Using a pragmatically adapted, low-cost contingency management intervention to promote heroin abstinence in individuals undergoing treatment for heroin use disorder in UK drug services (PRAISE): a cluster randomised trial.

INTRODUCTION: Most individuals treated for heroin use disorder receive opioid agonist treatment (OAT)(methadone or buprenorphine). However, OAT is associated with high attrition and persistent, occasional heroin use. There is some evidence for the effectiveness of contingency management (CM), a behavioural intervention involving modest financial incentives, in encouraging drug abstinence when applied adjunctively with OAT. UK drug services have a minimal track record of applying CM and limited resources to implement it. We assessed a CM intervention pragmatically adapted for ease of implementation in UK drug services to promote heroin abstinence among individuals receiving OAT. DESIGN: Cluster randomised controlled trial. SETTING AND PARTICIPANTS: 552 adults with heroin use disorder (target 660) enrolled from 34 clusters (drug treatment clinics) in England between November 2012 and October 2015. INTERVENTIONS: Clusters were randomly allocated 1:1:1 to OAT plus 12× weekly appointments with: (1) CM targeted at opiate abstinence at appointments (CM Abstinence); (2) CM targeted at on-time attendance at appointments (CM Attendance); or (3) no CM (treatment as usual; TAU). Modifications included monitoring behaviour weekly and fixed incentives schedule. MEASUREMENTS: Primary outcome: heroin abstinence measured by heroin-free urines (weeks 9-12). SECONDARY OUTCOMES: heroin abstinence 12 weeks after discontinuation of CM (weeks 21-24); attendance; self-reported drug use, physical and mental health. RESULTS: CM Attendance was superior to TAU in encouraging heroin abstinence. Odds of a heroin-negative urine in weeks 9-12 was statistically significantly greater in CM Attendance compared with TAU (OR=2.1; 95% CI 1.1 to 3.9; p=0.030). CM Abstinence was not superior to TAU (OR=1.6; 95% CI 0.9 to 3.0; p=0.146) or CM Attendance (OR=1.3; 95% CI 0.7 to 2.4; p=0.438) (not statistically significant differences). Reductions in heroin use were not sustained at 21-24 weeks. No differences between groups in self-reported heroin use. CONCLUSIONS: A pragmatically adapted CM intervention for routine use in UK drug services was moderately effective in encouraging heroin abstinence compared with no CM only when targeted at attendance. CM targeted at abstinence was not effective. TRIAL REGISTRATION NUMBER: ISRCTN 01591254.

Estimating dose-response for time to remission with instrumental variable adjustment: the obscuring effects of drug titration in Genome Based Therapeutic Drugs for Depression Trial (GENDEP): clinical trial data.

BACKGROUND: Threshold regression, in which time to remission is modelled as a stochastic drift towards a boundary, is an alternative to the proportional hazards survival model and has a clear conceptual mechanism for examining the effects of drug dose. However, for both threshold regression and proportional hazard models, when dose titration occurs during treatment, the estimated causal effect of dose can be biased by confounding. An instrumental variable analysis can be used to minimise such bias. METHOD: Weekly antidepressant dose was measured in 380 men and women with major depression treated with escitalopram or nortriptyline for 12 weeks as part of the Genome Based Therapeutic Drugs for Depression (GENDEP) study. The averaged dose relative to maximum prescribing dose was calculated from the 12 trial weeks and tested for association with time to depression remission. We combined the instrumental variable approach, utilising randomised treatment as an instrument, with threshold regression and proportional hazard survival models. RESULTS: The threshold model was constructed with two linear predictors. In the naïve models, averaged daily dose was not associated with reduced time to remission. By contrast, the instrumental variable analyses showed a clear and significant relationship between increased dose and faster time to remission, threshold regression (velocity estimate: 0.878, 95% confidence interval [CI]: 0.152-1.603) and proportional hazards (log hazards ratio: 3.012, 95% CI: 0.086-5.938). CONCLUSIONS: We demonstrate, using the GENDEP trial, the benefits of these analyses to estimate causal parameters rather than those that estimate associations. The results for the trial dataset show the link between antidepressant dose and time to depression remission. The threshold regression model more clearly distinguishes the factors associated with initial severity from those influencing treatment effect. Additionally, applying the instrumental variable estimator provides a more plausible causal estimate of drug dose on treatment effect. This validity of these results is subject to meeting the assumptions of instrumental variable analyses. TRIAL REGISTRATION: EudraCT, 2004-001723-38; ISRCTN, 03693000. Registered on 27 September 2007.

Sertraline and Mirtazapine Versus Placebo in Subgroups of Depression in Dementia: Findings From the HTA-SADD Randomized Controlled Trial.

