Ketamine as potential treatment for postpartum depression: A narrative review.

BACKGROUND: Postpartum depression (PPD) is a severe, debilitating mood disorder with consequences for both mothers and children, highlighting the need for rapid-acting and effective treatments for PPD. The aim of this narrative review is to synthesize the available literature on the administration of ketamine for PPD and propose ketamine as a viable and advantageous treatment. METHODS: A search was conducted on MEDLINE/PubMed, PsycInfo, and Embase databases from inception to October 10, 2021 for preclinical studies, interventional studies (ie, open-label and randomized controlled trials), as well as systematic reviews and meta-analyses evaluating the use of ketamine in postpartum populations. Completed and ongoing clinical trials were identified on ClinicalTrials.gov. RESULTS: Four clinical trials were identified. Results from this review support additional investigation into ketamine as a potential treatment for PPD. CONCLUSIONS: Ketamine may be a favorable option for treating PPD due to its antidepressive and analgesic effects, short infusion time, and rapid clearance from the maternal bloodstream. However, there is insufficient evidence to support its use in this population, underscoring the importance of additional clinical research investigating ketamine for PPD.

An App-Based Digit Symbol Substitution Test for Assessment of Cognitive Deficits in Adults With Major Depressive Disorder: Evaluation Study.

BACKGROUND: Cognitive dysfunction is an impairing core symptom of depression. Among adults with major depressive disorder (MDD) treated with antidepressants, residual cognitive symptoms interfere with patient-reported outcomes. The foregoing characterization of cognitive symptoms provides the rationale for screening and assessing the severity of cognitive symptoms at point of care. However, clinical neurocognitive assessments are time-consuming and difficult, and they require specialist expertise to interpret them. A smartphone-delivered neurocognitive test may offer an effective and accessible tool that can be readily implemented into a measurement-based care framework. OBJECTIVE: We aimed to evaluate the use of a smartphone-delivered app-based version of the established Cognition Kit Digit Symbol Substitution Test (DSST) neurocognitive assessment compared to a traditional paper-and-pencil version. METHODS: Convergent validity and test-retest reliability of the 2 versions were evaluated. Patient satisfaction with the app was also assessed. RESULTS: Assessments made using the app-based Cognition Kit DSST were highly correlated with the standard paper-and-pencil version of the test, both at the baseline visit (r=0.69, df=27; P<.001) and at the end-of-study visit (r=0.82, df=27; P<.001), and they were positively evaluated by 30 patients as being user-friendly, easy to navigate, and preferable over the paper-and-pencil version of the DSST. However, although the app-based Cognition Kit DSST was validated in patients with MDD, it still needs to be evaluated in healthy controls. CONCLUSIONS: App-based DSST may facilitate a more personalized, convenient, and cost-effective method of cognitive assessment, helping to guide measurement-based care and psychotherapeutic and pharmacologic treatment options for patients with MDD. TRIAL REGISTRATION: ClinicalTrials.gov NCT03999567; https://tinyurl.com/2p8pnyv7.

A Research Domain Criteria (RDoC)-Guided Dashboard to Review Psilocybin Target Domains: A Systematic Review.

