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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.

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.

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.

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 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.

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.

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 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.

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.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.Four clinical trials were identified. Results from this review support additional investigation into ketamine as a potential treatment for PPD.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.

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.

Background The aim of this study was to determine the validity of using social media for depression screening. Method Article searches on PubMed and PsycINFO from database inception to August 20, 2019 were completed with a search string and filters. Results 15 articles made the inclusion criteria. Facebook, Twitter, and Instagram profiles of depressed people were distinguishable from nondepressed people shown by social media markers. Facebook studies showed that having fewer Facebook friends and mutual friends, posting frequently, and using fewer location tags positively correlated with depressive symptoms. Also, Facebook posts with explicit expression of depressive symptoms, use of personal pronouns, and words related to pain, depressive symptoms, aggressive emotions, and rumination predicted depression. Twitter studies showed that the use of “past focus” words, negative emotions and anger words, and fewer words per Tweet positively correlated with depression. Finally, Instagram studies showed that differences in follower patterns, photo posting and editing, and linguistic features between depressed people and nondepressed people could serve as a marker. Limitations The primary articles analyzed had different methods, which constricts the amount of comparisons that can be made. Further, only four social media platforms were explored. Conclusion Social media markers like number and content of Facebook messages, linguistic variability in tweets and tweet word count on Twitter, and number of followers, frequency of Instagram use and the content of messages on Instagram differed between depressed people and nondepressed people. Therefore, screening social media profiles on these platforms could be a valid way to detect depression.

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.

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 (1H-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.

Cognitive impairment is common in bipolar disorder and is emerging as a therapeutic target to enhance quality of life and function. A systematic search was conducted on PubMed, PsycInfo, Cochrane, clinicaltrials.gov, and Embase databases for blinded or open-label randomized controlled trials evaluating the pro-cognitive effects of pharmacological, neurostimulation, or psychological interventions for bipolar disorder. Twenty-two trials were identified, evaluating a total of 16 different pro-cognitive interventions. The methodological quality of the identified trials were assessed using the Cochrane Risk of Bias tool. Currently, no intervention (i.e., pharmacologic, neurostimulation, cognitive remediation) has demonstrated robust and independent pro-cognitive effects in adults with bipolar disorder. Findings are preliminary and methodological limitations limit the interpretation of results. Methodological considerations including, but not limited to, the enrichment with populations with pre-treatment cognitive impairment, as well as the inclusion of individuals who are in remission are encouraged. Future trials may also consider targeting interventions to specific cognitive subgroups and the use of biomarkers of cognitive function.

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.

Replicated evidence has documented cognitive deficits in populations with treatment-resistant depression (TRD). Approximately 40 % of patients with MDD present with impairment of one or more cognitive domains. As such, there is an unmet need to discover treatments that have pro-cognitive effects in TRD patients. Ketamine has demonstrated efficacy as a rapid-onset intervention for the treatment of depression. The objective of the current review was to assess the effects of ketamine on cognition in TRD patients. We systematically searched PubMed, Google Scholar and PsycINFO between database inception to March 24th, 2020. We identified five studies that evaluated cognition in TRD populations following ketamine treatment. All studies included a 0.5 mg/kg subanesthetic intravenous (IV) administration of ketamine. One study found significant improvements in complex (p = .008) and simple (p = .027) working memory and one study found improvements in visual learning memory following IV ketamine infusions (p = .014). Improvements in speed of processing and verbal learning memory were observed in anxious TRD participants only. Importantly, a subanesthetic dose of IV ketamine does not worsen cognitive function.

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.

BackgroundHigher 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).MethodsAdults (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).ResultsSimilar 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.ConclusionsThe 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.

