Combining endpoint and change data did not affect the summary standardised mean difference in pairwise and network meta-analyses: An empirical study in depression.

When studies use different scales to measure continuous outcomes, standardised mean differences (SMD) are required to meta-analyse the data. However, outcomes are often reported as endpoint or change from baseline scores. Combining corresponding SMDs can be problematic and available guidance advises against this practice. We aimed to examine the impact of combining the two types of SMD in meta-analyses of depression severity. We used individual participant data on pharmacological interventions (89 studies, 27,409 participants) and internet-delivered cognitive behavioural therapy (iCBT; 61 studies, 13,687 participants) for depression to compare endpoint and change from baseline SMDs at the study level. Next, we performed pairwise (PWMA) and network meta-analyses (NMA) using endpoint SMDs, change from baseline SMDs, or a mixture of the two. Study-specific SMDs calculated from endpoint and change from baseline data were largely similar, although for iCBT interventions 25% of the studies at 3 months were associated with important differences between study-specific SMDs (median 0.01, IQR -0.10, 0.13) especially in smaller trials with baseline imbalances. However, when pooled, the differences between endpoint and change SMDs were negligible. Pooling only the more favourable of the two SMDs did not materially affect meta-analyses, resulting in differences of pooled SMDs up to 0.05 and 0.13 in the pharmacological and iCBT datasets, respectively. Our findings have implications for meta-analyses in depression, where we showed that the choice between endpoint and change scores for estimating SMDs had immaterial impact on summary meta-analytic estimates. Future studies should replicate and extend our analyses to fields other than depression.

Absolute and relative outcomes of psychotherapies for eight mental disorders: a systematic review and meta-analysis.

Psychotherapies are first-line treatments for most mental disorders, but their absolute outcomes (i.e., response and remission rates) are not well studied, despite the relevance of such information for health care users, providers and policy makers. We aimed to examine absolute and relative outcomes of psychotherapies across eight mental disorders: major depressive disorder (MDD), social anxiety disorder, panic disorder, generalized anxiety disorder (GAD), specific phobia, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and borderline personality disorder (BPD). We used a series of living systematic reviews included in the Metapsy initiative (www.metapsy.org), with a common strategy for literature search, inclusion of studies and extraction of data, and a common format for the analyses. Literature search was conducted in major bibliographical databases (PubMed, PsycINFO, Embase, and the Cochrane Register of Controlled Trials) up to January 1, 2023. We included randomized controlled trials comparing psychotherapies for any of the eight mental disorders, established by a diagnostic interview, with a control group (waitlist, care-as-usual, or pill placebo). We conducted random-effects model pairwise meta-analyses. The main outcome was the absolute rate of response (at least 50% symptom reduction between baseline and post-test) in the treatment and control conditions. Secondary outcomes included the relative risk (RR) of response, and the number needed to treat (NNT). Random-effects meta-analyses of the included 441 trials (33,881 patients) indicated modest response rates for psychotherapies: 0.42 (95% CI: 0.39-0.45) for MDD; 0.38 (95% CI: 0.33-0.43) for PTSD; 0.38 (95% CI: 0.30-0.47) for OCD; 0.38 (95% CI: 0.33-0.43) for panic disorder; 0.36 (95% CI: 0.30-0.42) for GAD; 0.32 (95% CI: 0.29-0.37) for social anxiety disorder; 0.32 (95% CI: 0.23-0.42) for specific phobia; and 0.24 (95% CI: 0.15-0.36) for BPD. Most sensitivity analyses broadly supported these findings. The RRs were significant for all disorders, except BPD. Our conclusion is that most psychotherapies for the eight mental disorders are effective compared with control conditions, but absolute response rates are modest. More effective treatments and interventions for those not responding to a first-line treatment are needed.

The impact of continuity correction methods in Cochrane reviews with single-zero trials with rare events: A meta-epidemiological study.

