Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children and adolescents with ADHD find it difficult ...to pay attention and they are hyperactive and impulsive. Methylphenidate is the psychostimulant most often prescribed, but the evidence on benefits and harms is uncertain. This is an update of our comprehensive systematic review on benefits and harms published in 2015.
To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD.
We searched CENTRAL, MEDLINE, Embase, three other databases and two trials registers up to March 2022. In addition, we checked reference lists and requested published and unpublished data from manufacturers of methylphenidate.
We included all randomised clinical trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. The search was not limited by publication year or language, but trial inclusion required that 75% or more of participants had a normal intellectual quotient (IQ > 70). We assessed two primary outcomes, ADHD symptoms and serious adverse events, and three secondary outcomes, adverse events considered non-serious, general behaviour, and quality of life.
Two review authors independently conducted data extraction and risk of bias assessment for each trial. Six review authors including two review authors from the original publication participated in the update in 2022. We used standard Cochrane methodological procedures. Data from parallel-group trials and first-period data from cross-over trials formed the basis of our primary analyses. We undertook separate analyses using end-of-last period data from cross-over trials. We used Trial Sequential Analyses (TSA) to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the GRADE approach.
We included 212 trials (16,302 participants randomised); 55 parallel-group trials (8104 participants randomised), and 156 cross-over trials (8033 participants randomised) as well as one trial with a parallel phase (114 participants randomised) and a cross-over phase (165 participants randomised). The mean age of participants was 9.8 years ranging from 3 to 18 years (two trials from 3 to 21 years). The male-female ratio was 3:1. Most trials were carried out in high-income countries, and 86/212 included trials (41%) were funded or partly funded by the pharmaceutical industry. Methylphenidate treatment duration ranged from 1 to 425 days, with a mean duration of 28.8 days. Trials compared methylphenidate with placebo (200 trials) and with no intervention (12 trials). Only 165/212 trials included usable data on one or more outcomes from 14,271 participants. Of the 212 trials, we assessed 191 at high risk of bias and 21 at low risk of bias. If, however, deblinding of methylphenidate due to typical adverse events is considered, then all 212 trials were at high risk of bias.
methylphenidate versus placebo or no intervention may improve teacher-rated ADHD symptoms (standardised mean difference (SMD) -0.74, 95% confidence interval (CI) -0.88 to -0.61; I² = 38%; 21 trials; 1728 participants; very low-certainty evidence). This corresponds to a mean difference (MD) of -10.58 (95% CI -12.58 to -8.72) on the ADHD Rating Scale (ADHD-RS; range 0 to 72 points). The minimal clinically relevant difference is considered to be a change of 6.6 points on the ADHD-RS. Methylphenidate may not affect serious adverse events (risk ratio (RR) 0.80, 95% CI 0.39 to 1.67; I² = 0%; 26 trials, 3673 participants; very low-certainty evidence). The TSA-adjusted intervention effect was RR 0.91 (CI 0.31 to 2.68).
methylphenidate may cause more adverse events considered non-serious versus placebo or no intervention (RR 1.23, 95% CI 1.11 to 1.37; I² = 72%; 35 trials 5342 participants; very low-certainty evidence). The TSA-adjusted intervention effect was RR 1.22 (CI 1.08 to 1.43). Methylphenidate may improve teacher-rated general behaviour versus placebo (SMD -0.62, 95% CI -0.91 to -0.33; I² = 68%; 7 trials 792 participants; very low-certainty evidence), but may not affect quality of life (SMD 0.40, 95% CI -0.03 to 0.83; I² = 81%; 4 trials, 608 participants; very low-certainty evidence).
The majority of our conclusions from the 2015 version of this review still apply. Our updated meta-analyses suggest that methylphenidate versus placebo or no-intervention may improve teacher-rated ADHD symptoms and general behaviour in children and adolescents with ADHD. There may be no effects on serious adverse events and quality of life. Methylphenidate may be associated with an increased risk of adverse events considered non-serious, such as sleep problems and decreased appetite. However, the certainty of the evidence for all outcomes is very low and therefore the true magnitude of effects remain unclear. Due to the frequency of non-serious adverse events associated with methylphenidate, the blinding of participants and outcome assessors is particularly challenging. To accommodate this challenge, an active placebo should be sought and utilised. It may be difficult to find such a drug, but identifying a substance that could mimic the easily recognised adverse effects of methylphenidate would avert the unblinding that detrimentally affects current randomised trials. Future systematic reviews should investigate the subgroups of patients with ADHD that may benefit most and least from methylphenidate. This could be done with individual participant data to investigate predictors and modifiers like age, comorbidity, and ADHD subtypes.
