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.).

Can We Prevent Depression in At-Risk Older Adults Using Self-Help? The UK SHARD Trial of Behavioral Activation.

BACKGROUND: Treatment of established depression is the dominant approach to care of older adults, but prevention holds much promise. Self-help interventions are a feasible preventive approach, since they are scalable and low cost. There are few trials in this area. Behavioral Activation (BA) is a credible candidate psychological approach, which has been shown to work in therapist led care but not been trialled in a self-help form. AIM: To test the effectiveness of an unguided self-help intervention based on BA for older adults. METHODS: We compared a self-help intervention based on BA for older people (n = 172) to usual care (n = 160) in a pragmatic randomized controlled trial. Outcomes were depression status and severity (PHQ9) and health related quality of life (SF12). The primary timepoint of the primary outcome was depression at 4 months, with longer term follow up at 12 months to test sustained impact of the primary outcome. RESULTS: At 4 months adjusted PHQ-9 scores for BA self-help were 0.79 lower (95% CI: -1.70 to 0.13; p = 0.09) and the proportion of participants with case-level depression was significantly reduced (BA 31/137 (22.6%) versus usual care 41/141 (29.1%); Odds Ratio 0.48; 95% CI: 0.26-0.92; p = 0.03). There was no PHQ-9 difference at 12 months or for health related quality of life at any point (4 or 12 months). DISCUSSION: Self-help using BA for older people at risk of depression is a feasible and scalable intervention with potential short-term benefits in preventing depression.

The contribution of depressive 'disorder characteristics' to determinations of prognosis for adults with depression: an individual patient data meta-analysis.

BACKGROUND: This study aimed to investigate general factors associated with prognosis regardless of the type of treatment received, for adults with depression in primary care. METHODS: We searched Medline, Embase, PsycINFO and Cochrane Central (inception to 12/01/2020) for RCTs that included the most commonly used comprehensive measure of depressive and anxiety disorder symptoms and diagnoses, in primary care depression RCTs (the Revised Clinical Interview Schedule: CIS-R). Two-stage random-effects meta-analyses were conducted. RESULTS: Twelve (n = 6024) of thirteen eligible studies (n = 6175) provided individual patient data. There was a 31% (95%CI: 25 to 37) difference in depressive symptoms at 3-4 months per standard deviation increase in baseline depressive symptoms. Four additional factors: the duration of anxiety; duration of depression; comorbid panic disorder; and a history of antidepressant treatment were also independently associated with poorer prognosis. There was evidence that the difference in prognosis when these factors were combined could be of clinical importance. Adding these variables improved the amount of variance explained in 3-4 month depressive symptoms from 16% using depressive symptom severity alone to 27%. Risk of bias (assessed with QUIPS) was low in all studies and quality (assessed with GRADE) was high. Sensitivity analyses did not alter our conclusions. CONCLUSIONS: When adults seek treatment for depression clinicians should routinely assess for the duration of anxiety, duration of depression, comorbid panic disorder, and a history of antidepressant treatment alongside depressive symptom severity. This could provide clinicians and patients with useful and desired information to elucidate prognosis and aid the clinical management of depression.

Telephone interventions, delivered by healthcare professionals, for providing education and psychosocial support for informal caregivers of adults with diagnosed illnesses.