BACKGROUND: Preliminary results from randomized controlled studies as well as identified molecular, cellular, and circuit targets of select psychedelics (e.g., psilocybin) suggest that their effects are transdiagnostic. In this review, we exploit the Research Domain Criteria (RDoC) transdiagnostic framework, to synthesize extant literature on psilocybin. OBJECTIVE: We aimed to identify RDoC-based effects of psilocybin and vistas for future mechanistic and interventional research. METHODS: A systematic search in electronic databases (i.e., PubMed, Scopus, PsycINFO, and Web of Science) performed in January and February 2021 identified English articles published between 1990 and 2020 reporting the effects of psilocybin on mental health measures. Data from included articles were retrieved and organized according to the RDoC bio-behavioral matrix and its constituent six main domains, namely: positive valence systems, negative valence systems, cognitive systems, social processes, sensorimotor systems, and arousal and regulatory systems. RESULTS: The preponderance of research with psilocybin has differentially reported beneficial effects on positive valence systems, negative valence system, and social process domains. The data from the included studies support both short-term (23 assessments) and long-term (15 assessments) beneficial effects of psilocybin on the positive valence systems. While 12 of the extracted outcome measures suggest that psilocybin use is associated with increases in the "fear" construct of the negative valence systems domain, 19 findings show no significant effects on this construct, and seven parameters show lowered levels of the "sustained threat" construct in the long term. Thirty-four outcome measures revealed short-term alterations in the social systems' construct namely, "perception and understanding of self," and "social communications" as well as enhancements in "perception and understanding of others" and "affiliation and attachment". The majority of findings related to the cognitive systems' domain reported dyscognitive effects. There have been relatively few studies reporting outcomes of psilocybin on the remaining RDoC domains. Moreover, seven of the included studies suggest the transdiagnostic effects of psilocybin. The dashboard characterization of RDoC outcomes with psilocybin suggests beneficial effects in the measures of reward, threat, and arousal, as well as general social systems. CONCLUSIONS: Psilocybin possesses a multi-domain effectiveness. The field would benefit from highly rigorous proof-of-mechanism research to assess the effects of psilocybin using the RDoC framework. The combined effect of psilocybin with psychosocial interventions with RDoC-based outcomes is a priority therapeutic vista.

Sex differences in ketamine's therapeutic effects for mood disorders: A systematic review.

Replicated clinical trials have demonstrated rapid and robust antidepressant effects with ketamine in treatment resistant mood disorders. Sex (biological) and gender differences in therapeutic effects for any new intervention is an important consideration, however, the differential efficacy, safety and tolerability of ketamine in males versus females remains underexplored. The objective of the present systematic review is to identify and qualitatively synthesize all published clinical studies relevant to the sex differential effects of ketamine for mood disorders. A systematic search of PubMed, Medline, and PsycInfo from inception until January 20, 2021, yielded 27 reports including 1715 patients (742 males and 973 females) that met inclusion criteria. Results from the vast majority of studies (88.8%) do not support significant sex differences in antidepressant response, tolerability or safety of ketamine. Nine (33.3%) of the reports included a bioanalytical component in the analysis and only one reported on sex differences. Evidence from the present review does not support clinically or statistically significant sex differences in therapeutic effects with ketamine. Nevertheless, future studies should continue to consider sex and biological sex differences in study design and data analytic plans.

The effect of ketamine on anhedonia: improvements in dimensions of anticipatory, consummatory, and motivation-related reward deficits.

Anhedonia is a common, persistent, and disabling condition. However, available therapeutics primarily focus on the reduction of depressive and negative symptoms rather than amelioration of deficits in positive affect. As such, extant drug treatments remain largely ineffective in treating symptoms of anhedonia. Ketamine is a rapid-acting and novel therapeutic treatment for treatment-resistant depression, which has also been demonstrated to attenuate symptoms of anhedonia. However, the literature on the anti-anhedonic effects of ketamine is limited-especially within independent dimensions of this symptom domain. Herein, this review examined the impact of ketamine treatment on anhedonia and its dimensions on anticipatory, consummatory, and motivation-related reward deficits. Overall, the findings have shown a trend towards symptom reduction and/or improvements in anhedonia and their respective subdomains, in both human and preclinical studies, as well as its potential to provide additional benefit in reducing suicidality and improving quality-of-life. Although further research is required in understanding the long-term efficacy and mechanism, ketamine may provide an effective and rapid-acting therapeutic in an otherwise unmet domain.

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.

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.

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

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.

Frequency analysis of symptomatic worsening following ketamine infusions for treatment resistant depression in a real-world sample: Results from the canadian rapid treatment center of excellence.