Over the decades, a variety of psychological interventions for borderline personality disorder (BPD) have been developed. This review updates and replaces an earlier review (Stoffers-Winterling ...2012).
To assess the beneficial and harmful effects of psychological therapies for people with BPD.
In March 2019, we searched CENTRAL, MEDLINE, Embase, 14 other databases and four trials registers. We contacted researchers working in the field to ask for additional data from published and unpublished trials, and handsearched relevant journals. We did not restrict the search by year of publication, language or type of publication.
Randomised controlled trials comparing different psychotherapeutic interventions with treatment-as-usual (TAU; which included various kinds of psychotherapy), waiting list, no treatment or active treatments in samples of all ages, in any setting, with a formal diagnosis of BPD. The primary outcomes were BPD symptom severity, self-harm, suicide-related outcomes, and psychosocial functioning. There were 11 secondary outcomes, including individual BPD symptoms, as well as attrition and adverse effects.
At least two review authors independently selected trials, extracted data, assessed risk of bias using Cochrane's 'Risk of bias' tool and assessed the certainty of the evidence using the GRADE approach. We performed data analysis using Review Manager 5 and quantified the statistical reliability of the data using Trial Sequential Analysis.
We included 75 randomised controlled trials (4507 participants), predominantly involving females with mean ages ranging from 14.8 to 45.7 years. More than 16 different kinds of psychotherapy were included, mostly dialectical behaviour therapy (DBT) and mentalisation-based treatment (MBT). The comparator interventions included treatment-as-usual (TAU), waiting list, and other active treatments. Treatment duration ranged from one to 36 months. Psychotherapy versus TAU Psychotherapy reduced BPD symptom severity, compared to TAU; standardised mean difference (SMD) -0.52, 95% confidence interval (CI) -0.70 to -0.33; 22 trials, 1244 participants; moderate-quality evidence. This corresponds to a mean difference (MD) of -3.6 (95% CI -4.4 to -2.08) on the Zanarini Rating Scale for BPD (range 0 to 36), a clinically relevant reduction in BPD symptom severity (minimal clinical relevant difference (MIREDIF) on this scale is -3.0 points). Psychotherapy may be more effective at reducing self-harm compared to TAU (SMD -0.32, 95% CI -0.49 to -0.14; 13 trials, 616 participants; low-quality evidence), corresponding to a MD of -0.82 (95% CI -1.25 to 0.35) on the Deliberate Self-Harm Inventory Scale (range 0 to 34). The MIREDIF of -1.25 points was not reached. Suicide-related outcomes improved compared to TAU (SMD -0.34, 95% CI -0.57 to -0.11; 13 trials, 666 participants; low-quality evidence), corresponding to a MD of -0.11 (95% CI -0.19 to -0.034) on the Suicidal Attempt Self Injury Interview. The MIREDIF of -0.17 points was not reached. Compared to TAU, psychotherapy may result in an improvement in psychosocial functioning (SMD -0.45, 95% CI -0.68 to -0.22; 22 trials, 1314 participants; low-quality evidence), corresponding to a MD of -2.8 (95% CI -4.25 to -1.38), on the Global Assessment of Functioning Scale (range 0 to 100). The MIREDIF of -4.0 points was not reached. Our additional Trial Sequential Analysis on all primary outcomes reaching significance found that the required information size was reached in all cases. A subgroup analysis comparing the different types of psychotherapy compared to TAU showed no clear evidence of a difference for BPD severity and psychosocial functioning. Psychotherapy may reduce depressive symptoms compared to TAU but the evidence is very uncertain (SMD -0.39, 95% CI -0.61 to -0.17; 22 trials, 1568 participants; very low-quality evidence), corresponding to a MD of -2.45 points on the Hamilton Depression Scale (range 0 to 50). The MIREDIF of -3.0 points was not reached. BPD-specific psychotherapy did not reduce attrition compared with TAU. Adverse effects were unclear due to too few data. Psychotherapy