BACKGROUND: Maintaining care for ill persons in the community is heavily dependent on support from unpaid caregivers. Many caregivers, however, find themselves in a caring role for which they are ill prepared and may require professional support. The telephone is an easily accessible method of providing support irrespective of geographical location. OBJECTIVES: The objective of this review was to evaluate the effectiveness of telephone support interventions, delivered by healthcare professionals, when compared to usual care or non-telephone-based support interventions for providing education and psychosocial support for informal caregivers of people with acute and chronic diagnosed illnesses, and to evaluate the cost-effectiveness of telephone interventions in this population. SEARCH METHODS: We searched the following databases from inception to 16 November 2018: the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; PsycINFO; ProQuest Dissertations and Theses A&I; and CINAHL Complete. We also searched 11 caregiver-specific websites, three conference links, and two clinical trial registries. SELECTION CRITERIA: We included randomised controlled trials (RCTs) (including cluster-RCTs) and quasi-RCTs. We excluded cross-over trials because of the high risk of carry-over effects from one intervention to another. DATA COLLECTION AND ANALYSIS: Two authors independently screened citations against the review's inclusion criteria, extracted data, and assessed the included studies using the Cochrane 'Risk of bias' tool. The review's prespecified primary (quality of life and burden) and secondary outcomes (skill acquisition, psychological health, knowledge, health status and well-being, family functioning, satisfaction, and economic outcomes), where reported, were assessed at the end of intervention delivery and at short-term (≤ 3 months), medium-term (> 3 to ≤ 6 months) and longer-term time points (> 6 to 12 months) following the intervention. Where possible, meta-analyses were conducted, otherwise results were reported narratively. MAIN RESULTS: We included 21 randomised studies involving 1,690 caregivers; 19 studies compared telephone support interventions and usual care, of which 18 contributed data to the analyses. Two studies compared telephone and non-telephone professional support interventions. Caregiver ages ranged from 19 years to 87 years across studies. The majority of participants were female (> 70.53%), with two trials including females only. Most caregivers were family members, educated beyond secondary or high school level or had the equivalent in years of education. All caregivers were based in the community. Overall risk of bias was high for most studies.The results demonstrated that there is probably little or no difference between telephone support interventions and usual care for the primary outcome of quality of life at the end of intervention (SMD -0.02, 95% CI -0.24 to 0.19, 4 studies, 364 caregivers) (moderate-certainty evidence) or burden at the end of intervention (SMD -0.11, 95% CI -0.30 to 0.07, 9 studies, 788 caregivers) (low-certainty evidence). For one study where quality of life at the end of intervention was reported narratively, the findings indicated that a telephone support intervention may result in slightly higher quality of life, compared with usual care. Two further studies on caregiver burden were reported narratively; one reported that telephone support interventions may decrease burden, the other reported no change in the intervention group, compared with usual care.We are uncertain about the effects of telephone support interventions on caregiver depression at the end of intervention (SMD -0.37, 95% CI -0.70 to -0.05, 9 studies, 792 caregivers) due to very low-certainty evidence for this outcome. Depression was reported narratively for three studies. One reported that the intervention may reduce caregiver depression at the end of intervention, but this effect was not sustained at short-term follow-up. The other two studies reported there may be little or no difference between telephone support and usual care for depression at the end of intervention. Six studies measured satisfaction with the intervention but did not report comparative data. All six reported high satisfaction scores with the intervention. No adverse events, including suicide or suicide ideation, were measured or reported by any of the included studies.Our analysis indicated that caregiver anxiety may be slightly reduced (MD -6.0, 95% CI -11.68 to -0.32, 1 study, 61 caregivers) and preparedness to care slightly improved (SMD 0.37, 95% CI 0.09 to 0.64, 2 studies, 208 caregivers) at the end of intervention, following telephone-only support interventions compared to usual care. Findings indicated there may be little or no difference between telephone support interventions and usual care for all of the following outcomes at the end of intervention: problem-solving, social activity, caregiver competence, coping, stress, knowledge, physical health, self-efficacy, family functioning, and satisfaction with supports (practical or social). There may also be little or no effect of telephone support interventions for quality of life and burden at short-term follow-up or for burden and depression at medium-term follow-up.Litttle or no difference was found between groups for any of the reported outcomes in studies comparing telephone and non-telephone professional support interventions. We are uncertain as to the effects of telephone support interventions compared to non-telephone support interventions for caregiver burden and depression at the end of intervention. No study reported on quality of life or satisfaction with the intervention and no adverse events were reported or noted in the two studies reporting on this comparison. AUTHORS' CONCLUSIONS: Although our review indicated slight benefit may exist for telephone support interventions on some outcomes (e.g. anxiety and preparedness to care at the end of intervention), for most outcomes, including the primary outcomes, telephone-only interventions may have little or no effect on caregiver outcomes compared to usual care. The findings of the review were mainly based on studies with overall high risk of bias, and few participants. Further high-quality trials, with larger sample sizes are required.

