Antidepressants for pain management in adults with chronic pain: a network meta-analysis.

BACKGROUND: Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients' global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis (NMA) examining all antidepressants across all chronic pain conditions. OBJECTIVES: To assess the comparative efficacy and safety of antidepressants for adults with chronic pain (except headache). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, AMED and PsycINFO databases, and clinical trials registries, for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions in January 2022. SELECTION CRITERIA: We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant, or the same antidepressant at different doses, then we required the study to be double-blind. We included RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) but rated them as high risk of bias. We excluded RCTs where the follow-up was less than two weeks and those with fewer than 10 participants in each arm.  DATA COLLECTION AND ANALYSIS: Two review authors separately screened, data extracted, and judged risk of bias. We synthesised the data using Bayesian NMA and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve (SUCRA). We primarily used Confidence in Meta-Analysis (CINeMA) and Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used GRADE to assess the certainty of the evidence. Our primary outcomes were substantial (50%) pain relief, pain intensity, mood, and adverse events. Our secondary outcomes were moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events, and withdrawal. MAIN RESULTS: This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (83), and parallel-armed (141). The most common pain conditions examined were fibromyalgia (59 studies); neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks. Seven studies provided no useable data and were omitted from the NMA. The majority of studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. In duloxetine studies, standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain.  Primary efficacy outcomes Duloxetine standard dose (60 mg) showed a small to moderate effect for substantial pain relief (odds ratio (OR) 1.91, 95% confidence interval (CI) 1.69 to 2.17; 16 studies, 4490 participants; moderate-certainty evidence) and continuous pain intensity (standardised mean difference (SMD) -0.31, 95% CI -0.39 to -0.24; 18 studies, 4959 participants; moderate-certainty evidence). For pain intensity, milnacipran standard dose (100 mg) also showed a small effect (SMD -0.22, 95% CI -0.39 to 0.06; 4 studies, 1866 participants; moderate-certainty evidence). Mirtazapine (30 mg) had a moderate effect on mood (SMD -0.5, 95% CI -0.78 to -0.22; 1 study, 406 participants; low-certainty evidence), while duloxetine showed a small effect (SMD -0.16, 95% CI -0.22 to -0.1; 26 studies, 7952 participants; moderate-certainty evidence); however it is important to note that most studies excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the 'normal' or 'subclinical' ranges at baseline already. Secondary efficacy outcomes Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life, and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were as efficacious as high doses. Safety There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events, and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes. AUTHORS' CONCLUSIONS: Our review and NMAs show that despite studies investigating 25 different antidepressants, the only antidepressant we are certain about for the treatment of chronic pain is duloxetine. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Evidence for all other antidepressants was low certainty. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for the safety of antidepressants for chronic pain at any time point.

Mindfulness-based programmes for mental health promotion in adults in nonclinical settings: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: There is an urgent need for mental health promotion in nonclinical settings. Mindfulness-based programmes (MBPs) are being widely implemented to reduce stress, but a comprehensive evidence synthesis is lacking. We reviewed trials to assess whether MBPs promote mental health relative to no intervention or comparator interventions. METHODS AND FINDINGS: Following a detailed preregistered protocol (PROSPERO CRD42018105213) developed with public and professional stakeholders, 13 databases were searched to August 2020 for randomised controlled trials (RCTs) examining in-person, expert-defined MBPs in nonclinical settings. Two researchers independently selected, extracted, and appraised trials using the Cochrane Risk-of-Bias Tool 2.0. Primary outcomes were psychometrically validated anxiety, depression, psychological distress, and mental well-being questionnaires at 1 to 6 months after programme completion. Multiple testing was performed using p < 0.0125 (Bonferroni) for statistical significance. Secondary outcomes, meta-regression and sensitivity analyses were prespecified. Pairwise random-effects multivariate meta-analyses and prediction intervals (PIs) were calculated. A total of 11,605 participants in 136 trials were included (29 countries, 77% women, age range 18 to 73 years). Compared with no intervention, in most but not all scenarios MBPs improved average anxiety (8 trials; standardised mean difference (SMD) = -0.56; 95% confidence interval (CI) -0.80 to -0.33; p-value < 0.001; 95% PI -1.19 to 0.06), depression (14 trials; SMD = -0.53; 95% CI -0.72 to -0.34; p-value < 0.001; 95% PI -1.14 to 0.07), distress (27 trials; SMD = -0.45; 95% CI -0.58 to -0.31; p-value < 0.001; 95% PI -1.04 to 0.14), and well-being (9 trials; SMD = 0.33; 95% CI 0.11 to 0.54; p-value = 0.003; 95% PI -0.29 to 0.94). Compared with nonspecific active control conditions, in most but not all scenarios MBPs improved average depression (6 trials; SMD = -0.46; 95% CI -0.81 to -0.10; p-value = 0.012, 95% PI -1.57 to 0.66), with no statistically significant evidence for improving anxiety or distress and no reliable data on well-being. Compared with specific active control conditions, there is no statistically significant evidence of MBPs' superiority. Only effects on distress remained when higher-risk trials were excluded. USA-based trials reported smaller effects. MBPs targeted at higher-risk populations had larger effects than universal MBPs. The main limitation of this review is that confidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach is moderate to very low, mainly due to inconsistency and high risk of bias in many trials. CONCLUSIONS: Compared with taking no action, MBPs of the included studies promote mental health in nonclinical settings, but given the heterogeneity between studies, the findings do not support generalisation of MBP effects across every setting. MBPs may have specific effects on some common mental health symptoms. Other preventative interventions may be equally effective. Implementation of MBPs in nonclinical settings should be partnered with thorough research to confirm findings and learn which settings are most likely to benefit.

