Specialist physiotherapy for functional motor disorder in England and Scotland (Physio4FMD): a pragmatic, multicentre, phase 3 randomised controlled trial.

BACKGROUND: Functional motor disorder-the motor variant of functional neurological disorder-is a disabling condition that is commonly associated with poor health outcomes. Pathophysiological models have inspired new treatment approaches such as specialist physiotherapy, although evidence from large randomised controlled trials is absent. We aimed to assess the clinical effectiveness of a specialist physiotherapy intervention for functional motor disorder compared with treatment as usual. METHODS: In this pragmatic, multicentre, phase 3 randomised controlled trial at 11 hospitals in England and Scotland, adults with a clinically definite diagnosis of functional motor disorder, diagnosed by a neurologist, were included. Participants were randomly assigned (1:1, stratified by site) using a remote web-based application to either specialist physiotherapy (a protocolised intervention of nine sessions plus follow-up) or treatment as usual (referral to local community neurological physiotherapy). Individuals working on data collection and analysis were masked to treatment allocation. The primary outcome was the physical functioning domain of the 36-item short form health questionnaire (SF36) at 12 months after randomisation. The primary analysis followed a modified intention-to-treat principle, using a complete case approach; participants who were unable to receive their randomised treatment due to the suspension of health-care services during the COVID-19 pandemic were excluded from the primary analysis. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN56136713, and is completed. FINDINGS: Recruitment occurred between Oct 19, 2018, and March 11, 2020, pausing during the COVID-19 lockdown, and resuming from Aug 3, 2021, to Jan 31, 2022. Of 355 participants who were enrolled, 179 were randomly assigned to specialist physiotherapy and 176 to treatment as usual. 89 participants were excluded from the primary analysis due to COVID-19 interruption to treatment (27 were assigned to specialist physiotherapy and 62 to treatment as usual). After accounting for withdrawals (n=11) and loss to follow-up (n=14), the primary analysis included data from 241 participants (138 [91%] assigned specialist physiotherapy and 103 [90%] assigned treatment as usual). Physical functioning, as assessed by SF36, did not differ significantly between groups (adjusted mean difference 3·5, 95% CI -2·3 to 9·3; p=0·23). There were no serious adverse events related to the trial interventions. 35 serious adverse events were recorded in the specialist physiotherapy group by 24 participants (17·0%), and 24 serious adverse events were recorded in the treatment as usual group by 18 participants (17·0%); one death occurred in the specialist physiotherapy group (cause of death was recorded as suicide). All were considered unrelated to specialist physiotherapy. INTERPRETATION: Although more participants who were assigned specialist physiotherapy self-rated their motor symptoms as improved and had better scores on subjective measures of mental health, the intervention did not result in better self-reported physical functioning at 12 months. Both the specialist and community neurological physiotherapy appeared to be a safe and a valued treatment for selected patients with functional motor disorder. Future research should continue to refine interventions for people with functional motor disorder and develop evidence-based methods to guide treatment triage decisions. FUNDING: National Institute for Health and Care Research and Health Technology Assessment Programme.

Feasibility randomised controlled trial of face-to-face counselling and mobile phone messages compared to usual care for smokeless tobacco cessation in Indian primary care: Project CERTAIN.

INTRODUCTION: Smokeless tobacco (SLT) use in low- and middle-income countries (LMICs) has adverse health consequences. We hypothesize that it is feasible to test an intervention of mobile phone messages and face-to-face counselling session for SLT cessation in India. METHODS: We conducted an exploratory, individual parallel two group, randomised controlled trial (RCT), with baseline -and end-point (three months from randomisation) assessments in urban primary health centres in Odisha, India. A total of 250 current (i.e., users in the last three months) SLT users or dual users (i.e., smokers and SLT users) were recruited to the trial (125 in each group). Participants were randomised to either routine care, face-to-face counselling, and reminder mobile messages or routine care only. The primary outcomes were to assess the feasibility of running a full RCT including recruitment, compliance, and retention. RESULTS: A total seven (77.8%) out of nine primary care centres took part in the trial. Out of the 315 SLT users invited to participate, 250 provided consent and were randomised [79.4% (95% CI: 74.5, 83.7)]. Out of the 250 randomised SLT users, 238 [95% (95% CI: 91.8, 97.5)] were followed up at three months (117 in the intervention group and 121 in the control group). Of the participants in the intervention group, 74 (63.8%) reported that they received the mobile messages. CONCLUSIONS: This exploratory trial demonstrated the feasibility of delivering and evaluating an intervention of mobile phone messages and face-to-face counselling for SLT users in Indian primary care in a full randomised trial. IMPLICATIONS: This study found that combining mobile messages with face-to-face counselling for smokeless tobacco users visiting primary health care settings in India is feasible in terms of recruitment of users, compliance with the intervention, and retention of study participants within the trial.The biochemically verified smokeless tobacco abstinence rate was higher in the intervention group compared with the control groupThere was poor agreement between self-reported tobacco cessation and the measured salivary cotinine in smokeless tobacco users.The findings support the feasibility and acceptability of the intervention signalling the need for a larger clinical trial to test effectiveness of the intervention.

