Changes in Clinical Trials Methodology Over Time: A Systematic Review of Six Decades of Research in Psychopharmacology

Background: There have been many changes in clinical trials methodology since the introduction of lithium and the beginning of the modern era of psychopharmacology in 1949. The nature and importance of these changes have not been fully addressed to date. As methodological flaws in trials can lead to false-negative or false-positive results, the objective of our study was to evaluate the impact of methodological changes in psychopharmacology clinical research over the past 60 years. Methodology/Principal Findings: We performed a systematic review from 1949 to 2009 on MEDLINE and Web of Science electronic databases, and a hand search of high impact journals on studies of seven major drugs (chlorpromazine, clozapine, risperidone, lithium, fluoxetine and lamotrigine). All controlled studies published 100 months after the first trial were included. Ninety-one studies met our inclusion criteria. We analyzed the major changes in abstract reporting, study design, participants' assessment and enrollment, methodology and statistical analysis. Our results showed that the methodology of psychiatric clinical trials changed substantially, with quality gains in abstract reporting, results reporting, and statistical methodology. Recent trials use more informed consent, periods of washout, intention-to-treat approach and parametric tests. Placebo use remains high and unchanged over time. Conclusions/Significance: Clinical trial quality of psychopharmacological studies has changed significantly in most of the aspects we analyzed. There was significant improvement in quality reporting and internal validity. These changes have increased study efficiency; however, there is room for improvement in some aspects such as rating scales, diagnostic criteria and better trial reporting. Therefore, despite the advancements observed, there are still several areas that can be improved in psychopharmacology clinical trials

Repetitive Transcranial Magnetic Stimulation for Major Depressive Disorder in Older Adults: Systematic Review and Meta-analysis

Background Major depressive disorder (MDD) in older adults is a serious public health concern. Repetitive transcranial magnetic stimulation (rTMS) is a nonpharmacological intervention approved for MDD treatment in adults, but its value in older adults remains unknown. This study aims to systematically review and meta-analyze evidence of rTMS efficacy in MDD treatment among older adults. Methods We systematically reviewed the literature for randomized controlled trials (RCTs) and open-label studies assessing rTMS for the treatment of MDD in patients older than 50 years, published until June 2020. Random-effects meta-analyses using standardized mean differences (SMDs) were conducted to assess change in depression severity score (primary outcome), while odds ratios (ORs) were used to assess secondary categorical outcomes (response and remission). Additionally, univariate meta-regression analyses were performed to identify potential predictors of change in depression severity scores. Results Fourteen RCTs were included in meta-analyses and 26 studies (10 RCTs and 16 open-label studies) in meta-regression. Active rTMS was significantly superior to sham treatment for reduction of severity (SMD = 0.36; 95% CI = 0.13–0.60), as well as response (OR = 3.26; 95% CI = 2.11–5.04) and remission (OR = 4.63; 95% CI = 2.24–9.55). Studies were of moderate to high quality, with funnel plots and Egger’s regression test not suggestive of publication bias. In meta-regressions, higher mean age and number of sessions were significantly associated with greater improvement. Conclusions Our results support that rTMS is an effective, safe, and well-tolerated treatment for MDD in older adults and that it should be considered in the treatment of this vulnerable population.info:eu-repo/semantics/publishedVersio

Taxas de suicídio e tendências em São Paulo, Brasil, de acordo com gênero, faixa etária e aspectos demográficos

OBJECTIVE: To evaluate suicide rates and trends in São Paulo by sex, age-strata, and methods. METHODS: Data was collected from State registry from 1996 to 2009. Population was estimated using the National Census. We utilized joinpoint regression analysis to explore temporal trends. We also evaluated marital status, ethnicity, birthplace and methods for suicide. RESULTS: In the period analyzed, 6,002 suicides were accrued with a rate of 4.6 per 100,000 (7.5 in men and 2.0 in women); the male-to-female ratio was around 3.7. Trends for men presented a significant decline of 5.3% per year from 1996 to 2002, and a significant increase of 2.5% from 2002 onwards. Women did not present significant changes. For men, the elderly (> 65 years) had a significant reduction of 2.3% per year, while younger men (25-44 years) presented a significant increase of 8.6% from 2004 onwards. Women did not present significant trend changes according to age. Leading suicide methods were hanging and poisoning for men and women, respectively. Other analyses showed an increased suicide risk ratio for singles and foreigners. CONCLUSIONS: Specific epidemiological trends for suicide in the city of São Paulo that warrant further investigation were identified. High-risk groups - such as immigrants - could benefit from targeted strategies of suicide prevention