Meta-analyses examining dichotomous outcomes often include single-zero studies, where no events occur in intervention or control groups. These pose challenges, and several methods have been proposed to address them. A fixed continuity correction method has been shown to bias estimates, but it is frequently used because sometimes software (e.g., RevMan software in Cochrane reviews) uses it as a default. We aimed to empirically compare results using the continuity correction with those using alternative models that do not require correction. To this aim, we reanalyzed the original data from 885 meta-analyses in Cochrane reviews using the following methods: (i) Mantel-Haenszel model with a fixed continuity correction, (ii) random effects inverse variance model with a fixed continuity correction, (iii) Peto method (the three models available in RevMan), (iv) random effects inverse variance model with the treatment arm continuity correction, (v) Mantel-Haenszel model without correction, (vi) logistic regression, and (vii) a Bayesian random effects model with binominal likelihood. For each meta-analysis we calculated ratios of odds ratios between all methods, to assess how the choice of method may impact results. Ratios of odds ratios <0.8 or <1.25 were seen in ~30% of the existing meta-analyses when comparing results between Mantel-Haenszel model with a fixed continuity correction and either Mantel-Haenszel model without correction or logistic regression. We concluded that injudicious use of the fixed continuity correction in existing Cochrane reviews may have substantially influenced effect estimates in some cases. Future updates of RevMan should incorporate less biased statistical methods.

Utility of RAND/UCLA appropriateness method in validating multiple-choice questions on ECG.

OBJECTIVES: This study aimed to investigate the utility of the RAND/UCLA appropriateness method (RAM) in validating expert consensus-based multiple-choice questions (MCQs) on electrocardiogram (ECG). METHODS: According to the RAM user's manual, nine panelists comprising various experts who routinely handle ECGs were asked to reach a consensus in three phases: a preparatory phase (round 0), an online test phase (round 1), and a face-to-face expert panel meeting (round 2). In round 0, the objectives and future timeline of the study were elucidated to the nine expert panelists with a summary of relevant literature. In round 1, 100 ECG questions prepared by two skilled cardiologists were answered, and the success rate was calculated by dividing the number of correct answers by 9. Furthermore, the questions were stratified into "Appropriate," "Discussion," or "Inappropriate" according to the median score and interquartile range (IQR) of appropriateness rating by nine panelists. In round 2, the validity of the 100 ECG questions was discussed in an expert panel meeting according to the results of round 1 and finally reassessed as "Appropriate," "Candidate," "Revision," and "Defer." RESULTS: In round 1 results, the average success rate of the nine experts was 0.89. Using the median score and IQR, 54 questions were classified as " Discussion." In the expert panel meeting in round 2, 23% of the original 100 questions was ultimately deemed inappropriate, although they had been prepared by two skilled cardiologists. Most of the 46 questions categorized as "Appropriate" using the median score and IQR in round 1 were considered "Appropriate" even after round 2 (44/46, 95.7%). CONCLUSIONS: The use of the median score and IQR allowed for a more objective determination of question validity. The RAM may help select appropriate questions, contributing to the preparation of higher-quality tests.

Prevalence of hazardous drinking and suspected alcohol dependence in Japanese primary care settings.

OBJECTIVE: We aimed to assess the prevalence of hazardous drinking and potential alcohol dependence among Japanese primary care patients, and their readiness to change and awareness of others' concerns. METHODS: From July to August 2023, we conducted a multi-site cross-sectional study as a screening survey for participants in a cluster randomized controlled trial. The trial included outpatients aged 20-74 from primary care clinics. Using the Alcohol Use Disorders Identification Test (AUDIT) alongside a self-administered questionnaire, we evaluated the prevalence of hazardous drinking and suspected alcohol dependence, patients' readiness to change, and their awareness of others' concerns. RESULTS: Among the 1388 participants from 18 clinics, 22% (95% confidence interval (CI): 20% to 24%) were identified as engaging in hazardous drinking or suspected of being alcohol dependent. As the AUDIT scores increased, so did their readiness to change. However, only 22% (95%CI: 16% to 28%) of those with scores ranging from 8 to 14 reported that others, including physicians, had expressed concerns about their drinking during the past year. For those with scores of 15 or higher, the figure was 74%. CONCLUSIONS: This study underscores the need for universal or high-risk alcohol screening and brief intervention in Japanese primary care settings. Trial registry UMIN-CTR (https://www.umin.ac.jp/ctr/) (UMIN000051388).

