Yiyun Liu

Comparative efficacy and acceptability of psychotherapies for depression in children and adolescents: A systematic review and network meta-analysis

Previous meta‐analyses of psychotherapies for child and adolescent depression were limited because of the small number of trials with direct comparisons between two treatments. A network meta‐analysis, a novel approach that integrates direct and indirect evidence from randomized controlled studies, was undertaken to investigate the comparative efficacy and acceptability of psychotherapies for depression in children and adolescents. Systematic searches resulted in 52 studies (total N=3805) of nine psychotherapies and four control conditions. We assessed the efficacy at post‐treatment and at follow‐up, as well as the acceptability (all‐cause discontinuation) of psychotherapies and control conditions. At post‐treatment, only interpersonal therapy (IPT) and cognitive‐behavioral therapy (CBT) were significantly more effective than most control conditions (standardized mean differences, SMDs ranged from −0.47 to −0.96). Also, IPT and CBT were more beneficial than play therapy. Only psychodynamic therapy and play therapy were not significantly superior to waitlist. At follow‐up, IPT and CBT were significantly more effective than most control conditions (SMDs ranged from −0.26 to −1.05), although only IPT retained this superiority at both short‐term and long‐term follow‐up. In addition, IPT and CBT were more beneficial than problem‐solving therapy. Waitlist was significantly inferior to other control conditions. With regard to acceptability, IPT and problem‐solving therapy had significantly fewer all‐cause discontinuations than cognitive therapy and CBT (ORs ranged from 0.06 to 0.33). These data suggest that IPT and CBT should be considered as the best available psychotherapies for depression in children and adolescents. However, several alternative psychotherapies are understudied in this age group. Waitlist may inflate the effect of psychotherapies, so that psychological placebo or treatment‐as‐usual may be preferable as a control condition in psychotherapy trials.

Comparative efficacy, acceptability, and tolerability of augmentation agents in treatment-resistant depression: systematic review and network meta-analysis.

OBJECTIVE To comparatively analyze the efficacy, acceptability, and tolerability of various augmentation agents in adult patients with treatment-resistant depression. DATA SOURCES An electronic literature search of PubMed, EMBASE, the Cochrane Library, Web of Science, EBSCO, PsycINFO, EAGLE, and NTIS for trials published up to December 2013 was conducted. Several clinical trial registry agencies and US Food and Drug Administration reports were also reviewed. No language, publication date, or publication status restrictions were imposed. STUDY SELECTION Randomized controlled trials comparing 11 augmentation agents (aripiprazole, bupropion, buspirone, lamotrigine, lithium, methylphenidate, olanzapine, pindolol, quetiapine, risperidone, and thyroid hormone) with each other and with placebo for adult treatment-resistant depression were included. DATA EXTRACTION The proportion of patients who responded to treatment was defined as primary efficacy, and the proportion of all-cause discontinuation and side-effects discontinuation were respectively defined as acceptability and tolerability, which were assessed with odds ratios (ORs) and a Bayesian random-effects model with 95% credible intervals (CrIs). RESULTS A total of 48 trials consisting of 6,654 participants were eligible. In terms of the primary efficacy, quetiapine (OR = 1.92; 95% CrI, 1.39-3.13), aripiprazole (OR = 1.85; 95% CrI, 1.27-2.27), thyroid hormone (OR = 1.84; 95% CrI, 1.06-3.56), and lithium (OR = 1.56; 95% CrI, 1.05-2.55) were significantly more effective than placebo. Sensitivity analyses indicated that efficacy estimates for aripiprazole and quetiapine were more robust than those for thyroid hormone and lithium. In terms of acceptability, no significant difference was found between active agents and placebo. In terms of tolerability, compared to placebo, quetiapine (OR = 3.85; 95% CrI, 1.92-8.33), olanzapine (OR = 3.36; 95% CrI, 1.60-8.61), aripiprazole (OR = 2.51; 95% CrI, 1.11-7.69), and lithium (OR = 2.30; 95% CrI, 1.04-6.03) were significantly less well tolerated. CONCLUSIONS Quetiapine and aripiprazole appear to be the most robust evidence-based options for augmentation therapy in patients with treatment-resistant depression, but clinicians should interpret these findings cautiously in light of the evidence of potential treatment-related side effects.