Suicidal thoughts, suicide attempt and non-suicidal self-harm amongst lesbian, gay and bisexual adults compared with heterosexual adults: analysis of data from two nationally representative English household surveys.

PURPOSE: We aimed to compare differences in suicidality and self-harm between specific lesbian, gay and bisexual (LGB) groups, and investigate whether minority stress factors might contribute to any associations, addressing methodological limitations of previous research. METHODS: We analysed data combined from two population-based representative household surveys of English adults (N = 10,443) sampled in 2007 and 2014. Using multivariable logistic regression models adjusted for age, gender, educational attainment, area-level deprivation, and common mental disorder, we tested the association between sexuality and three suicide-related outcomes: past-year suicidal thoughts, past-year suicide attempt, and lifetime non-suicidal self-harm (NSSH). We added bullying and discrimination (separately) to final models to explore whether these variables might mediate the associations. We tested for interactions with gender and survey year. RESULTS: Lesbian/gay people were more likely to report past-year suicidal thoughts [adjusted odds ratio (AOR) = 2.20; 95% CI 1.08-4.50] than heterosexuals. No minority group had an increased probability of suicide attempt. Bisexual (AOR = 3.02; 95% CI = 1.78-5.11) and lesbian/gay (AOR = 3.19; 95% CI = 1.73-5.88) individuals were more likely to report lifetime NSSH than heterosexuals. There was some evidence to support a contribution of bullying in the association between lesbian/gay identity and past-year suicidal thoughts, and of each minority stress variable in the associations with NSSH. There was no interaction with gender or survey year. CONCLUSION: Specific LGB groups are at elevated risk of suicidal thoughts and NSSH, with a possible contribution of lifetime bullying and homophobic discrimination. These disparities show no temporal shift despite apparent increasing societal tolerance towards sexual minorities.

Validation of Mobile Messages for an mHealth Intervention for Smokeless Tobacco Cessation in India.

BACKGROUND: With the growth in use of mobile messages for behaviour change, the need to incorporate personal needs and cultural characteristics of target users has been promoted. The study aimed to describe the findings of content validation of mobile messages designed to promote smokeless tobacco cessation in primary care. METHODS: This study used a concurrent mixed-method approach with 13 patients who were tobacco users at urban primary care clinics. The clarity and appeal of 32 messages were rated on a Likert scale from 1 to 10. A mean clarity and appeal score per message was generated. A 5-item discussion guide was used for in-depth interviews and data was analysed using framework analysis. RESULTS: Participants found the content of the messages useful, and preferred shorter and audio formatted messages. The clarity scores for the messages ranged from 7.9 to 9.4 with an average score of 8.7 (SD 0.5). The appeal scores ranged from 7.3 to 9.2, with an average score of 8.5 (SD 0.6). CONCLUSIONS: Twenty-six from a total of 32 messages were found appropriate and finalised for use. This methodology can be used when developing contextually relevant mobile message interventions in other low resource settings.

Classic ketogenic diet versus further antiseizure medicine in infants with drug-resistant epilepsy (KIWE): a UK, multicentre, open-label, randomised clinical trial.