The short and long-term efficacy of nurse-led interventions for improving blood pressure control in people with hypertension in primary care settings: a systematic review and meta-analysis.

BACKGROUND: Previous systematic reviews suggest that nurse-led interventions improve short-term blood pressure (BP) control for people with hypertension. However, the long-term effects, adverse events, and appropriate target BP level are unclear. This study aimed to evaluate the long-term efficacy and safety of nurse-led interventions. METHODS: We conducted a systematic review and meta-analysis. We searched the Cochrane Central Register of Controlled Trials, PubMed, and CINAHL, as well as three Japanese article databases, as relevant randomized controlled trials from the oldest possible to March 2021. This search was conducted on 17 April 2021. We did an update search on 17 October 2023. We included studies on adults aged 18 years or older with hypertension. The treatments of interest were community-based nurse-led BP control interventions in addition to primary physician-provided care as usual. The comparator was usual care only. Primary outcomes were long-term achievement of BP control goals and serious adverse events (range: 27 weeks to 3 years). Secondary outcomes were short-term achievement of BP control goals and serious adverse events (range: 4 to 26 weeks), change of systolic and diastolic BP from baseline, medication adherence, incidence of hypertensive complications, and total mortality. RESULTS: We included 35 studies. Nurse-led interventions improved long-term BP control (RR 1.10, 95%CI 1.03 to 1.18). However, no significant differences were found in the short-term effects of nurse-led intervention compared to usual care about BP targets. Little information on serious adverse events was available. There was no difference in mortality at both terms between the two groups. Establishing the appropriate target BP from the extant trials was impossible. CONCLUSIONS: Nurse-led interventions may be more effective than usual care for achieving BP control at long-term follow-up. It is important to continue lifestyle modification for people with hypertension. We must pay attention to adverse events, and more studies examining appropriate BP targets are needed. Nurse-led care represents an important complement to primary physician-led usual care.

Heterogeneity of outcome measures in depression trials and the relevance of the content of outcome measures to patients: a systematic review.

Research waste occurs when randomised controlled trial (RCT) outcomes are heterogeneous or overlook domains that matter to patients (eg, relating to symptoms or functions). In this systematic review, we reviewed the outcome measures used in 450 RCTs of adult unipolar and bipolar depression registered between 2018 and 2022 and identified 388 different measures. 40% of the RCTs used the same measure (Hamilton Depression Rating Scale [HAMD]). Patients and clinicians matched each item within the 25 most frequently used measures with 80 previously identified domains of depression that matter to patients. Seven (9%) domains were not covered by the 25 most frequently used outcome measures (eg, mental pain and irritability). The HAMD covered a maximum of 47 (59%) of the 80 domains that matter to patients. An interim solution to facilitate evidence synthesis before a core outcome set is developed would be to use the most common measures and choose complementary scales to optimise domain coverage. TRANSLATIONS: For the French and Dutch translations of the abstract see Supplementary Materials section.

Multicomponent Intervention for Overactive Bladder in Women: A Randomized Clinical Trial.