versus waiting list or no treatment Greater improvements in BPD symptom severity (SMD -0.49, 95% CI -0.93 to -0.05; 3 trials, 161 participants), psychosocial functioning (SMD -0.56, 95% CI -1.01 to -0.11; 5 trials, 219 participants), and depression (SMD -1.28, 95% CI -2.21 to -0.34, 6 trials, 239 participants) were observed in participants receiving psychotherapy versus waiting list or no treatment (all low-quality evidence). No evidence of a difference was found for self-harm and suicide-related outcomes. Individual treatment approaches DBT and MBT have the highest numbers of primary trials, with DBT as subject of one-third of all included trials, followed by MBT with seven RCTs. Compared to TAU, DBT was more effective at reducing BPD severity (SMD -0.60, 95% CI -1.05 to -0.14; 3 trials, 149 participants), self-harm (SMD -0.28, 95% CI -0.48 to -0.07; 7 trials, 376 participants) and improving psychosocial functioning (SMD -0.36, 95% CI -0.69 to -0.03; 6 trials, 225 participants). MBT appears to be more effective than TAU at reducing self-harm (RR 0.62, 95% CI 0.49 to 0.80; 3 trials, 252 participants), suicidality (RR 0.10, 95% CI 0.04, 0.30, 3 trials, 218 participants) and depression (SMD -0.58, 95% CI -1.22 to 0.05, 4 trials, 333 participants). All findings are based on low-quality evidence. For secondary outcomes see review text.
Our assessments showed beneficial effects on all primary outcomes in favour of BPD-tailored psychotherapy compared with TAU. However, only the outcome of BPD severity reached the MIREDIF-defined cut-off for a clinically meaningful improvement. Subgroup analyses found no evidence of a difference in effect estimates between the different types of therapies (compared to TAU) . The pooled analysis of psychotherapy versus waiting list or no treatment found significant improvement on BPD severity, psychosocial functioning and depression at end of treatment, but these findings were based on low-quality evidence, and the true magnitude of these effects is uncertain. No clear evidence of difference was found for self-harm and suicide-related outcomes. However, compared to TAU, we observed effects in favour of DBT for BPD severity, self-harm and psychosocial functioning and, for MBT, on self-harm and suicidality at end of treatment, but these were all based on low-quality evidence. Therefore, we are unsure whether these effects would alter with the addition of more data.
Attention deficit hyperactivity disorder (ADHD) in children is associated with hyperactivity and impulsivity, attention problems, and difficulties with social interactions. Pharmacological treatment ...may alleviate the symptoms of ADHD but this rarely solves difficulties with social interactions. Children with ADHD may benefit from interventions designed to improve their social skills. We examined the benefits and harms of social skills training on social skills, emotional competencies, general behaviour, ADHD symptoms, performance in school of children with ADHD, and adverse events.
To assess the beneficial and harmful effects of social skills training in children and adolescents with ADHD.
In July 2018, we searched CENTRAL, MEDLINE, Embase, PsycINFO, 4 other databases and two trials registers.We also searched online conference abstracts, and contacted experts in the field for information about unpublished or ongoing randomised clinical trials. We did not limit our searches by language, year of publication, or type or status of publication, and we sought translation of the relevant sections of non-English language articles.
Randomised clinical trials investigating social skills training versus either no intervention or waiting-list control, with or without pharmacological treatment of both comparison groups of children and adolescents with ADHD.
We conducted the review in accordance with the Cochrane Handbook for Systematic Reviews of Intervention. We performed the analyses using Review Manager 5 software and Trial Sequential Analysis. We assessed bias according to domains for systematic errors. We assessed the certainty of the evidence with the GRADE approach.
