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EClinicalMedicine Aug 2023Intranasal esketamine has received regulatory approvals for the treatment of depression. Recently a large trial of repeated dose racemic ketamine also demonstrated...
BACKGROUND
Intranasal esketamine has received regulatory approvals for the treatment of depression. Recently a large trial of repeated dose racemic ketamine also demonstrated efficacy in severe depression. However, uncertainties remain regarding comparative efficacy, dosage, and the time course of response.
METHODS
In this systematic review and meta-analysis, we searched Embase, Medline, Pubmed, PsycINFO, and CENTRAL up to April 13, 2023, for randomised controlled trials (RCTs) investigating ketamine for depression. Two investigators independently assessed study eligibility and risk of bias and extracted the data on depression severity scores, response and remission rates, and all-cause dropouts. Multivariable mixed-effects meta-regressions incorporated drug formulation (racemic (Rac) or esketamine (Esket)) and dose (Low or High) as covariates. Treatment effects were assessed: immediately following the first dose, during further repeated dosing, and follow-up after the final dose of a treatment course. This study is registered with PROSPERO (CRD42021221157).
FINDINGS
The systematic review identified 687 articles, of which 49 RCTs were eligible for analysis, comprising 3299 participants. Standardised mean differences (95% confidence intervals) immediately following the first/single treatment were moderate-high for all conditions (Rac-High: -0.73, -0.91 to -0.56; Esket-High: -0.48, -0.75 to -0.20; Rac-Low: -0.33, -0.54 to -0.12; Esket-Low: -0.55, -0.87 to -0.24). Ongoing effects during repeated dosing were significantly greater than the control for Rac-High (-0.61; -1.02 to -0.20) and Rac-Low (-0.55, -1.09 to -0.00), but not Esket-Low (-0.15, -0.49 to 0.19) or Esket-High (-0.22, -0.54 to 0.10). At follow-up effects remained significant for racemic ketamine (-0.65; -1.23 to -0.07) but not esketamine (-0.33; -0.96 to 0.31). All-cause dropout was similar between experiment and control conditions for both formulations combined (Odds Ratio = 1.18, 0.85-1.64). Overall heterogeneity varied from 5.7% to 87.6.
INTERPRETATION
Our findings suggested that effect sizes for depression severity, as well as response and remission rates, were numerically greater for racemic ketamine than esketamine. Higher doses were more effective than low doses. Differences were evident in initial effects, ongoing treatment, and lasting effects after the final dose.
FUNDING
None.
PubMed: 37593223
DOI: 10.1016/j.eclinm.2023.102127 -
The Lancet. Psychiatry Oct 2023Ketamine is an effective antidepressant, but there is substantial variability in patient response and the precise mechanism of action is unclear. Neuroimaging can... (Review)
Review
Ketamine is an effective antidepressant, but there is substantial variability in patient response and the precise mechanism of action is unclear. Neuroimaging can provide predictive and mechanistic insights, but findings are limited by small sample sizes. This systematic review covers neuroimaging studies investigating baseline (pre-treatment) and longitudinal (post-treatment) biomarkers of responses to ketamine. All modalities were included. We performed searches of five electronic databases (from inception to April 26, 2022). 69 studies were included (with 1751 participants). There was substantial methodological heterogeneity and no well replicated biomarker. However, we found convergence across some significant results, particularly in longitudinal biomarkers. Response to ketamine was associated with post-treatment increases in gamma power in frontoparietal regions in electrophysiological studies, post-treatment increases in functional connectivity within the prefrontal cortex, and post-treatment increases in the functional activation of the striatum. Although a well replicated neuroimaging biomarker of ketamine response was not identified, there are biomarkers that warrant further investigation.
