•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).
Rationale
Immune dysfunction has been strongly implicated in the pathophysiology of bipolar disorder (BD). As such, numerous clinical trials have investigated the effects of anti-inflammatory agents ...in the treatment of BD.
Objectives
Review clinical studies evaluating the effects of anti-inflammatory agents in the treatment of BD during all illness phases (e.g., depression, mania, and euthymia).
Methods
Relevant databases were searched from inception to August 27, 2018 for clinical studies evaluating the effects of anti-inflammatory agents in BD.
Results
The majority of identified clinical trials evaluated adjunctive anti-inflammatory agents in the acute treatment of bipolar depression, demonstrating antidepressant effects with N-acetylcysteine (NAC), pioglitazone, minocycline, and coenzyme Q10, along with mixed evidence for omega-3s, and non-steroidal anti-inflammatory drugs (NSAIDs). The anti-manic effects of adjunctive anti-inflammatory agents have been minimally studied, with some promising preliminary results supporting potential anti-manic effects of adjunctive celecoxib and NAC. Maintenance studies are also limited, with inadequate evidence to support mood stabilizing effects of anti-inflammatories while euthymic. Regardless of illness phase, early results suggest that anti-inflammatory agents are likely most beneficial in the subgroup of BD with immune dysregulation.
Conclusions
Several proof-of-concept clinical trials have shown promising results for anti-inflammatory agents in the treatment of bipolar depression with moderate effect sizes and good tolerability. The effects of anti-inflammatory agents during manic and euthymic periods remains uncertain. Future larger studies, using stratified samples, enriched for participants with immune dysfunction, are required to determine the role of immune modulating agents in the treatment of BD.
Minocycline has been identified as a potential novel treatment for depression. The objective of the current review is to determine the overall antidepressant efficacy and tolerability of minocycline.
...Completed and ongoing clinical trials of minocycline for depression (both bipolar and unipolar) published prior to September 12, 2017 were identified through searching relevant databases. Using a random-effects model, data from randomized controlled trials (RCTs) were pooled to determine the antidepressant effect size of minocycline compared to placebo. Relative risk of all-cause discontinuation was determined to assess overall tolerability.
Eighteen clinical studies (including published and unpublished RCTs, open label studies, ongoing clinical trials and a case report) were identified for inclusion in the qualitative synthesis. Only three RCTs (n = 158) met inclusion criteria for quantitative synthesis. The overall antidepressant effect size of minocycline compared to placebo was − 0.78 95% confidence interval − 0.4 to − 1.33 (P = 0.005), indicative of a large and statistically significant antidepressant effect. Heterogeneity of the pooled sample was moderate (I2 = 62%). There was no statistically significant difference in reported adverse effects or all-cause discontinuation in the minocycline group compared to placebo (p = 0.16).
The small number of published RCTs, small sample sizes, heterogeneity of included studies, and potential publication bias were significant limitations.
Overall, a large antidepressant effect was observed for minocycline compared to placebo with good tolerability. The current analysis provides a proof-of-concept for the antidepressant effects of minocycline and provides impetus for future larger RCTs as well as identification of subgroups more likely to benefit from this intervention.
•A large antidepressant effect was observed for minocycline compared to placebo.•Minocycline had good tolerability with low rates of adverse effects and discontinuation.•Future larger RCTs of minocycline for depression are merited.•Future studies should also identify subgroups more likely to benefit from minocycline.
Following recovery from COVID-19, an increasing proportion of individuals have reported the persistence and/or new onset of symptoms which collectively have been identified as post-COVID-19 syndrome ...by the National Institute for Health and Care Excellence. Although depressive symptoms in the acute phase of COVID-19 have been well characterized, the frequency of depression following recovery of the acute phase remains unknown. Herein, we sought to determine the frequency of depressive symptoms and clinically-significant depression more than 12 weeks following SARS-CoV-2 infection. A systematic search of PubMed, Ovid Medline and Google Scholar for studies published between January 1, 2020 and June 5, 2021 was conducted. Frequency and factors associated with depression in post-COVID-19 syndrome were recorded and qualitatively assessed through narrative synthesis. Methodological quality and risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale (NOS) for prospective cohort studies. Of 316 articles identified through our systematic search, eight studies were included. The frequency of depressive symptoms +12 weeks following SARS-CoV-2 infection ranged from 11 to 28%. The frequency of clinically-significant depression and/or severe depressive symptoms ranged from 3 to 12%. The severity of acute COVID-19 was not associated with the frequency of depressive symptoms. However, the component studies were highly heterogeneous with respect to mode of ascertainment, time of assessment, and location and age of patients. The majority of studies did not include an unexposed control group. Future research should endeavour to produce a standardized classification of post-COVID-19 syndrome, and as well as include unexposed control groups.