Public involvement in an aggregate and individual participant data meta-analysis of mindfulness-based programmes for mental health promotion.

BACKGROUND: Involving the public in evidence synthesis research is challenging due to the highly analytic nature of the projects, so it is important that involvement processes are documented, reflected upon, and shared to devise best practices. There is a literature gap on the involvement of the public in individual participant data meta-analyses, particularly in public health projects. We aimed to document and reflect on our collective experiences of involving and being involved as public stakeholders at all stages of a systematic review and individual participant data meta-analysis project. METHODS: We formed a stakeholder group made of four members of the public at the beginning of our evidence synthesis project comprising a systematic review, an aggregate data meta-analysis, and an individual participant data meta-analysis of mindfulness-based programmes for mental health promotion in non-clinical adults. Following each group meeting, members and participating researchers completed written reflections; one group member collected and collated these. At the end of the project, a reflective writing workshop was held before all members completed their final reflections. Everyone completed an adapted, open-ended questionnaire which asked about what did and did not work well, the overall experience, what could be improved, and the felt impact the stakeholder group had on the research. RESULTS: Overall, the stakeholders and researchers reported a positive experience of working together. Positives from the stakeholders' point of view included learning new skills, experiencing research, and making new friends. For the researchers, stakeholders helped them focus on what matters to the public and were reinvigorating research partners. The challenges stakeholders experienced included having long gaps between meetings and feeling overwhelmed. The researchers found it challenging to strike the balance between asking stakeholders to be involved and for them to learn research-related skills without overburdening them and making sure that the learning was engaging. When looking back at their experience, stakeholders described seeing their impact on the project in hindsight but that this was not felt while the project was being carried out. CONCLUSION: Successfully involving the public in complex evidence synthesis projects is possible and valuable from the points of view of the researchers and the stakeholders. However, it requires a significant time, skill, and resource investment that needs to be factored in from project inception. Further guidance and stakeholder training materials would be helpful. Specific suggestions are provided.

Improving patient experience for people prescribed medicines with a risk of dependence or withdrawal: co-designed solutions using experience based co-design.

BACKGROUND: Significant concerns have been raised regarding how medications with a risk of dependence or withdrawal are managed and how care is experienced by patients. This study sought to co-design solutions to improve the experience of care for patients prescribed benzodiazepines, z-drugs, opioids for chronic non-cancer pain, gabapentinoids and antidepressants. METHOD: Twenty patients and fifteen healthcare professionals from five different GP practices were recruited to take part. The study used Experience Based Co-Design. Patients and healthcare professionals completed semi-structured interviews and took part in feedback groups and co-design workshops to collaboratively identify priorities for improvement and to co-design solutions to improve the experience of care. RESULTS: Poor patient experience was common among people prescribed medications with a risk of dependence or withdrawal. Patients and healthcare professionals identified three main priority areas to improve the experience of care: (i) ensuring patients are provided with detailed information in relation to their medication, (ii) ensuring continuity of care for patients, and (iii) providing alternative treatment options to medication. Solutions to improve care were co-designed by patients and healthcare staff and implemented within participating GP practices to improve the experience of care. CONCLUSION: Good patient experience is a key element of quality care. This study highlights that the provision of in-depth medication related information, continuity of care and alternative treatment to medication are important to patients prescribed medicines with a risk of dependence or withdrawal. Improving these aspects of care should be a priority for future improvement and delivery plans.