Topics: Humans; Ketamine; Brain; Antidepressive Agents; Neuroimaging; Biomarkers
PubMed: 37625426
DOI: 10.1016/S2215-0366(23)00183-9 -
Frontiers in Neuroscience 2023There are previous epidemiological studies reporting associations between antibiotic use and psychiatric symptoms. Antibiotic-induced gut dysbiosis and alteration of... (Review)
Review
There are previous epidemiological studies reporting associations between antibiotic use and psychiatric symptoms. Antibiotic-induced gut dysbiosis and alteration of microbiota-gut-brain axis communication has been proposed to play a role in this association. In this systematic review and meta-analysis, we reviewed published articles that have presented results on changes in cognition, emotion, and behavior in rodents (rats and mice) after antibiotic-induced gut dysbiosis. We searched three databases-PubMed, Web of Science, and SCOPUS to identify such articles using dedicated search strings and extracted data from 48 articles. Increase in anxiety and depression-like behavior was reported in 32.7 and 40.7 percent of the study-populations, respectively. Decrease in sociability, social novelty preference, recognition memory and spatial cognition was found in 18.1, 35.3, 26.1, and 62.5 percent of the study-populations, respectively. Only one bacterial taxon (increase in gut ) showed statistically significant association with behavioral changes (increase in anxiety). There were no consistent findings with statistical significance for the potential biomarkers [Brain-derived neurotrophic factor (BDNF) expression in the hippocampus, serum corticosterone and circulating IL-6 and IL-1β levels]. Results of the meta-analysis revealed a significant association between symptoms of negative valence system (including anxiety and depression) and cognitive system (decreased spatial cognition) with antibiotic intake ( < 0.05). However, between-study heterogeneity and publication bias were statistically significant ( < 0.05). Risk of bias was evaluated to be high in the majority of the studies. We identified and discussed several reasons that could contribute to the heterogeneity between the results of the studies examined. The results of the meta-analysis provide promising evidence that there is indeed an association between antibiotic-induced gut dysbiosis and psychopathologies. However, inconsistencies in the implemented methodologies make generalizing these results difficult. Gut microbiota depletion using antibiotics may be a useful strategy to evaluate if and how gut microbes influence cognition, emotion, and behavior, but the heterogeneity in methodologies used precludes any definitive interpretations for a translational impact on clinical practice.
PubMed: 37719161
DOI: 10.3389/fnins.2023.1237177 -
Neuropsychology Review Sep 2023Previous research into the phenomenological differences of post-stroke depression (PSD) has typically focused on comparisons of symptom profiles between stroke and... (Review)
Review
Previous research into the phenomenological differences of post-stroke depression (PSD) has typically focused on comparisons of symptom profiles between stroke and non-stroke population controls. This systematic review aimed to synthesize these findings with results from other methodological approaches that contribute to an understanding of phenomenological differences. Articles were identified via a systematic search of seven databases and additional manual searching. A narrative synthesis approach was adopted because of the high methodological heterogeneity. Twelve articles comparing the symptomatology of depression between stroke and non-stroke controls were included. Three distinct methodological approaches, relevant to the aim, were identified: comparisons of profiles among groups with similar overall depression severity, comparisons of the strengths of correlations between a symptom and depression, and comparisons of latent symptom severity. The symptomatology of depression was generally similar between the groups, including somatic symptoms, despite the hypothesized interference of comorbid physical stroke effects. Despite high heterogeneity, there was a tentative indication that post-stroke depression manifests with comparatively less severe/prevalent anhedonia. Possible mechanisms for the observed similarities and differences are explored, including suggestions for future research.