Antidepressants are associated with symptomatic worsening in a subgroup of patients. Replicated evidence has demonstrated rapid and robust antidepressant effects with intravenous (IV) ketamine in treatment resistant depression (TRD); however, the risk of ketamine worsening depressive symptoms in a subgroup of patients remains unknown. Herein we report a retrospective analysis on the rates of symptomatic worsening during an acute course of IV ketamine in individuals with unipolar (n = 142) and bipolar (n = 22) TRD. Adults (N = 164; mean age = 45.97) with TRD underwent four sub-anesthetic infusions (0.5-0.75 mg/kg over 40 min) of IV ketamine over two weeks, and were assessed with the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SR16) at baseline and after each infusion. The primary outcome was the proportion of patients experiencing clinically significant worsening of depressive symptoms (≥20% increase on the QIDS-SR16) at each time point relative to baseline. Secondary analyses explored trends in the results. The frequency of clinically significant worsening fluctuated between 1.83% to 5.49%, with no identifiable trend across time. Zero individuals with bipolar TRD reported symptomatic worsening. Limitations include the single-centered, uncontrolled, retrospective nature of this study. Rates of symptomatic worsening associated with IV ketamine therapy for TRD appear to be very low and similar to conventional antidepressants.

Ketamine for psychotic depression: An overview of the glutamatergic system and ketamine's mechanisms associated with antidepressant and psychotomimetic effects.

Approximately 0.35-1% of the general population is afflicted with psychotic depression at some time in their life. Psychotic depression is a subtype of major depressive disorder characterized by mood congruent hallucinations and/or delusions. Patients with psychotic depression often represent the most severe cases, with high relapse and mortality rate. Although treatment guidelines recommend a combination of antidepressants and antipsychotics or electroconvulsive therapy, most patients subsequently relapse due to treatment resistance. Furthermore, with the concern of antipsychotic drug's side effects (e.g., tardive dyskinesia), there is a need for an alternative pharmacotherapy for psychotic depression. Recently, several case studies demonstrated that treatment with ketamine not only ameliorated mood, but also improved psychotic symptoms in patients with treatment-resistant depression and psychotic features. However, the safety of ketamine in these patients is controversial since ketamine is known to induce psychotomimetic and dissociative effects. Additionally, the efficacy and safety of ketamine in patients with psychotic depression has not been established as most clinical trials have excluded these persons due to the theorized risk of aggravating psychotic symptoms. Notwithstanding, it is not established empirically that ketamine treatment in psychotic depression would predictably amplify psychotic symptoms and/or overall illness presentation. Future trials evaluating ketamine in depression should include patients with psychotic features to inform whether ketamine is safe and effective in this subpopulation.

Trace amine-associated receptor 1 (TAAR1): Potential application in mood disorders: A systematic review.

There is a need for innovation with respect to therapeutics in psychiatry. Available evidence indicates that the trace amine-associated receptor 1 (TAAR1) agonist SEP-363856 is promising, as it improves measures of cognitive and reward function in schizophrenia. Hedonic and cognitive impairments are transdiagnostic and constitute major burdens in mood disorders. Herein, we systematically review the behavioural and genetic literature documenting the role of TAAR1 in reward and cognitive function, and propose a mechanistic model of TAAR1's functions in the brain. Notably, TAAR1 activity confers antidepressant-like effects, enhances attention and response inhibition, and reduces compulsive reward seeking without impairing normal function. Further characterization of the responsible mechanisms suggests ion-homeostatic, metabolic, neurotrophic, and anti-inflammatory enhancements in the limbic system. Multiple lines of evidence establish the viability of TAAR1 as a biological target for the treatment of mood disorders. Furthermore, the evidence suggests a role for TAAR1 in reward and cognitive function, which is attributed to a cascade of events that are relevant to the cellular integrity and function of the central nervous system.

Suicide reduction in Canada during the COVID-19 pandemic: lessons informing national prevention strategies for suicide reduction.