BACKGROUND: Many infancy-onset epilepsies have poor prognosis for seizure control and neurodevelopmental outcome. Ketogenic diets can improve seizures in children older than 2 years and adults who are unresponsive to antiseizure medicines. We aimed to establish the efficacy of a classic ketogenic diet at reducing seizure frequency compared with further antiseizure medicine in infants with drug-resistant epilepsy. METHODS: In this phase 4, open-label, multicentre, randomised clinical trial, infants aged 1-24 months with drug-resistant epilepsy (defined as four or more seizures per week and two or more previous antiseizure medications) were recruited from 19 hospitals in the UK. Following a 1-week or 2-week observation period, participants were randomly assigned using a computer-generated schedule, without stratification, to either a classic ketogenic diet or a further antiseizure medication for 8 weeks. Treatment allocation was masked from research nurses involved in patient care, but not from participants. The primary outcome was the median number of seizures per day, recorded during weeks 6-8. All analyses were by modified intention to treat, which included all participants with available data. Participants were followed for up to 12 months. All serious adverse events were recorded. The trial is registered with the European Union Drug Regulating Authorities Clinical Trials Database (2013-002195-40). The trial was terminated early before all participants had reached 12 months of follow-up because of slow recruitment and end of funding. FINDINGS: Between Jan 1, 2015, and Sept 30, 2021, 155 infants were assessed for eligibility, of whom 136 met inclusion criteria and were randomly assigned; 75 (55%) were male and 61 (45%) were female. 78 infants were assigned to a ketogenic diet and 58 to antiseizure medication, of whom 61 and 47, respectively, had available data and were included in the modifified intention-to-treat analysis at week 8. The median number of seizures per day during weeks 6-8, accounting for baseline rate and randomised group, was similar between the ketogenic diet group (5 [IQR 1-16]) and antiseizure medication group (3 [IQR 2-11]; IRR 1·33, 95% CI 0·84-2·11). A similar number of infants with at least one serious adverse event was reported in both groups (40 [51%] of 78 participants in the ketogenic diet group and 26 [45%] of 58 participants in the antiseizure medication group). The most common serious adverse events were seizures in both groups. Three infants died during the trial, all of whom were randomly assigned a ketogenic diet: one child (who also had dystonic cerebral palsy) was found not breathing at home; one child died suddenly and unexpectedly at home; and one child went into cardiac arrest during routine surgery under anaesthetic. The deaths were judged unrelated to treatment by local principal investigators and confirmed by the data safety monitoring committee. INTERPRETATION: In this phase 4 trial, a ketogenic diet did not differ in efficacy and tolerability to a further antiseizure medication, and it appears to be safe to use in infants with drug-resistant epilepsy. A ketogenic diet could be a treatment option in infants whose seizures continue despite previously trying two antiseizure medications. FUNDING: National Institute for Health and Care Research.

Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling long-term condition of unknown cause. The National Institute for Health and Care Excellence (NICE) published a guideline in 2021 that highlighted the seriousness of the condition, but also recommended that graded exercise therapy (GET) should not be used and cognitive-behavioural therapy should only be used to manage symptoms and reduce distress, not to aid recovery. This U-turn in recommendations from the previous 2007 guideline is controversial.We suggest that the controversy stems from anomalies in both processing and interpretation of the evidence by the NICE committee. The committee: (1) created a new definition of CFS/ME, which 'downgraded' the certainty of trial evidence; (2) omitted data from standard trial end points used to assess efficacy; (3) discounted trial data when assessing treatment harm in favour of lower quality surveys and qualitative studies; (4) minimised the importance of fatigue as an outcome; (5) did not use accepted practices to synthesise trial evidence adequately using GRADE (Grading of Recommendations, Assessment, Development and Evaluations trial evidence); (6) interpreted GET as mandating fixed increments of change when trials defined it as collaborative, negotiated and symptom dependent; (7) deviated from NICE recommendations of rehabilitation for related conditions, such as chronic primary pain and (8) recommended an energy management approach in the absence of supportive research evidence.We conclude that the dissonance between this and the previous guideline was the result of deviating from usual scientific standards of the NICE process. The consequences of this are that patients may be denied helpful treatments and therefore risk persistent ill health and disability.

Integrated therapist and online CBT for depression in primary care (INTERACT): study protocol for a multi-centre randomised controlled trial.

BACKGROUND: Cognitive behavioural therapy (CBT) is an effective treatment for depression. Self-directed online CBT interventions have made CBT more accessible at a lower cost. However, adherence is often poor and, in the absence of therapist support, effects are modest and short-term. Delivering CBT online using instant messaging is clinically and cost-effective; however, most existing platforms are limited to instant messaging sessions, without the support of between-session "homework" activities. The INTERACT intervention integrates online CBT materials and 'high-intensity' therapist-led CBT, delivered remotely in real-time. The INTERACT trial will evaluate this novel integration in terms of clinical and cost-effectiveness, and acceptability to therapists and clients. METHODS: Pragmatic, two parallel-group multi-centre individually randomised controlled trial, with 434 patients recruited from primary care practices in Bristol, London and York. Participants with depression will be identified via General Practitioner record searches and direct referrals. INCLUSION CRITERIA: aged ≥ 18 years; score ≥ 14 on Beck Depression Inventory (BDI-II); meeting International Classification of Diseases (ICD-10) criteria for depression. EXCLUSION CRITERIA: alcohol or substance dependency in the past year; bipolar disorder; schizophrenia; psychosis; dementia; currently under psychiatric care for depression (including those referred but not yet seen); cannot complete questionnaires unaided or requires an interpreter; currently receiving CBT/other psychotherapy; received high-intensity CBT in the past four years; participating in another intervention trial; unwilling/unable to receive CBT via computer/laptop/smartphone. Eligible participants will be randomised to integrated CBT or usual care. Integrated CBT utilises the standard Beckian intervention for depression and comprises nine live therapist-led sessions, with (up to) a further three if clinically appropriate. The first session is 60-90 min via videocall, with subsequent 50-min sessions delivered online, using instant messaging. Participants allocated integrated CBT can access integrated online CBT resources (worksheets/information sheets/videos) within and between sessions. Outcome assessments at 3-, 6-, 9- and 12-month post-randomisation. The primary outcome is the Beck Depression Inventory (BDI-II) score at 6 months (as a continuous variable). A nested qualitative study and health economic evaluation will be conducted. DISCUSSION: If clinically and cost-effective, this model of integrated CBT could be introduced into existing psychological services, increasing access to, and equity of, CBT provision. TRIAL REGISTRATION: ISRCTN, ISRCTN13112900. Registered on 11/11/2020. Currently recruiting participants. Trial registration data are presented in Table 1.