Atypical Antipsychotic Augmentation for Treatment-Resistant Depression: A Systematic Review and Network Meta-Analysis

Background: Previous meta-analyses of atypical antipsychotics for depression were limited by few trials with direct comparisons between two treatments. We performed a network meta-analysis, which integrates direct and indirect evidence from randomized controlled trials (RCTs), to investigate the comparative efficacy and tolerability of adjunctive atypical antipsychotics for treatment-resistant depression (TRD). Methods: Systematic searches resulted in 18 RCTs (total n = 4422) of seven different types and different dosages of atypical antipsychotics and a placebo that were included in the review. Results: All standard-dose atypical antipsychotics were significantly more efficacious than placebo in the efficacy (standardized mean differences [SMDs] ranged from -0.27 to -0.43). There were no significant differences between these drugs. Low-dose atypical antipsychotics were not significantly more efficacious than the placebo. In terms of tolerability, all standard-dose atypical antipsychotics, apart from risperidone, had significantly more side-effect discontinuations than placebo (odds ratios [ORs] ranged from 2.72 to 6.40). In terms of acceptability, only quetiapine (mean 250–350mg daily) had significantly more all-cause discontinuation than placebo (OR = 1.89). In terms of quality of life/functioning, standard-dose risperidone and standard-dose aripiprazole were more beneficial than placebo (SMD = -0.38; SMD = -0.26, respectively), and standard-dose risperidone was superior to quetiapine (mean 250–350mg daily). Conclusions: All standard-dose atypical antipsychotics for the adjunctive treatment of TRD are efficacious in reducing depressive symptoms. Risperidone and aripiprazole also showed benefits in improving the quality of life of patients. Atypical antipsychotics should be prescribed with caution due to abundant evidence of side effects.

Selective serotonin reuptake inhibitors versus tricyclic antidepressants in young patients: a meta-analysis of efficacy and acceptability.

PURPOSE A meta-analysis comparing the efficacy and acceptability of selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs) in depressed children, adolescents, and young adults was performed. METHODS A comprehensive literature search of the PubMed, Cochrane, Embase, Web of Science, and PsycINFO databases was conducted from 1970 to December 2013. Only clinical trials that randomly assigned one SSRI or TCA to patients aged 7 to 25 years who met the diagnostic criteria for unipolar depressive disorder were included. Primary efficacy was determined by the pooling of standardized mean differences (SMDs) calculated from the difference in the reduction in mean depression rating scale scores for the 2 antidepressants. Acceptability was determined by pooling the risk ratios (RRs) of dropouts for all reasons and for adverse effects as well as the suicide-risk outcome. FINDINGS Five trials with a total of 422 patients were considered to be eligible for inclusion. SSRIs were significantly more effective than TCAs in primary efficacy (SMD = -0.52; 95% CI, -0.81 to -0.24; P = 0.0003). Patients taking SSRIs had a significantly greater response to depressive symptoms than patients taking TCAs (RR = 1.55; 95% CI, 1.04 to 2.29; P = 0.03). On an individual SSRI basis, fluoxetine had a significantly greater efficacy than TCAs (SMD = -0.82; 95% CI, -1.34 to -0.29; P = 0.003). On an individual TCA basis, only imipramine was not significantly worse than SSRIs (SMD = -0.27; 95% CI, -0.56 to 0.02; P = 0.06). Significantly more patients taking TCAs discontinued treatment than patients taking SSRIs (35.8% vs 25.1%; RR = 0.70; 95% CI, 0.52 to 0.93; P = 0.02). IMPLICATIONS SSRI therapy has a superior efficacy and is better tolerated compared with TCA therapy in young patients.

Meta-Analysis of Infectious Agents and Depression

Depression is a debilitating psychiatric disorder and a growing global public health issue. However, the relationships between microbial infections and depression remains uncertain. A computerized literature search of Medline, ISI Web of Knowledge, PsycINFO, and the Cochrane Library was conducted up to May 2013, and 6362 studies were initially identified for screening. Case-control studies detected biomarker of microorganism were included. Based on inclusion and exclusion criteria, 28 studies were finally included to compare the detection of 16 infectious agents in unipolar depressed patients and healthy controls with a positive incident being defined as a positive biochemical marker of microbial infection. A customized form was used for data extraction. Pooled analysis revealed that the majority of the 16 infectious agents were not significantly associated with depression. However, there were statistically significant associations between depression and infection with Borna disease virus, herpes simplex virus-1, varicella zoster virus, Epstein-Barr virus, and Chlamydophila trachomatis.