Importance: Although the cognitive components of behavioral therapy for overactive bladder (OAB) are widely recognized, there is a lack of studies evaluating the effectiveness of multicomponent interventions that include cognitive components as a treatment for OAB. Objective: To examine the efficacy of a multicomponent intervention in improving health-related quality of life (HRQOL) for women with moderate to severe OAB. Design, Setting, and Participants: This multicenter, open-label, randomized clinical trial was conducted in Japan among women aged 20 to 80 years who had moderate to severe OAB. Participants were recruited from 4 institutions between January 16, 2020, and December 31, 2022, through self-referral via advertisement or referral from the participating institutions. Interventions: Participants were randomized 1:1 by minimization algorithm using an internet-based central cloud system to four 30-minute weekly sessions of a multicomponent intervention or waiting list. Both groups continued to receive baseline treatment throughout the study period. Main Outcomes and Measures: The primary outcome was the least-squares mean changes from baseline through week 13 in HRQOL total scores of the OAB questionnaire between 2 groups. Secondary outcomes included OAB symptom score and frequency volume chart. Results: A total of 79 women were randomized to either the intervention group (39 participants; mean [SD] age, 63.5 [14.6] years) or the waiting list control group (40 participants; mean [SD] age, 63.5 [12.9] years). One participant from each group dropped out from the allocated intervention, while 5 participants in the intervention group and 2 in the control group dropped out from the primary outcome assessment at week 13. Thirty-six participants (92.3%) in the intervention group and 35 (87.5%) in the control group had moderate OAB. The change in HRQOL total score from baseline to week 13 was 23.9 points (95% CI, 18.4-29.5 points) in the intervention group and 11.3 points (95% CI, 6.2-16.4 points) in the waiting list group, a significant difference of 12.6 points (95% CI, 6.6-18.6 points; P < .001). Similar superiority of the intervention was confirmed for frequency of micturition and urgency but not for OAB symptom score. Conclusions and Relevance: These findings demonstrate that a multicomponent intervention improves HRQOL for women with moderate to severe OAB and suggest that the cognitive component may be an effective treatment option for women with OAB. Trial Registration: UMIN Clinical Trials Registry Identifier: UMIN000038513.

Understanding effect size: an international online survey among psychiatrists, psychologists, physicians from other medical specialities, dentists and other health professionals.

BACKGROUND AND OBJECTIVE: Various ways exist to display the effectiveness of medical treatment options. This study examined various psychiatric, medical and allied professionals' understanding and perceived usefulness of eight effect size indices for presenting both dichotomous and continuous outcome data. METHODS: We surveyed 1316 participants from 13 countries using an online questionnaire. We presented hypothetical treatment effects of interventions versus placebo concerning chronic pain using eight different effect size measures. For each index, the participants had to judge the magnitude of the shown effect, to indicate how certain they felt about their own answer and how useful they found the given effect size index. FINDINGS: Overall, 762 (57.9%) participants fully completed the questionnaire. In terms of understanding, the best results emerged when both the control event rate (CER) and the experimental event rate (EER) were presented. The difference in minimal importance difference units (MID unit) was understood worst. Respondents also found CER and EER to be the most useful presentation approach while they rated MID unit as the least useful. Confidence in the risk ratio ranked high, even though it was rather poorly understood. CONCLUSIONS AND CLINICAL IMPLICATIONS: For dichotomous outcomes, presenting the effects in terms of the CER and EER could lead to the most correct interpretation. Relative measures including the risk ratio must be supplemented with absolute measures such as the CER and EER. Effects on continuous outcomes were better understood through standardised mean differences than mean differences. These can also be supplemented by dichotomised CER and EER.

Are the results of open randomised controlled trials comparing antipsychotic drugs in schizophrenia biased? Exploratory meta- and subgroup analysis.

A recent meta-epidemiological study did not reveal major differences between the results of blinded and open randomised-controlled trials (RCTs). Fewer patients may consent to double-blind RCTs than to open RCTs, compromising generalisability, making this question very important. However, the issue has not been addressed in schizophrenia. We used a database of randomised, acute-phase antipsychotic drug trials. Whenever at least one open and one blinded RCT was available for a comparison of two drugs, we contrasted the results by random-effects meta-analysis with subgroup tests. The primary outcome was overall symptoms as measured by the Positive and Negative Syndrome Scale, supplemented by seven secondary efficacy and side-effect outcomes. We also examined whether open RCTs were biased in favour of more recently introduced antipsychotics, less efficacious or more prone to side-effects antipsychotics, and pharmaceutical sponsors. 183 RCTs (155 blinded and 28 open) with 34715 participants comparing two active drugs were available. The results did not suggest general differences between open and blinded RCTs, which examined two active drugs. Only 12 out of 122 subgroup tests had a p-value below 0.1, four below 0.05, and if a Bonferroni correction for multiple tests had been applied, only one would have been significant. There were some exceptions which, however, did not always confirm the originally hypothesized direction of bias. Due to the relatively small number of open RCTs, our analysis is exploratory, but this fundamental question should be given more scientific attention. Currently, open RCTs should be excluded from meta-analyses, at least in sensitivity analyses.