Highlights • The coronavirus disease 2019 (COVID-19) pandemic has resulted in unprecedented hazards to mental health globally. • Relatively high rates of anxiety, depression, post-traumatic stress disorder, psychological distress, and stress were reported in the general population during the COVID-19 pandemic in eight countries. • Common risk factors associated with mental distress during the COVID-19 pandemic include female gender, younger age group (≤40 years), presence of chronic/psychiatric illnesses, unemployment, student status, and frequent exposure to social media/news concerning COVID-19. • Mitigation of COVID-19 induced psychological distress requires government intervention and individual efforts., Background As a major virus outbreak in the 21st century, the Coronavirus disease 2019 (COVID-19) pandemic has led to unprecedented hazards to mental health globally. While psychological support is being provided to patients and healthcare workers, the general public's mental health requires significant attention as well. This systematic review aims to synthesize extant literature that reports on the effects of COVID-19 on psychological outcomes of the general population and its associated risk factors. Methods A systematic search was conducted on PubMed, Embase, Medline, Web of Science, and Scopus from inception to 17 May 2020 following the PRISMA guidelines. A manual search on Google Scholar was performed to identify additional relevant studies. Articles were selected based on the predetermined eligibility criteria. Results: Relatively high rates of symptoms of anxiety (6.33% to 50.9%), depression (14.6% to 48.3%), post-traumatic stress disorder (7% to 53.8%), psychological distress (34.43% to 38%), and stress (8.1% to 81.9%) are reported in the general population during the COVID-19 pandemic in China, Spain, Italy, Iran, the US, Turkey, Nepal, and Denmark. Risk factors associated with distress measures include female gender, younger age group (≤40 years), presence of chronic/psychiatric illnesses, unemployment, student status, and frequent exposure to social media/news concerning COVID-19. Limitations A significant degree of heterogeneity was noted across studies. Conclusions The COVID-19 pandemic is associated with highly significant levels of psychological distress that, in many cases, would meet the threshold for clinical relevance. Mitigating the hazardous effects of COVID-19 on mental health is an international public health priority.

Ketamine is established as a rapid and effective treatment in adults with treatment-resistant depression (TRD). The availability of different formulations and routes of delivery invites the need for evaluating relative effect sizes.Effect size with respect to depression symptom reduction for each formulation and route of delivery was compared at discrete time-points (i.e., 24 h, 2-6 days, 7-20 days, 21-28 days) in adults with TRD. A random-effects meta-analysis was conducted to evaluate the effect size across intravenous, intranasal and oral routes of administration. Analysis was also conducted evaluating the effect size of racemic ketamine to esketamine.The pooled effect size for intranasal ketamine/esketamine at 24 h was g = 1.247 (n = 5, 95% CI: 0.591-1.903, p 0.01). At 2-6 days, the pooled effect size for intravenous ketamine/esketamine was g = 0.949 (n = 14, 95% CI: -0.308-2.206, p = 0.139). At 7-20 days, intranasal ketamine had a pooled effect size of g = 1.018 (n = 4, 95% CI: 0.499-1.538, p 0.01). At 21-28 days, oral ketamine had a pooled effect size of g = 0.633 (n = 2, 95% CI: 0.368-0.898, p 0.01).Additional comparative studies are needed with regards to the efficacy of different formulations and routes of delivery.The short-term efficacy of intravenous and intranasal ketamine/esketamine for adults with TRD was established. Interpreting the efficacy of oral ketamine was limited by the need for studies with larger samples across independent sites. No conclusions regarding comparative efficacy of the disparate formulations and routes of delivery can be derived from this analysis. Direct comparative studies are needed to further inform treatment options for TRD.

Background Major Depressive Disorder (MDD) is a common and debilitating mood disorder. Individuals with MDD are often misdiagnosed or diagnosed in an untimely manner, exacerbating existing functional impairments. Ecological momentary assessment (EMA) involves the repeated sampling of an individual's symptoms within their natural environment and has been demonstrated to assist in illness assessment and characterization. Capturing data in this way would set the stage for improved treatment outcomes and serve as a complementary resource in the management and treatment of depressive symptoms. Methods Online databases PubMed/MedLine and PsycINFO were searched using PRISMA guidelines and combinations of the following keywords: EMA, depression, smartphone app, diagnosing, symptoms, phone, app, ecological momentary assessment, momentary assessment, data mining, unobtrusive, passive data, GPS, sensor. Results A total of nineteen original articles were identified using our search parameters and ten articles met the inclusion criteria for full-text review. Among the ten relevant studies, three studies evaluated feasibility, seven evaluated detection, and three evaluated treatment of MDD. Limitations Limitations include that the design of all of the studies included in this review are non-randomized. It should be noted that most of the studies included were pilot studies and/or exploratory trials lacking a control group. Conclusions Available evidence suggests that the use of passive smartphone-based applications may lead to improved management of depressive symptoms. This review aids the creation of new EMA applications, highlights the potential of EMA usage in clinical settings and drug development, emphasizes the importance for regulation of applications in the mental health field, and provides insight into future directions.

