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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 -
Journal of Neuroscience Methods Jul 2023Exposing rats to repeated unpredictable stressors is a popular method for modelling depression. The sucrose preference test is used to assess the validity of this...
BACKGROUND
Exposing rats to repeated unpredictable stressors is a popular method for modelling depression. The sucrose preference test is used to assess the validity of this method, as it measures a rat´s preference for a sweet solution as an indicator of its ability to experience pleasure. Typically, if stressed rats show a lower preference compared to unstressed rats, it is concluded they are experiencing stress-induced anhedonia.
METHODS
While conducting a systematic review, we identified 18 studies that used thresholds to define anhedonia and to distinguish "susceptible" from "resilient" individuals. Based on their definitions, researchers either excluded "resilient" animals from further analyses or treated them as a separate cohort. We performed a descriptive analysis to understand the rationale behind these criteria.
RESULTS
we found that the methods used for characterizing the stressed rats were largely unsupported. Many authors failed to justify their choices or relied exclusively on referencing previous studies. When tracing back the method to its origins, we converged on a pioneering article that, although employed as a universal evidence-based justification, cannot be regarded as such. What is more, through a simulation study, we provided evidence that removing or splitting data, based on an arbitrary threshold, introduces statistical bias by overestimating the effect of stress.
CONCLUSION
Caution must be exercised when implementing a predefined cut-off for anhedonia. Researchers should be aware of potential biases introduced by their data treatment strategies and strive for transparent reporting of methodological decisions.
Topics: Rats; Animals; Anhedonia; Sucrose; Depression; Food Preferences; Stress, Psychological; Disease Models, Animal
PubMed: 37394102
DOI: 10.1016/j.jneumeth.2023.109910 -
Neurobiology and Symptomatology of Post-Acute Alcohol Withdrawal: A Mixed-Studies Systematic Review.Journal of Studies on Alcohol and Drugs Jul 2022This study aims to review the neurobiology and symptomatology of post-acute alcohol withdrawal syndrome (PAWS).
OBJECTIVE
This study aims to review the neurobiology and symptomatology of post-acute alcohol withdrawal syndrome (PAWS).
METHOD
We conducted a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)-guided systematic review of articles from two databases for English-language randomized and nonrandomized studies involving PAWS published between database inception and December 2020.
RESULTS
Twenty-seven studies met inclusion criteria. PAWS involves predominantly negative affect, which develops in early abstinence and can persist for 4-6 months or longer. Symptoms include anxiety, dysphoria, anhedonia, sleep disturbance, cognitive impairment, cravings, and irritability. PAWS symptoms appear to be risk factors for recurrent alcohol consumption. They have been associated with reported neurobiological differences in evoked potentials; measures of orexins, cortisol, serotonin, and pancreatic polypeptides; and neuroadaptation changes in the nucleus accumbens and the prefrontal cortex.
CONCLUSIONS
There is credible evidence to support the concept of PAWS based on this review's findings. There remains a need to develop and test specific criteria for PAWS. High-quality treatment studies involving agents addressing its neurobiological underpinnings are also recommended.
Topics: Humans; Alcohol Drinking; Alcoholism; Craving; Neurobiology; Substance Withdrawal Syndrome
PubMed: 35838422
DOI: 10.15288/jsad.2022.83.461 -
Current Neuropharmacology 2023Alcohol withdrawal syndrome (AWS) is characterized by different phases (acute, early and protracted). Protracted alcohol withdrawal (PAW) presents some symptoms, which...
BACKGROUND
Alcohol withdrawal syndrome (AWS) is characterized by different phases (acute, early and protracted). Protracted alcohol withdrawal (PAW) presents some symptoms, which may persist for several weeks, months or even years after drinking cessation.
METHODS
We conducted a systematic review of the literature in major scientific databases on selected AWS symptoms (craving, sleep disorders, and anhedonia) in patients with alcohol use disorder.
RESULTS
Of the 102 eligible publications (70 RCTs and 32 cohort studies), 88 provided data on craving, 21 on sleep disorders, and 1 on anhedonia. Overall, 37 studies assessed craving using the Obsessive Compulsive Drinking Scale (OCDS). Pooled OCDS decreased from 24.2 at baseline to 18.8 at 1 week, 10.3 at 1 month and 9.7 at 3 months. The corresponding estimates for treated individuals were 23.9, 18.8, 8.7, and 8.8, and for non-treated subjects, they were 25.3, 13.9, 13.2, and 11.4, respectively. In 4 studies assessing sleep disorders using the Epworth Sleeping Scale (ESS), the scale remained stable in time, i.e., 7.3 at baseline, 7.3 at 1 week, 7.2 at 1 month, and 7.1 at 3 months.
