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Is the efficacy of antidepressants in panic disorder mediated by adverse events? A mediational analysis.

ABSTRACT: It has been hypothesised that the perception of adverse events in placebo-controlled antidepressant clinical trials may induce patients to conclude that they have been randomized to the active arm of the trial, leading to the breaking of blind. This may enhance the expectancies for improvement and the therapeutic response. The main objective of this study is to test the hypothesis that the efficacy of antidepressants in panic disorder is mediated by the perception of adverse events. The present analysis is based on a systematic review of published and unpublished randomised trials comparing antidepressants with placebo for panic disorder. The Baron and Kenny approach was applied to investigate the mediational role of adverse events in the relationship between antidepressants treatment and efficacy. Fourteen placebo-controlled antidepressants trials were included in the analysis. We found that: (a) antidepressants treatment was significantly associated with better treatment response (ß = 0.127, 95% CI 0.04 to 0.21, p = 0.003); (b) antidepressants treatment was not associated with adverse events (ß = 0.094, 95% CI -0.05 to 0.24, p = 0.221); (c) adverse events were negatively associated with treatment response (ß = 0.035, 95% CI -0.06 to -0.05, p = 0.022). Finally, after adjustment for adverse events, the relationship between antidepressants treatment and treatment response remained statistically significant (ß = 0.122, 95% CI 0.01 to 0.23, p = 0.039). These findings do not support the hypothesis that the perception of adverse events in placebo-controlled antidepressant clinical trials may lead to the breaking of blind and to an artificial inflation of the efficacy measures. Based on these results, we argue that the moderate therapeutic effect of antidepressants in individuals with panic disorder is not an artefact, therefore reflecting a genuine effect that doctors can expect to replicate under real-world conditions.

SUBMITTER: Bighelli I

PROVIDER: S-EPMC5456299 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Is the efficacy of antidepressants in panic disorder mediated by adverse events? A mediational analysis.

Bighelli Irene I Borghesani Anna A Barbui Corrado C

PloS one 20170602 6

It has been hypothesised that the perception of adverse events in placebo-controlled antidepressant clinical trials may induce patients to conclude that they have been randomized to the active arm of the trial, leading to the breaking of blind. This may enhance the expectancies for improvement and the therapeutic response. The main objective of this study is to test the hypothesis that the efficacy of antidepressants in panic disorder is mediated by the perception of adverse events. The present ...[more]

PMID: 28575031

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Project description:BackgroundPanic disorder (PD) is characterized by recurrent panic attacks and higher affection of women as compared to men. The lifetime prevalence of PD is about 2-3% in the general population leading to tremendous distress and disability. Etiologically, genetic and environmental factors, such as stress, contribute to the onset and relapse of PD. In the present study, we investigated epigenome-wide DNA methylation (DNAm) in respond to a cumulative, stress-weighted life events score (wLE) in patients with PD and its boundary to major depressive disorder (MDD), frequently co-occurring with symptoms of PD.MethodsDNAm was assessed by the Illumina HumanMethylation450 BeadChip. In a meta-analytic approach, epigenome-wide DNAm changes in association with wLE were first analyzed in two PD cohorts (with a total sample size of 183 PD patients and 85 healthy controls) and lastly in 102 patients with MDD to identify possible overlapping and opposing effects of wLE on DNAm. Additionally, analysis of differentially methylated regions (DMRs) was conducted to identify regional clusters of association.ResultsTwo CpG-sites presented with p-values below 1 × 10-05 in PD: cg09738429 (p = 6.40 × 10-06, located in an intergenic shore region in next proximity of PYROXD1) and cg03341655 (p = 8.14 × 10-06, located in the exonic region of GFOD2). The association of DNAm at cg03341655 and wLE could be replicated in the independent MDD case sample indicating a diagnosis independent effect. Genes mapping to the top hits were significantly upregulated in brain and top hits have been implicated in the metabolic system. Additionally, two significant DMRs were identified for PD only on chromosome 10 and 18, including CpG-sites which have been reported to be associated with anxiety and other psychiatric phenotypes.ConclusionThis first DNAm analysis in PD reveals first evidence of small but significant DNAm changes in PD in association with cumulative stress-weighted life events. Most of the top associated CpG-sites are located in genes implicated in metabolic processes supporting the hypothesis that environmental stress contributes to health damaging changes by affecting a broad spectrum of systems in the body.

Project description:ImportanceRegistry data show that maternal panic disorder, or anxiety disorders in general, increase the risk for adverse pregnancy outcomes. However, diagnoses from registries may be imprecise and may not consider potential confounding factors, such as treatment with medication and maternal substance use.ObjectiveTo determine whether panic disorder or generalized anxiety disorder (GAD) in pregnancy, or medications used to treat these conditions, are associated with adverse maternal or neonatal pregnancy outcomes.Design, setting, and participantsThis cohort study conducted between July 1, 2005, and July 14, 2009, recruited women at 137 obstetric practices in Connecticut and Massachusetts before 17 weeks of pregnancy and reassessed them at 28 (±4) weeks of pregnancy and 8 (±4) weeks postpartum. Psychiatric diagnoses were determined by answers to the World Mental Health Composite International Diagnostic Interview. Assessments also gathered information on treatment with medications and confounding factors, such as substance use, previous adverse birth outcomes, and demographic factors.ExposurePanic disorder, GAD, or use of benzodiazepines or serotonin reuptake inhibitors.Main outcomes and measuresAmong mothers: preterm birth, cesarean delivery, and hypertensive diseases of pregnancy. Among neonates: low birth weight, use of minor respiratory interventions, and use of ventilatory support.ResultsOf the 2654 women in the final analysis (mean [SD] age, 31.0 [5.7] years), most were non-Hispanic white (1957 [73.7%]), 98 had panic disorder, 252 had GAD, 67 were treated with a benzodiazepine, and 293 were treated with a serotonin reuptake inhibitor during pregnancy. In adjusted models, neither panic disorder nor GAD was associated with maternal or neonatal complications of interest. Most medication exposures occurred early in pregnancy. Maternal benzodiazepine use was associated with cesarean delivery (odds ratio [OR], 2.45; 95% CI, 1.36-4.40), low birth weight (OR, 3.41; 95% CI, 1.61-7.26), and use of ventilatory support for the newborn (OR, 2.85; 95% CI, 1.2-6.9). Maternal serotonin reuptake inhibitor use was associated with hypertensive diseases of pregnancy (OR, 2.82; 95% CI, 1.58-5.04), preterm birth (OR, 1.56; 95% CI, 1.02-2.38), and use of minor respiratory interventions (OR, 1.81; 95% CI, 1.39-2.37). With maternal benzodiazepine treatment, rates of ventilatory support increased by 61 of 1000 neonates and duration of gestation was shortened by 3.6 days; with maternal serotonin reuptake inhibitor use, gestation was shortened by 1.8 days, 152 of 1000 additional newborns required minor respiratory interventions, and 53 of 1000 additional women experienced hypertensive diseases of pregnancy.Conclusions and relevancePanic disorder and GAD do not contribute to adverse pregnancy complications. Women may require treatment with medications during pregnancy, which can shorten the duration of gestation slightly. Maternal treatment with a serotonin reuptake inhibitor is also associated with hypertensive disease of pregnancy and cesarean delivery.

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Is the efficacy of antidepressants in panic disorder mediated by adverse events? A mediational analysis.

Publications

Is the efficacy of antidepressants in panic disorder mediated by adverse events? A mediational analysis.

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