PubMed: 37667057
DOI: 10.1007/s11065-023-09611-5 -
European Neuropsychopharmacology : the... Jun 2024Ketamine, an N-methyl-D-aspartate receptor antagonist, is a racemic mixture of esketamine and arketamine used to treat unipolar and bipolar depression. Preliminary... (Review)
Review
Ketamine, an N-methyl-D-aspartate receptor antagonist, is a racemic mixture of esketamine and arketamine used to treat unipolar and bipolar depression. Preliminary reports indicate that it may be beneficial for depressed patients reporting symptoms of anhedonia. In this systematic review we aim to assess and analyze the existing body of evidence regarding the therapeutic effects of ketamine on the domain of anhedonia. Electronic databases (PubMed, APA Psycinfo and Web of Science) were searched from inception to November 2023. Protocol was registered in PROSPERO under the identifier CRD42023476603. A total of twenty-two studies, including four randomized-controlled trials and eighteen open-label trials were included. All studies reported alleviation of anhedonia symptoms following ketamine or esketamine administration, regardless of the number of infusions. Several important limitations were included, first and foremost low number of placebo-controlled randomized-controlled trials. This review indicates a potential anti-anhedonic effect of ketamine in patients with depression. Several trials used neuroimaging techniques which confirm ketamine's effect on functional connectivity correlating with the improvement in anhedonia. Despite considerable variations in methodology and the specific brain regions investigated, these studies collectively point towards ketamine's neuroplastic effects in mitigating anhedonia.
PubMed: 38917771
DOI: 10.1016/j.euroneuro.2024.04.014 -
Journal of Affective Disorders Jul 2024Major depressive disorder (MDD) is a heterogeneous group of mood disorders. A prominent symptom domain is anhedonia narrowly defined as a loss of interest and ability to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Major depressive disorder (MDD) is a heterogeneous group of mood disorders. A prominent symptom domain is anhedonia narrowly defined as a loss of interest and ability to experience pleasure. Anhedonia is associated with depressive symptom severity, MDD prognosis, and suicidality. We perform a systematic review and meta-analysis of extant literature investigating the effects of anhedonia on health-related quality of life (HRQoL) and functional outcomes in persons with MDD.
METHODS
A literature search was conducted on PubMed, OVID databases, and SCOPUS for published articles from inception to November 2023, reporting on anhedonia and patient-reported outcomes in persons with MDD. The reported correlation coefficients between anhedonia and self-reported measures of both HRQoL and functional outcomes were pooled using a random effects model.
RESULTS
We identified 20 studies that investigated anhedonia with HRQoL and/or functional outcomes in MDD. Anhedonia as measured by the Snaith-Hamilton Pleasure Scale (SHAPS) scores had a statistically significant correlation with patient-reported HRQoL (r = -0.41 [95 % CI = -0.60, -0.18]) and functional impairment (r = 0.39 [95 % CI = 0.22, 0.54]).
LIMITATIONS
These preliminary results primarily investigate correlations with consummatory anhedonia and do not distinguish differences in anticipatory anhedonia, reward valuation or reward learning; therefore, these results require replication.
CONCLUSIONS
Persons with MDD experiencing symptoms of anhedonia are more likely to have worse prognosis including physical, psychological, and social functioning deficits. Anhedonia serves as an important predictor and target for future therapeutic and preventative tools in persons with MDD.
Topics: Humans; Anhedonia; Depressive Disorder, Major; Quality of Life
PubMed: 38657767
DOI: 10.1016/j.jad.2024.04.086 -
CNS Neuroscience & Therapeutics Mar 2024Noninvasive brain stimulation (NIBS) techniques are a promising tool for treating the negative symptoms of schizophrenia. Growing evidence suggests that different... (Meta-Analysis)
Meta-Analysis
Is it more effective for anhedonia and avolition? A systematic review and meta-analysis of non-invasive brain stimulation interventions for negative symptoms in schizophrenia.
BACKGROUND
Noninvasive brain stimulation (NIBS) techniques are a promising tool for treating the negative symptoms of schizophrenia. Growing evidence suggests that different dimensions of negative symptoms have partly distinct underlying pathophysiological mechanisms. Previous randomized controlled trials (RCTs) have shown inconsistent impacts of NIBS across dimensions.
OBJECTIVE
This systematic review and meta-analysis evaluated the effects of NIBS on general negative symptoms, and on specific domains, including blunted affect, alogia, asociality, anhedonia, and avolition.