Homeopathy for treatment of irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a common, chronic disorder that leads to decreased health-related quality of life and work productivity. A previous version of this review was not able to draw firm conclusions about the effectiveness of homeopathic treatment for IBS and recommended that further high quality RCTs were conducted to explore the clinical and cost effectiveness of homeopathic treatment for IBS. Two types of homeopathic treatment were evaluated in this systematic review: 1. Clinical homeopathy where a specific remedy is prescribed for a specific condition; 2. Individualised homeopathic treatment, where a homeopathic remedy based on a person's individual symptoms is prescribed after a detailed consultation. OBJECTIVES: To assess the effectiveness and safety of homeopathic treatment for IBS. SEARCH METHODS: For this update we searched MEDLINE, CENTRAL, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine Database (AMED), the Cochrane IBD Group Specialised Register and trials registers from inception to 31 August 2018. SELECTION CRITERIA: Randomised controlled trials (RCTs), cohort and case-control studies that compared homeopathic treatment with placebo, other control treatments, or usual care, in adults with IBS were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias and extracted data. The primary outcome was global improvement in IBS as measured by an IBS symptom severity score. Secondary outcomes included quality of life, abdominal pain, stool frequency, stool consistency, and adverse events. The overall certainty of the evidence supporting the primary and secondary outcomes was assessed using the GRADE criteria. We used the Cochrane risk of bias tool to assess risk of bias. We calculated the mean difference (MD) and 95% confidence interval (CI) for continuous outcomes and the risk ratio (RR) and 95% CI for dichotomous outcomes. MAIN RESULTS: Four RCTs (307 participants) were included. Two studies compared clinical homeopathy (homeopathic remedy, asafoetida or asafoetida plus nux vomica) to placebo for IBS with constipation (IBS-C). One study compared individualised homeopathic treatment (consultation plus remedy) to usual care for the treatment of IBS in female patients. One study was a three armed RCT comparing individualised homeopathic treatment to supportive listening or usual care. The risk of bias in three studies (the two studies assessing clinical homeopathy and the study comparing individualised homeopathic treatment to usual care) was unclear on most criteria and high for selective reporting in one of the clinical homeopathy studies. The three armed study comparing individualised homeopathic treatment to usual care and supportive listening was at low risk of bias in four of the domains and high risk of bias in two (performance bias and detection bias).A meta-analysis of the studies assessing clinical homeopathy, (171 participants with IBS-C) was conducted. At short-term follow-up of two weeks, global improvement in symptoms was experienced by 73% (46/63) of asafoetida participants compared to 45% (30/66) of placebo participants (RR 1.61, 95% CI 1.18 to 2.18; 2 studies, very low certainty evidence). In the other clinical homeopathy study at two weeks, 68% (13/19) of those in the asafoetida plus nux vomica arm and 52% (12/23) of those in the placebo arm experienced a global improvement in symptoms (RR 1.31, 95% CI 0.80 to 2.15; very low certainty evidence). In the study comparing individualised homeopathic treatment to usual care (N = 20), the mean global improvement score (feeling unwell) at 12 weeks was 1.44 + 4.55 (n = 9) in the individualised homeopathic treatment arm compared to 1.41 + 1.97 (n=11) in the usual care arm (MD 0.03; 95% CI -3.16 to 3.22; very low certainty evidence).In the study comparing individualised homeopathic treatment to usual care, the mean IBS symptom severity score at 6 months was 210.44 + 112.4 (n = 16) in the individualised homeopathic treatment arm compared to 237.3 + 110.22 (n = 60) in the usual care arm (MD -26.86, 95% CI -88.59 to 34.87; low certainty evidence). The mean quality of life score (EQ-5D) at 6 months in homeopathy participants was 69.07 (SD 17.35) compared to 63.41 (SD 23.31) in usual care participants (MD 5.66, 95% CI -4.69 to 16.01; low certainty evidence).For In the study comparing individualised homeopathic treatment to supportive listening, the mean IBS symptom severity score at 6 months was 210.44 + 112.4 (n = 16) in the individualised homeopathic treatment arm compared to 262 + 120.72 (n = 18) in the supportive listening arm (MD -51.56, 95% CI -129.94 to 26.82; very low certainty evidence). The mean quality of life score at 6 months in homeopathy participants was 69.07 (SD 17.35) compared to 63.09 (SD 24.38) in supportive listening participants (MD 5.98, 95% CI -8.13 to 20.09; very low certainty evidence).None of the included studies reported on abdominal pain, stool frequency, stool consistency, or adverse events. AUTHORS' CONCLUSIONS: The results for the outcomes assessed in this review are uncertain. Thus no firm conclusions regarding the effectiveness and safety of homeopathy for the treatment of IBS can be drawn. Further high quality, adequately powered RCTs are required to assess the efficacy and safety of clinical and individualised homeopathy for IBS compared to placebo or usual care.

Telephone-supported computerised cognitive-behavioural therapy: REEACT-2 large-scale pragmatic randomised controlled trial.

BackgroundComputerised cognitive-behavioural therapy (cCBT) for depression has the potential to be efficient therapy but engagement is poor in primary care trials.AimsWe tested the benefits of adding telephone support to cCBT.MethodWe compared telephone-facilitated cCBT (MoodGYM) (n = 187) to minimally supported cCBT (MoodGYM) (n = 182) in a pragmatic randomised trial (trial registration: ISRCTN55310481). Outcomes were depression severity (Patient Health Questionnaire (PHQ)-9), anxiety (Generalized Anxiety Disorder Questionnaire (GAD)-7) and somatoform complaints (PHQ-15) at 4 and 12 months.ResultsUse of cCBT increased by a factor of between 1.5 and 2 with telephone facilitation. At 4 months PHQ-9 scores were 1.9 points lower (95% CI 0.5-3.3) for telephone-supported cCBT. At 12 months, the results were no longer statistically significant (0.9 PHQ-9 points, 95% CI -0.5 to 2.3). There was improvement in anxiety scores and for somatic complaints.ConclusionsTelephone facilitation of cCBT improves engagement and expedites depression improvement. The effect was small to moderate and comparable with other low-intensity psychological interventions.

Smoking cessation in severe mental ill health: what works? an updated systematic review and meta-analysis.

