Relapse and its modifiers in major depressive disorder after antidepressant discontinuation: meta-analysis and meta-regression.
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SUBMITTER: Kishi T
PROVIDER: S-EPMC10005929 | biostudies-literature | 2023 Mar
REPOSITORIES: biostudies-literature
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Relapse and its modifiers in major depressive disorder after antidepressant discontinuation: meta-analysis and meta-regression.
Kishi Taro T Sakuma Kenji K Hatano Masakazu M Okuya Makoto M Matsuda Yuki Y Kato Masaki M Iwata Nakao N
Molecular psychiatry 20221223 3
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Project description:A significant clinical issue encountered after a successful acute major depressive disorder (MDD) treatment is the relapse of depressive symptoms. Although continuing maintenance therapy with antidepressants is generally recommended, there is no established protocol on whether or not it is necessary to prescribe the antidepressant used to achieve remission. In this meta-analysis, the risk of relapse and treatment failure when either continuing with the same drug used to achieved remission or switching to a placebo was assessed in several clinically significant subgroups. The pooled odds ratio (OR) (±95% confidence intervals (CI)) was calculated using a random effects model. Across 40 studies (n = 8890), the relapse rate was significantly lower in the antidepressant group than the placebo group by about 20% (OR = 0.38, CI: 0.33-0.43, p < 0.00001; 20.9% vs 39.7%). The difference in the relapse rate between the antidepressant and placebo groups was greater for tricyclics (25.3%; OR = 0.30, CI: 0.17-0.50, p < 0.00001), SSRIs (21.8%; OR = 0.33, CI: 0.28-0.38, p < 0.00001), and other newer agents (16.0%; OR = 0.44, CI: 0.36-0.54, p < 0.00001) in that order, while the effect size of acceptability was greater for SSRIs than for other antidepressants. A flexible dose schedule (OR = 0.30, CI: 0.23-0.48, p < 0.00001) had a greater effect size than a fixed dose (OR = 0.41, CI: 0.36-0.48, p < 0.00001) in comparison to placebo. Even in studies assigned after continuous treatment for more than 6 months after remission, the continued use of antidepressants had a lower relapse rate than the use of a placebo (OR = 0.40, CI: 0.29-0.55, p < 0.00001; 20.2% vs 37.2%). The difference in relapse rate was similar from a maintenance period of 6 months (OR = 0.41, CI: 0.35-0.48, p < 0.00001; 19.6% vs 37.6%) to over 1 year (OR = 0.35, CI: 0.29-0.41, p < 0.00001; 19.9% vs 39.8%). The all-cause dropout of antidepressant and placebo groups was 43% and 58%, respectively, (OR = 0.47, CI: 0.40-0.55, p < 0.00001). The tolerability rate was ~4% for both groups. The rate of relapse (OR = 0.32, CI: 0.18-0.64, p = 0.0010, 41.0% vs 66.7%) and all-cause dropout among adolescents was higher than in adults. To prevent relapse and treatment failure, maintenance therapy, and careful attention for at least 6 months after remission is recommended. SSRIs are well-balanced agents, and flexible dose adjustments are more effective for relapse prevention.
| S-EPMC7815511 | biostudies-literature
Project description:EPIC array data were generated from 2 MDD case control cohorts. EWAS was performed in each cohort, followed by meta-analysis between the 2 cohort. Cohort 1: A total of 191 blood samples from 112 patients with MDD was collected up till the interim analysis (wave 1 samples) from an observational clinical study OBSERVEMDD0001 (ClinicalTrials.gov Identifier: NCT02489305) compared to 32 healthy controls; Cohort 2: The MDD cases (N = 359) were drawn from the Molecular Biomarkers of Antidepressant Response study compared to 68 healthy controls.
2022-11-03 | GSE198904 | GEO
Project description:BackgroundTo compare response to antidepressants between randomized controlled trials (RCTs) and observational trials.Methods and findingsPublished and unpublished studies (from 1989 to 2009) were searched for by 2 reviewers on Medline, the Cochrane library, Embase, clinicaltrials.gov, Current Controlled Trial, bibliographies and by mailing key organisations and researchers. RCTs and observational studies on fluoxetine or venlafaxine in first-line treatment for major depressive disorder reported in English, French or Spanish language were included in the main analysis. Studies including patients from a wider spectrum of depressive disorders (anxious depression, minor depressive episode, dysthymia) were added in a second analysis. The main outcome was the pre-/post-treatment difference on depression scales standardised to 100 (17-item or 21-item Hamilton Rating Scale for Depression or Montgomery and Åsberg Rating Scale) in each study arm. A meta-regression was conducted to adjust the comparison between observational studies and RCTs on treatment type, study characteristics and average patient characteristics. 12 observational studies and 109 RCTs involving 6757 and 11035 patients in 12 and 149 arms were included in the main analysis. Meta-regression showed that the standardised treatment response in RCTs is greater by a magnitude of 4.59 (2.61 to 6.56). Study characteristics were related to standardised treatment response, positively (study duration, number of follow-up assessments, outpatients versus inpatients, per protocol analysis versus intention to treat analysis) or negatively (blinded design, placebo design). At patient level, response increased with baseline severity and decreased with age. Results of the second analysis were consistent with this.ConclusionsResponse to antidepressants is greater in RCTs than in observational studies. Observational studies should be considered as a necessary complement to RCTs.