Trace amine-associated receptor 1 (TAAR1) agonism for psychosis: a living systematic review and meta-analysis of human and non-human data.

Background: Trace amine-associated receptor 1 (TAAR1) agonism shows promise for treating psychosis, prompting us to synthesise data from human and non-human studies. Methods: We co-produced a living systematic review of controlled studies examining TAAR1 agonists in individuals (with or without psychosis/schizophrenia) and relevant animal models. Two independent reviewers identified studies in multiple electronic databases (until 17.11.2023), extracted data, and assessed risk of bias. Primary outcomes were standardised mean differences (SMD) for overall symptoms in human studies and hyperlocomotion in animal models. We also examined adverse events and neurotransmitter signalling. We synthesised data with random-effects meta-analyses. Results: Nine randomised trials provided data for two TAAR1 agonists (ulotaront and ralmitaront), and 15 animal studies for 10 TAAR1 agonists. Ulotaront and ralmitaront demonstrated few differences compared to placebo in improving overall symptoms in adults with acute schizophrenia (N=4 studies, n=1291 participants; SMD=0.15, 95%CI: -0.05, 0.34), and ralmitaront was less efficacious than risperidone (N=1, n=156, SMD=-0.53, 95%CI: -0.86, -0.20). Large placebo response was observed in ulotaront phase-III trials. Limited evidence suggested a relatively benign side-effect profile for TAAR1 agonists, although nausea and sedation were common after a single dose of ulotaront. In animal studies, TAAR1 agonists improved hyperlocomotion compared to control (N=13 studies, k=41 experiments, SMD=1.01, 95%CI: 0.74, 1.27), but seemed less efficacious compared to dopamine D 2 receptor antagonists (N=4, k=7, SMD=-0.62, 95%CI: -1.32, 0.08). Limited human and animal data indicated that TAAR1 agonists may regulate presynaptic dopaminergic signalling. Conclusions: TAAR1 agonists may be less efficacious than dopamine D 2 receptor antagonists already licensed for schizophrenia. The results are preliminary due to the limited number of drugs examined, lack of longer-term data, publication bias, and assay sensitivity concerns in trials associated with large placebo response. Considering their unique mechanism of action, relatively benign side-effect profile and ongoing drug development, further research is warranted. Registration: PROSPERO-ID: CRD42023451628.

There is a need for more effective treatments for psychosis, including schizophrenia. Psychosis is a collection of mental health symptoms, such as hearing voices, that can cause distress and impair functioning. These symptoms are thought to be caused by changes in a chemical messenger system in the brain called dopamine. Currently used antipsychotic medications target brain receptors that respond to dopamine. They are not effective in some people and can cause uncomfortable adverse events, such as weight gain and movement disorders, especially with long-term use. A new type of drug is the trace amine-associated receptor 1 (TAAR1) agonists. These drugs act on different brain receptors that can affect the activity of the dopamine system, but do not directly bind to dopamine receptors. We aimed to understand if TAAR1 agonists can reduce symptoms of psychosis, what adverse events they might have, and how they work. We did this by reviewing and collating all available evidence until November 2023. This is a "living" systematic review, so it will be regularly updated in the future. We looked at both human and animal studies investigating TAAR1 agonists. Human studies suggested that two TAAR1 agonists (namely, ulotaront or ralmitaront) might have little to no effect on reducing symptoms of psychosis compared to placebo in people with schizophrenia. They seemed to cause fewer adverse events than current antipsychotics. Data from animal studies suggested that TAAR1 agonists had some positive effects but potentially smaller than other antipsychotics. There were little to no data from both human and animal studies about how TAAR1 agonists actually work. From the current evidence we are uncertain about these results. With the ongoing development of new TAAR1 agonists, more evidence is needed to understand their potential role in the treatment of psychosis.