Neurophysiologic Correlates of Post-stroke Mood and Emotional Control

Objective: Emotional disturbance is a common complication of stroke significantly affecting functional recovery and quality of life. Identifying relevant neurophysiologic markers associated with post-stroke emotional disturbance may lead to a better understanding of this disabling condition, guiding the diagnosis, development of new interventions and the assessments of treatment response. Methods: Thirty-five subjects with chronic stroke were enrolled in this study. The emotion sub-domain of Stroke Impact Scale (SIS-Emotion) was used to assess post-stroke mood and emotional control. The relation between SIS-Emotion and neurophysiologic measures was assessed by using covariance mapping and univariate linear regression. Multivariate analyses were conducted to identify and adjust for potential confounders. Neurophysiologic measures included power asymmetry and coherence assessed by electroencephalography (EEG); and motor threshold, intracortical inhibition (ICI) and intracortical facilitation (ICF) measured by transcranial magnetic stimulation (TMS). Results: Lower scores on SIS-Emotion was associated with (1) frontal EEG power asymmetry in alpha and beta bands, (2) central EEG power asymmetry in alpha and theta bands, and (3) lower inter-hemispheric coherence over frontal and central areas in alpha band. SIS-Emotion also correlated with higher ICF and MT in the unlesioned hemisphere as measured by TMS. Conclusions: To our knowledge, this is the first study using EEG and TMS to index neurophysiologic changes associated with post-stroke mood and emotional control. Our results suggest that inter-hemispheric imbalance measured by EEG power and coherence, as well as an increased ICF in the unlesioned hemisphere measured by TMS might be relevant markers associated with post-stroke mood and emotional control which can guide future studies investigating new diagnostic and treatment modalities in stroke rehabilitation

Negative life events and migraine: a cross-sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) baseline data

Abstract\ud \ud Background\ud Stress is a typical migraine trigger. However, the impact of negative life events on migraine activity is poorly studied. The aim of this study is to investigate the association between negative life events and migraine using data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) baseline assessment.\ud \ud \ud Methods\ud ELSA-Brasil is a multicenter cohort study conducted in six Brazilian cities. Baseline assessment included validated questionnaires for headache classification and the occurrence of five pre-specified negative life events (financial hardship, hospitalization other than for childbirth, death of a close relative, robbery and end of a love relationship), focusing on a 12-month period before evaluation. We built crude and adjusted logistic regression models to study the association between the occurrences of negative life events and migraine diagnosis and activity.\ud \ud \ud Results\ud We included 4,409 individuals with migraine and 4,457 participants without headache (reference). After adjustment for age, sex, race, income and educational level, we found that the occurrence of a negative life event (Odds ratio = 1.31; 95% confidence interval = 1.19 – 1.45) was associated with migraine. However, after stratifying with subgroup analyses, only financial hardship (Odds ratio = 1.65; 95% confidence interval = 1.47 – 1.87) and hospitalization (Odds ratio = 1.47; 95% confidence interval = 1.25 – 1.72) were independently associated with migraine. Further adjustment for a current major depression episode and report of religious activity did not significantly change the results. Considering migraine frequency as (a) less than once per month, (b) once per month to once per week, or (c) more than once per week, financial hardship and hospitalization remained significantly associated with migraine in all episode frequency strata, with higher odds ratios for higher frequencies in adjusted models. We also observed a significant association between the death of a close relative and the highest migraine frequency stratum (Odds ratio = 1.38; 95% confidence interval = 1.09 – 1.75) in full-adjusted model.\ud \ud \ud Conclusions\ud The occurrence of financial hardship and hospitalization had a direct and independent association with migraine diagnosis and frequency. The death of a close relative was also independently associated with the highest migraine frequency stratum.Brazilian Ministry of Health (Science and Technology Department)Brazilian Ministry of Science and Technology (Financiadora de Estudos e\ud Projetos and CNPq National Research Council) (grants 01 06 0010.00 RS, 0106 0212.00 BA, 01 06 0300.00 ES, 01 06 0278.00 MG, 01 06 0115.00 SP, 01 060071.00 RJ

Effect of transcranial direct current stimulation on exercise performance: a systematic review and meta-analysis