BACKGROUND: People with severe mental ill health are more likely to smoke than those in the general population. It is therefore important that effective smoking cessation strategies are used to help people with severe mental ill health to stop smoking. This study aims to assess the effectiveness and cost -effectiveness of smoking cessation and reduction strategies in adults with severe mental ill health in both inpatient and outpatient settings. METHODS: This is an update of a previous systematic review. Electronic databases were searched during September 2016 for randomised controlled trials comparing smoking cessation interventions to each other, usual care, or placebo. Data was extracted on biochemically-verified, self-reported smoking cessation (primary outcome), as well as on smoking reduction, body weight, psychiatric symptom, and adverse events (secondary outcomes). RESULTS: We included 26 trials of pharmacological and/or behavioural interventions. Eight trials comparing bupropion to placebo were pooled showing that bupropion improved quit rates significantly in the medium and long term but not the short term (short term RR = 6.42 95% CI 0.82-50.07; medium term RR = 2.93 95% CI 1.61-5.34; long term RR = 3.04 95% CI 1.10-8.42). Five trials comparing varenicline to placebo showed that that the addition of varenicline improved quit rates significantly in the medium term (RR = 4.13 95% CI 1.36-12.53). The results from five trials of specialised smoking cessation programmes were pooled and showed no evidence of benefit in the medium (RR = 1.32 95% CI 0.85-2.06) or long term (RR = 1.33 95% CI 0.85-2.08). There was insufficient data to allowing pooling for all time points for varenicline and trials of specialist smoking cessation programmes. Trials suggest few adverse events although safety data were not always reported. Only one pilot study reported cost effectiveness data. CONCLUSIONS: Bupropion and varenicline, which have been shown to be effective in the general population, also work for people with severe mental ill health and their use in patients with stable psychiatric conditions. Despite good evidence for the effectiveness of smoking cessation interventions for people with severe mental ill health, the percentage of people with severe mental ill health who smoke remains higher than that for the general population.

The clinical management of functional neurological disorder: A scoping review of the literature.

OBJECTIVE: To date, there have been no reviews bringing together evidence on the clinical management of functional neurological disorder (FND) and patients', caregivers', and healthcare workers' experiences. This review provides an overview of the literature focused on the clinical management of FND. METHODS: Four databases were searched, and a consultation exercise was conducted to retrieve relevant records dated from September 2010 to September 2020. Articles documenting diagnostic methods, treatments or interventions, or the experiences and perspectives of patients and healthcare workers in the clinical management of FND were included. RESULTS: In total, 2756 records were retrieved, with 162 included in this review. The diagnostic methods reported predominantly included positive clinical signs, v-EEG and EEG. Psychological treatments and medication were the most reported treatments. Mixed findings of the effectiveness of CBT were found. Haloperidol, physiotherapy and scripted diagnosis were found to be effective in reducing FND symptoms. Several facilitators and barriers for patients accessing treatment for FND were reported. CONCLUSION: The literature describing the clinical management for FND has increased considerably in recent times. A wide variety of diagnostic tools and treatments and interventions were found, with more focus being placed on tests that confirm a diagnosis than 'rule-out' tests. The main treatment type found in this review was medication. This review revealed that there is a lack of high-quality evidence and reflects the need for official clinical guidelines for FND, providing healthcare workers and patients the support needed to navigate the process to diagnose and manage FND.

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.

Cost-effectiveness of acupuncture for irritable bowel syndrome: findings from an economic evaluation conducted alongside a pragmatic randomised controlled trial in primary care.

BACKGROUND: There is insufficient evidence to determine whether acupuncture is a cost-effective treatment for irritable bowel syndrome. The objective of this study is to assess the cost-effectiveness of acupuncture as an adjunct to usual care versus usual care alone for the treatment of Irritable Bowel Syndrome (IBS). METHODS: Cost-utility analysis conducted alongside a pragmatic, multicentre, randomised controlled trial. 233 patients with irritable bowel syndrome were randomly allocated to either acupuncture plus usual care, or usual care alone. Cost-effectiveness outcomes are expressed in terms of incremental cost per quality adjusted life year (QALY) at one year after randomisation. Costs were estimated from the UK National Health Service perspective for a time horizon of one year. Cost-utility ratios were estimated based on complete case analysis for the base case analysis, where only patients with available EQ-5D and cost data were included. Sensitivity analyses comprised a multiple imputation approach for missing data and a subgroup analysis for the more severe cases of IBS. RESULTS: The base case analysis showed acupuncture to be marginally more effective than usual care (gain of 0.0035 QALYs, 95% CI: -0.00395 to 0.0465) and more expensive (incremental cost of £218 per patient (95% CI: 55.87 to 492.87) resulting in an incremental cost-effectiveness ratio of approximately £62,500. Sensitivity analysis using multiple imputation for missing data resulted in acupuncture appearing less effective and more costly than usual care, so usual care is dominant. Subgroup analysis selecting the most severe cases of IBS (Symptom Severity Score of over 300) suggested that acupuncture may be a cost-effective treatment option for this group, with a cost-per-QALY of £6,500. CONCLUSIONS: Acupuncture as an adjunct to usual care is not a cost-effective option for the whole IBS population; however it may be cost-effective for those with more severe irritable bowel syndrome. TRIAL REGISTRATION: Current Controlled Trials ISRCTN08827905.