DATA SOURCES
PubMed, Web of Science, Embase, Cochrane CENTRAL, PsycINFO, OpenGrey, and Clinicaltrials.gov from the first date available to October, 2023.
RESULTS
Among 1049 studies, we identified eight high-quality RCTs. NIBS significantly affects general negative symptoms (SMD = -0.54, 95% CI [-0.88, -0.21]) and all five domains (SMD = -0.32 to -0.63). Among dimensions, better effects have been shown for improvement of avolition (SMD = -0.47, 95% CI [-0.81, -0.13]) and anhedonia (SMD = -0.63, 95% CI [-0.98, -0.28]). Subgroup analyses of studies that applied once daily stimulation or >10 sessions showed significantly reduced negative symptom severity.
CONCLUSION
NIBS exerts distinct effects across multiple dimensions of negative symptom, with treatment effects related to stimulation frequency and total sessions. These results need to be confirmed in dedicated studies.
Topics: Humans; Anhedonia; Brain; PubMed; Schizophrenia; Electric Stimulation Therapy
PubMed: 38432851
DOI: 10.1111/cns.14645 -
European Neuropsychopharmacology : the... Dec 2023Anhedonia is described as a decreased ability to experience rewarding and enjoyable activities, a core symptom of major depressive disorder. The sucrose preference test... (Review)
Review
Anhedonia is described as a decreased ability to experience rewarding and enjoyable activities, a core symptom of major depressive disorder. The sucrose preference test (SPT) is a widely used and reliable behavioural test to assess anhedonia in rodents, based on a two-bottle choice paradigm. To date, different protocols are in use, inducing variability between researchers and hampering comparisons between studies. We performed a systematic review of the SPT protocols used in 2021 to identify the parameters in which they differ and their potential impact. We searched a total of four databases (PubMed, Scopus, Web of Science and Science Direct), from 1st January 2021 to 31st December 2021, and screened a total of 1066 articles. After screening by title and abstract, a total of 415 articles were included in this review. We extracted and analysed the different procedures used, the type of sweet solution and the habituation, deprivation, and testing protocols. The overall quality of the studies was considered very good, however, SPT protocols were extremely variable between studies with a total of 65 different habituation protocols and 104 combinations of food/water deprivation and preference testing duration. As the SPT is one of the most used tests to assess anhedonia in rodents, this work raises awareness of the great variability in SPT protocols being currently used. Furthermore, we call for standardization in the protocol used, and overall improvement of data reporting of methodologies and results, to increase the consistency between studies and allow a better comparison of results between different labs.
Topics: Animals; Anhedonia; Depressive Disorder, Major; Food; Rodentia; Sucrose
PubMed: 37741164
DOI: 10.1016/j.euroneuro.2023.08.496 -
JAMA Network Open Oct 2023Reliable screening for major depressive disorder (MDD) relies on valid and accurate screening tools. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Reliable screening for major depressive disorder (MDD) relies on valid and accurate screening tools.
OBJECTIVE
To examine the validity, accuracy, and reliability of the Spanish-language Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) to screen for MDD.
DATA SOURCES
PubMed, Web of Science, Embase, and PsycINFO from data initiation through February 27, 2023.
STUDY SELECTION
English- and Spanish-language studies evaluating the validity of the Spanish-language PHQ-2 or PHQ-9 in screening adults for MDD compared with a standardized clinical interview (gold standard). Search terms included PHQ-2, PHQ-9, depression, and Spanish.
DATA EXTRACTION AND SYNTHESIS
Two reviewers performed abstract and full-text reviews, data extraction, and quality assessment. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Random-effects meta-analyses of sensitivity, specificity, and area under the curve (AUC) were performed. Internal consistency was evaluated using Cronbach α and McDonald ψ.