CONCLUSION
This study confirms the presence of PAW after the resolution of the acute phase of AWS. The pharmacological approach to managing PAW may ensure a more rapid reduction of symptoms in three weeks. We highlight the importance of studying PAW and the ability of pharmacological treatment to reduce its symptoms. This review protocol is registered in Prospero (registration number: CRD42020211265).
SUMMARY
This systematic review summarizes literature on major symptoms of protracted alcohol withdrawal in patients with alcohol use disorder. The pharmacological approach to manage protracted alcohol withdrawal ensures a more rapid reduction of symptoms (craving in particular), achieving in three weeks similar results obtained only after almost 6 months without treatment.
Topics: Humans; Alcoholism; Substance Withdrawal Syndrome; Anhedonia; Alcohol Drinking; Sleep Wake Disorders
PubMed: 35794766
DOI: 10.2174/1570159X20666220706105253 -
Molecular Psychiatry Sep 2022(R,S)-ketamine (ketamine) and its enantiomer (S)-ketamine (esketamine) can produce rapid and substantial antidepressant effects. However, individual response to... (Meta-Analysis)
Meta-Analysis
(R,S)-ketamine (ketamine) and its enantiomer (S)-ketamine (esketamine) can produce rapid and substantial antidepressant effects. However, individual response to ketamine/esketamine is variable, and there are no well-accepted methods to differentiate persons who are more likely to benefit. Numerous potential peripheral biomarkers have been reported, but their current utility is unclear. We conducted a systematic review/meta-analysis examining the association between baseline levels and longitudinal changes in blood-based biomarkers, and response to ketamine/esketamine. Of the 5611 citations identified, 56 manuscripts were included (N = 2801 participants), and 26 were compatible with meta-analytical calculations. Random-effect models were used, and effect sizes were reported as standardized mean differences (SMD). Our assessments revealed that more than 460 individual biomarkers were examined. Frequently studied groups included neurotrophic factors (n = 15), levels of ketamine and ketamine metabolites (n = 13), and inflammatory markers (n = 12). There were no consistent associations between baseline levels of blood-based biomarkers, and response to ketamine. However, in a longitudinal analysis, ketamine responders had statistically significant increases in brain-derived neurotrophic factor (BDNF) when compared to pre-treatment levels (SMD [95% CI] = 0.26 [0.03, 0.48], p = 0.02), whereas non-responders showed no significant changes in BDNF levels (SMD [95% CI] = 0.05 [-0.19, 0.28], p = 0.70). There was no consistent evidence to support any additional longitudinal biomarkers. Findings were inconclusive for esketamine due to the small number of studies (n = 2). Despite a diverse and substantial literature, there is limited evidence that blood-based biomarkers are associated with response to ketamine, and no current evidence of clinical utility.
Topics: Humans; Ketamine; Brain-Derived Neurotrophic Factor; Antidepressive Agents; Biomarkers; Depressive Disorder, Treatment-Resistant
PubMed: 35760879
DOI: 10.1038/s41380-022-01652-1 -
Neuropsychiatric Disease and Treatment 2022There is variation in the safety profile of antidepressants. Rates of adverse events along with the costs of treating them can be an important factor influencing the...
PURPOSE
There is variation in the safety profile of antidepressants. Rates of adverse events along with the costs of treating them can be an important factor influencing the choice of depression treatment. This study sought to estimate the comparative safety of commonly prescribed antidepressants, and how the costs of treating these varied across European countries.
METHODS
A systematic literature review was conducted (in Medline, Embase, PsycINFO and CENTRAL) to identify placebo-controlled trials reporting rates of at least one type of sexual dysfunction, weight change, insomnia, anxiety, and anhedonia. Eight antidepressants were considered: duloxetine, escitalopram, fluoxetine, paroxetine, sertraline, trazodone, venlafaxine, and vortioxetine. This evidence was synthesised via Bayesian random effects network meta-analyses to provide comparative estimates of safety. A systematic search identified country-specific costs of managing depression and adverse events of antidepressants. Evidence on costs and safety was combined in an economic model to provide country-specific costs for Bulgaria, the Czech Republic, Greece, Hungary, Italy, Romania, Slovakia, Portugal, and Poland.
