus for outcome measures that have been validated as sensitive to change with rapid-acting treatments. Herein, we provide results validating the McIntyre and Rosenblat Rapid Response Scale (MARRRS).

Methods: Adults with treatment-resistant depression (TRD) receiving intravenous (IV) ketamine had depressive symptoms measured with the 16-Item Quick Inventory Depressive Symptoms Self-Report (QIDS-SR-16) and MARRRS at baseline and as a repeated measure across an acute course of four infusions. The MARRRS is a self-report measure assessing depressive symptoms during the past 72 hours.

Results: Sixty-four patients (M = 45.4 ± 13.5) were included. The MARRRS had a high internal consistency across acute infusions as determined by Cronbach's alpha (0.84 to 0.94). There was significant convergent validity between the QIDS-SR-16 and MARRRS total scores across infusions (rs(292) = .87, p < .001); the MARRRS was also sensitive to change (rs(49) = .70, p < .001). Exploratory factor analysis revealed that MARRRS items loaded onto two factors (i.e., dysphoria and psychic anxiety) accounting for 63.4% of the total variance.

Limitations: Heterogenous sample of adults with TRD receiving open-label treatment without placebo comparison.

Conclusion: The MARRRS is a brief validated self-report metric of depression symptom severity that is sensitive to change with the rapid-acting antidepressant ketamine. Measuring outcomes with the MARRRS informs treatment progress and facilitates treatment decisions in persons receiving the rapid-acting antidepressant ketamine. Studies of other rapid-acting antidepressants should incorporate outcome measures that are validated as sensitive to change with rapid-acting antidepressants.
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http://dx.doi.org/10.1016/j.jad.2021.03.053DOI Listing
June 2021

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

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

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

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

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

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

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

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

Ketamine-induced urological toxicity: potential mechanisms and translation for adults with mood disorders receiving ketamine treatment.

Psychopharmacology (Berl) 2021 Apr 23;238(4):917-926. Epub 2021 Jan 23.

Mood Disorder Psychopharmacology Unit, University Health Network, 399 Bathurst Street, MP 9-325, Toronto, ON, M5T 2S8, Canada.

Intravenous (IV) ketamine has been shown to have rapid and robust antidepressant effects in adults with treatment-resistant depression (TRD). Urological toxicity has been observed in chronic ketamine abusers as evidenced by dysuria, urgency, and hematuria. The foregoing observation provides the basis for evaluating whether ketamine-induced urological toxicity (KIUT) is associated with sub-anesthetic doses of ketamine (0.5-1.0 mg/kg) in adults with mood disorders. The overarching objective of this article is to identify potential mechanisms of KIUT which appears to be dose and frequency dependent. Available research indicates that high-frequency ketamine is associated with disruption of the urothelial barrier as well as direct ketamine toxicity (i.e., decreased expression of junction proteins) in KIUT of the bladder. Chronic and high-frequency ketamine use is also associated with bladder inflammation mediated via neurogenic and IgE inflammation. Other non-mutually exclusive causes are nerve hyperplasia, hypersensitivity, cell apoptosis, microvascular damage, and overexpression of carcinogenic genes. Notwithstanding the evidence of KIUT in ketamine abusers, there is no evidence that ketamine and/or esketamine treatment in adults with mood disorders is associated with KIUT. However, all patients receiving ketamine/esketamine for mood disorder treatment should be queried about genitourinary symptoms during acute and, where applicable, maintenance dosing.
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http://dx.doi.org/10.1007/s00213-021-05767-1DOI Listing
April 2021

Safety, Tolerability, and Real-World Effectiveness of Intravenous Ketamine in Older Adults With Treatment-Resistant Depression: A Case Series.

Am J Geriatr Psychiatry 2021 09 9;29(9):899-913. Epub 2021 Jan 9.

Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network (OL, JDV, NBR, DSC, YL, MS, RSM, JDR), Toronto, ON, Canada; Canadian Rapid Treatment Center of Excellence (OL, NBR, YL, DG, KMT, MS, KK RSM, JDR), Mississauga, ON, Canada; Department of Psychiatry, University of Toronto (AJF, RSM, JDR), Toronto, ON, Canada.

Objective: To evaluate the safety, tolerability, and effectiveness of repeated doses of intravenous (IV) ketamine in older adults (i.e., ≥60 years of age) with treatment-resistant depression.