Mood disorders have been recognized by the World Health Organization (WHO) as the leading cause of disability worldwide. Notwithstanding the established efficacy of conventional mood agents, many ...treated individuals continue to remain treatment refractory and/or exhibit clinically significant residual symptoms, cognitive dysfunction, and psychosocial impairment. Therefore, a priority research and clinical agenda is to identify pathophysiological mechanisms subserving mood disorders to improve therapeutic efficacy.
During the past decade, inflammation has been revisited as an important etiologic factor of mood disorders. Therefore, the purpose of this synthetic review is threefold: 1) to review the evidence for an association between inflammation and mood disorders, 2) to discuss potential pathophysiologic mechanisms that may explain this association and 3) to present novel therapeutic options currently being investigated that target the inflammatory–mood pathway.
Accumulating evidence implicates inflammation as a critical mediator in the pathophysiology of mood disorders. Indeed, elevated levels of pro-inflammatory cytokines have been repeatedly demonstrated in both major depressive disorder (MDD) and bipolar disorder (BD) patients. Further, the induction of a pro-inflammatory state in healthy or medically ill subjects induces ‘sickness behavior’ resembling depressive symptomatology.
Potential mechanisms involved include, but are not limited to, direct effects of pro-inflammatory cytokines on monoamine levels, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, pathologic microglial cell activation, impaired neuroplasticity and structural and functional brain changes.
Anti-inflammatory agents, such as acetyl-salicylic acid (ASA), celecoxib, anti-TNF-α agents, minocycline, curcumin and omega-3 fatty acids, are being investigated for use in mood disorders. Current evidence shows improved outcomes in mood disorder patients when anti-inflammatory agents are used as an adjunct to conventional therapy; however, further research is needed to establish the therapeutic benefit and appropriate dosage.
•Inflammation and mood disorders have a bidirectional interaction.•Cytokines, monoamines, the HPA axis and microglial cells are key players involved.•Anti-inflammatory agents show promise for use in the treatment of mood disorders.
•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.
Bipolar disorder (BD) is strongly associated with immune dysfunction. Replicated epidemiological studies have demonstrated that BD has high rates of inflammatory medical comorbidities, including ...autoimmune disorders, chronic infections, cardiovascular disease and metabolic disorders. Cytokine studies have demonstrated that BD is associated with chronic low-grade inflammation with further increases in pro-inflammatory cytokine levels during mood episodes. Several mechanisms have been identified to explain the bidirectional relationship between BD and immune dysfunction. Key mechanisms include cytokine-induced monoamine changes, increased oxidative stress, pathological microglial over-activation, hypothalamic-pituitary-adrenal (HPA) axis over-activation, alterations of the microbiome-gut-brain axis and sleep-related immune changes. The inflammatory-mood pathway presents several potential novel targets in the treatment of BD. Several proof-of-concept clinical trials have shown a positive effect of anti-inflammatory agents in the treatment of BD; however, further research is needed to determine the clinical utility of these treatments. Immune dysfunction is likely to only play a role in a
of BD patients and as such, future clinical trials should also strive to identify which specific group(s) of BD patients may benefit from anti-inflammatory treatments.
•Childhood maltreatment is an important stressor associated with stress & depression.•Stress- and depression-associated changes were mostly found in NRC31 and SLCA4.•Epigenetic changes occurring at ...different loci may have variable downstream effects.•Most studies measured epigenetic changes using peripheral tissue samples.•Future studies should evaluate epigenetic effects of psychotropic medication use.
Environmental stressors, such as childhood maltreatment, have been recognized to contribute to the development of depression. Growing evidence suggests that epigenetic changes are a key mechanism by which stressors interact with the genome leading to stable changes in DNA structure, gene expression, and behaviour. The current review aimed to evaluate the relationship between stress-associated epigenetic changes and depression. Human studies were identified via systematic searching of PubMed/Medline from inception to February 2018. Seventeen articles were identified. Stress-associated epigenetic changes in the following genes were correlated with depression: NRC31, SLCA4, BDNF, FKBP5, SKA2, OXTR, LINGO3, POU3F1 and ITGB1. Epigenetic changes in glucocorticoid signaling (e.g., NR3C1, FKBP5), serotonergic signaling (e.g. SLC6A4), and neurotrophin (e.g., BDNF) genes appear to be the most promising therapeutic targets for future research. However, continued research is warranted due to inconsistent findings regarding the directionality of epigenetic modification. Future studies should also aim to control for the use of psychotropic agents due to their widespread use in depressed populations and established effects on DNA methylation.