COVID-19 and the Physio4FMD trial: Impact, mitigating strategies and analysis plans.

Introduction: Functional motor disorder (FMD) is a common cause of disabling neurological symptoms such as weakness and tremor. Physio4FMD is a pragmatic, multicentre single blind randomised controlled trial to evaluate effectiveness and cost effectiveness of specialist physiotherapy for FMD. Like many other studies this trial was affected by the COVID-19 pandemic. Methods: The planned statistical and health economics analyses for this trial are described, as well as the sensitivity analyses designed to assess the disruption caused by COVID-19. The trial treatment of at least 89 participants (33%) was disrupted due to the pandemic. To account for this, we have extended the trial to increase the sample size. We have identified four groups based on how participants' involvement in Physio4FMD was affected; A: 25 were unaffected; B: 134 received their trial treatment before the start of the COVID-19 pandemic and were followed up during the pandemic; C: 89 were recruited in early 2020 and had not received any randomised treatment before clinical services closed because of COVID-19; D: 88 participants were recruited after the trial was restarted in July 2021. The primary analysis will involve groups A, B and D. Regression analysis will be used to assess treatment effectiveness. We will conduct descriptive analyses for each of the groups identified and sensitivity regression analyses with participants from all groups, including group C, separately. Discussion: The COVID-19 mitigation strategy and analysis plans are designed to maintain the integrity of the trial while providing meaningful results. Trial registration: ISRCTN56136713.

The value of blood-based measures of liver function and urate in lung cancer risk prediction: A cohort study and health economic analysis.

BACKGROUND: Several studies have reported associations between low-cost blood-based measurements and lung cancer but their role in risk prediction is unclear. We examined the value of expanding lung cancer risk models for targeting low-dose computed tomography (LDCT), including blood measurements of liver function and urate. METHODS: We analysed a cohort of 388,199 UK Biobank participants with 1873 events and calculated the c-index and fraction of new information (FNI) for models expanded to include combinations of blood measurements, lung function (forced expiratory volume in 1 s - FEV1), alcohol status and waist circumference. We calculated the hypothetical cost per lung cancer case detected by LDCT for different scenarios using a threshold of ≥ 1.51 % risk at 6 years. RESULTS: The c-index was 0.805 (95 %CI:0.794-0.816) for the model containing conventional predictors. Expanding to include blood measurements increased the c-index to 0.815 (95 %CI: 0.804-0.826;p < 0.0001;FNI:0.06). Expanding to include FEV1, alcohol status, and waist circumference increased the c-index to 0.811 (95 %CI: 0.800-0.822;p < 0.0001;FNI: 0.04). The c-index for the fully expanded model containing all variables was 0.819 (95 %CI:0.808-0.830;p < 0.0001;FNI:0.09). Model expansion had a greater impact on the c-index and FNI for people with a history of smoking cigarettes relative to the full cohort. Compared with the conventional risk model, the expanded models reduced the number of participants meeting the criteria for LDCT screening by 15-21 %, and lung cancer cases detected by 7-8 %. The additional cost per lung cancer case detected relative to the conventional model was £ 1018 for adding blood tests and £ 9775 for the fully expanded model. CONCLUSION: Blood measurements of liver function and urate made a modest improvement to lung cancer risk prediction compared with a model containing conventional risk factors. There was no evidence that model expansion would improve the cost per lung cancer case detected in UK healthcare settings.