Components and Delivery Formats of Cognitive Behavioral Therapy for Chronic Insomnia in Adults: A Systematic Review and Component Network Meta-Analysis.

Importance: Chronic insomnia disorder is highly prevalent, disabling, and costly. Cognitive behavioral therapy for insomnia (CBT-I), comprising various educational, cognitive, and behavioral strategies delivered in various formats, is the recommended first-line treatment, but the effect of each component and delivery method remains unclear. Objective: To examine the association of each component and delivery format of CBT-I with outcomes. Data Sources: PubMed, Cochrane Central Register of Controlled Trials, PsycInfo, and International Clinical Trials Registry Platform from database inception to July 21, 2023. Study Selection: Published randomized clinical trials comparing any form of CBT-I against another or a control condition for chronic insomnia disorder in adults aged 18 years and older. Insomnia both with and without comorbidities was included. Concomitant treatments were allowed if equally distributed among arms. Data Extraction and Synthesis: Two independent reviewers identified components, extracted data, and assessed trial quality. Random-effects component network meta-analyses were performed. Main Outcomes and Measures: The primary outcome was treatment efficacy (remission defined as reaching a satisfactory state) posttreatment. Secondary outcomes included all-cause dropout, self-reported sleep continuity, and long-term remission. Results: A total of 241 trials were identified including 31 452 participants (mean [SD] age, 45.4 [16.6] years; 21 048 of 31 452 [67%] women). Results suggested that critical components of CBT-I are cognitive restructuring (remission incremental odds ratio [iOR], 1.68; 95% CI, 1.28-2.20) third-wave components (iOR, 1.49; 95% CI, 1.10-2.03), sleep restriction (iOR, 1.49; 95% CI, 1.04-2.13), and stimulus control (iOR, 1.43; 95% CI, 1.00-2.05). Sleep hygiene education was not essential (iOR, 1.01; 95% CI, 0.77-1.32), and relaxation procedures were found to be potentially counterproductive(iOR, 0.81; 95% CI, 0.64-1.02). In-person therapist-led programs were most beneficial (iOR, 1.83; 95% CI, 1.19-2.81). Cognitive restructuring, third-wave components, and in-person delivery were mainly associated with improved subjective sleep quality. Sleep restriction was associated with improved subjective sleep quality, sleep efficiency, and wake after sleep onset, and stimulus control with improved subjective sleep quality, sleep efficiency, and sleep latency. The most efficacious combination-consisting of cognitive restructuring, third wave, sleep restriction, and stimulus control in the in-person format-compared with in-person psychoeducation, was associated with an increase in the remission rate by a risk difference of 0.33 (95% CI, 0.23-0.43) and a number needed to treat of 3.0 (95% CI, 2.3-4.3), given the median observed control event rate of 0.14. Conclusions and Relevance: The findings suggest that beneficial CBT-I packages may include cognitive restructuring, third-wave components, sleep restriction, stimulus control, and in-person delivery but not relaxation. However, potential undetected interactions could undermine the conclusions. Further large-scale, well-designed trials are warranted to confirm the contribution of different treatment components in CBT-I.

Estimating the smallest worthwhile difference of antidepressants: a cross-sectional survey.