Psychological, social and academic functioning in university students with chronic pain: A systematic review.

OBJECTIVE: Chronic pain is a prevalent health issue among young adults; however, there is limited understanding on how it affects university students. This is the first systematic review of evidence relating to the association between chronic pain and psychological, social and academic functioning in university students. Participants: Four databases were searched for relevant published studies. Data from 18 studies including 10,069 university students, of which 2895 reported having chronic pain, were included in the synthesis. Methods: Due to heterogeneity of data and methodologies, meta-analysis was not possible; therefore, data were synthesized narratively. Results: Our findings showed that students with chronic pain have poorer psychological, social and academic functioning and quality of life, compared to students without chronic pain. Conclusions: These findings suggest that chronic pain presents a challenge in university settings. Research is urgently needed to enable an understanding of how universities can support students who experience chronic pain.

Individual participant data systematic review and meta-analysis of randomised controlled trials assessing adult mindfulness-based programmes for mental health promotion in non-clinical settings.

Introduction: Mindfulness-based programmes (MBPs) are widely used to prevent mental ill-health that is becoming the leading global cause of morbidity. Evidence suggests beneficial average effects but wide variability. We aimed to confirm the effect of MBPs on psychological distress, and to understand whether and how baseline distress, gender, age, education, and dispositional mindfulness modify the effect of MBPs on distress among adults in non-clinical settings. Methods: We conducted a pre-registered systematic review and individual participant data (IPD) meta-analysis (PROSPERO CRD42020200117). Thirteen databases were searched in December 2020 for randomised controlled trials satisfying a quality threshold and comparing in-person, expert-defined MBPs in non-clinical settings with passive control groups. Two researchers independently selected, extracted, and appraised trials using the revised Cochrane Risk-of-Bias Tool (RoB2). Anonymised IPD of eligible trials were sought from collaborating authors. The primary outcome was psychological distress (unpleasant mental or emotional experiences including anxiety and depression) at 1 to 6 months after programme completion. Data were checked and imputed if missing. Pairwise, random-effects, two-stage IPD meta-analyses were conducted. Effect modification analyses followed a within-studies approach. Public and professional stakeholders were involved in the planning, conduct and dissemination of this study. Results: Fifteen trials were eligible, 13 trialists shared IPD (2,371 participants representing 8 countries, median age 34 years-old, 71% women, moderately distressed on average, 20% missing outcome data). In comparison with passive control groups, MBPs reduced average distress between one- and six-months post-intervention with a small to moderate effect size (standardised mean difference (SMD) -0.32; 95% confidence interval (CI) -0.41 to -0.24; p-value < 0.001; 95% prediction interval (PI) -0.41 to -0.24 (no heterogeneity)). Results were robust to sensitivity analyses, and similar for the other psychological distress time point ranges. Confidence in the primary outcome result is high. We found no clear indication that this effect is modified by baseline psychological distress, gender, age, education level, or dispositional mindfulness. Conclusions: Group-based teacher-led MBPs generally reduce psychological distress among community adults who volunteer to receive this type of intervention. More research is needed to identify sources of variability in outcomes at an individual level.

Pro-dopaminergic pharmacological interventions for anhedonia in depression: protocol for a living systematic review of human and non-human studies.

Background: Anhedonia is a key symptom of depression, and it has been suggested as a potential target for future individualised treatments. However, much is unknown about how interventions enhancing dopaminergic pathways may affect anhedonia symptoms in the context of depression. Methods: We will perform independent searches in multiple electronic databases to identify clinical and animal experimental studies on pro-dopaminergic interventions in individuals with depression or animal models for depression. The primary outcomes will be overall anhedonia symptoms and their behavioural proxies in animals. Secondary outcomes will include side effects and neurobiological measures. At least two independent reviewers will conduct the study selection, data extraction, and risk of bias assessments using pre-defined tools according to each record's study design. We will develop ontologies to facilitate study identification and data extraction. We will synthesise data from clinical and animal studies separately. If appropriate, we will use random-effects meta-analyses, or synthesis without meta-analyses. We will investigate study characteristics as potential sources of heterogeneity. We will evaluate the confidence in the evidence for each outcome and source of evidence, considering the summary of the association, potential concerns regarding internal and external validity, and reporting biases. When multiple sources of evidence are available for an outcome, we will draw an overall conclusion in a triangulation meeting involving a multidisciplinary team of experts. We plan updates of the review every 6 months, and any future modifications to the protocol will be documented. We will co-produce this review with multiple stakeholders. PROSPERO registration: CRD42023451821.

