Ramona Meister

Effect of Disorder-Specific vs Nonspecific Psychotherapy for Chronic Depression: A Randomized Clinical Trial

Importance Chronic depression is a highly prevalent and disabling disorder. There is a recognized need to assess the value of long-term disorder-specific psychotherapy. Objective To evaluate the efficacy of the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) compared with that of nonspecific supportive psychotherapy (SP). Design, Setting, and Participants A prospective, multicenter, evaluator-blinded, randomized clinical trial was conducted among adult outpatients with early-onset chronic depression who were not taking antidepressant medication. Patients were recruited between March 5, 2010, and October 16, 2012; the last patient finished treatment on October 14, 2013. Data analysis was conducted from March 5, 2014, to October 27, 2016. Interventions The treatment included 24 sessions of CBASP or SP for 20 weeks in the acute phase, followed by 8 continuation sessions during the next 28 weeks. Main Outcomes and Measures The primary outcome was symptom severity after 20 weeks (blinded observer ratings) as assessed by the 24-item Hamilton Rating Scale for Depression (HRSD-24). Secondary outcomes were rates of response (reduction in HRSD-24 score of ≥50% from baseline) and remission (HRSD-24 score ⩽8), as well as self-assessed ratings of depression, global functioning, and quality of life. Results Among 622 patients assessed for eligibility, 268 were randomized: 137 to CBASP (96 women [70.1%] and 41 men [29.9%]; mean [SD] age, 44.7 [12.1] years) and 131 to SP (81 women [61.8%] and 50 men [38.2%]; mean [SD] age, 45.2 [11.6] years). The mean (SD) baseline HRSD-24 scores of 27.15 (5.49) in the CBASP group and 27.05 (5.74) in the SP group improved to 17.19 (10.01) and 20.39 (9.65), respectively, after 20 weeks, with a significant adjusted mean difference of –2.51 (95% CI, –4.16 to –0.86; P = .003) and a Cohen d of 0.31 in favor of CBASP. After 48 weeks, the HRSD-24 mean (SD) scores were 14.00 (9.72) for CBASP and 16.49 (9.96) for SP, with an adjusted difference of –3.13 (95% CI, –5.01 to –1.25; P = .001) and a Cohen d of 0.39. Patients undergoing CBASP were more likely to reach response (48 of 124 [38.7%] vs 27 of 111 [24.3%]; adjusted odds ratio, 2.02; 95% CI, 1.09 to 3.73; P = .03) or remission (27 of 124 [21.8%] vs 14 of 111 [12.6%]; adjusted odds ratio, 3.55; 95% CI, 1.61 to 7.85; P = .002) after 20 weeks. Patients undergoing CBASP showed significant advantages in most other secondary outcomes. Conclusions and Relevance Highly structured specific psychotherapy was moderately more effective than nonspecific therapy in outpatients with early-onset chronic depression who were not taking antidepressant medication. Adding an extended phase to acute psychotherapy seems promising in this population. Trial Registration clinicaltrials.gov Identifier: NCT00970437.

Adverse event methods were heterogeneous and insufficiently reported in randomized trials on persistent depressive disorder.

OBJECTIVES To investigate adverse event (AE) reporting practices in a systematic review of randomized controlled trials for persistent depressive disorder (PDD). STUDY DESIGN AND SETTING A systematic electronic database search was conducted up to October 2014 to identify randomized controlled trials investigating pharmacologic, psychotherapeutic, and combined treatments for PDD in adults. We calculated the number and percentage of studies that reported predefined AE information. All calculations were carried out including all studies and stratified for study type (pharmacologic, psychotherapeutic, and mixed) and publication year [before and after the publication of the Consolidated Standards of Reporting Trials (CONSORT) extension for harms in 2004], respectively. RESULTS Sixty studies, reported in 126 publications, were included. Across all studies, reporting of AE information was insufficient. Substantial differences between studies that investigated different treatments emerged. Most pharmacologic studies (39/42) and mixed studies (7/9) reported any AE information, although the amount of information varied and the reported methods to assess and analyze AEs were heterogeneous. We found no substantial change in reporting practices after the publication of the CONSORT extension. Psychotherapeutic studies, although almost entirely published after the CONSORT extension, largely neglected reporting of any AE information (1/9). CONCLUSIONS There is a strong need to improve the current practice of assessing, analyzing, and reporting AEs, especially for psychotherapeutic studies.