Acupuncture for irritable bowel syndrome: primary care based pragmatic randomised controlled trial.

BACKGROUND: Acupuncture is used by patients as a treatment for irritable bowel syndrome (IBS) but the evidence on effectiveness is limited. The purpose of the study was to evaluate the effectiveness of acupuncture for irritable bowel syndrome in primary care when provided as an adjunct to usual care. DESIGN: A two-arm pragmatic randomised controlled trial. SETTING: Primary care in the United Kingdom. PATIENTS: 233 patients had irritable bowel syndrome with average duration of 13 years and score of at least 100 on the IBS Symptom Severity Score (SSS). INTERVENTIONS: 116 patients were offered 10 weekly individualised acupuncture sessions plus usual care, 117 patients continued with usual care alone. MEASUREMENTS: Primary outcome was the IBS SSS at three months, with outcome data collected every three months to 12 months. RESULTS: There was a statistically significant difference between groups at three months favouring acupuncture with a reduction in IBS Symptom Severity Score of -27.43 (95% CI: -48.66 to -6.21, p=0.012). The number needed to treat for successful treatment (≥50 point reduction in the IBS SSS) was six (95% CI: 3 to 17), based on 49% success in the acupuncture group vs. 31% in the control group, a difference between groups of 18% (95% CI: 6% to 31%). This benefit largely persisted at 6, 9 and 12 months. CONCLUSIONS: Acupuncture for irritable bowel syndrome provided an additional benefit over usual care alone. The magnitude of the effect was sustained over the longer term. Acupuncture should be considered as a treatment option to be offered in primary care alongside other evidenced based treatments. TRIAL REGISTRATION: Current Controlled Trials ISRCTN08827905.

Digital interventions in mental health: evidence syntheses and economic modelling.

BACKGROUND: Economic evaluations provide evidence on whether or not digital interventions offer value for money, based on their costs and outcomes relative to the costs and outcomes of alternatives. OBJECTIVES: (1) Evaluate and summarise published economic studies about digital interventions across different technologies, therapies, comparators and mental health conditions; (2) synthesise clinical evidence about digital interventions for an exemplar mental health condition; (3) construct an economic model for the same exemplar mental health condition using the previously synthesised clinical evidence; and (4) consult with stakeholders about how they understand and assess the value of digital interventions. METHODS: We completed four work packages: (1) a systematic review and quality assessment of economic studies about digital interventions; (2) a systematic review and network meta-analysis of randomised controlled trials on digital interventions for generalised anxiety disorder; (3) an economic model and value-of-information analysis on digital interventions for generalised anxiety disorder; and (4) a series of knowledge exchange face-to-face and digital seminars with stakeholders. RESULTS: In work package 1, we reviewed 76 economic evaluations: 11 economic models and 65 within-trial analyses. Although the results of the studies are not directly comparable because they used different methods, the overall picture suggests that digital interventions are likely to be cost-effective, compared with no intervention and non-therapeutic controls, whereas the value of digital interventions compared with face-to-face therapy or printed manuals is unclear. In work package 2, we carried out two network meta-analyses of 20 randomised controlled trials of digital interventions for generalised anxiety disorder with a total of 2350 participants. The results were used to inform our economic model, but when considered on their own they were inconclusive because of the very wide confidence intervals. In work package 3, our decision-analytic model found that digital interventions for generalised anxiety disorder were associated with lower net monetary benefit than medication and face-to-face therapy, but greater net monetary benefit than non-therapeutic controls and no intervention. Value for money was driven by clinical outcomes rather than by intervention costs, and a value-of-information analysis suggested that uncertainty in the treatment effect had the greatest value (£12.9B). In work package 4, stakeholders identified several areas of benefits and costs of digital interventions that are important to them, including safety, sustainability and reducing waiting times. Four factors may influence their decisions to use digital interventions, other than costs and outcomes: increasing patient choice, reaching underserved populations, enabling continuous care and accepting the 'inevitability of going digital'. LIMITATIONS: There was substantial uncertainty around effect estimates of digital interventions compared with alternatives. This uncertainty was driven by the small number of studies informing most comparisons, the small samples in some of these studies and the studies' high risk of bias. CONCLUSIONS: Digital interventions may offer good value for money as an alternative to 'doing nothing' or 'doing something non-therapeutic' (e.g. monitoring or having a general discussion), but their added value compared with medication, face-to-face therapy and printed manuals is uncertain. Clinical outcomes rather than intervention costs drive 'value for money'. FUTURE WORK: There is a need to develop digital interventions that are more effective, rather than just cheaper, than their alternatives. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018105837. 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. 26, No. 1. See the NIHR Journals Library website for further project information.