•The dynamic changes of sTREM2 levels in AD progression were examined.•Soluble TREM2 levels were significantly elevated across the clinical course of AD, from preclinical stage to clinical AD.•The ...increase of CSF sTREM2 was more significant in older AD patients.•Soluble TREM2 is a potential biomarker implicated in the onset and progression of Alzheimer’s disease.
Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a potential and novel biomarker of neuroinflammation implicated in the onset and progression of Alzheimer’s disease (AD). However, previous studies evaluating levels of sTREM2 in different clinical stages of AD have yielded inconsistent results. To clarify the dynamic change of sTREM2 in AD progression, we conducted a meta-analysis of case-control and cohort studies to determine the role of cerebral spinal fluid (CSF) and plasma sTREM2 levels in preclinical AD (pre-AD), mild cognitive impairment (MCI) and AD dementia. We searched PubMed, MEDLINE, EMBASE, the Cochrane Library for English articles and Sinomed, CNKI for Chinese. The associations between sTREM2 levels and AD continuum groups (pre-AD, MCI and AD) were analyzed. We further performed detailed subgroup analysis and meta-regression to detect the sources of heterogeneity. 17 reports comprising 82 patients with pre-AD, 159 with MCI, 598 with AD, as well as 754 controls were included in this analysis. Regarding the sTREM2 levels in CSF, the overall pooled standard mean difference (SMD) revealed significantly elevated sTREM2 levels in the whole AD continuum groups (SMD = 0.48; 95% CI: 0.23, 0.73; P < 0.001) compared with controls. The levels of sTREM2 significantly increased in pre-AD (SMD = 0.47; 95% CI: 0.21, 0.73; P < 0.001), the highest increase occurred in MCI group (SMD = 0.77; 95% CI: -0.05, 1.59; P = 0.066), and the effect size of AD group (SMD = 0.39; 95% CI: 0.13, 0.65; P = 0.004) was also higher compared with control. However, for sTREM2 levels measured in plasma, no significant differences were found (SMD = 0.11; 95% CI: -0.06, 0.27; P = 0.217). Therefore, our study showed that sTREM2 levels increased in the earlier course of AD, and slightly attenuated in dementia stage. The current results indicated that sTREM2 levels fluctuate as a function of clinical stage in AD and it might be a novel inflammatory biomarker involved in different stages of AD.
Background:
Cognitive dysfunction is often present in major depressive disorder (MDD). Several clinical trials have noted a pro-cognitive effect of antidepressants in MDD. The objective of the ...current systematic review and meta-analysis was to assess the pooled efficacy of antidepressants on various domains of cognition in MDD.
Methods:
Trials published prior to April 15, 2015, were identified through searching the Cochrane Central Register of Controlled Trials, PubMed, Embase, PsychINFO, Clinicaltrials.gov, and relevant review articles. Data from randomized clinical trials assessing the cognitive effects of antidepressants were pooled to determine standard mean differences (SMD) using a random-effects model.
Results:
Nine placebo-controlled randomized trials (2 550 participants) evaluating the cognitive effects of vortioxetine (n = 728), duloxetine (n = 714), paroxetine (n = 23), citalopram (n = 84), phenelzine (n = 28), nortryptiline (n = 32), and sertraline (n = 49) were identified. Antidepressants had a positive effect on psychomotor speed (SMD 0.16; 95% confidence interval CI 0.05–0.27; I2 = 46%) and delayed recall (SMD 0.24; 95% CI 0.15–0.34; I2 = 0%). The effect on cognitive control and executive function did not reach statistical significance. Of note, after removal of vortioxetine from the analysis, statistical significance was lost for psychomotor speed. Eight head-to-head randomized trials comparing the effects of selective serotonin reuptake inhibitors (SSRIs; n = 371), selective serotonin and norepinephrine reuptake inhibitors (SNRIs; n = 25), tricyclic antidepressants (TCAs; n = 138), and norepinephrine and dopamine reuptake inhibitors (NDRIs; n = 46) were identified. No statistically significant difference in cognitive effects was found when pooling results from head-to-head trials of SSRIs, SNRIs, TCAs, and NDRIs. Significant limitations were the heterogeneity of results, limited number of studies, and small sample sizes.
Conclusions:
Available evidence suggests that antidepressants have a significant positive effect on psychomotor speed and delayed recall.
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