Method: In this case series, fifty-three older adults (M = 67, SD = 6; 57% female [n = 30]) received 4 IV ketamine infusions, administered over 1-2 weeks. Effectiveness of IV ketamine was measured using the Quick Inventory for Depressive Symptomatology-Self Report 16 (QIDS-SR16) approximately 2 days after infusions 1-3, and 1-2 weeks after infusion 4. Safety was measured as hemodynamic changes before, during, immediately after, and 20 minutes after each infusion. Tolerability was assessed via systematic reporting of treatment-emergent adverse events during and after each infusion, in addition to symptoms of dissociation measured using the Clinician Administered Dissociative States Scale. Partial response (25%-50% symptomatic improvement from baseline), response (≥50% symptomatic improvement from baseline), clinically significant improvements (≥25% symptomatic improvement from baseline), and remission rates (QIDS-SR16 ≤5) were also calculated.

Results: Participants reported significant decreases in depressive symptoms (i.e., as measured by the QIDS-SR16) with repeated ketamine infusions (F(4, 92) = 7.412, p <0.001). The mean QIDS-SR16 score was 17.12 (SD = 5.33) at baseline and decreased to 12.52 (SD = 5.79) following 4 infusions. After 4 infusions, 31% (n = 8) of participants partially responded to IV ketamine, 27% (n = 7) responded, 58% (n = 15) experienced clinically significant improvements, and 10% (n = 3) met remission criteria. Thirty-six participants (69%) experienced treatment-emergent hypertension during at least 1 infusion, and 10 (19%) required intervention with an antihypertensive. Drowsiness was the most commonly reported adverse event (50% of infusions; n = 73).

Conclusion: Ketamine was associated with transient treatment-emergent hypertension. Response and remission rates were comparable to those reported in general adult samples. Findings are limited by the open-label, chart review nature of this study.
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http://dx.doi.org/10.1016/j.jagp.2020.12.032DOI Listing
September 2021

Insulin resistance is associated with deficits in hedonic, self-reported cognitive, and psychosocial functional response to antidepressant treatment in individuals with major depressive disorder.

J Affect Disord 2021 03 24;282:448-453. Epub 2020 Dec 24.

Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.

Background: To assess the effect of insulin resistance (IR) on treatment response to the antidepressant, vortioxetine, in patients with Major Depressive Disorder (MDD).

Methods: This is a secondary analysis of an 8-week, open-label clinical trial. Ninety-five adults in a primary care setting experiencing a major depressive episode were included. Response to vortioxetine was measured using the THINC-integrated tool, Montgomery Åsberg Depression Rating Scale (MADRS), the Snaith-Hamilton Pleasure Scale (SHAPS), the Perceived Deficits Questionnaire (PDQ-5), and the Sheehan Disability Scale (SDS). Generalized estimating equation models were utilized for data analysis.

Results: When adjusted for age, gender, dose, and BMI, there was a significant baseline IR by time interaction for SHAPS (p = 0.022), PDQ-5 (p = 0.037), and SDS (p = 0.013). Higher baseline IR predicted decreased early improvements in anhedonia. It also predicted poorer subjective assessments of cognition and increased functional impairment at the endpoint of treatment. For functional capacity (i.e. SDS) other covariates including severity of symptoms, illness course, other metabolic factors (e.g. cholesterol), and physical activity were included with no changes to the moderating effect of baseline IR.

Limitations: This was a post-hoc analysis of a primarily non-diabetic sample. Also, only one agent was assessed.

Conclusions: IR was a predictor of response to vortioxetine. This persisted after controlling for other factors including, but not limited to, BMI. These findings strengthen the link between depression and IR and may point to another novel metabolic predictor of response. These findings should be replicated using other antidepressants.
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http://dx.doi.org/10.1016/j.jad.2020.12.074DOI Listing
March 2021

A simplified 6-Item clinician administered dissociative symptom scale (CADSS-6) for monitoring dissociative effects of sub-anesthetic ketamine infusions.

J Affect Disord 2021 03 29;282:160-164. Epub 2020 Dec 29.

Mood Disorders Psychopharmacology Unit, University Health Network; University of Toronto, Toronto, ON, Canada; Canadian Rapid Treatment Center of Excellence, Mississauga, ON, Canada; Brain and Cognition Discovery Foundation, Canada; University of Toronto, Toronto, ON, Canada.

Background: Dissociation is a treatment-emergent adverse event commonly associated with IV ketamine, often measured using the 23-item Clinician-Administered Dissociative States Scale (CADSS). The objective of this study was to develop a short form version of the CADSS for easier clinical use.

Methods: Retrospective data of 260 patients with treatment-resistant depression (TRD) receiving IV ketamine were randomly divided into two datasets. The first dataset (n = 130) was leveraged to develop a brief 6-item version of the CADSS (CADSS-6) based on items most sensitive to ketamine-induced dissociation. The CADSS-6 questions were then applied to the second dataset (n = 130) and the Spearman's correlation between the full-length CADSS and the CADSS-6 were assessed.