Digital interventions are activities accessed via technology platforms (e.g. computers, smartphones and virtual reality) that can improve users' mental health and reduce addiction problems. To assess whether or not digital interventions offer 'value for money', we needed to compare their costs and outcomes with the costs and outcomes of alternatives, such as face-to-face therapy and medication. This was done through economic evaluations. This project consisted of four work packages. In work package 1, we reviewed 76 published economic evaluations of digital interventions for different mental health and addiction problems. We could not directly compare their results because of differences in the methods that were used, but the overall picture suggested that digital interventions could offer good value for money as an alternative to 'doing nothing' or simply monitoring someone or giving them general information. The picture was unclear when digital interventions were compared with face-to-face therapy. In work package 2, we pooled research studies that evaluated the outcomes of digital interventions in reducing anxiety and worry; the results were inconclusive because we were uncertain about the differences in outcomes between digital interventions and alternatives. In work package 3, an economic model suggested that value for money in digital interventions is driven by how good they are and not by how much they cost. In work package 4, we presented our methods and results to service users, mental health professionals and researchers who wanted to know more about the value of digital interventions for specific groups (e.g. children and older adults) and for outcomes other than reducing symptoms (e.g. reducing waiting times for treatment and improving attendance for therapy). Finally, the stakeholders highlighted four factors that may influence their decisions to use digital interventions, other than costs and outcomes: increasing choice, reaching underserved populations, enabling continuous care and accepting the 'inevitability of going digital'.

Socioeconomic Indicators of Treatment Prognosis for Adults With Depression: A Systematic Review and Individual Patient Data Meta-analysis.

Importance: Socioeconomic factors are associated with the prevalence of depression, but their associations with prognosis are unknown. Understanding this association would aid in the clinical management of depression. Objective: To determine whether employment status, financial strain, housing status, and educational attainment inform prognosis for adults treated for depression in primary care, independent of treatment and after accounting for clinical prognostic factors. Data Sources: The Embase, International Pharmaceutical Abstracts, MEDLINE, PsycINFO, and Cochrane (CENTRAL) databases were searched from database inception to October 8, 2021. Study Selection: Inclusion criteria were as follows: randomized clinical trials that used the Revised Clinical Interview Schedule (CIS-R; the most common comprehensive screening and diagnostic measure of depressive and anxiety symptoms in primary care randomized clinical trials), measured socioeconomic factors at baseline, and sampled patients with unipolar depression who sought treatment for depression from general physicians/practitioners or who scored 12 or more points on the CIS-R. Exclusion criteria included patients with depression secondary to a personality or psychotic disorder or neurologic condition, studies of bipolar or psychotic depression, studies that included children or adolescents, and feasibility studies. Studies were independently assessed against inclusion and exclusion criteria by 2 reviewers. Data Extraction and Synthesis: Data were extracted and cleaned by data managers for each included study, further cleaned by multiple reviewers, and cross-checked by study chief investigators. Risk of bias and quality were assessed using the Quality in Prognosis Studies (QUIPS) and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tools, respectively. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses-Individual Participant Data (PRISMA-IPD) reporting guidelines. Main Outcomes and Measures: Depressive symptoms at 3 to 4 months after baseline. Results: This systematic review and individual patient data meta-analysis identified 9 eligible studies that provided individual patient data for 4864 patients (mean [SD] age, 42.5 (14.0) years; 3279 women [67.4%]). The 2-stage random-effects meta-analysis end point depressive symptom scale scores were 28% (95% CI, 20%-36%) higher for unemployed patients than for employed patients and 18% (95% CI, 6%-30%) lower for patients who were homeowners than for patients living with family or friends, in hostels, or homeless, which were equivalent to 4.2 points (95% CI, 3.6-6.2 points) and 2.9 points (95% CI, 1.1-4.9 points) on the Beck Depression Inventory II, respectively. Financial strain and educational attainment were associated with prognosis independent of treatment, but unlike employment and housing status, there was little evidence of associations after adjusting for clinical prognostic factors. Conclusions and Relevance: Results of this systematic review and meta-analysis revealed that unemployment was associated with a poor prognosis whereas home ownership was associated with improved prognosis. These differences were clinically important and independent of the type of treatment received. Interventions that address employment or housing difficulties could improve outcomes for patients with depression.

Assessment of cytokines, microRNA and patient related outcome measures in conversion disorder/functional neurological disorder (CD/FND): The CANDO clinical feasibility study.