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.

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.

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

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.

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.

BackgroundPatients 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.MethodsThis 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).ResultsFollowing 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.ConclusionIV 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.

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.

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-SR16) and Generalized Anxiety Disorder 7-item (GAD7) scales. The difference in QIDS-SR16 total score, QIDS-SR16 suicidal ideation (SI) item and GAD7 score were analyzed between groups. Results: A total of 209 adults with MDD ( n = 177) and BD ( n = 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-SR16 total score following four infusions ( p = 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 ( p < 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 ( p = 0.02) and four infusions ( p < 0.001). Conclusion: Patients with TRD and prominent anxiety receiving IV ketamine exhibited a significant reduction in depressive, SI and anxiety symptoms.

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.

Mental illness has a chronic course of illness with a number of clinical manifestations. Affected individuals experience significant functional, emotional, cognitive, and/or behavioral impairments. The growing prevalence of mental illness has been associated with significant social and economic costs. Indeed, the economic burden of mental illness is estimated to exceed $1.8 trillion USD over the next 30 years. A significant number of individuals affected by mental illness fail to respond to first-line treatment options. Therefore, there remains an unmet need for rapidly attenuating therapeutic options for mental health disorders with minimal social and economic burden.The paucity of novel treatment options warrants a renewed investigation of psychedelic-based psychotherapy. Herein, the authors will evaluate the therapeutic potential of traditional psychedelics, psilocybin, and MDMA, in the treatment of mental illness with a narrative review of available literature.Psychedelics, such as psilocybin and MDMA, offer an alternative avenue of therapy for many mental health disorders. Available evidence indicates that psychedelics may offer a single-dose, rapid effect model that have robust effects with treatment-resistant mental disorders and a unique advantage as a possible monotherapy for mental illness. Novel clinical trials that evaluate the safety, tolerability, and efficacy in clinically representative populations are warranted.

Objective Converging evidence suggests abnormalities in monetary reward processing may underlie the shared pathophysiology between major depressive disorder and obesity. As such, there is a need to parse deficits in specific subcomponents of monetary reward functioning (i.e., valuation, learning and anticipation). Methods PsycINFO, Google Scholar and PubMed databases were searched for English-language articles published between database inception to June 6th, 2020. Studies were identified using the following medical search heading (MeSH) terms and search strings: (reward (valuation OR motivation OR anticipation OR learning OR functioning OR decision-making OR reinforcement)) AND ((obesity OR overweight OR obese). Results Findings were reviewed from 11 studies evaluating the association between obesity and monetary reward processing. Four studies found significant differences in reward learning in individuals with obesity compared to normal-weight participants. Five studies found body mass index (BMI) to be predictive of willingness to expend effort (i.e., valuation) for a monetary reward. Three studies found changes in neural activations in the ventral striatum during anticipatory phases preceding receipt of a monetary reward in participants with obesity. Conclusions Participants with obesity demonstrated significantly poorer performance in task-based measures of reward learning, valuation, and anticipation, resulting in lower monetary reward outcomes across all studies compared to healthy controls. Notably, participants with obesity and comorbid depression performed worse than participants with no comorbid depression. Limitations There persists heterogeneity between studies with regards to inclusion of mood disorder populations and exclusion of psychiatric comorbidities in groups with obesity.

OBJECTIVE To determine the effectiveness of intravenous (IV) ketamine on anxiety, irritability, agitation, and suicidality, in adults with treatment-resistant major depressive disorder (MDD) or bipolar disorder (BD). METHOD Adults (N = 201) with treatment-resistant MDD or BD received repeat-dose IV ketamine treatment at a community-based clinic. Mixed features were measured using symptoms of anxiety, irritability, and agitation (AIA), as measured by the Generalized Anxiety Disorder-7 (GAD-7) scale. The Quick Inventory for Depressive Symptomatology Self-Report-16 (QIDS-SR16 ) was used to measure overall treatment response, and the QIDS-SR16 suicidal ideation (SI) item was used to measure change in SI symptoms with ketamine treatment. The anxiety, irritability, and agitation items on the GAD-7 were used to assess effectiveness of IV ketamine in treating symptoms of mixed features. RESULTS In this retrospective analysis, 113 participants met AIA criteria. Participants with AIA experienced a significantly greater reduction in overall depressive symptoms (F(1, 558) = 9.49, P = .002), SI (F(1, 558) = 3.103, P = .079), anxiety (F(1, 198) = 5.52, P = .007), irritability (F(1, 198) = 28.35, P