BACKGROUND: Approximately 30% of patients experience substantial improvement in depression after 2 months without treatment, and 45% with antidepressants. The smallest worthwhile difference (SWD) refers to an intervention's smallest beneficial effect over a comparison patients deem worthwhile given treatment burdens (harms, expenses and inconveniences), but is undetermined for antidepressants. OBJECTIVE: Estimating the SWD of commonly prescribed antidepressants for depression compared to no treatment. METHODS: The SWD was estimated as a patient-required difference in response rates between antidepressants and no treatment after 2 months. An online cross-sectional survey using Prolific, MQ Mental Health and Amazon Mechanical Turk crowdsourcing services in the UK and USA between October 2022 and January 2023 garnered participants (N=935) that were a mean age of 44.1 (SD=13.9) and 66% women (n=617). FINDINGS: Of 935 participants, 124 reported moderate-to-severe depressive symptoms but were not in treatment, 390 were in treatment and 495 reported absent-to-mild symptoms with or without treatment experiences. The median SWD was a 20% (IQR=10-30%) difference in response rates for people with moderate-to-severe depressive symptoms, not in treatment, and willing to consider antidepressants, and 25% (IQR=10-35%) for the full sample. CONCLUSIONS: Our observed SWDs mean that the current 15% antidepressant benefit over no treatment was sufficient for one in three people to accept antidepressants given the burdens, but two in three expected greater treatment benefits. IMPLICATIONS: While a minority may be satisfied with the best currently available antidepressants, more effective and/or less burdensome medications are needed, with more attention given to patient perspectives.

A chatbot to improve adherence to internet-based cognitive-behavioural therapy among workers with subthreshold depression: a randomised controlled trial.

BACKGROUND: Internet-based cognitive-behavioural therapy (iCBT) is effective for subthreshold depression. However, iCBT has problems with adherence, especially when unaccompanied by human guidance. Knowledge on how to enhance adherence to iCBT without human involvement can contribute to improving the effectiveness of iCBT. OBJECTIVE: This is an implementation study to examine the effect of an automated chatbot to improve the adherence rate of iCBT. METHODS: We developed a chatbot to increase adherence to an existing iCBT programme, and a randomised controlled trial was conducted with two groups: one group using iCBT plus chatbot (iCBT+chatbot group) and one group not using the chatbot (iCBT group). Participants were full-time employees with subthreshold depression working in Japan (n=149, age mean=41.4 (SD=11.1)). The primary endpoint was the completion rate of the iCBT programme at 8 weeks. FINDINGS: We analysed data from 142 participants for the primary outcome. The completion rate of the iCBT+chatbot group was 34.8% (24/69, 95% CI 23.5 to 46.0), that of the iCBT group was 19.2% (14/73, 95% CI 10.2 to 28.2), and the risk ratio was 1.81 (95% CI 1.02 to 3.21). CONCLUSIONS: Combining iCBT with a chatbot increased participants' iCBT completion rate. CLINICAL IMPLICATIONS: Encouraging messages from the chatbot could improve participation in an iCBT programme. Further studies are needed to investigate whether chatbots can improve adherence to the programme in the long term and to assess their impact on depression, anxiety and well-being. TRIAL REGISTRATION NUMBER: UMIN000047621.

The definition of treatment resistance in anxiety disorders: a Delphi method-based consensus guideline.

Anxiety disorders are very prevalent and often persistent mental disorders, with a considerable rate of treatment resistance which requires regulatory clinical trials of innovative therapeutic interventions. However, an explicit definition of treatment-resistant anxiety disorders (TR-AD) informing such trials is currently lacking. We used a Delphi method-based consensus approach to provide internationally agreed, consistent and clinically useful operational criteria for TR-AD in adults. Following a summary of the current state of knowledge based on international guidelines and an available systematic review, a survey of free-text responses to a 29-item questionnaire on relevant aspects of TR-AD, and an online consensus meeting, a panel of 36 multidisciplinary international experts and stakeholders voted anonymously on written statements in three survey rounds. Consensus was defined as ≥75% of the panel agreeing with a statement. The panel agreed on a set of 14 recommendations for the definition of TR-AD, providing detailed operational criteria for resistance to pharmacological and/or psychotherapeutic treatment, as well as a potential staging model. The panel also evaluated further aspects regarding epidemiological subgroups, comorbidities and biographical factors, the terminology of TR-AD vs. "difficult-to-treat" anxiety disorders, preferences and attitudes of persons with these disorders, and future research directions. This Delphi method-based consensus on operational criteria for TR-AD is expected to serve as a systematic, consistent and practical clinical guideline to aid in designing future mechanistic studies and facilitate clinical trials for regulatory purposes. This effort could ultimately lead to the development of more effective evidence-based stepped-care treatment algorithms for patients with anxiety disorders.