Designing a mobile health smokeless tobacco cessation intervention in Odisha, India: User and provider perspectives.

Objective: There is limited evidence on the development of mobile health (mHealth) interventions for smokeless tobacco (SLT) cessation, despite its widespread use in South Asia. This formative qualitative study explored the perceptions of tobacco users and healthcare providers (HCPs) regarding developing a mHealth intervention for SLT cessation. Methods: This was a qualitative study using in-depth interviews (IDIs) with tobacco users (n = 26) and primary care physicians (PCPs) (n = 5) and focus group discussions (FGDs) with counsellors (n = 2) in four urban primary health centres (UPHCs) in Berhampur, Odisha from February to March 2020. The data were coded and analysed by two researchers using a framework analysis method. The discussion guides and initial codes were developed based on the Transtheoretical Model (TTM) of behaviour change. Results: The results were elaborated under four themes: (1) Current scenario of SLT use; (2) Barriers and facilitators for quitting SLT; (3) Barriers and facilitators for mHealth counselling; and (4) Design and delivery of the proposed intervention. SLT use was prevalent in the community regardless of sociodemographic factors. Peer factors accounted for both tobacco consumption as well as considering cessation. Participants considered mobile message counselling helpful and acceptable. Not having a mobile phone and illiteracy were identified as barriers while ease of access and rising popularity of social media applications were considered facilitators to the use of mHealth for quitting tobacco. Participants preferred messages that were pictorial, short and simple, in the local language, and tailored to individual's needs. Conclusions: This is the first study that provides evidence within the Indian context that the text messaging platform may be used for delivering an SLT cessation intervention. The integration of a theoretical basis and research findings from target users can guide future intervention development.

Developing and internally validating a prognostic model (P Risk) to improve the prediction of psychosis in a primary care population using electronic health records: The MAPPED study.

BACKGROUND: An accurate risk prediction algorithm could improve psychosis outcomes by reducing duration of untreated psychosis. OBJECTIVE: To develop and validate a risk prediction model for psychosis, for use by family doctors, using linked electronic health records. METHODS: A prospective prediction study. Records from family practices were used between 1/1/2010 to 31/12/2017 of 300,000 patients who had consulted their family doctor for any nonpsychotic mental health problem. Records were selected from Clinical Practice Research Datalink Gold, a routine database of UK family doctor records linked to Hospital Episode Statistics, a routine database of UK secondary care records. Each patient had 5-8 years of follow up data. Study predictors were consultations, diagnoses and/or prescribed medications, during the study period or historically, for 13 nonpsychotic mental health problems and behaviours, age, gender, number of mental health consultations, social deprivation, geographical location, and ethnicity. The outcome was time to an ICD10 psychosis diagnosis. FINDINGS: 830 diagnoses of psychosis were made. Patients were from 216 family practices; mean age was 45.3 years and 43.5 % were male. Median follow-up was 6.5 years (IQR 5.6, 7.8). Overall 8-year psychosis incidence was 45.8 (95 % CI 42.8, 49.0)/100,000 person years at risk. A risk prediction model including age, sex, ethnicity, social deprivation, consultations for suicidal behaviour, depression/anxiety, substance abuse, history of consultations for suicidal behaviour, smoking history and prescribed medications for depression/anxiety/PTSD/OCD and total number of consultations had good discrimination (Harrell's C = 0.774). Identifying patients aged 17-100 years with predicted risk exceeding 1.0 % over 6 years had sensitivity of 71 % and specificity of 84 %. FUNDING: NIHR, School for Primary Care Research, Biomedical Research Centre.

Exploratory randomised trial of face-to-face and mobile phone counselling against usual care for tobacco cessation in Indian primary care: a randomised controlled trial protocol for project CERTAIN.

INTRODUCTION: Despite widespread use of smokeless tobacco products by people within the Indian subcontinent, there is little awareness among Indians of its health hazards when compared with smoked tobacco. We hypothesise that mobile phone counselling will be feasible and effective for smokeless tobacco cessation intervention in India. This paper presents the protocol of the development and conduct of an exploratory trial before progression to a full randomised controlled trial. METHODS AND ANALYSIS: An exploratory randomised controlled trial will be conducted in urban primary health centres in the state of Odisha, India. A total of 250 smokeless tobacco users will be recruited to the study (125 in each arm). Participants in the intervention arm will receive routine care together with a face-to-face counselling intervention followed by advice and reminder mobile messages. The control arm will receive routine care, delivered by a primary care physician based on 'Ask' and 'Advice'. All participants will be followed up for 3 months from the first counselling session. The primary outcome of this trial is to assess the feasibility to carry out a full randomised controlled trial. ETHICS AND DISSEMINATION: Ethical approvals were obtained from the Institutional Ethics Committee of Public Health Foundation of India, Health Ministry's Screening Committee, Odisha State Ethics Board and also from University College London Research Ethics Committee, UK. The study findings will be published in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: CTRI/2019/05/019484.