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

Anhedonia is a trans-diagnostic, multidimensional phenotype that mediates patient outcomes and suicidality. Convergent evidence suggests that ketamine may be effective in targeting measures of anhedonia in adults with treatment resistant depression (TRD).This retrospective, post-hoc analysis included 203 (x̄ = 45 ± 14.6 years of age) patients receiving four infusions of intravenous (IV) ketamine at a community-based clinic. The primary outcome measure was change in anhedonia severity, as measured by the Snaith-Hamilton Pleasure Scale (SHAPS). Secondary measures sought to determine if improvement on the SHAPS mediated the effect of repeated IV ketamine infusions on symptoms of depression and suicidal ideations, as measured by the Quick Inventory for Depression Symptomatology-Self Report 16-Item (QIDS-SRAfter adjusting for age, sex, primary diagnosis, concomitant medication, body mass index, and baseline depression severity, there was a statistically significant reduction in symptoms of anhedonia with IV ketamine treatment (F (2, 235.6) = 31.6, p0.001). Improvements in depressive symptoms, suicidal ideation, and anxiety symptoms with repeated-dose IV ketamine were significantly partially mediated by reduction in anhedonic severity. Moreover, the combination of number of infusions received and change in anhedonic severity accounted for 26% of the variance in depressive score improvements.This is a post-hoc analysis of retrospective data and lacks a control group.Ketamine was effective in improving measures of anhedonia in this large, well-characterized community-based sample of adults with TRD. Improvements in anhedonia also partially mediated the significant improvement in depressive symptoms, suicidality, and anxiety.

Antidepressant medications are the first-line treatment option for moderate to severe major depressive disorder. However, most antidepressants have numerous documented adverse events, including cardiometabolic effects and weight gain, which are major public health concerns. Antidepressant agents provide varying risk of associated weight gain, including significant within-class differences. Some agents, such as mirtazapine, show significant levels of weight gain, while others, such as bupropion, demonstrate weight-loss effects. Current findings suggest the role of histamine and serotonin off-target appetite-promoting pathways in adverse weight-gain effects. Therefore, controlling for undesired weight effects is an important consideration for the selection of antidepressants.

Background The effectiveness, tolerability, and safety of intravenous (IV) ketamine in adults with treatment resistant depression (TRD) receiving care in real-word settings is insufficiently characterized. Herein, results from a naturalistic, retrospective study are presented from a Canadian outpatient IV ketamine clinic. Methods Adults (N = 213; Mage = 45) with Major Depressive Disorder or Bipolar Disorder, with a minimum of Stage 2 antidepressant resistance, received IV ketamine at a community-based multi-disciplinary clinic. The primary outcome measure was change from baseline to post-infusion 4 on the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SR16; n = 190). Secondary measures included QIDS-SR16-measured response and remission rates, changes from baseline to endpoint in Generalized Anxiety Disorder-7 Scale (GAD-7; n = 188) and the Sheehan Disability Scale (SDS; n = 168). Results Significant improvement in total depressive symptoms severity (p Limitations This was a naturalistic, retrospective study, without a control group. Conclusions IV ketamine was safe, well-tolerated, and effective at improving depressive, anxiety, and functional impairment symptoms in a well-characterized cohort of adults with TRD.