The identification of metabolic disturbances in the prefrontal cortex of the chronic restraint stress rat model of depression.

Major depressive disorder, with serious impairment in cognitive and social functioning, is a complex psychiatric disorder characterized by pervasive and persistent low mood and a loss of interest or pleasure. However, the underlying molecular mechanisms of depression remain largely unknown. In this study, we used a non-targeted metabolomics approach based on gas chromatography-mass spectrometry of the prefrontal cortex in chronic restraint stress (CRS)-treated rats. CRS was induced in the stress group by restraining rats in a plastic restrainer for 6h every day. This stress paradigm continued for 21 days. Body weight measurement and behavior tests were applied, including the sucrose preference test for anhedonia, the forced swimming test for despair-like behavior, and open field test and the elevated plus-maze to test for anxiety-like behaviors in rats after CRS. Differentially expressed metabolites associated with CRS-treated rats were identified by combining multivariate and univariate statistical analysis and corrected for multiple testing using the Benjamini-Hochberg procedure. A heat map of differential metabolites was constructed using Matlab. Ingenuity Pathways Analysis was applied to identify the predicted pathways and biological functions relevant to the bio-molecules of interest. Our findings showed that CRS induces depression-like behaviors and not anxiety-like behaviors. Thirty-six metabolites were identified as potential depression biomarkers involved in amino acid metabolism, energy metabolism and lipid metabolism, as well as a disturbance in neurotransmitters. Consequently, this study provides useful insights into the molecular mechanisms of depression.

Efficacy and tolerability of antidepressants in the treatment of adolescents and young adults with depression and substance use disorders: a systematic review and meta‐analysis

AIMS To measure the effectiveness of antidepressants for adolescents and young adults with co-occurring depression and substance use disorder. DESIGN, SETTING AND PARTICIPANTS Meta-analysis of randomized controlled clinical trials. A comprehensive literature search of PubMed, Cochrane, Embase, Web of Science and PsychINFO was conducted (from 1970 to 2013). Prospective, parallel groups, double-blind, controlled trials with random assignment to an antidepressant or placebo on young patients (age ≤ 25 years) who met diagnostic criteria of both substance use and unipolar depressive disorder were included. Five trials were selected for this analysis and included 290 patients. MEASUREMENTS Our efficacy outcome measures were depression outcomes (dichotomous and continuous measures) and substance-use outcomes (change of frequency or quantity of substance-use). Secondary analysis was conducted to access the tolerability of antidepressant treatment. FINDINGS For dichotomous depression outcome, antidepressants group was significantly more effective than placebo group [risk ratio (RR) = 1.21; 95% confidence interval (CI) 1.01-1.45], with low heterogeneity (I(2)  = 0%). Although no statistically significant effects for continuous depression outcome [standardized mean differences (SMD) = -0.13; 95% CI, -0.55 to 0.30] were found with moderate heterogeneity (I(2)  = 63%), subgroup analysis showed that the medicine group with a sample size of more than 50 showed statistically significant efficacy compared with the placebo group (SMD -0.53, 95% CI -0.82 to -0.25). Moreover, there was no significant difference for substance-use outcomes and tolerability outcomes between the medication and placebo groups. CONCLUSIONS Antidepressant medication has a small overall effect in reducing depression in young patients with combined depressive and substance-use disorders, but does not appear to improve substance use outcomes.

Efficacy of ketamine in the rapid treatment of major depressive disorder: a meta-analysis of randomized, double-blind, placebo-controlled studies.

Background An increasing number of studies are reporting that ketamine could be treated as a novel antidepressant for major depressive disorder (MDD). Therefore, we performed this meta-analysis to comprehensively and systematically assess the efficacy of ketamine for treating patients with MDD. Method Randomized, double-blind, placebo-controlled studies on ketamine versus placebo for treating MDD were searched up to April 2016 in medical databases (PubMed, CCTR, Web of Science, Embase, CBM-disc, and CNKI). Three treatment time points (24 and 72 h, and day 7) were chosen. Response and remission rates were the main outcomes. The random effects model was used. An intention-to-treat analysis was conducted. Results Nine high-quality studies that included 368 patients were selected to compare the efficacy of ketamine to placebo. The therapeutic effects of ketamine at 24 and 72 h, and day 7 were found to be significantly better than placebo. Response and remission rates in the ketamine group at 24 and 72 h, and day 7 were 52.2% and 20.6%; 47.9% and 23.8%; and 39.8% and 26.2%, respectively. No significant heterogeneity existed, and the Egger’s test showed no publication bias. Conclusion These results indicated that ketamine could yield a good efficacy in the rapid treatment of MDD. Future large-scale clinical studies are needed to confirm our results and investigate the mid- and long-term efficacy of ketamine in treating MDD.