Comparative Safety of Pharmacologic Treatments for Persistent Depressive Disorder: A Systematic Review and Network Meta-Analysis

We aimed to compare the safety of antidepressants for the treatment of persistent depressive disorder (PDD) with each other and with placebo. We conducted a systematic electronic search and included randomized controlled trials that investigated antidepressants for the treatment of PDD in adults. Outcomes were the incidence of experiencing any adverse event, specific adverse events and related treatment discontinuations. We analyzed the data using traditional and network meta-analyses. Thirty-four studies that comprised 4,769 patients and examined 20 individual agents in nine substance classes were included. Almost all analyzed substance classes were associated with higher discontinuation rates than placebo including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), antipsychotics, and the serotonin antagonist and reuptake inhibitor (SARI) trazodone. The odds of experiencing any adverse event were significantly higher for TCAs and serotonin noradrenaline reuptake inhibitors (SNRIs) compared to placebo. Pairwise comparisons among the substance classes revealed that more patients receiving TCAs or SNRIs experienced any adverse event and that more patients receiving TCAs or the SARI trazodone discontinued treatment. The complementary treatment with acetyl-l-carnitine showed lower rates of experiencing any adverse event and related discontinuations than all other comparators. TCAs were primarily associated with (anti-)cholinergic and sedating adverse events. SSRIs primarily showed gastrointestinal adverse events. Patients treated with the antipsychotic amisulpride were more likely to manifest weight gain and endocrine adverse events. The comparative evidence for further agents was insufficient or lacking. The identified safety differences may be used to inform the selection among the antidepressants.

Odds ratios of treatment response were well approximated from continuous rating scale scores for meta-analysis.

OBJECTIVES To empirically evaluate the performance of methods for estimating odds ratios and their corresponding standard errors from continuous end point data for meta-analysis. STUDY DESIGN AND SETTING A database of randomized controlled trials of chronic depression treatments was used. Trials that reported both continuous and dichotomous end points for symptom improvement were considered. Odds ratios and standard errors were calculated from the dichotomous data and estimated from the continuous data using currently available methods: Hasselblad and Hedges (HH), Cox and Snell (CS), Furukawa (F), Suissa (S), and Kraemer and Kupfer (KK). Single and meta-analytically pooled observed and estimated values were compared. RESULTS A total of 26 trials were included. At the trial level, four of five (HH, CS, F, and S) and three of four (HH, F, and S) methods for estimating odds ratios and standard errors performed well, respectively. We found considerable differences in the performance of all methods across trials with more accurate estimates for smaller treatment effects. At the level of meta-analysis, three of four methods (CS, F, and S) performed acceptably. CONCLUSION Odds ratios and standard errors can be approximated from continuous end points, but we recommend sensitivity and subgroup analyses to test robustness of the findings.

Placebo and nocebo reactions in randomized trials of pharmacological treatments for persistent depressive disorder. A meta-regression analysis

BACKGROUND We aimed to investigate placebo and nocebo reactions in randomized controlled trials (RCT) of pharmacological treatments for persistent depressive disorder (PDD). METHODS We conducted a systematic electronic search and included RCTs investigating antidepressants for the treatment of PDD. Outcomes were the number of patients experiencing response and remission in placebo arms (=placebo reaction). Additional outcomes were the incidence of patients experiencing adverse events and related discontinuations in placebo arms (=nocebo reaction). A priori defined effect modifiers were analyzed using a series of meta-regression analyses. RESULTS Twenty-three trials were included in the analyses. We found a pooled placebo response rate of 31% and a placebo remission rate of 22%. The pooled adverse event rate and related discontinuations were 57% and 4%, respectively. All placebo arm outcomes were positively associated with the corresponding medication arm outcomes. Placebo response rate was associated with a greater proportion of patients with early onset depression, a smaller chance to receive placebo and a larger sample size. The adverse event rate in placebo arms was associated with a greater proportion of patients with early onset depression, a smaller proportion of females and a more recent publication. CONCLUSIONS Pooled placebo and nocebo reaction rates in PDD were comparable to those in episodic depression. The identified effect modifiers should be considered to assess unbiased effects in RCTs, to influence placebo and nocebo reactions in practice. LIMITATIONS Limitations result from the methodology applied, the fact that we conducted only univariate analyses, and the number and quality of included trials.

Incorporating uncertainty regarding applicability of evidence from meta-analyses into clinical decision making

OBJECTIVES Judging applicability (relevance) of meta-analytical findings to particular clinical decision-making situations remains challenging. We aimed to describe an evidence synthesis method that accounts for possible uncertainty regarding applicability of the evidence. STUDY DESIGN AND SETTING We conceptualized uncertainty regarding applicability of the meta-analytical estimates to a decision-making situation as the result of uncertainty regarding applicability of the findings of the trials that were included in the meta-analysis. This trial-level applicability uncertainty can be directly assessed by the decision maker and allows for the definition of trial inclusion probabilities, which can be used to perform a probabilistic meta-analysis with unequal probability resampling of trials (adaptive meta-analysis). A case study with several fictitious decision-making scenarios was performed to demonstrate the method in practice. RESULTS We present options to elicit trial inclusion probabilities and perform the calculations. The result of an adaptive meta-analysis is a frequency distribution of the estimated parameters from traditional meta-analysis that provides individually tailored information according to the specific needs and uncertainty of the decision maker. CONCLUSION The proposed method offers a direct and formalized combination of research evidence with individual clinical expertise and may aid clinicians in specific decision-making situations.

