•Short-term efficacy of IV and IN ketamine/esketamine is established for TRD.•Interpretation the efficacy of oral ketamine in TRD is limited.•Insufficient data on disparate formulations and routes of ...delivery of ketamine.
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.
•Fatigue and cognitive impairment are amongst the most common and debilitating symptoms of post-COVID-19 syndrome.•Approximately 1 in 3 individuals experienced fatigue 12 or more weeks following ...COVID-19 diagnosis.•Approximately 1 in 5 individuals exhibited cognitive impairment 12 or more weeks following COVID-19 diagnosis.•There was an elevation in proinflammatory markers and functional impairment in a subset of post-COVID individuals.
COVID-19 is associated with clinically significant symptoms despite resolution of the acute infection (i.e., post-COVID-19 syndrome). Fatigue and cognitive impairment are amongst the most common and debilitating symptoms of post-COVID-19 syndrome.
To quantify the proportion of individuals experiencing fatigue and cognitive impairment 12 or more weeks following COVID-19 diagnosis, and to characterize the inflammatory correlates and functional consequences of post-COVID-19 syndrome.
Systematic searches were conducted without language restrictions from database inception to June 8, 2021 on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, and select reference lists.
Primary research articles which evaluated individuals at least 12 weeks after confirmed COVID-19 diagnosis and specifically reported on fatigue, cognitive impairment, inflammatory parameters, and/or functional outcomes were selected.
Two reviewers independently extracted published summary data and assessed methodological quality and risk of bias. A meta-analysis of proportions was conducted to pool Freeman-Tukey double arcsine transformed proportions using the random-effects restricted maximum-likelihood model.
The co-primary outcomes were the proportions of individuals reporting fatigue and cognitive impairment, respectively, 12 or more weeks following COVID-19 infection. The secondary outcomes were inflammatory correlates and functional consequences associated with post-COVID-19 syndrome.
The literature search yielded 10,979 studies, and 81 studies were selected for inclusion. The fatigue meta-analysis comprised 68 studies, the cognitive impairment meta-analysis comprised 43 studies, and 48 studies were included in the narrative synthesis. Meta-analysis revealed that the proportion of individuals experiencing fatigue 12 or more weeks following COVID-19 diagnosis was 0.32 (95% CI, 0.27, 0.37; p < 0.001; n = 25,268; I2 = 99.1%). The proportion of individuals exhibiting cognitive impairment was 0.22 (95% CI, 0.17, 0.28; p < 0.001; n = 13,232; I2 = 98.0). Moreover, narrative synthesis revealed elevations in proinflammatory markers and considerable functional impairment in a subset of individuals.
A significant proportion of individuals experience persistent fatigue and/or cognitive impairment following resolution of acute COVID-19. The frequency and debilitating nature of the foregoing symptoms provides the impetus to characterize the underlying neurobiological substrates and how to best treat these phenomena.
PROSPERO (CRD42021256965).
•Loneliness has been associated with adverse health outcomes, but few studies have evaluated its comparative effects on distinct health outcomes.•A scoping review reveals medium to large effects of ...loneliness on all health outcomes, with the largest effects on mental health outcomes and overall well-being.•Healthcare providers should be adequately trained to perceive and respond to loneliness due to its strong associations with adverse health outcomes.
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.
Type 2 Diabetes Mellitus (T2DM) and Major Depressive Disorder (MDD) are leading causes of disability worldwide. Indeed, both are costly and burdensome diseases at both individual and socio-economic ...levels. Notably, there are similar pathophysiological elements, which might explain the overlap in phenotypic symptoms and the high rate of comorbidity. Brain insulin resistance is a shared metabolic abnormality amongst many individuals with T2DM and MDD. Patients with either or both diseases often exhibit disturbances in cognition and mood, as well as the presence of anhedonia-like symptoms. However, individuals with T2DM with high glycemic control have reduced cognitive and depressive symptom burden. Based on this evidence, it is possible that repurposing therapies approved for treating insulin resistance may be useful in treating cognitive and anhedonia symptoms in depression. The objective of this review is to discuss the relationship between brain insulin resistance and depression, as well as possible disease modifying therapeutic agents targeting insulin signalling.
•We hypothesized that timely government implementation of stringent measures to reduce COVID-19 transmission would benefit mental health, as evidenced by reduced rates of depressive symptoms.•We ...evaluated data from 33 countries (k=114, N=640,037) in our systematic review (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.•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.
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).
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.
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.
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.
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.
•We surveyed the use of machine learning to inform predictive models in mood disorders.•We include studies that use machine learning algorithms to identify predictors of therapeutic outcomes in ...uni/bipolar depression.•Classification algorithms informed by neuroimaging, phenomenological, and genetic data were able to predict therapeutic outcomes with an overall accuracy of 0.82.•Predictive models integrating multiple data types performed better when compared to models with single lower-dimension data types (p <0.01).•Machine learning provides opportunity to parse clinical heterogeneity and characterize moderators of disease risk and trajectory.
No previous study has comprehensively reviewed the application of machine learning algorithms in mood disorders populations. Herein, we qualitatively and quantitatively evaluate previous studies of machine learning-devised models that predict therapeutic outcomes in mood disorders populations.
We searched Ovid MEDLINE/PubMed from inception to February 8, 2018 for relevant studies that included adults with bipolar or unipolar depression; assessed therapeutic outcomes with a pharmacological, neuromodulatory, or manual-based psychotherapeutic intervention for depression; applied a machine learning algorithm; and reported predictors of therapeutic response. A random-effects meta-analysis of proportions and meta-regression analyses were conducted.