RESULTS
Trazodone had the lowest rates of both insomnia (odds ratio 0.66, 95% credible interval 0.31 to 1.38) and anxiety (0.13, <0.01 to 1.80). All antidepressants were associated with increased rates of sexual dysfunction relative to placebo. Weight change was largest for fluoxetine (kg change -1.01, -1.40 to -0.60) and sertraline (-1.00, -1.36 to -0.65), although heterogeneity was extreme for this outcome. No evidence was identified for anhedonia. Total costs were lowest for trazodone in all nine of the countries evaluated. This was primarily due to reduced rates of treatment discontinuation.
CONCLUSION
Trazodone generally had the best safety profile of the antidepressants evaluated. This led to healthcare costs being lowest for trazodone in all nine European countries, emphasising the importance of considering rates of adverse events when choosing a pharmacological treatment to treat symptoms of depression.
PubMed: 35698594
DOI: 10.2147/NDT.S356414 -
Journal of Patient-reported Outcomes Jun 2022Life engagement in the context of mental health is a broad term that describes positive health aspects relating to cognition, vitality, motivation and reward, and the... (Review)
Review
BACKGROUND
Life engagement in the context of mental health is a broad term that describes positive health aspects relating to cognition, vitality, motivation and reward, and the ability to feel pleasure-concepts that are meaningful to patients. The aim of this systematic literature review was to identify validated patient-reported outcomes (PROs) that can assess any aspect of life engagement in adults, in the field of general mental health.
METHODS
This was a systematic literature review of articles in English from the MEDLINE database (date of search: September 9, 2020). The search strategy had three components: (1) terms to capture PROs; (2) terms to capture mental health; and (3) terms to capture aspects of life engagement. Articles were eligible if they included a PRO that: (1) is named; (2) can be used across mental health disorders; (3) is used to assess any aspect of life engagement; and (4) has undergone psychometric validation and/or qualitative content validation. A list of PROs was extracted.
RESULTS
A total of 1585 records were screened and 233 articles were eligible for inclusion. Within these 233 articles, 49 distinct PROs were identified, two of which specifically captured their authors' interpretation of life engagement: the Engaged Living Scale (ELS) and the Life Engagement Test (LET). However, while the ELS and LET covered motivation and reward, life fulfillment, and value-based living, neither scale captured the cognitive or vitality aspects of life engagement. The remaining identified PROs generally captured single aspects of life engagement, most commonly motivation/reward/energy-apathy, pleasure-anhedonia, and mental/psychological well-being.
CONCLUSION
Numerous PROs are available that may capture aspects of life engagement. However, a need remains for a new PRO that can be used in clinical trials to provide a more comprehensive description of the improvements in life engagement that patients with mental health disorders may experience with successful treatment.
PubMed: 35689159
DOI: 10.1186/s41687-022-00468-5 -
Translational Psychiatry May 2022Neuroscience research presents contradictory evidence in support of both the protective and destructive effects of cannabinoids in depression. Therefore, this systematic... (Meta-Analysis)
Meta-Analysis
Neuroscience research presents contradictory evidence in support of both the protective and destructive effects of cannabinoids in depression. Therefore, this systematic review and meta-analysis summarizes the existing preclinical literature on the effects of cannabinoid administration in the chronic unpredictable stress model of depression in order to evaluate the effects of cannabinoids and identify gaps in the literature. After protocol registration (PROSPERO #CRD42020219986), we systematically searched Scopus, Embase, Psychology & Behavioral Sciences Collection, APA PsychINFO, PubMed, CINAHL Complete, and ProQuest Dissertations & Theses Global from the earliest record of the databases, February 1964, to November 2020 for articles that met inclusion criteria (e.g., rodent subjects and administration of a cannabinoid. A total of 26 articles were included representing a sample size estimate of 1132 rodents with the majority of articles administering daily intraperitoneal injections during chronic unpredictable stress. These articles were evaluated using a modified SYRCLE's risk-of-bias tool. For each continuous behavioral measure, the standardized mean difference was calculated between cannabinoid and vehicle groups in rodents subjected to chronic unpredictable stress. The effects of cannabinoids on depressive-like behavior was evaluated using a multilevel mixed-effects model with effect size weights nested within control groups. Cannabinoid administration moderately improved the pooled negative effects of chronic unpredictable stress on anhedonia, learned helplessness, novelty suppressed feeding, time in the anxiogenic context, and entries into the anxiogenic context. Although the interpretations are limited, these findings suggest that with further investigation, cannabinoids may be a viable long-term treatment for stress-related psychopathologies such as depression.