Diagnostic accuracy and usability of the EMBalance decision support system for vestibular disorders in primary care: proof of concept randomised controlled study results.

BACKGROUND: Dizziness and imbalance are common symptoms that are often inadequately diagnosed or managed, due to a lack of dedicated specialists. Decision Support Systems (DSS) may support first-line physicians to diagnose and manage these patients based on personalised data. AIM: To examine the diagnostic accuracy and application of the EMBalance DSS for diagnosis and management of common vestibular disorders in primary care. METHODS: Patients with persistent dizziness were recruited from primary care in Germany, Greece, Belgium and the UK and randomised to primary care clinicians assessing the patients with (+ DSS) versus assessment without (- DSS) the EMBalance DSS. Subsequently, specialists in neuro-otology/audiovestibular medicine performed clinical evaluation of each patient in a blinded way to provide the "gold standard" against which the + DSS, - DSS and the DSS as a standalone tool (i.e. without the final decision made by the clinician) were validated. RESULTS: One hundred ninety-four participants (age range 25-85, mean = 57.7, SD = 16.7 years) were assigned to the + DSS (N = 100) and to the - DSS group (N = 94). The diagnosis suggested by the + DSS primary care physician agreed with the expert diagnosis in 54%, compared to 41.5% of cases in the - DSS group (odds ratio 1.35). Similar positive trends were observed for management and further referral in the + DSS vs. the - DSS group. The standalone DSS had better diagnostic and management accuracy than the + DSS group. CONCLUSION: There were trends for improved vestibular diagnosis and management when using the EMBalance DSS. The tool requires further development to improve its diagnostic accuracy, but holds promise for timely and effective diagnosis and management of dizzy patients in primary care. TRIAL REGISTRATION NUMBER: NCT02704819 (clinicaltrials.gov).

Cost-Utility Analysis of Discontinuing Antidepressants in England Primary Care Patients Compared with Long-Term Maintenance: The ANTLER Study.

BACKGROUND: Depression is a common mental health condition with considerable negative impact on health and well-being. Although antidepressants are recommended as first-line treatment, there is limited evidence regarding the cost effectiveness of long-term maintenance antidepressants for preventing relapse. OBJECTIVES: Our objective was to calculate the mean incremental costs and quality-adjusted life-years (QALYs) over 12 months of discontinuing long-term antidepressant medication in well patients compared with maintenance, using patient-level trial data. METHODS: We conducted a cost-utility analysis of 478 participants from 150 UK general practices recruited to a randomised, double-blind trial (ANTLER). QALYs were calculated from EQ-5D-5L and 12-Item Short Form survey (SF-12) results, with primary analysis using the EQ-5D-5L value set for England. Resource use was collected from primary care patient electronic medical records and self-completed questionnaires capturing mental-health-related resource use. Costs were calculated by applying standard UK unit costs to resource use. Adjustments were made for baseline variables. RESULTS: Participants randomised to discontinuation had significantly worse utility scores at 3 months (- 0.032; 95% confidence interval [CI] - 0.053 to - 0.011) but no significant difference in QALYs (- 0.011; 95% CI - 0.026 to 0.003) or costs (£3.11; 95% CI - 41.28 to 47.50) at 12 months. The probability that discontinuation was cost effective compared with maintenance was 12.9% at a threshold of £20,000 per QALY gained. CONCLUSIONS: Discontinuation of antidepressants was unlikely to be cost effective compared with maintenance for currently well patients on long-term antidepressants. However, this analysis provides no information on the wider impact of antidepressants. Our findings provide information on the potential impact of discontinuing long-term maintenance antidepressants and facilitate improving guidance for shared patient-clinician decision making. TRIAL REGISTRATION: EudraCT number 2015-004210-26; ISRCTN number ISRCTN15969819.

Cardiovascular outcomes of type 2 diabetic patients treated with DPP­4 inhibitors versus sulphonylureas as add-on to metformin in clinical practice.