As interest has grown in the potential psychiatric applications of ketamine, the number of registered clinical trials has grown substantially. Herein, we summarize and analyze clinical trials registered with ClinicalTrials.gov that assess the treatment of any psychiatric disorder with ketamine or ketamine enantiomers (e.g., S-ketamine, R-ketamine), with a focus on ongoing clinical trials. A ClinicalTrials.gov search on February 21, 2020 returned 140 registered trials. Frequency data was analyzed to determine the distribution of study designs. The majority of trials (70%) investigated the therapeutic effect of ketamine in mood disorders (unipolar: 60%, bipolar: 0.7%, both: 5.7%). Suicidal ideation (13.1%), post-traumatic stress disorder (5.4%), and obsessive-compulsive disorder (3.6%) were also investigated. Intravenous (IV) administration was the most common route with 87% of the studies using IV ketamine. Single-dose studies represented 50% of IV ketamine studies. Few studies were assessing maintenance treatment. Most studies were phase I or II with few definitive phase III trials registered. Given the large number of ongoing studies assessing psychiatric application of ketamine, researchers and relevant stakeholders should consider not only completed, published studies, but also ongoing registered studies in adjudicating the most relevant research questions. More definitive phase III trials and maintenance studies of IV ketamine for mood disorders are required, as numerous completed and ongoing studies have already assessed and demonstrated the proof-of-concept of acute antidepressant effects in phase I and II trials.

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-SR

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.

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.

Numerous clinical trials have reported that intravenous (IV) ketamine demonstrates rapid antidepressant and anti-suicidal effects in patients with treatment-resistant depression (TRD). These studies, however, have not characterized whether these antidepressant effects translate to improvements in workplace productivity and functionality. Adults with TRD received repeated doses of IV ketamine at a community-based clinic (n = 171). We evaluated patient outcomes at two timepoints of interest: (1) acute-phase (i.e., following 4–6 infusions, 17.6 ± 12.6 days from baseline) and (2) maintenance-phase (i.e., following 7–10 infusions, 153.9 ± 63.4 days from baseline). The primary outcome measure was change from baseline to maintenance-phase scores on the Sheehan Disability Scale (SDS) workplace/school item as well as days underproductive (i.e., presenteeism) and days lost (i.e., absenteeism). Secondary measures included the Quick Inventory for Depression Symptomatology-Self Report 16-Item (QIDS-SR16). There was a significant reduction in workplace/school disability, and significantly reduced symptoms of presenteeism and absenteeism. At the acute-phase outcome, this translated to 2 more days of productivity and 1.5 less days absent from work. Additionally, IV ketamine exhibited a sustained antidepressant effect across the ten infusions. IV ketamine was associated with a significant reduction in workplace/school disability and demonstrated improvements in symptoms of presenteeism and absenteeism.

Importance: Loneliness has been associated with adverse health outcomes. However, few studies have evaluated its comparative effects on distinct health outcomes. Objective: The primary objective was to evaluate the comparative effects of loneliness on multiple health outcomes. The literature was qualitatively reviewed to identify risk factors associated with loneliness, explore mechanisms, and discuss potential evidence-based interventions for targeting loneliness. Data Sources: A systematic review and meta-analysis of studies were conducted to examine the association between loneliness and health outcomes. We searched the databases Ovid MEDLINE/PubMed, Embase, and PsycINFO from inception to April/01/2019 for relevant peer-reviewed publications. Study Selection: We selected studies that measured the association between subjective ratings of loneliness (i.e., UCLA Loneliness Scale or de Jong Gierveld Loneliness Scale) and one or more health outcome(s). Only validated measurement scales for health outcomes were used. Data Extraction and Synthesis: Data was extracted by four independent reviewers using a standardized data extraction form. A total of 114 identified studies were systematically evaluated to extract study characteristics, risk of bias, and loneliness-health associations required for the calculation of pooled effects (i.e., correlations). Main Outcome(s) and Measures: Loneliness and health outcomes were measured. Health outcomes were broadly defined to include measures of mental health (i.e., depression, anxiety, suicidality, general mental health), general health (i.e., overall self-rated health), well-being (i.e., quality of life, life satisfaction), physical health (i.e., functional disability), sleep, and cognition. Results: Loneliness had medium to large effects on all health outcomes, with the largest effects on mental health and overall well-being. No significant effects of age, health condition, or stigma were observed. However, we observed a significant effect of gender on the association between loneliness and cognition (i.e., more pronounced in studies with a greater proportion of males). We also observed a significant effect of geographical distribution on the associations between loneliness and overall well-being, sleep, and cognition (i.e., lower among European nations and higher among Asian nations). Conclusions and Relevance: Loneliness is associated with adverse effects on health, particularly mental health outcomes. Future research should explore the potential moderating effects of gender and geographical distribution. From a public health perspective, the adequate training of health care providers (HCPs) to perceive, detect, and respond to loneliness among patients should be prioritized. Funding Statement: The authors stated: "This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors." Declaration of Interests: Roger S. McIntyre is a consultant to speak on behalf of, and/or has received research support from Lundbeck, Janssen, Shire, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Stanley Medical Research Institute, and CIHR/GACD/Chinese National Natural Research Foundation. All other authors have no conflicts of interest to disclose. Ethics Approval Statement: The current systematic review and meta-analysis adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for transparent and comprehensive reporting of study methods and results.