Correction: Electronic Health Record-Nested Reminders for Serum Lithium Level Monitoring in Patients With Mood Disorder: Randomized Controlled Trial.

[This corrects the article DOI: 10.2196/40595.].

When does the placebo effect have an impact on network meta-analysis results?

The placebo effect is the 'effect of the simulation of treatment that occurs due to a participant's belief or expectation that a treatment is effective'. Although the effect might be of little importance for some conditions, it can have a great role in others, mostly when the evaluated symptoms are subjective. Several characteristics that include informed consent, number of arms in a study, the occurrence of adverse events and quality of blinding may influence response to placebo and possibly bias the results of randomised controlled trials. Such a bias is inherited in systematic reviews of evidence and their quantitative components, pairwise meta-analysis (when two treatments are compared) and network meta-analysis (when more than two treatments are compared). In this paper, we aim to provide red flags as to when a placebo effect is likely to bias pairwise and network meta-analysis treatment effects. The classic paradigm has been that placebo-controlled randomised trials are focused on estimating the treatment effect. However, the magnitude of placebo effect itself may also in some instances be of interest and has also lately received attention. We use component network meta-analysis to estimate placebo effects. We apply these methods to a published network meta-analysis, examining the relative effectiveness of four psychotherapies and four control treatments for depression in 123 studies.

Treatment Outcomes With Licensed and Unlicensed Stimulant Doses for Adults With Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis.

Importance: Stimulants (methylphenidate and amphetamines) are often prescribed at unlicensed doses for adults with attention-deficit/hyperactivity disorder (ADHD). Whether dose escalation beyond US Food and Drug Administration recommendations is associated with positive risk benefits is unclear. Objective: To investigate the impact, based on averages, of stimulant doses on treatment outcomes in adults with ADHD and to determine, based on averages, whether unlicensed doses are associated with positive risk benefits compared with licensed doses. Data Sources: Twelve databases, including published (PubMed, Cochrane Library, Embase, Web of Sciences) and unpublished (ClinicalTrials.gov) literature, up to February 22, 2023, without language restrictions. Study Selection: Two researchers independently screened records to identify double-blinded randomized clinical trials of stimulants against placebo in adults (18 years and older) with ADHD. Data Extraction and Synthesis: Aggregate data were extracted and synthesized in random-effects dose-response meta-analyses and network meta-analyses. Main Outcome Measures: Change in ADHD symptoms and discontinuations due to adverse events. Results: A total of 47 randomized clinical trials (7714 participants; mean age, 35 (SD, 11) years; 4204 male [56%]) were included. For methylphenidate, dose-response curves indicated additional reductions of symptoms with increments in doses, but the gains were progressively smaller and accompanied by continued additional risk of adverse events dropouts. Network meta-analyses showed that unlicensed doses were associated with greater reductions of symptoms compared with licensed doses (standardized mean difference [SMD], -0.23; 95% CI, -0.44 to -0.02; very low certainty of evidence), but the additional gain was small and accompanied by increased risk of adverse event dropouts (odds ratio, 2.02; 95% CI, 1.19-3.43; moderate certainty of evidence). For amphetamines, the dose-response curve approached a plateau and increments in doses did not indicate additional reductions of symptoms, but there were continued increments in the risk of adverse event dropouts. Network meta-analysis did not identify differences between unlicensed and licensed doses for reductions of symptoms (SMD, -0.08; 95% CI, -0.24 to 0.08; very low certainty of evidence). Conclusions and Relevance: Based on group averages, unlicensed doses of stimulants may not have positive risk benefits compared with licensed doses for adults with ADHD. In general, practitioners should consider unlicensed doses cautiously. Practitioners may trial unlicensed doses if needed and tolerated but should be aware that there may not be large gains in the response to the medication with those further increments in dose. However, the findings are averages and will not generalize to every patient.