Trace amine-associated receptor 1 (TAAR1) agonists for psychosis: protocol for a living systematic review and meta-analysis of human and non-human studies.

BACKGROUND: There is an urgent need to develop more effective and safer antipsychotics beyond dopamine 2 receptor antagonists. An emerging and promising approach is TAAR1 agonism. Therefore, we will conduct a living systematic review and meta-analysis to synthesize and triangulate the evidence from preclinical animal experiments and clinical studies on the efficacy, safety, and underlying mechanism of action of TAAR1 agonism for psychosis. METHODS: Independent searches will be conducted in multiple electronic databases to identify clinical and animal experimental studies comparing TAAR1 agonists with licensed antipsychotics or other control conditions in individuals with psychosis or animal models for psychosis, respectively. The primary outcomes will be overall psychotic symptoms and their behavioural proxies in animals. Secondary outcomes will include side effects and neurobiological measures. Two independent reviewers will conduct study selection, data extraction using predefined forms, and risk of bias assessment using suitable tools based on the study design. Ontologies will be developed to facilitate study identification and data extraction. Data from clinical and animal studies will be synthesized separately using random-effects meta-analysis if appropriate, or synthesis without meta-analysis. Study characteristics will be investigated as potential sources of heterogeneity. Confidence in the evidence for each outcome and source of evidence will be evaluated, considering the summary of the association, potential concerns regarding internal and external validity, and reporting biases. When multiple sources of evidence are available for an outcome, an overall conclusion will be drawn in a triangulation meeting involving a multidisciplinary team of experts. We plan trimonthly updates of the review, and any modifications in the protocol will be documented. The review will be co-produced by multiple stakeholders aiming to produce impactful and relevant results and bridge the gap between preclinical and clinical research on psychosis. PROTOCOL REGISTRATION: PROSPERO-ID: CRD42023451628.

Mindfulness-based programmes for mental health promotion in adults in non-clinical settings: protocol of an individual participant data meta-analysis of randomised controlled trials.

INTRODUCTION: With mental ill health listed as a top cause of global disease burden, there is an urgent need to prioritise mental health promotion programmes. Mindfulness-based programmes (MBPs) are being widely implemented to reduce stress in non-clinical settings. In a recent aggregate-level meta-analysis we found that, compared with no intervention, these MBPs reduce average psychological distress. However, heterogeneity between studies impedes generalisation of effects across every setting. Study-level effect modifiers were insufficient to reduce heterogeneity; studying individual-level effect modifiers is warranted. This requires individual participant data (IPD) and larger samples than those found in existing individual trials. METHODS AND ANALYSIS: We propose an IPD meta-analysis. Our primary aim is to see if, and how, baseline psychological distress, gender, age, education and dispositional mindfulness moderate the effect of MBPs on distress. We will search 13 databases for good-quality randomised controlled trials comparing in-person, expert-defined MBPs in non-clinical settings with passive controls. Two researchers will independently select, extract and appraise trials using the revised Cochrane risk-of-bias tool. Anonymised IPD of eligible trials will be sought from authors, who will be invited to collaborate.The primary outcome will be psychological distress measured using psychometrically validated questionnaires at 1-6 months after programme completion. Pairwise random-effects two-stage IPD meta-analyses will be conducted. Moderator analyses will follow a 'deft' approach. We will estimate subgroup-specific intervention effects. Secondary outcomes and sensitivity analyses are prespecified. Multiple imputation strategies will be applied to missing data. ETHICS AND DISSEMINATION: The findings will refine our knowledge on the effectiveness of MBPs and help improve the targeting of MBPs in non-clinical settings. They will be shared in accessible formats with a range of stakeholders. Public and professional stakeholders are being involved in the planning, conduct and dissemination of this project. PROSPERO REGISTRATION NUMBER: CRD42020200117.