We included 25 randomised clinical trials described in 45 reports. The trials included a total of 2690 participants aged between five and 17 years. In 17 trials, participants were also diagnosed with various comorbidities.The social skills interventions were described as: 1) social skills training, 2) cognitive behavioural therapy, 3) multimodal behavioural/psychosocial therapy, 4) child life and attention skills treatment, 5) life skills training, 6) the "challenging horizon programme", 7) verbal self-instruction, 8) meta-cognitive training, 9) behavioural therapy, 10) behavioural and social skills treatment, and 11) psychosocial treatment. The control interventions were no intervention or waiting list.The duration of the interventions ranged from five weeks to two years. We considered the content of the social skills interventions to be comparable and based on a cognitive-behavioural model. Most of the trials compared child social skills training or parent training combined with medication versus medication alone. Some of the experimental interventions also included teacher consultations.More than half of the trials were at high risk of bias for generation of the allocation sequence and allocation concealment. No trial reported on blinding of participants and personnel. Most of the trials did not report on differences between groups in medication for comorbid disorders. We used all eligible trials in the meta-analyses, but downgraded the certainty of the evidence to low or very low.We found no clinically relevant treatment effect of social skills interventions on the primary outcome measures: teacher-rated social skills at end of treatment (standardised mean difference (SMD) 0.11, 95% confidence interval (CI) 0.00 to 0.22; 11 trials, 1271 participants; I
= 0%; P = 0.05); teacher-rated emotional competencies at end of treatment (SMD -0.02, 95% CI -0.72 to 0.68; two trials, 129 participants; I
= 74%; P = 0.96); or on teacher-rated general behaviour (SMD -0.06 (negative value better), 95% CI -0.19 to 0.06; eight trials, 1002 participants; I
= 0%; P = 0.33). The effect on the primary outcome, teacher-rated social skills at end of treatment, corresponds to a MD of 1.22 points on the social skills rating system (SSRS) scale (95% CI 0.09 to 2.36). The minimal clinical relevant difference (10%) on the SSRS is 10.0 points (range 0 to 102 points on SSRS).We found evidence in favour of social skills training on teacher-rated core ADHD symptoms at end of treatment for all eligible trials (SMD -0.26, 95% CI -0.47 to -0.05; 14 trials, 1379 participants; I
= 69%; P = 0.02), but the finding is questionable due to lack of support from sensitivity analyses, high risk of bias, lack of clinical significance, high heterogeneity, and low certainty.The studies did not report any serious or non-serious adverse events.
The review suggests that there is little evidence to support or refute social skills training for children and adolescents with ADHD. We may need more trials that are at low risk of bias and a sufficient number of participants to determine the efficacy of social skills training versus no training for ADHD. The evidence base regarding adolescents is especially weak.
The Australian National COVID-19 Clinical Evidence Taskforce is a consortium of 31 Australian health professional organisations developing living, evidence-based guidelines for care of people with ...COVID-19, which are updated weekly. This article describes the methods used to develop and maintain the guidelines.
The guidelines use the GRADE methods and are designed to meet Australian NHMRC standards. Each week, new evidence is reviewed, current recommendations are revised, and new recommendations made. These are published in MAGIC and disseminated through traditional and social media. Relevant new questions to be addressed are continually sought from stakeholders and practitioners. For prioritized questions, the evidence is actively monitored and updated. Evidence surveillance combines horizon scans and targeted searches. An evidence team appraises and synthesizes evidence and prepares evidence-to-decision frameworks to inform development of recommendations. A guidelines leadership group oversees the development of recommendations by multidisciplinary guidelines panels and is advised by a consumer panel.
: The Taskforce formed in March 2020, and the first recommendations were published 2 weeks later. The guidelines have been revised and republished on a weekly basis for 24 weeks, and as of October 2020, contain over 90 treatment recommendations, suggesting that living methods are feasible in this context.
The Australian guidelines for care of people with COVID-19 provide an example of the feasibility of living guidelines and an opportunity to test and improve living evidence methods.
Among people with a diagnosis of borderline personality disorder (BPD) who are engaged in clinical care, prescription rates of psychotropic medications are high, despite the fact that medication use ...is off-label as a treatment for BPD. Nevertheless, people with BPD often receive several psychotropic drugs at a time for sustained periods.
To assess the effects of pharmacological treatment for people with BPD.