DPP-4 inhibitors (DPP-4i) and sulphonylureas remain the most widely prescribed add-on treatments after metformin. However, there is limited evidence from clinical practice comparing major adverse cardiovascular events (MACE) in patients prescribed these treatments, particularly among those without prior history of MACE and from vulnerable population groups. Using electronic health records from UK primary care, we undertook a retrospective cohort study with people diagnosed type-2 diabetes mellitus, comparing incidence of MACE (myocardial infarction, stroke, major cardiovascular surgery, unstable angina) and all-cause mortality among those prescribed DPP-4i versus sulphonylureas as add-on to metformin. We stratified analysis by history of MACE, age, social deprivation and comorbidities and adjusted for HbA1c, weight, smoking-status, comorbidities and medications. We identified 17,570 patients prescribed sulphonylureas and 6,267 prescribed DPP-4i between 2008-2017. Of these, 16.3% had pre-existing MACE. Primary incidence of MACE was similar in patients prescribed DPP-4i and sulphonylureas (10.3 vs 8.5 events per 1000 person-years; adjusted Hazard Ratio (adjHR): 0.94; 95%CI 0.80-1.14). For those with pre-existing MACE, rates for recurrence were higher overall, but similar between the two groups (21.8 vs 17.2 events per 1000 person-years; adjHR: 0.93; 95%CI 0.69-1.24). For those aged over 75 and with BMI less than 25 kg/m2 there was a protective effect for DPP-I, warranting further investigation. Patients initiating a DPP-4i had similar risk of cardiovascular outcomes to those initiating a sulphonylurea. This indicates the choice should be based on safety and cost, not cardiovascular prognosis, when deciding between a DPP-4i or sulphonylurea as add-on to metformin.

Antidepressant medication to prevent depression relapse in primary care: the ANTLER RCT.

BACKGROUND: There has been a steady increase in the number of primary care patients receiving long-term maintenance antidepressant treatment, despite limited evidence of a benefit of this treatment beyond 8 months. OBJECTIVE: The ANTidepressants to prevent reLapse in dEpRession (ANTLER) trial investigated the clinical effectiveness and cost-effectiveness of antidepressant medication in preventing relapse in UK primary care. DESIGN: This was a Phase IV, double-blind, pragmatic, multisite, individually randomised parallel-group controlled trial, with follow-up at 6, 12, 26, 39 and 52 weeks. Participants were randomised using minimisation on centre, type of antidepressant and baseline depressive symptom score above or below the median using Clinical Interview Schedule - Revised (two categories). Statisticians were blind to allocation for the outcome analyses. SETTING: General practices in London, Bristol, Southampton and York. PARTICIPANTS: Individuals aged 18-74 years who had experienced at least two episodes of depression and had been taking antidepressants for ≥ 9 months but felt well enough to consider stopping their medication. Those who met an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnosis of depression or with other psychiatric conditions were excluded. INTERVENTION: At baseline, participants were taking citalopram 20 mg, sertraline 100 mg, fluoxetine 20 mg or mirtazapine 30 mg. They were randomised to either remain on their current medication or discontinue medication after a tapering period. MAIN OUTCOME MEASURES: The primary outcome was the time, in weeks, to the beginning of the first depressive episode after randomisation. This was measured by a retrospective Clinical Interview Schedule - Revised that assessed the onset of a depressive episode in the previous 12 weeks, and was conducted at 12, 26, 39 and 52 weeks. The depression-related resource use was collected over 12 months from medical records and patient-completed questionnaires. Quality-adjusted life-years were calculated using the EuroQol-5 Dimensions, five-level version. RESULTS: Between 9 March 2017 and 1 March 2019, we randomised 238 participants to antidepressant continuation (the maintenance group) and 240 participants to antidepressant discontinuation (the discontinuation group). The time to relapse of depression was shorter in the discontinuation group, with a hazard ratio of 2.06 (95% confidence interval 1.56 to 2.70; p < 0.0001). By 52 weeks, relapse was experienced by 39% of those who continued antidepressants and 56% of those who discontinued antidepressants. The secondary analysis revealed that people who discontinued experienced more withdrawal symptoms than those who remained on medication, with the largest difference at 12 weeks. In the discontinuation group, 37% (95% confidence interval 28% to 45%) of participants remained on their randomised medication until the end of the trial. In total, 39% (95% confidence interval 32% to 45%) of participants in the discontinuation group returned to their original antidepressant compared with 20% (95% confidence interval 15% to 25%) of participants in maintenance group. The health economic evaluation demonstrated that participants randomised to discontinuation had worse utility scores at 3 months (-0.037, 95% confidence interval -0.059 to -0.015) and fewer quality-adjusted life-years over 12 months (-0.019, 95% confidence interval -0.035 to -0.003) than those randomised to continuation. The discontinuation pathway, besides giving worse outcomes, also cost more [extra £2.71 per patient over 12 months (95% confidence interval -£36.10 to £37.07)] than the continuation pathway, although the cost difference was not significant. CONCLUSIONS: Patients who discontinue long-term maintenance antidepressants in primary care are at increased risk of relapse and withdrawal symptoms. However, a substantial proportion of patients can discontinue antidepressants without relapse. Our findings will give patients and clinicians an estimate of the likely benefits and harms of stopping long-term maintenance antidepressants and improve shared decision-making. The participants may not have been representative of all people on long-term maintenance treatment and we could study only a restricted range of antidepressants and doses. Identifying patients who will not relapse if they discontinued antidepressants would be clinically important. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15969819 and EudraCT 2015-004210-26. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 69. See the NIHR Journals Library website for further project information.