Topics: Anti-Anxiety Agents; Antidepressive Agents; Cannabinoids; Humans
PubMed: 35641487
DOI: 10.1038/s41398-022-01967-1 -
The Journal of International Medical... Feb 2022Chronic restraint stress (CRS) is widely used to recapitulate depression phenotypes in rodents but is frequently criticized for a perceived lack of efficacy. The aim of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Chronic restraint stress (CRS) is widely used to recapitulate depression phenotypes in rodents but is frequently criticized for a perceived lack of efficacy. The aim of this study was to evaluate anhedonic-like behavior in the CRS model in rodents by performing a meta-analysis of studies that included sucrose preference tests.
METHODS
This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. We comprehensively searched for eligible studies published before June 2021 in the PubMed, Embase, Medline, and Web of Science databases. We chose sucrose preference ratio as the indicative measure of anhedonia because it is a core symptom of depression in humans.
RESULTS
Our pooled analysis included 34 articles with 57 studies and seven rodent species/strains and demonstrated decreased sucrose preference in the stress group compared with controls. The duration of CRS differentially affected the validity of anhedonic-like behavior in the models. Rats exhibited greater susceptibility to restraint stress than mice, demonstrating inter-species variability.
CONCLUSIONS
Our meta-analysis of studies that used the CRS paradigm to evaluate anhedonic-like behavior in rodents was focused on a core symptom of depression (anhedonia) as the main endpoint of the model and identified species-dependent susceptibility to restraint stress.
Topics: Anhedonia; Animals; Depression; Disease Models, Animal; Mice; Rats; Restraint, Physical; Rodentia; Stress, Psychological
PubMed: 35196899
DOI: 10.1177/03000605221075816 -
Frontiers in Psychiatry 2022Consistent evidence suggests residual depressive symptomology are the strongest predictors of depression relapse following cognitive-behavioral therapy (CBT) and...
A Systematic Review and Individual Patient Data Network Analysis of the Residual Symptom Structure Following Cognitive-Behavioral Therapy and Escitalopram, Mirtazapine and Venlafaxine for Depression.
OBJECTIVE
Consistent evidence suggests residual depressive symptomology are the strongest predictors of depression relapse following cognitive-behavioral therapy (CBT) and antidepressant medications (ADM's). Psychometric network models help detecting and understanding central symptoms that remain post-treatment, along with their complex co-occurrences. However, individual psychometric network studies show inconsistent findings. This systematic review and IPD network analysis aimed to estimate and compare the symptom network structures of residual depressive symptoms following CBT, ADM's, and their combination.
METHODS
PsycINFO, PsycArticles, and PubMed were systematically searched through October 2020 for studies that have assessed individuals with major depression at post-treatment receiving either CBT and/or ADM's (venlafaxine, escitalopram, mirtazapine). IPD was requested from eligible samples to estimate and compare residual symptom psychometric network models post-CBT and post-ADM's.
RESULTS
In total, 25 from 663 eligible samples, including 1,389 patients qualified for the IPD. Depressed mood and anhedonia were consistently central residual symptoms post-CBT and post-ADM's. For CBT, fatigue-related and anxiety symptoms were also central post-treatment. A significant difference in network structure across treatments (CBT vs. ADM) was observed for samples measuring depression severity using the MADRS. Specifically, stronger symptom occurrences were present amongst post-CBT (vs. ADM's) and amongst post-ADM's (vs. CBT). No significant difference in global strength was observed across treatments.
CONCLUSIONS
Core major depression symptoms remain central across treatments, strategies to target these symptoms should be considered. Anxiety and fatigue related complaints also remain central post-CBT. Efforts must be made amongst researchers, institutions, and journals to permit sharing of IPD. A protocol was prospectively registered on PROSPERO (CRD42020141663; https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=141663).
PubMed: 35178002
DOI: 10.3389/fpsyt.2022.746678