For this update, we searched CENTRAL, MEDLINE, Embase, 14 other databases and four trials registers up to February 2022. We contacted researchers working in the field to ask for additional data from published and unpublished trials, and handsearched relevant journals. We did not restrict the search by year of publication, language or type of publication.
Randomised controlled trials comparing pharmacological treatment to placebo, other pharmacologic treatments or a combination of pharmacologic treatments in people of all ages with a formal diagnosis of BPD. The primary outcomes were BPD symptom severity, self-harm, suicide-related outcomes, and psychosocial functioning. Secondary outcomes were individual BPD symptoms, depression, attrition and adverse events.
At least two review authors independently selected trials, extracted data, assessed risk of bias using Cochrane's risk of bias tool and assessed the certainty of the evidence using the GRADE approach. We performed data analysis using Review Manager 5 and quantified the statistical reliability of the data using Trial Sequential Analysis.
We included 46 randomised controlled trials (2769 participants) in this review, 45 of which were eligible for quantitative analysis and comprised 2752 participants with BPD in total. This is 18 more trials than the 2010 review on this topic. Participants were predominantly female except for one trial that included men only. The mean age ranged from 16.2 to 39.7 years across the included trials. Twenty-nine different types of medications compared to placebo or other medications were included in the analyses. Seventeen trials were funded or partially funded by the pharmaceutical industry, 10 were funded by universities or research foundations, eight received no funding, and 11 had unclear funding. For all reported effect sizes, negative effect estimates indicate beneficial effects by active medication. Compared with placebo, no difference in effects were observed on any of the primary outcomes at the end of treatment for any medication. Compared with placebo, medication may have little to no effect on BPD symptom severity, although the evidence is of very low certainty (antipsychotics: SMD -0.18, 95% confidence interval (CI) -0.45 to 0.08; 8 trials, 951 participants; antidepressants: SMD -0.27, 95% CI -0.65 to 1.18; 2 trials, 87 participants; mood stabilisers: SMD -0.07, 95% CI -0.43 to 0.57; 4 trials, 265 participants). The evidence is very uncertain about the effect of medication compared with placebo on self-harm, indicating little to no effect (antipsychotics: RR 0.66, 95% CI 0.15 to 2.84; 2 trials, 76 participants; antidepressants: MD 0.45 points on the Overt Aggression Scale-Modified-Self-Injury item (0-5 points), 95% CI -10.55 to 11.45; 1 trial, 20 participants; mood stabilisers: RR 1.08, 95% CI 0.79 to 1.48; 1 trial, 276 participants). The evidence is also very uncertain about the effect of medication compared with placebo on suicide-related outcomes, with little to no effect (antipsychotics: SMD 0.05, 95 % CI -0.18 to 0.29; 7 trials, 854 participants; antidepressants: SMD -0.26, 95% CI -1.62 to 1.09; 2 trials, 45 participants; mood stabilisers: SMD -0.36, 95% CI -1.96 to 1.25; 2 trials, 44 participants). Very low-certainty evidence shows little to no difference between medication and placebo on psychosocial functioning (antipsychotics: SMD -0.16, 95% CI -0.33 to 0.00; 7 trials, 904 participants; antidepressants: SMD -0.25, 95% CI -0.57 to 0.06; 4 trials, 161 participants; mood stabilisers: SMD -0.01, 95% CI -0.28 to 0.26; 2 trials, 214 participants). Low-certainty evidence suggests that antipsychotics may slightly reduce interpersonal problems (SMD -0.21, 95% CI -0.34 to -0.08; 8 trials, 907 participants), and that mood stabilisers may result in a reduction in this outcome (SMD -0.58, 95% CI -1.14 to -0.02; 4 trials, 300 participants). Antidepressants may have little to no effect on interpersonal problems, but the corresponding evidence is very uncertain (SMD -0.07, 95% CI -0.69 to 0.55; 2 trials, 119 participants). The evidence is very uncertain about dropout rates compared with placebo by antipsychotics (RR 1.11, 95% CI 0.89 to 1.38; 13 trials, 1216 participants). Low-certainty evidence suggests there may be no difference in dropout rates between antidepressants (RR 1.07, 95% CI 0.65 to 1.76; 6 trials, 289 participants) and mood stabilisers (RR 0.89, 95% CI 0.69 to 1.15; 9 trials, 530 participants), compared to placebo. Reporting on adverse events was poor and mostly non-standardised. The available evidence on non-serious adverse events was of very low certainty for antipsychotics (RR 1.07, 95% CI 0.90 to 1.29; 5 trials, 814 participants) and mood stabilisers (RR 0.84, 95% CI 0.70 to 1.01; 1 trial, 276 participants). For antidepressants, no data on adverse events were identified.