Background: Transcranial direct current stimulation (tDCS) has been used to improve exercise performance, though the protocols used, and results found are mixed. Objective: We aimed to analyze the effect of tDCS on improving exercise performance. Methods: A systematic search was performed on the following databases, until December 2017: PubMed/MEDLINE, Embase, Web of Science, SCOPUS, and SportDiscus. Full-text articles that used tDCS for exercise performance improvement in adults were included. We compared the effect of anodal (anode near nominal target) and cathodal (cathode near nominal target) tDCS to a sham/control condition on the outcome measure (performance in isometric, isokinetic or dynamic strength exercise and whole-body exercise). Results: 22 studies (393 participants) were included in the qualitative synthesis and 11 studies (236 participants) in the meta-analysis. The primary motor cortex (M1) was the main nominal tDCS target (n = 16; 72.5%). A significant effect favoring anodal tDCS (a-tDCS) applied before exercise over M1 was found on cycling time to exhaustion (mean difference = 93.41 s; 95%CI = 27.39 s to 159.43 s) but this result was strongly influenced by one study (weight = 84%), no effect was found for cathodal tDCS (c-tDCS). No significant effect was found for a-tDCS applied on M1 before or during exercise on isometric muscle strength of the upper or lower limbs. Studies regarding a-tDCS over M1 on isokinetic muscle strength presented mixed results. Individual results of studies using a-tDCS applied over the prefrontal and motor cortices either before or during dynamic muscle strength testing showed positive results, but performing meta-analysis was not possible. Conclusion: For the protocols tested, a-tDCS but not c-tDCS vs. sham over M1 improved exercise performance in cycling only. However, this result was driven by a single study, which when removed was no longer significant. Further well-controlled studies with larger sample sizes and broader exploration of the tDCS montages and doses are warranted

Common mental disorders and sociodemographic characteristics: baseline findings of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)

Objective: To assess the prevalence of common mental disorders (CMD) and the association of CMD with sociodemographic characteristics in the Brazilian Longitudinal Study of Adult Health (ELSABrasil) cohort. Methods: We analyzed data from the cross-sectional baseline assessment of the ELSA-Brasil, a cohort study of 15,105 civil servants from six Brazilian cities. The Clinical Interview Schedule-Revised (CIS-R) was used to investigate the presence of CMD, with a score X 12 indicating a current CMD (last week). Specific diagnostic algorithms for each disorder were based on the ICD-10 diagnostic criteria. Prevalence ratios (PR) of the association between CMD and sociodemographic characteristics were estimated by Poisson regression. Results: CMD (CIS-R score X 12) was found in 26.8% (95% confidence intervals [95%CI] 26.1-27.5). The highest burden occurred among women (PR 1.9; 95%CI 1.8-2.0), the youngest (PR 1.7; 95%CI 1.5-1.9), non-white individuals, and those without a university degree. The most frequent diagnostic category was anxiety disorders (16.2%), followed by depressive episodes (4.2%). Conclusion: The burden of CMD was high, particularly among the more socially vulnerable groups. These findings highlight the need to strengthen public policies aimed to address health inequities related to mental disorders

Treatment resistance in schizophrenia: a meta-analysis of prevalence and correlates

Objectives: To determine the prevalence and correlates of treatment-resistant schizophrenia (TRS) through a systematic review and meta-analysis. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, an electronic search was performed in PubMed and Embase through May 17, 2022. All study designs that assessed a minimum of 20 schizophrenia-spectrum patients and provided data on TRS prevalence or allowed its calculation were included. Estimates were produced using a random-effects model meta-analysis. Results: The TRS prevalence across 50 studies (n = 29,390) was 36.7% (95%CI 33.1-40.5, p < 0.0001). The prevalence ranged from 22% (95%CI 18.4-25.8) in first-episode to 39.5% (95%CI 32.2-47.0) in multiple-episode samples (Q = 18.27, p < 0.0001). Primary treatment resistance, defined as no response from the first episode, was 23.6% (95%CI 20.5-26.8) vs. 9.3% (95%CI 6.8-12.2) for later-onset/secondary (≥ 6 months after initial treatment response). Longer illness duration and recruitment from long-term hospitals or clozapine clinics were associated with higher prevalence estimates. In meta-regression analyses, older age and poor functioning predicted greater TRS. When including only studies with lower bias risk, the TRS prevalence was 28.4%. Conclusion: Different study designs and recruitment strategies accounted for most of the observed heterogeneity in TRS prevalence rates. The results point to early-onset and later-onset TRS as two separate disease pathways requiring clinical attention. Registration number: PROSPERO CRD42018092033