BACKGROUND: Conversion disorder/functional neurological disorder (CD/FND) occurs often in neurological settings and can lead to long-term distress, disability and demand on health care services. Systemic low-grade inflammation might play a role, however, the pathogenic mechanism is still unknown. AIM: 1) To explore the feasibility to establish and assess a cohort of CD/FND with motor symptoms, involving persons with lived experience (PPI). 2) To generate proof of concept regarding a possible role for cytokines, microRNA, cortisol levels and neurocognitive symptoms in patients with motor CD/FND. METHOD: Feasibility study. RESULTS: The study showed active involvement of patients despite high clinical illness burden and disability, neurocognitive symptoms, childhood adverse experiences (ACE) and current life events. The study provided valuable knowledge regarding the feasibility of conducting a study in these patients that will inform future study phases. In the sample there were elevated levels of IL6, IL12, IL17A, IFNg, TNFa and VEGF-a, suggesting systemic low-grade inflammation. Also, microRNAs involved in inflammation and vascular inflammation were correlated with TNFa and VEGFa respectively, suggesting proof of concept for an epigenetic mechanism. Owing to the COVID-19 outbreak, the patient sample was limited to 15 patients. CONCLUSION: It is a novelty that this study is conducted in the clinical setting. This innovative, translational study explores stress-related SLI in CD/FND patients and the feasibility of a larger project aiming to develop new treatments for this vulnerable population. Given the positive findings, there is scope to conduct further research into the mechanism of disease in CD/FND.

Systematic Review and Critique of Methods for Economic Evaluation of Digital Mental Health Interventions.

OBJECTIVES: Investment in digital interventions for mental health conditions is growing rapidly, offering the potential to elevate systems that are currently overstretched. Despite a growing literature on economic evaluation of digital mental health interventions (DMHIs), including several systematic reviews, there is no conclusive evidence regarding their cost-effectiveness. This paper reviews the methodology used to determine their cost-effectiveness and assesses whether this meets the requirements for decision-making. In doing so we consider the challenges specific to the economic evaluation of DMHIs, and identify where consensus and possible further research is warranted. METHODS: A systematic review was conducted to identify all economic evaluations of DMHIs published between 1997 and December 2018. The searches included databases of published and unpublished research, reference lists and citations of all included studies, forward citations on all identified protocols and conference abstracts, and contacting authors researchers in the field. The identified studies were critiqued against a published set of requirements for decision-making in healthcare, identifying methodological challenges and areas where consensus is required. RESULTS: The review identified 67 papers evaluating DMHIs. The majority of the evaluations were conducted alongside trials, failing to capture all relevant available evidence and comparators, and long-term impact of mental health disorders. The identified interventions are complex and heterogeneous. As a result, there are a number of challenges specific to their evaluation, including estimation of all costs and outcomes, conditional on analysis viewpoint, and identification of relevant comparators. A taxonomy for DMHIs may be required to inform what interventions can reasonably be pooled and compared. CONCLUSIONS: This study represents the first attempt to understand the appropriateness of the methodologies used to evaluate the value for money of DMHIs, helping work towards consensus and methods' harmonisation on these complex interventions.

Nature-based outdoor activities for mental and physical health: Systematic review and meta-analysis.

Mental health problems are associated with lower quality of life, increased unscheduled care, high economic and social cost, and increased mortality. Nature-based interventions (NBIs) that support people to engage with nature in a structured way are asset-based solutions to improve mental health for community based adults. However, it is unclear which NBIs are most effective, or what format and dose is most efficacious. We systematically reviewed the controlled and uncontrolled evidence for outdoor NBIs. The protocol was registered at PROSPERO (CRD42020163103). Studies that included adults (aged ≥18 years) in community-based settings with or without mental and/or physical health problems were eligible for inclusion. Eligible interventions were structured outdoor activities in green and/or blue space for health and wellbeing. We searched ASSIA, CENTRAL, Embase, Greenfile, MEDLINE, PsycINFO, and Web of Science in October 2019; the search was updated in September 2020. We screened 14,321 records and included 50 studies. Sixteen studies were randomised controlled trials (RCTs); 18 were controlled studies; and 16 were uncontrolled before and after studies. Risk of bias for RCTs was low to moderate; and moderate to high for controlled and uncontrolled studies. Random effects meta-analysis of RCTs showed that NBIs were effective for improving depressive mood -0.64 (95% CI: 1.05 to -0.23), reducing anxiety -0.94 (95% CI: 0.94 to -0.01), improving positive affect 0.95 (95% CI: 0.59 to 1.31), and reducing negative affect -0.52 (95% CI: 0.77 to -0.26). Results from controlled and uncontrolled studies largely reflected findings from RCTs. There was less evidence that NBIs improved physical health. The most effective interventions were offered for between 8 and 12 weeks, and the optimal dose ranged from 20 to 90 min. NBIs, specifically gardening, green exercise and nature-based therapy, are effective for improving mental health outcomes in adults, including those with pre-existing mental health problems.

A Patient Stratification Approach to Identifying the Likelihood of Continued Chronic Depression and Relapse Following Treatment for Depression.