We identified 639 records: 75 full-text publications were assessed for eligibility; 26 studies (n=17,499) and 20 studies (n=6325) were included in qualitative and quantitative review, respectively. Classification algorithms were able to predict therapeutic outcomes with an overall accuracy of 0.82 (95% confidence interval CI of 0.77, 0.87). Pooled estimates of classification accuracy were significantly greater (p < 0.01) in models informed by multiple data types (e.g., composite of phenomenological patient features and neuroimaging or peripheral gene expression data; pooled proportion 95% CI = 0.930.86, 0.97) when compared to models with lower-dimension data types (pooledproportion=0.680.62,0.74to0.850.81,0.88).
Most studies were retrospective; differences in machine learning algorithms and their implementation (e.g., cross-validation, hyperparameter tuning); cannot infer importance of individual variables fed into learning algorithm.
Machine learning algorithms provide a powerful conceptual and analytic framework capable of integrating multiple data types and sources. An integrative approach may more effectively model neurobiological components as functional modules of pathophysiology embedded within the complex, social dynamics that influence the phenomenology of mental disorders.
Excessive smartphone use has been associated with numerous psychiatric disorders. This study aimed to investigate the prevalence of smartphone addiction and its association with depression, anxiety, ...and attention-deficit hyperactivity disorder (ADHD) symptoms in a large sample of Korean adolescents.
A total of 4512 (2034 males and 2478 females) middle- and high-school students in South Korea were included in this study. Subjects were asked to complete a self-reported questionnaire, including measures of the Korean Smartphone Addiction Scale (SAS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Conners-Wells' Adolescent Self-Report Scale (CASS). Smartphone addiction and non-addiction groups were defined using SAS score of 42 as a cut-off. The data were analyzed using multivariate logistic regression analyses.
338 subjects (7.5%) were categorized to the addiction group. Total SAS score was positively correlated with total CASS score, BDI score, BAI score, female sex, smoking, and alcohol use. Using multivariate logistic regression analyses, the odds ratio of ADHD group compared to the non-ADHD group for smartphone addiction was 6.43, the highest among all variables (95% CI 4.60-9.00).
Our findings indicate that ADHD may be a significant risk factor for developing smartphone addiction. The neurobiological substrates subserving smartphone addiction may provide insights on to both shared and discrete mechanisms with other brain-based disorders.
Cognitive dysfunction is a symptomatic domain identified across many mental disorders. Cognitive deficits in individuals with major depressive disorder (MDD) contribute significantly to occupational ...and functional disability. Notably, cognitive subdomains such as learning and memory, executive functioning, processing speed, and attention and concentration are significantly impaired during, and between, episodes in individuals with MDD. Most antidepressants have not been developed and/or evaluated for their ability to directly and independently ameliorate cognitive deficits. Multiple interacting neurobiological mechanisms (eg, neuroinflammation) are implicated as subserving cognitive deficits in MDD. A testable hypothesis, with preliminary support, posits that improving performance across cognitive domains in individuals with MDD may improve psychosocial function, workplace function, quality of life, and other patient-reported outcomes, independent of effects on core mood symptoms. Herein we aim to (1) provide a rationale for prioritizing cognitive deficits as a therapeutic target, (2) briefly discuss the neurobiological substrates subserving cognitive dysfunction, and (3) provide an update on current and future treatment avenues.
•Intravenous administration of ketamine is not associated with anti-cognitive effects.•IV ketamine in patients with TRD may have pro-cognitive effects in brain areas associated with visual learning ...and working memory.•Future studies should focus on cognition as a domain of depressive psychopathology.•Anxious and non-anxious TRD patients may vary in their response to intravenous ketamine treatment.
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.
Abstract Background Bipolar disorder (BD) has been associated with cognitive impairment during depressed, manic and euthymic periods. Inflammation has been shown to be involved in the pathophysiology ...of BD and cognitive impairment. Methods For this systematic review, the MEDLINE/PubMed, Embase, Google Scholar and ClinicalTrials.gov databases were searched for relevant articles assessing the association between cognitive function and inflammatory markers in BD subjects. A discussion of potential mechanisms and therapeutic implications is also included to provide further context to the subject matter. Results Eight studies, including a total of 555 BD subjects, assessing the association between cognitive function and inflammatory markers were identified. Cognitive dysfunction was associated with elevated levels of pro-inflammatory markers YKL40, IL-6, sCD40L, IL-1Ra, hsCRP and TNF-α. Mechanistically, elevation in inflammatory cytokines alters monoamine levels leading to cognitive and affective dysfunction. Neuro-inflammation, manifesting as microglial activation, leads to increased oxidative stress, pathologic synaptic pruning and impaired neuroplasticity in key brain regions sub-serving mood and cognition. Immune dysfunction also activates the hypothalamic–pituitary–adrenal (HPA) axis leading to hypercortisolemia and metabolic dysfunction, further promoting neuronal dysfunction. Anti-inflammatory agents are therefore currently being investigated in the treatment of BD and appear to exert an antidepressant effect; however, cognitive outcomes have yet to be reported. Conclusion Several studies suggest that immune dysfunction is associated with cognitive impairment in BD. Several neurobiological pathways have been identified whereby immune dysfunction may promote cognitive impairment in BD. Future investigations of anti-inflammatory agents targeting cognitive function as a treatment outcome are merited.
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