MAIN OUTCOMES AND MEASURES
Test accuracy and internal consistency. The PHQ-2 is composed of the first 2 questions of the PHQ-9 (targeting core depression symptoms of depressed mood and anhedonia; a score of 3 or higher (score range, 0-6) is generally considered a positive depression screen. If a patient screens positive with the PHQ-2, a follow-up assessment with the PHQ-9 and a clinical diagnostic evaluation are recommended. Once depression is diagnosed, a PHQ-9 score of 10 or higher (score range, 0-27) is often considered an acceptable threshold for treating depression.
RESULTS
Ten cross-sectional studies involving 5164 Spanish-speaking adults (mean age range, 34.1-71.8 years) were included; most studies (n = 8) were in primary care settings. One study evaluated the PHQ-2, 7 evaluated the PHQ-9, and 2 evaluated both the PHQ-2 and PHQ-9. For the PHQ-2, optimal cutoff scores ranged from greater than or equal to 1 to greater than or equal to 2, with an overall pooled sensitivity of 0.89 (95% CI, 0.81-0.95), overall pooled specificity of 0.89 (95% CI, 0.81-0.95), and overall pooled AUC of 0.87 (95% CI, 0.83-0.90); Cronbach α was 0.71 to 0.75, and McDonald ψ was 0.71. For the PHQ-9, optimal cutoff scores ranged from greater than or equal to 5 to greater than or equal to 12, with an overall pooled sensitivity of 0.86 (95% CI, 0.82-0.90), overall pooled specificity of 0.80 (95% CI, 0.75-0.85), and overall pooled AUC of 0.88 (95% CI, 0.87-0.90); Cronbach α was 0.78 to 0.90, and McDonald ψ was 0.79 to 0.90. Four studies were considered to have low risk of bias; 6 studies had indeterminate risk of bias due to a lack of blinding information.
CONCLUSIONS AND RELEVANCE
In this systematic review and meta-analysis, limited available evidence supported the use of the Spanish-language PHQ-2 and PHQ-9 in screening for MDD, but optimal cutoff scores varied greatly across studies, and few studies reported on blinding schemes. These results suggest that MDD should be considered in Spanish-speaking individuals with lower test scores. Given the widespread clinical use of the tools and the heterogeneity of existing evidence, further investigation is needed.
Topics: Adult; Humans; Middle Aged; Aged; Patient Health Questionnaire; Depressive Disorder, Major; Reproducibility of Results; Cross-Sectional Studies; Surveys and Questionnaires; Language
PubMed: 37847505
DOI: 10.1001/jamanetworkopen.2023.36529 -
PsyCh Journal Apr 2024Anhedonia is a transdiagnostic symptom found in patients with schizophrenia and depression. Current pharmacological interventions for anhedonia are unsatisfactory in a... (Meta-Analysis)
Meta-Analysis Review
Anhedonia is a transdiagnostic symptom found in patients with schizophrenia and depression. Current pharmacological interventions for anhedonia are unsatisfactory in a considerable proportion of patients. There has been growing interest in applying noninvasive brain stimulation (NIBS) to patients with anhedonia. However, evidence for the efficacy of NIBS for anhedonia remain inconsistent. This study systematically identified all studies that measured anhedonia and applied NIBS in patients with schizophrenia or depression. We conducted a search using the various databases in English (PubMed, EBSCOHost (PsycInfo/PsycArticles), Web of Science) and Chinese (China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform) languages, and reviewed original research articles on NIBS published from January 1989 to July 2023. Our search had identified 15 articles for quantitative synthesis, with three concerning schizophrenia samples, 11 concerning samples with depression, and one concerning both clinical samples. We conducted a meta-analysis based on the 15 included studies, and the results suggested that NIBS could improve anhedonia symptoms in schizophrenia patients and patients with depression, with a medium-to-large effect size. Our findings are preliminary, given the limited number of included studies. Future NIBS research should measure anhedonia as a primary outcome and should recruit transdiagnostic samples.
Topics: Humans; Schizophrenia; Anhedonia; Depression; Brain; China
PubMed: 38151800
DOI: 10.1002/pchj.723