OBJECTIVE: The objective of this research was to evaluate the impact of federal, public health and social support programs on national suicide rates in Canada. DESIGN: Cross-sectional study. SETTING: Canadian National Database (i.e., Statistics Canada) and Statista. PARTICIPANTS: Population-level data, and economic and consumer market data. MAIN OUTCOME MEASURES: Suicide mortality data, population data and unemployment data were obtained from available statistical databases (e.g. Statistics Canada). We quantified suicide rate by dividing the total number of suicide deaths by the national population expressed as a rate per 100,000 population. RESULTS: Overall suicide mortality rate decreased in Canada from 10.82 deaths per 100,000 in the March 2019 - February 2020 period to 7.34 per 100,000 (i.e. absolute difference of 1300 deaths) in the March 2020 - February 2021 period. The overall Canadian unemployment rate changed from an average monthly rate of 5.7% in 2019 to 9.5% in 2020. CONCLUSION: Our results indicate that for the first post-pandemic interval evaluated (i.e., March 2020 - February 2021), suicide rates in Canada decreased against a background of extraordinary public health measures intended to mitigate community spread of COVID-19. An externality of public health measures was a significant rise in national unemployment rates in population measures of distress. Our results suggest that government interventions that broadly aim to reduce measures of insecurity (i.e., economic, housing, health), and timely psychiatric services, should be prioritised as part of a national suicide reduction strategy, not only during but after termination of the COVID-19 pandemic.

Prevention and Management of Common Adverse Effects of Ketamine and Esketamine in Patients with Mood Disorders.

The emerging roles of ketamine and esketamine as effective rapid-acting antidepressants hold promise for patients suffering from treatment-resistant depression and/or major depressive disorder with suicidality. Practitioner familiarity with common tolerability/safety concerns along with pragmatic prevention and management strategies are needed to reduce patient burden and improve the acceptability and accessibility of these treatments. The most common treatment-emergent adverse events associated with ketamine/esketamine are dissociation, anxiety, nausea, increased blood pressure, and headache. The majority of side effects are mild, transient, dose dependent, and attenuate with subsequent treatments. Patient selection, baseline physical and psychiatric assessments, and an appropriate setting are critical first steps in the prevention and mitigation of adverse events. Patient education and supportive interventions play central roles in the prevention and management of select adverse events. Severe and/or clinically significant adverse effects may necessitate the judicious use of adjunctive medications. Moreover, practitioners must remain vigilant to the potential for abuse liability and long-term adverse events, for which there are insufficient data. This article succinctly reviews common treatment-emergent adverse events of ketamine and esketamine within the context of mood disorders, and provides practical suggestions for prevention and management at point-of-care.

Examining the association between inflammation and motivational anhedonia in neuropsychiatric disorders: A systematic review.

BACKGROUND: Inflammation, motivational anhedonia, and neuropsychiatric disorders are associated with significant functional impairment and are a major public health concern. The objective of this systematic review is to examine the relationship between inflammatory activity and motivational anhedonia in neuropsychiatric disorders. METHODS: Preclinical and clinical studies were qualitatively synthesized and summarized. RESULTS: We found an association between inflammation and neuropsychiatric disorders, and a transdiagnostic association between motivational anhedonia and neuropsychiatric disorders. This review also identified brain regions associated with motivational processes that might have a latent vulnerability to persistent inflammatory activity. Motivational processes might be impacted early in the development of neuropsychiatric disorders, and could lead to a precursory manifestation of motivational anhedonia before (eg, prodromal phase) or early in the clinical course of the disorder. CONCLUSIONS: Although inflammation, motivational anhedonia, and neuro psychiatric disorders are strongly associated, direct evidence of causal interactions are limited. Further research is required to understand the association and mechanical underpinnings, and improve assessment of this construct. The immune system could serve as a novel treatment target to improve symptoms of motivational anhedonia across diverse neuro psychiatric disorders; however, well-designed interventional studies are required to assess this hypothesis.

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

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.

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

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.

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.

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.

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

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 η2 = 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.

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

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; Mage = 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.

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

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.

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).

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.