Antidepressants are used to treat depression when someone is unwell, but are also used as maintenance treatment to prevent the reoccurrence of depression. There has been a large increase in the use of long-term maintenance antidepressant treatment, but the evidence for the benefits of maintenance beyond 8 months is very poor. The ANTidepressants to prevent reLapse in dEpRession (ANTLER) trial was a randomised controlled trial that examined the effectiveness of long-term maintenance treatment with antidepressants. The participants were well enough to consider stopping antidepressant medication, were recruited from primary care and had taken antidepressants for ≥ 9 months. In total, 238 participants were randomised to continue taking antidepressants and 240 were randomised to receive a visually identical tablet that contained no active ingredients after a period when the antidepressants were gradually reduced. Neither the participants nor those interviewing them knew which group they had been placed in, and they were followed up for 1 year. Participants who discontinued antidepressants were more likely to experience relapse than those who continued antidepressants. By 52 weeks, 39% of those who continued antidepressants had experienced a relapse, compared with 56% in the group that discontinued antidepressants. In other words, over a 52-week period, one in every six patients who stopped antidepressants would experience a relapse that may not have occurred if they had remained on their antidepressants. Patients in the discontinuation group reported more symptoms of anxiety and depression and experienced more withdrawal symptoms than those in the maintenance group, mostly in the first 3­4 months after stopping the antidepressants. Participants in the discontinuation group also reported lower quality of life than those in the maintenance group but both groups used similar amounts of health-care and social care resources over the 12-month period. About one-third of participants who were allocated to the discontinuation group in the ANTLER trial decided to restart their antidepressants. However, another one-third of participants in that group remained on trial medication for 12 months and managed without antidepressants. Long-term maintenance treatment with antidepressants is effective in reducing the rate of relapses. For those who are considering stopping their antidepressant, our findings will provide estimates of the likely benefits and harms, to improve shared decision-making and support the regular review of long-term antidepressant prescription.

Maintenance or Discontinuation of Antidepressants in Primary Care.

BACKGROUND: Patients with depression who are treated in primary care practices may receive antidepressants for prolonged periods. Data are limited on the effects of maintaining or discontinuing antidepressant therapy in this setting. METHODS: We conducted a randomized, double-blind trial involving adults who were being treated in 150 general practices in the United Kingdom. All the patients had a history of at least two depressive episodes or had been taking antidepressants for 2 years or longer and felt well enough to consider stopping antidepressants. Patients who had received citalopram, fluoxetine, sertraline, or mirtazapine were randomly assigned in a 1:1 ratio to maintain their current antidepressant therapy (maintenance group) or to taper and discontinue such therapy with the use of matching placebo (discontinuation group). The primary outcome was the first relapse of depression during the 52-week trial period, as evaluated in a time-to-event analysis. Secondary outcomes were depressive and anxiety symptoms, physical and withdrawal symptoms, quality of life, time to stopping an antidepressant or placebo, and global mood ratings. RESULTS: A total of 1466 patients underwent screening. Of these patients, 478 were enrolled in the trial (238 in the maintenance group and 240 in the discontinuation group). The average age of the patients was 54 years; 73% were women. Adherence to the trial assignment was 70% in the maintenance group and 52% in the discontinuation group. By 52 weeks, relapse occurred in 92 of 238 patients (39%) in the maintenance group and in 135 of 240 (56%) in the discontinuation group (hazard ratio, 2.06; 95% confidence interval, 1.56 to 2.70; P<0.001). Secondary outcomes were generally in the same direction as the primary outcome. Patients in the discontinuation group had more symptoms of depression, anxiety, and withdrawal than those in the maintenance group. CONCLUSIONS: Among patients in primary care practices who felt well enough to discontinue antidepressant therapy, those who were assigned to stop their medication had a higher risk of relapse of depression by 52 weeks than those who were assigned to maintain their current therapy. (Funded by the National Institute for Health Research; ANTLER ISRCTN number, ISRCTN15969819.).