| S-EPMC3110792 | biostudies-literature
Project description:BackgroundUnderstanding patterns of relapse in patients who respond to antidepressant treatment can inform strategies for prevention of relapse. We aimed to identify distinct trajectories of depression severity, assess whether similar or different trajectory classes exist for patients who continued or discontinued active treatment, and test whether clinical predictors of trajectory class membership exist using pooled data from clinical trials.MethodsWe analysed individual patient data from four double-blind discontinuation clinical trials of duloxetine or fluoxetine versus placebo in major depression from before 2012 (n=1462). We modelled trajectories of relapse up to 26 weeks during double-blind treatment. Trajectories of depression severity, as measured by the Hamilton Depression Rating Scale score, were identified in the entire sample, and separately in groups in which antidepressants had been continued or discontinued, using growth mixture models. Predictors of trajectory class membership were assessed with weighted logistic regression.FindingsWe identified similar relapse trajectories and two trajectories of stable depression scores in the normal range on active medication and on placebo. Active treatment significantly lowered the odds of membership in the relapse trajectory (odds ratio 0·47, 95% CI 0·37-0·61), whereas female sex (1·56, 1·23-2·06), shorter length of time with clinical response by 1 week (1·10, 1·06-1·15), and higher Clinical Global Impression score at baseline (1·28, 1·01-1·62) increased the odds. Overall, the protective effect of antidepressant medication relative to placebo on the risk of being classified as a relapser was about 13% (33% vs 46%).InterpretationThe existence of similar relapse trajectories on active medication and on placebo suggests that there is no specific relapse signature associated with antidepressant discontinuation. Furthermore, continued treatment offers only modest protection against relapse. These data highlight the need to incorporate treatment strategies that prevent relapse as part of the treatment of depression.FundingNational Institutes of Health, the US Department of Veterans Affairs Alcohol Research Center, and National Center for Post-Traumatic Stress Disorder.
| S-EPMC5340978 | biostudies-literature
Project description:Objectives To examine the risk of relapse and time to relapse after discontinuation of antidepressants in patients with anxiety disorder who responded to antidepressants, and to explore whether relapse risk is related to type of anxiety disorder, type of antidepressant, mode of discontinuation, duration of treatment and follow-up, comorbidity, and allowance of psychotherapy.Design Systematic review and meta-analyses of relapse prevention trials.Data sources PubMed, Cochrane, Embase, and clinical trial registers (from inception to July 2016).Study selection Eligible studies included patients with anxiety disorder who responded to antidepressants, randomised patients double blind to either continuing antidepressants or switching to placebo, and compared relapse rates or time to relapse.Data extraction Two independent raters selected studies and extracted data. Random effect models were used to estimate odds ratios for relapse, hazard ratios for time to relapse, and relapse prevalence per group. The effect of various categorical and continuous variables was explored with subgroup analyses and meta-regression analyses respectively. Bias was assessed using the Cochrane tool.Results The meta-analysis included 28 studies (n=5233) examining relapse with a maximum follow-up of one year. Across studies, risk of bias was considered low. Discontinuation increased the odds of relapse compared with continuing antidepressants (summary odds ratio 3.11, 95% confidence interval 2.48 to 3.89). Subgroup analyses and meta-regression analyses showed no statistical significance. Time to relapse (n=3002) was shorter when antidepressants were discontinued (summary hazard ratio 3.63, 2.58 to 5.10; n=11 studies). Summary relapse prevalences were 36.4% (30.8% to 42.1%; n=28 studies) for the placebo group and 16.4% (12.6% to 20.1%; n=28 studies) for the antidepressant group, but prevalence varied considerably across studies, most likely owing to differences in the length of follow-up. Dropout was higher in the placebo group (summary odds ratio 1.31, 1.06 to 1.63; n=27 studies).Conclusions Up to one year of follow-up, discontinuation of antidepressant treatment results in higher relapse rates among responders compared with treatment continuation. The lack of evidence after a one year period should not be interpreted as explicit advice to discontinue antidepressants after one year. Given the chronicity of anxiety disorders, treatment should be directed by long term considerations, including relapse prevalence, side effects, and patients' preferences.