Comparative efficacy and acceptability of electroconvulsive therapy versus repetitive transcranial magnetic stimulation for major depression: A systematic review and multiple-treatments meta-analysis.

HighlightsECT was the most efficacious, but least tolerated.R‐rTMS was the best tolerated treatment for MDD.B‐rTMS appears to have the most favorable balance between efficacy and acceptability. Backgrounds: The effects of electroconvulsive therapy (ECT) and bilateral, left prefrontal, and right prefrontal repetitive transcranial magnetic stimulation (rTMS) on major depressive disorder (MDD) have not been adequately addressed by previous studies. Here, a multiple‐treatments meta‐analysis, which incorporates evidence from direct and indirect comparisons from a network of trials, was performed to assess the efficacy and acceptability of these four treatment modalities on MDD. Method: The literature was searched for randomized controlled trials (RCTs) on ECT, bilateral rTMS, and unilateral rTMS for treating MDD up to May 2016. The main outcome measures were response and drop‐out rates. Results: Data were obtained from 25 studies consisting of 1288 individuals with MDD. ECT was non‐significantly more efficacious than B‐rTMS, R‐rTMS, and L‐rTMS. Left prefrontal rTMS was non −significantly less efficacious than all other treatment modalities. In terms of acceptability, R‐rTMS was non‐significantly better tolerated than ECT, B‐rTMS, and L‐rTMS. ECT was the most efficacious treatment with the cumulative probabilities of being the most efficacious treatment being: ECT (65%), B‐rTMS (25%), R‐rTMS (8%), and L‐rTMS (2%). R‐rTMS was the best‐tolerated treatment with the cumulative probabilities of being the best‐tolerated treatment being: R‐rTMS (52%), B‐rTMS (17%), L‐rTMS (16%), and ECT (14%). Coherence analysis detected no statistically significant incoherence in any comparisons of direct with indirect evidence for the response rate and drop‐out rate. Conclusions: ECT was the most efficacious, but least tolerated, treatment, while R‐rTMS was the best tolerated treatment for MDD. B‐rTMS appears to have the most favorable balance between efficacy and acceptability.

Recombinant Tissue Plasminogen Activator Induces Neurological Side Effects Independent on Thrombolysis in Mechanical Animal Models of Focal Cerebral Infarction: A Systematic Review and Meta-Analysis

Background and Purpose Recombinant tissue plasminogen activator (rtPA) is the only effective drug approved by US FDA to treat ischemic stroke, and it contains pleiotropic effects besides thrombolysis. We performed a meta-analysis to clarify effect of tissue plasminogen activator (tPA) on cerebral infarction besides its thrombolysis property in mechanical animal stroke. Methods Relevant studies were identified by two reviewers after searching online databases, including Pubmed, Embase, and ScienceDirect, from 1979 to 2016. We identified 6, 65, 17, 12, 16, 12 and 13 comparisons reporting effect of endogenous tPA on infarction volume and effects of rtPA on infarction volume, blood-brain barrier, brain edema, intracerebral hemorrhage, neurological function and mortality rate in all 47 included studies. Standardized mean differences for continuous measures and risk ratio for dichotomous measures were calculated to assess the effects of endogenous tPA and rtPA on cerebral infarction in animals. The quality of included studies was assessed using the Stroke Therapy Academic Industry Roundtable score. Subgroup analysis, meta-regression and sensitivity analysis were performed to explore sources of heterogeneity. Funnel plot, Trim and Fill method and Egger’s test were obtained to detect publication bias. Results We found that both endogenous tPA and rtPA had not enlarged infarction volume, or deteriorated neurological function. However, rtPA would disrupt blood-brain barrier, aggravate brain edema, induce intracerebral hemorrhage and increase mortality rate. Conclusions This meta-analysis reveals rtPA can lead to neurological side effects besides thrombolysis in mechanical animal stroke, which may account for clinical exacerbation for stroke patients that do not achieve vascular recanalization with rtPA.