Effectiveness of metacognitive interventions for mental disorders in adults: a systematic review protocol (METACOG)

Introduction Whereas the efficacy of cognitive-behavioural therapy has been demonstrated for a variety of mental disorders, there is still need for improvement, especially regarding less prevalent or more severe disorders. Recently, metacognitive interventions have been developed and are now available for a variety of diagnoses. Still, a systematic review investigating the effectiveness of different metacognitive interventions for various mental disorders is missing. Methods and analysis Randomised controlled trials (RCTs), cross-over and cluster RCTs and non-randomised controlled trials on metacognitive interventions (ie, metacognitive therapy, metacognitive training, others) in adults with any mental disorder will be included. As comparators, another psychological or pharmacological treatment, a combined psychological and pharmacological treatment, treatment as usual or no active treatment are eligible. Outcomes refer to efficacy and acceptability of metacognitive interventions. Ethics and dissemination In light of the popularity of metacognitive interventions, the systematic review will provide researchers, clinicians and patients with substantial information on the intervention’s effectiveness across different mental disorders. Results will be published in peer-reviewed journals and disseminated through a patient workshop.

Treatment patterns in inpatient depression care

This study aimed to identify latent patterns of treatment combinations in inpatient depression care. A secondary analysis of routinely collected data on inpatient depression treatment from 2133 patients was conducted. Exploratory latent class modeling was used to identify distinct classes of treatment combinations based on antidepressant medication, psychotherapeutic interventions, and additional treatments. The classes were compared with regard to patient characteristics and treatment outcomes. Eight different classes of inpatient treatment combinations could be identified: 22.8% of the patients were treated with a combination labelled “standard modern antidepressants”, 14.6% with “standard tricyclic antidepressants”, 12.2% with “high intensity innovative strategies”, 12.1% with “standard selective‐reuptake‐inhibitors”, and 11.6% with “low intensity”, 9.6% with “somatic”, 8.8% with “high intensity traditional”, and 8.3% with “high intensity psychosocial” care, respectively. Patients treated with different patterns of interventions differed statistically significantly regarding demographic and clinical characteristics. Responder rates ranged from 68.4% to 86.6% across treatment classes. The presented attempt of empirical modeling of a complex multifactorial intervention by means of latent class analysis proved to be a promising way of capturing the complexity of routine inpatient depression treatment. The identified classes of treatment combinations may provide relevant information for a re‐evaluation and improvement of inpatient depression treatment strategies. Copyright

How often do general practitioners use placebos and non-specific interventions? Systematic review and meta-analysis of surveys

Background In a systematic review and meta-analysis we summarize the available evidence on how frequently general practitioners/family physicians (GPs) use pure placebos (e.g., placebo pills) and non-specific therapies (sometimes referred to as impure placebos; e.g., antibiotics for common cold). Methods We searched Medline, PubMed and SCOPUS up to July 2018 to identify cross-sectional quantitative surveys among GPs. Outcomes of primary interest were the percentages of GPs having used any placebo, pure placebos or non-specific therapies at least once in their career, at least once in the last year, at least monthly or at least weekly. Outcomes were described as proportions and pooled with random-effects meta-analysis. Results Of 674 publications, 16 studies from 13 countries with a total of 2.981 participating GPs (range 27 to 783) met the inclusion criteria. The percentage of GPs having used any form of placebo at least once in their career ranged from 29% to 97%, in the last year at least once from 46% to 95%, at least monthly from 15% to 89%, and at least weekly from 1% to 75%. The use of non-specific therapies by far outnumbered the use of pure placebo. For example, the proportion of GPs using pure placebos at least monthly varied between 2% and 15% compared to 53% and 89% for non-specific therapies; use at least weekly varied between 1% and 3% for pure placebos and between 16% and 75% for non-specific therapies. Besides eliciting placebos effects, many other reasons related to patient expectations, demands and medical problems were reported as reasons for applying placebo interventions. Conclusion High prevalence estimates of placebo use among GPs are mainly driven by the frequent use of non-specific therapies; pure placebos are used rarely. The interpretation of our quantitative findings is complicated by the diversity of definitions and survey methods.