BACKGROUND: Subgrouping methods have the potential to support treatment decision making for patients with depression. Such approaches have not been used to study the continued course of depression or likelihood of relapse following treatment. METHOD: Data from individual participants of seven randomised controlled trials were analysed. Latent profile analysis was used to identify subgroups based on baseline characteristics. Associations between profiles and odds of both continued chronic depression and relapse up to one year post-treatment were explored. Differences in outcomes were investigated within profiles for those treated with antidepressants, psychological therapy, and usual care. RESULTS: Seven profiles were identified; profiles with higher symptom severity and long durations of both anxiety and depression at baseline were at higher risk of relapse and of chronic depression. Members of profile five (likely long durations of depression and anxiety, moderately-severe symptoms, and past antidepressant use) appeared to have better outcomes with psychological therapies: antidepressants vs. psychological therapies (OR (95% CI) for relapse = 2.92 (1.24-6.87), chronic course = 2.27 (1.27-4.06)) and usual care vs. psychological therapies (relapse = 2.51 (1.16-5.40), chronic course = 1.98 (1.16-3.37)). CONCLUSIONS: Profiles at greater risk of poor outcomes could benefit from more intensive treatment and frequent monitoring. Patients in profile five may benefit more from psychological therapies than other treatments.

How can we estimate QALYs based on PHQ-9 scores? Equipercentile linking analysis of PHQ-9 and EQ-5D.

BACKGROUND: Quality-adjusted life years (QALYs) are widely used to measure the impact of various diseases on both the quality and quantity of life and in their economic valuations. It will be clinically important and informative if we can estimate QALYs based on measurements of depression severity. OBJECTIVE: To construct a conversion table from the Patient Health Questionnaire-9 (PHQ-9), the most frequently used depression scale in recent years, to the Euro-Qol Five Dimensions Three Levels (EQ-5D-3L), one of the most commonly used instruments to assess QALYs. METHODS: We obtained individual participant data of randomised controlled trials of internet cognitive-behavioural therapy which had administered depression severity scales and the EQ-5D-3L at baseline and at end of treatment. Scores from depression scales were all converted into the PHQ-9 according to the validated algorithms. We used equipercentile linking to establish correspondences between the PHQ-9 and the EQ-5D-3L. FINDINGS: Individual-level data from five trials (total N=2457) were available. Subthreshold depression (PHQ-9 scores between 5 and 10) corresponded with EQ-5D-3L index values of 0.9-0.8, mild major depression (10-15) with 0.8-0.7, moderate depression (15-20) with 0.7-0.5 and severe depression (20 or higher) with 0.6-0.0. A five-point improvement in PHQ-9 corresponded approximately with an increase in EQ-5D-3L score by 0.03 and a ten-point improvement by approximately 0.25. CONCLUSIONS AND CLINICAL IMPLICATIONS: The conversion table between the PHQ-9 and the EQ-5D-3L scores will enable fine-grained assessment of burden of depression at its various levels of severity and of impacts of its various treatments.

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.

Dismantling, optimising, and personalising internet cognitive behavioural therapy for depression: a systematic review and component network meta-analysis using individual participant data.

BACKGROUND: Internet cognitive behavioural therapy (iCBT) is a viable delivery format of CBT for depression. However, iCBT programmes include training in a wide array of cognitive and behavioural skills via different delivery methods, and it remains unclear which of these components are more efficacious and for whom. METHODS: We did a systematic review and individual participant data component network meta-analysis (cNMA) of iCBT trials for depression. We searched PubMed, PsycINFO, Embase, and the Cochrane Library for randomised controlled trials (RCTs) published from database inception to Jan 1, 2019, that compared any form of iCBT against another or a control condition in the acute treatment of adults (aged ≥18 years) with depression. Studies with inpatients or patients with bipolar depression were excluded. We sought individual participant data from the original authors. When these data were unavailable, we used aggregate data. Two independent researchers identified the included components. The primary outcome was depression severity, expressed as incremental mean difference (iMD) in the Patient Health Questionnaire-9 (PHQ-9) scores when a component is added to a treatment. We developed a web app that estimates relative efficacies between any two combinations of components, given baseline patient characteristics. This study is registered in PROSPERO, CRD42018104683. FINDINGS: We identified 76 RCTs, including 48 trials contributing individual participant data (11 704 participants) and 28 trials with aggregate data (6474 participants). The participants' weighted mean age was 42·0 years and 12 406 (71%) of 17 521 reported were women. There was suggestive evidence that behavioural activation might be beneficial (iMD -1·83 [95% credible interval (CrI) -2·90 to -0·80]) and that relaxation might be harmful (1·20 [95% CrI 0·17 to 2·27]). Baseline severity emerged as the strongest prognostic factor for endpoint depression. Combining human and automated encouragement reduced dropouts from treatment (incremental odds ratio, 0·32 [95% CrI 0·13 to 0·93]). The risk of bias was low for the randomisation process, missing outcome data, or selection of reported results in most of the included studies, uncertain for deviation from intended interventions, and high for measurement of outcomes. There was moderate to high heterogeneity among the studies and their components. INTERPRETATION: The individual patient data cNMA revealed potentially helpful, less helpful, or harmful components and delivery formats for iCBT packages. iCBT packages aiming to be effective and efficient might choose to include beneficial components and exclude ones that are potentially detrimental. Our web app can facilitate shared decision making by therapist and patient in choosing their preferred iCBT package. FUNDING: Japan Society for the Promotion of Science.