Results: The CADSS-6 was developed from questions 1, 2, 6, 7, 15, and 22 from the full length CADSS. There was a strong significant correlation between the CADSS-6 total score and the CADSS total score at infusions 1 (rs(106) = 0.92, p < 0.001), 2 (rs(100) = 0.91, p < 0.001), 3(rs(99) = 0.95, p < 0.001) and 4 (rs(102) = 0.94, p < 0.001).

Limitations: The CADSS-6 was developed using a retrospective data; therefore, the scale remains unvalidated in this population.

Conclusions: The CADSS-6 presented herein was sensitive to dissociation experienced by patients receiving IV ketamine. Overall, the CADSS-6 was strongly correlated at each infusion with the full-length CADSS. While future studies should look to validate the CADSS-6 in a TRD sample, this scale offers clinicians a brief assessment that can be used to characterize symptoms of dissociation.
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http://dx.doi.org/10.1016/j.jad.2020.12.119DOI Listing
March 2021

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

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

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

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

Effectiveness of intravenous ketamine in mood disorder patients with a history of neurostimulation.

CNS Spectr 2020 Dec 10:1-7. Epub 2020 Dec 10.

Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network, Toronto, Ontario, Canada.

Background: Patients unsuccessfully treated by neurostimulation may represent a highly intractable subgroup of depression. While the efficacy of intravenous (IV) ketamine has been established in patients with treatment-resistant depression (TRD), there is an interest to evaluate its effectiveness in a subpopulation with a history of neurostimulation.

Methods: This retrospective, posthoc analysis compared the effects of four infusions of IV ketamine in 135 (x̄ = 44 ± 15.4 years of age) neurostimulation-naïve patients to 103 (x̄ = 47 ± 13.9 years of age) patients with a history of neurostimulation. The primary outcome evaluated changes in depression severity, measured by the Quick Inventory for Depression Symptomatology-Self Report 16-Item (QIDS-SR16). Secondary outcomes evaluated suicidal ideation (SI), anxiety severity, measured by the Generalized Anxiety Disorder 7-Item (GAD-7), and consummatory anhedonia, measured by the Snaith-Hamilton Pleasure Scale (SHAPS).

Results: Following four infusions, both cohorts reported a significant reduction in QIDS-SR16 Total Score (F (4, 648) = 73.4, P < .001), SI (F (4, 642) = 28.6, P < .001), GAD-7 (F (2, 265) = 53.8, P < .001), and SHAPS (F (2, 302) = 45.9, P < .001). No between-group differences emerged. Overall, the neurostimulation-naïve group had a mean reduction in QIDS-SR16 Total Score of 6.4 (standard deviation [SD] = 5.3), whereas the history of neurostimulation patients reported a 4.3 (SD = 5.3) point reduction.

Conclusion: IV ketamine was effective in reducing symptoms of depression, SI, anxiety, and anhedonia in both cohorts in this large, well-characterized community-based sample of adults with TRD.
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http://dx.doi.org/10.1017/S1092852920002187DOI Listing
December 2020

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

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

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

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

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

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

Does body mass index predict response to intravenous ketamine treatment in adults with major depressive and bipolar disorder? Results from the Canadian Rapid Treatment Center of Excellence.

CNS Spectr 2020 Dec 3:1-9. Epub 2020 Dec 3.

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

Background: Higher body mass index (BMI) has been found to predict greater antidepressant response to intravenous (IV) ketamine treatment. We evaluated the association between BMI and response to repeat-dose IV ketamine in patients with treatment-resistant depression (TRD).

Methods: Adults (N = 230) with TRD received four infusions of IV ketamine at a community-based clinic. Changes in symptoms of depression (ie, Quick Inventory for Depressive Symptomatology-Self-Report 16; QIDS-SR16), suicidal ideation (SI; ie, QIDS-SR16 SI item), anxiety (ie, Generalized Anxiety Disorder-7 Scale), anhedonic severity (ie, Snaith-Hamilton Pleasure Scale), and functioning (ie, Sheehan Disability Scale) following infusions were evaluated. Participants were stratified by BMI as normal (18.0-24.9 kg/m2; n = 72), overweight (25-29.9 kg/m2; n = 76), obese I (30-34.9 kg/m2; n = 47), or obese II (≥35.0 kg/m2; n = 35).