| S-EPMC5596392 | biostudies-literature
Project description:IntroductionThe question remains to be elucidated: "Is treatment with antidepressants at doses approved in Japan effective for Japanese patients with MDD?" It is crucial to confirm this in order to provide appropriate treatments for Japanese patients with major depressive disorder (MDD). Therefore, we conducted a systematic review and random-effects pairwise meta-analysis including these nine double-blind, randomized, placebo-controlled trials.MethodsWe calculated the standardized mean difference (SMD) and risk ratio (RR) with a 95% confidence interval (95% CI).ResultsPooled newer antidepressants outperformed placebo regarding improvement of depressive symptom scale scores [SMD (95% CI) = -0.20 (-0.27, -0.12), p < 0.00001], response to treatment [RR (95% CI) = 1.23 (1.13, 1.32), p < 0.00001], and remission rate [RR (95% CI) = 1.30 (1.16, 1.45), p < 0.00001]. Although all-cause discontinuation was not significantly different between the treatment groups, the pooled antidepressant group showed a higher discontinuation rate due to adverse event [RR (95% CI) = 1.60 (1.13, 2.26), p = 0.007] and a higher incidence of at least one adverse event than the placebo group [RR (95% CI) = 1.13 (1.08, 1.18), p < 0.00001].DiscussionWe concluded that newer antidepressants are effective for Japanese adults with MDD although the clinicians must monitor the health conditions of these individuals.
| S-EPMC10932784 | biostudies-literature
Project description:Omega-3 polyunsaturated fatty acid (PUFA) supplementation has been proposed as (adjuvant) treatment for major depressive disorder (MDD). In the present meta-analysis, we pooled randomized placebo-controlled trials assessing the effects of omega-3 PUFA supplementation on depressive symptoms in MDD. Moreover, we performed meta-regression to test whether supplementation effects depended on eicosapentaenoic acid (EPA) or docosahexaenoic acid dose, their ratio, study duration, participants' age, percentage antidepressant users, baseline MDD symptom severity, publication year and study quality. To limit heterogeneity, we only included studies in adult patients with MDD assessed using standardized clinical interviews, and excluded studies that specifically studied perinatal/perimenopausal or comorbid MDD. Our PubMED/EMBASE search resulted in 1955 articles, from which we included 13 studies providing 1233 participants. After taking potential publication bias into account, meta-analysis showed an overall beneficial effect of omega-3 PUFAs on depressive symptoms in MDD (standardized mean difference=0.398 (0.114-0.682), P=0.006, random-effects model). As an explanation for significant heterogeneity (I(2)=73.36, P<0.001), meta-regression showed that higher EPA dose (β=0.00037 (0.00009-0.00065), P=0.009), higher percentage antidepressant users (β=0.0058 (0.00017-0.01144), P=0.044) and earlier publication year (β=-0.0735 (-0.143 to 0.004), P=0.04) were significantly associated with better outcome for PUFA supplementation. Additional sensitivity analyses were performed. In conclusion, present meta-analysis suggested a beneficial overall effect of omega-3 PUFA supplementation in MDD patients, especially for higher doses of EPA and in participants taking antidepressants. Future precision medicine trials should establish whether possible interactions between EPA and antidepressants could provide targets to improve antidepressant response and its prediction. Furthermore, potential long-term biochemical side effects of high-dosed add-on EPA supplementation should be carefully monitored.
| S-EPMC4872453 | biostudies-literature
Project description:BackgroundRepetitive transcranial magnetic stimulation (rTMS) is frequently used as an adjunctive treatment with antidepressants for depression. We aimed to evaluate the clinical efficacy and safety of antidepressant classes when administered concurrently with rTMS for the management of major depressive disorder (MDD).MethodsIn this systematic review and meta-analysis, MEDLINE, Embase, PsycINFO, and the Cochrane Library were searched from inception to April 12th 2024 for terms relating to medication, depression, and rTMS and appraised by 2 independent screeners. All randomized clinical trials that prospectively evaluated a specific antidepressant adjunctively with sham rTMS as a control in MDD were included. The study was registered with PROSPERO (CRD42023418435). The primary outcome measure assessed symptomatic improvement measured by formal depression scales. We used a random-effects model with pooled Standardized Mean Differences (SMDs) and log odds ratios (OR). All studies were assessed for their methodological quality and bias using the Cochrane Collaboration Risk of Bias tool version 2 (RoB2).Findings14 articles from 5376 identified studies were included in the systematic review and meta-analysis. There was only sufficient trial data to evaluate the effects of rTMS and combination therapy with selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs). Across studies, 848 participants (mean [SD] age:41.1 [18.7] years for SSRIs, 51.8 [3.8] years for SNRIs) prospectively examined the efficacy of antidepressant medication with rTMS. Combining rTMS with SSRIs led to significantly lower depression scores, (SMD [CI] of -0.65 [-0.98, -0.31], p = 0.0002, I2 = 66.1%), higher response (OR = 0.97 [0.50, 1.44], p < 0.0001, I2 = 25.33%) and remission rates (OR = 1.04 [0.55, 1.52], p < 0.0001, I2 = 0.00%) than medication with sham rTMS. No additive benefit was found for SNRIs with rTMS (SMD of 0.10 [-0.14, 0.34], p = 0.42, I2 = 0.00%; OR = 0.12 [-0.39, 0.62], p = 0.64, I2 = 0.00%; OR = -0.31 [-0.90, 0.28], p = 0.86, I2 = 39.9%). The overall risk of bias for the included studies ranged from low to high, with 1 study having a high risk of bias.InterpretationThe combination of rTMS with SSRIs, but not SNRIs, significantly reduced depression severity, increasing response and remission rates. Some analyses demonstrated high heterogeneity, which was influenced by an SSRI trial with a high effect size. Overall, these results suggest that not all antidepressant combination therapies are alike, and SSRIs should be considered when initiating rTMS.FundingDonald T. Stuss Young Investigator Research Innovation Award from the Sandra Black Centre for Brain Resilience & Recovery and the Harquail Centre for Neuromodulation through the Sunnybrook Foundation.