This review included 18 more trials than the 2010 version, so larger meta-analyses with more statistical power were feasible. We found mostly very low-certainty evidence that medication may result in no difference in any primary outcome. The rest of the secondary outcomes were inconclusive. Very limited data were available for serious adverse events. The review supports the continued understanding that no pharmacological therapy seems effective in specifically treating BPD pathology. More research is needed to understand the underlying pathophysiologic mechanisms of BPD better. Also, more trials including comorbidities such as trauma-related disorders, major depression, substance use disorders, or eating disorders are needed. Additionally, more focus should be put on male and adolescent samples.
Background
Many people suffering from migraine combine pharmacological and non-pharmacological treatments. The purpose of this systematic review is to provide an updated guideline for some widely ...used non-pharmacological treatment options for migraine.
Methods
We conducted a systematic literature review of randomized studies of adults with migraine treated with manual joint mobilisation techniques, supervised physical activity, psychological treatment, acupuncture and patient education. The main outcomes measured were days with headache and quality of life. Recommendations were formulated based on the Grade of Recommendation, Assessment, Development and Evaluation (GRADE) approach including patient preferences based on expert opinion and questionnaire data.
Results
The overall level of certainty of the evidence was low to very low. Manual therapy techniques and psychological treatment did not change the studied outcomes. Supervised physical activity might have a positive impact on quality of life, acupuncture on headache frequency, intensity, quality of life and the use of attack-medicine. Patient education might improve self-rated health and quality of life and increase the number of well-informed patients.
Conclusion
Based on observed effects, the lack of serious adverse events, and patients’ preferences, we make weak recommendations for considering the investigated interventions as a supplement to standard treatment.
Protocol registration: Prospero CRD42020220132.
Obsessive-compulsive disorder: Insights from animal models Szechtman, Henry; Ahmari, Susanne E.; Beninger, Richard J. ...
Neuroscience & biobehavioral reviews/Neuroscience and biobehavioral reviews,
05/2017, Letnik:
76, Številka:
Pt B
Journal Article
Recenzirano
Odprti dostop
•Utility of animal models in research on OCD is considered and insights gained reviewed.•Optogenetic studies in mice demonstrate that hyperactivity in CBGTC circuits can result in compulsive ...behavior.•Parallel use of several animal models indicates DBS targets may depend on specific OCD endophenotypes.•Mechanisms of compulsive behavior are revealed by considering spontaneous behavior in deer mice, animal models of enhanced SIP, and compulsive checking induced by quinpirole.•Methods of analysis in animal models provide tools for translational research and clinical tests in OCD patients.
Research with animal models of obsessive-compulsive disorder (OCD) shows the following: (1) Optogenetic studies in mice provide evidence for a plausible cause-effect relation between increased activity in cortico-basal ganglia-thalamo-cortical (CBGTC) circuits and OCD by demonstrating the induction of compulsive behavior with the experimental manipulation of the CBGTC circuit. (2) Parallel use of several animal models is a fruitful paradigm to examine the mechanisms of treatment effects of deep brain stimulation in distinct OCD endophenotypes. (3) Features of spontaneous behavior in deer mice constitute a rich platform to investigate the neurobiology of OCD, social ramifications of a compulsive phenotype, and test novel drugs. (4) Studies in animal models for psychiatric disorders comorbid with OCD suggest comorbidity may involve shared neural circuits controlling expression of compulsive behavior. (5) Analysis of compulsive behavior into its constitutive components provides evidence from an animal model for a motivational perspective on OCD. (6) Methods of behavioral analysis in an animal model translate to dissection of compulsive rituals in OCD patients, leading to diagnostic tests.
PDF