Results: Similar antidepressant effects with repeat-dose ketamine were reported between BMI groups (P = .261). In addition, categorical partial response (P = .149), response (P = .526), and remission (P = .232) rates were similar between the four BMI groups.

Conclusions: The findings are limited by the observational, open-label design of this retrospective analysis. Pretreatment BMI did not predict response to IV ketamine, which was effective regardless of BMI.
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http://dx.doi.org/10.1017/S1092852920002102DOI Listing
December 2020

The influence of prescriber and patient gender on the prescription of benzodiazepines: evidence for stereotypes and biases?

Soc Psychiatry Psychiatr Epidemiol 2021 Jun 30;56(6):1083-1089. Epub 2020 Nov 30.

Department of Healthcare Administration, Asia University, No. 500, Lioufeng Rd, Wufeng, Taichung, 41354, Taiwan.

Purpose: Benzodiazepines are commonly prescribed globally. We hypothesize that gender stereotypes influence benzodiazepine prescriptions insofar as male prescribers are more likely to prescribe benzodiazepines to female patients.

Methods: Our nationwide cohort study included 2,127,441 patients with a psychiatric disorder (ICD-9 codes 290-319) and 38,932 prescribers as part of the Taiwan National Health Insurance Research Database (1997-2013). We evaluated the effects of patient and prescriber gender on the proportion of patients prescribed benzodiazepines and the cumulative dosage of benzodiazepine prescription (mg) using generalized estimating equation and general linear models.

Results: The proportion of patients prescribed benzodiazepines was higher among male (vs. female) prescribers [odds ratio (OR) = 1.06, 95% confidence interval (CI) = 1.05-1.07] and among female (vs. male) patients (OR = 1.08, 95% CI = 1.08-1.09). Similarly, male prescriber gender (β = 10,292.2, SE = 1265.5, p < 0.001) and female patient gender (β = 7913.7, SE = 627.1, p < 0.001) predicted higher cumulative dosages of benzodiazepine prescription. Mean cumulative dosage was highest among female patients seen by male prescribers (β = 4283.7, SE = 717.6, p < 0.001). The results were consistent in sensitivity analyses of patients with anxiety disorder (n = 1,632,363), major depression (n = 1,122,796), or chronic administration (n = 1,981,819), and prescribers with psychiatrists (n = 1276), and non-psychiatrists (n = 33,268).

Conclusions: Male prescribers were more likely to prescribe benzodiazepines to female patients relative to male patients. This gender bias in prescription is significant and warrants careful attention at point of care. We hypothesize that internalized societal biases and stereotypes affect benzodiazepine prescribing behaviour.
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http://dx.doi.org/10.1007/s00127-020-01989-4DOI Listing
June 2021

The effectiveness of intravenous ketamine in adults with treatment-resistant major depressive disorder and bipolar disorder presenting with prominent anxiety: Results from the Canadian Rapid Treatment Center of Excellence.

J Psychopharmacol 2021 02 11;35(2):128-136. Epub 2020 Oct 11.

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

Background: Individuals meeting criteria for treatment-resistant depression (TRD) are differentially affected by high levels of anxiety symptoms.

Aims: There is a need to identify the efficacy of novel rapid-onset treatments in adults with mood disorders and comorbid anxious-distress.

Methods: This study included patients with treatment-resistant major depressive disorder (MDD) or bipolar disorder (BD) who were receiving intravenous (IV) ketamine treatment at a community-based clinic.Anxious-distress was proxied using items from the Quick Inventory of Depressive Symptomatology-Self Report 16-item (QIDS-SR) and Generalized Anxiety Disorder 7-item (GAD7) scales. The difference in QIDS-SR total score, QIDS-SR suicidal ideation (SI) item and GAD7 score were analyzed between groups.

Results: A total of 209 adults with MDD ( = 177) and BD ( = 26) were included in this analysis. From this sample, 94 patients (mean = 45 ± 13.9 years) met the criteria for anxious-distress. Individuals meeting the criteria for anxious-distress exhibited a significantly greater reduction in QIDS-SR total score following four infusions ( = 0.02) when compared with patients not meeting the anxious-distress criteria. Both anxious-distressed and low-anxiety patients exhibited a significant reduction in SI ( < 0.0001) following four infusions.Finally, there was a significantly greater reduction in anxiety symptoms in the anxious-distress group compared with the non-anxious distress group following three ( = 0.02) and four infusions ( < 0.001).

Conclusion: Patients with TRD and prominent anxiety receiving IV ketamine exhibited a significant reduction in depressive, SI and anxiety symptoms.
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http://dx.doi.org/10.1177/0269881120954048DOI Listing
February 2021

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

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

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

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

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

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

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

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