| S-EPMC11338161 | biostudies-literature
Project description:AimWhile evidence-based antidepressant treatment is available for major depressive disorder, standard approaches for discontinuation of antidepressants after remission have not yet been established. Decision aids are structured clinical tools that facilitate shared decision-making between patients and healthcare providers. This study aimed to describe the development process and acceptability of decision aids for major depressive disorder following discontinuation of antidepressant treatment after remission.MethodsWe systematically developed a decision aids according to the International Patient Decision Aid Standards. First, a decision aids prototype was created using the results of a systematic review and meta-analysis previously conducted to identify the consequences of continuing and discontinuing antidepressant treatment. Second, a mixed-methods questionnaire (alpha acceptability testing) was administered to patients and healthcare providers to improve the decision aids prototype and develop it into a final version acceptable for clinical settings.ResultsOur decision aids consisted of a description of major depressive disorder, the option to continue or discontinue antidepressant treatment, the advantages and disadvantages of each option, the consequences of each option, and value clarification exercises for each option. The patients (n = 22) reported that the decision aids had acceptable language (91%), adequate information (91%), and a well-balanced presentation (95%). Healthcare providers (n = 20) provided favorable feedback. The final decision aids fulfilled all six International Patient Decision Aid Standards qualifying criteria.ConclusionWe successfully developed a decision aids for discontinuation of antidepressant treatment after remission, which could be used during the shared decision-making process. Further studies are needed to verify the effects of using the decision aids during the shared decision-making process.
| S-EPMC9515698 | biostudies-literature
Project description:IntroductionCognitive dysfunction or deficits are common in patients with major depressive disorder (MDD). The current study systematically reviews and meta-analyzes multiple domains of cognitive impairment in patients with MDD.MethodsPubMed/MEDLINE, PsycINFO, Cochrane Library, Embase, Web of Science, and Google Scholar were searched from inception through May 17, 2023, with no language limits. Studies with the following inclusion criteria were included: (1) patients with a diagnosis of MDD using standardized diagnostic criteria; (2) healthy controls (i.e., those without MDD); (3) neuropsychological assessments of cognitive impairment using Cambridge Neuropsychological Test Automated Battery (CANTAB); and (4) reports of sufficient data to quantify standardized effect sizes. Hedges' g standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs) were used to quantify effect sizes of cognitive impairments in MDD. SMDs were estimated using a fixed- or random-effects models.ResultsOverall, 33 studies consisting of 2,596 subjects (n = 1,337 for patients with MDD and n = 1,259 for healthy controls) were included. Patients with MDD, when compared to healthy controls, had moderate cognitive deficits (SMD, -0.39 [95% CI, -0.47 to -0.31]). In our subgroup analyses, patients with treatment-resistant depression (SMD, -0.56 [95% CI, -0.78 to -0.34]) and older adults with MDD (SMD, -0.51 [95% CI, -0.66 to -0.36]) had greater cognitive deficits than healthy controls. The effect size was small among unmedicated patients with MDD (SMD, -0.19 [95% CI, -0.37 to -0.00]), and we did not find any statistical difference among children. Cognitive deficits were consistently found in all domains, except the reaction time. No publication bias was reported.ConclusionBecause cognitive impairment in MDD can persist in remission or increase the risk of major neurodegenerative disorders, remediation of cognitive impairment in addition to alleviation of depressive symptoms should be an important goal when treating patients with MDD.
| S-EPMC10880806 | biostudies-literature