Loneliness is a key determinant in the etiology of mental health disorders such as depression and has profound impacts on health, quality of life, and economic productivity. This narrative review uses extant neurobiology and evolutionary literature to propose a construct through which loneliness may induce depression in adulthood via the reward system (including symptom and treatment aspects). Early childhood (distal) factors were found to be important in influencing adult (proximal) factors, which lead to the formulation of the construct. Due to the heterogenous and comorbid nature of depression, a new subtype known as 'reward depression' was distinguished along with distinct symptoms to aid practitioners when assessing patient treatment options. Furthermore, an evolutionary perspective was applied to the current impaired reward construct to discuss how the ancestral purpose and environment (in terms of reward) clashes with the modern one. Finally, theoretical treatment and prevention ideas were examined and discussed, leading into future work that needs to build upon and confirm the outlined construct.

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-Report16 (QIDS-SR16) at baseline and post-infusions 1, 2, 3, and 4. Early improvement was defined as ≥20% reduction in QIDS-SR16 scores after the first or second infusion. Linear models were used to determine whether early improvement was associated with post-infusion 4 QIDS-SR16 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-SR16 scores post-infusion 4. Early improvers had significantly lower QIDS-SR16 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-SR16) 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.

Numerous pharmacological treatments for mood disorders are currently available; however, rates of treatment resistance, relapse and recurrence remain high. Therefore, novel treatments acting outside of the conventionally targeted monoamine system are urgently needed to improve patient outcomes. Emerging and converging evidence suggests that immune dysfunction, oxidative stress, impaired cerebral blood flow (CBF) and decreased neurotrophic factors all contribute to mood disorder pathophysiology and are therefore treatment targets of interest. Pentoxifylline (PTX) is a phosphodiesterase inhibitor with potent anti-inflammatory and antioxidant effects, with additional pleiotropic effects that lead to improved CBF and increases in brain derived neurotrophic factor (BDNF) levels. The direct effect of non-specific phosphodiesterase inhibition may also improve alertness and cognitive function through enhancing second messenger systems. Replicated preclinical studies have demonstrated antidepressant-like effects in animal models. Small preliminary clinical trials have demonstrated promising results for antidepressant and procognitive effects, however, have yet to be replicated in larger mood disorder samples. Only one randomized clinical trial (RCT) specifically assessed the effects of adjunctive PTX in major depressive disorder (MDD), showing clinically and statistically significant antidepressant effects compared to placebo. No studies have assessed PTX in bipolar disorder (BD), where inflammation and altered CBF have also been strongly implicated. Taken together, PTX presents as a promising pleiotropic agent with several potential novel mechanisms of action meriting further evaluation in clinical trials to evaluate target engagement, antidepressant, procognitive and mood stabilizing effects.

The primary objective was to evaluate the comparative effects of loneliness on multiple distinct health outcomes. The literature was qualitatively reviewed to identify loneliness risk factors, explore mechanisms, and discuss potential evidence-based interventions for targeting loneliness. 114 identified studies were systematically reviewed and analyzed to examine for associations between loneliness (as measured by the UCLA Loneliness or de Jong Gierveld Loneliness Scales) and one or more health outcome(s). Health outcomes were broadly defined to include measures of mental health (i.e., depression, anxiety, suicidality, general mental health), general health (i.e., overall self-rated health), well-being (i.e., quality of life, life satisfaction), physical health (i.e., functional disability), sleep, and cognition. Loneliness had medium to large effects on all health outcomes, with the largest effects on mental health and overall well-being; however, this result may have been confounded by the breadth of studies exploring the association between loneliness and mental health, as opposed to other health outcomes. A significant effect of gender on the association between loneliness and cognition (i.e., more pronounced in studies with a greater proportion of males) was also observed. The adequate training of health care providers to perceive and respond to loneliness among patients should be prioritized.