OBJECTIVE: Studies have shown that antidepressants are no better than placebo in treating depression in dementia. The authors examined antidepressant efficacy in subgroups of depression in dementia with different depressive symptom profiles. METHODS: This study focuses on exploratory secondary analyses on the randomized, parallel-group, double-blind, placebo-controlled Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia (HTA-SADD) trial. The setting included old-age psychiatry services in nine centers in England. The participants included 326 patients meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association probable/possible Alzheimer disease criteria, and Cornell Scale for Depression in Dementia (CSDD) scores of 8 or more. Intervention was placebo (n = 111), sertraline (n = 107), or mirtazapine (n = 108). Latent class analyses (LCA) on baseline CSDD items clustered participants into symptom-based subgroups. Mixed-model analysis evaluated CSDD improvement at 13 and 39 weeks by randomization in each subgroup. RESULTS: LCA yielded 4 subgroups: severe (n = 34), psychological (n = 86), affective (n = 129), and somatic (n = 77). Mirtazapine, but not sertraline, outperformed placebo in the psychological subgroup at week 13 (adjusted estimate: -2.77 [standard error (SE) 1.16; 95% confidence interval: -5.09 to -0.46]), which remained, but lost statistical significance at week 39 (adjusted estimate: -2.97 [SE 1.59; 95% confidence interval: -6.15 to 0.20]). Neither sertraline nor mirtazapine outperformed placebo in the other subgroups. CONCLUSION: Because of the exploratory nature of the analyses and the small sample sizes for subgroup analysis there is the need for caution in interpreting these data. Replication of the potential effects of mirtazapine in the subgroup of those with depression in dementia with "psychological" symptoms would be valuable. These data should not change clinical practice, but future trials should consider stratifying types of depression in dementia in secondary analyses.

Efficacy and cost-effectiveness of an adjunctive personalised psychosocial intervention in treatment-resistant maintenance opioid agonist therapy: a pragmatic, open-label, randomised controlled trial.

BACKGROUND: Opioid use disorder is a chronic, debilitating, and costly disorder that has increased in prevalence in many countries, with an associated sharp rise in mortality. Maintenance opioid agonist therapy is the first-line treatment, but many patients do not stop using illicit or non-prescribed drugs concomitantly. We aimed to test the efficacy and cost-effectiveness of a personalised psychosocial intervention implemented with a toolkit of behaviour-change techniques as an adjunct to opioid agonist therapy. METHODS: We did a pragmatic, open-label, randomised controlled trial at a specialist UK National Health Service community addictions clinic in London, UK. Eligible patients were aged 18 years or older, met criteria for opioid or cocaine dependence, or both, in the past 12 months, and voluntarily sought continued oral maintenance opioid agonist therapy, which they had been prescribed for at least 6 weeks. All participants were treatment resistant (ie, had used illicit or non-prescribed opioids or cocaine on one or more days in the past 28 days at study screening, which was verified by positive urine drug screen). Participants were allocated (1:1) by a web-accessed randomisation sequence (stratified by opioid agonist medication, current cocaine use, and current rug use) to receive a personalised psychosocial intervention (comprising a flexible toolkit of psychological-change methods, including contingency management to reinforce abstinence, recovery activities, and clinic attendance) in addition to treatment as usual, or treatment as usual only (control group). The primary outcome was treatment response at 18 weeks, which was defined as abstinence from illicit and non-prescribed opioids and cocaine in the past 28 days, as measured with treatment outcomes profiles and urine drug screening. Taking a societal cost perspective, we did an evaluation of cost-effectiveness with a wide range of willingness-to-pay values for a unit improvement in the probability of treatment response. We also calculated quality-adjusted life-years (QALYs). Efficacy was analysed in a modified-intention-to-treat population, including all participants who were randomly allocated but excluding those who had previously completed the intervention. This trial is registered with ISRCTN, number ISRCTN69313751. The trial is completed. FINDINGS: Between June 7, 2013, and Dec 21, 2015, we randomly allocated 136 participants to the psychosocial intervention group and 137 to the control group. The trial database was locked on April 19, 2017. Three patients (one in the psychosocial intervention group and two in the control group) who were re-randomised in error were excluded from the analysis. 22 (16%) of 135 patients in the psychosocial intervention group had a treatment response, compared with nine (7%) of 135 in the control group (adjusted log odds 1·20 [95% CI 0·01-2·37]; p=0·048). The psychosocial intervention had a higher probability of being cost-effective than treatment as usual. There was a probability range of 47-87% for willingness-to-pay thresholds of £0-1000 for a unit improvement in the probability of treatment response. QALYs were higher in the psychosocial intervention group than in the control group (mean difference 0·048 [95% CI 0·016-0·080]; p=0·004) in adjusted analyses, with 60% and 67% probabilities of cost-effectiveness at the UK National Institute for Health and Care Excellence's willingness-to-pay thresholds of £20 000 and £30 000 per QALY, respectively. The number of adverse events was similar between groups, and no severe adverse events in either group were judged to be treatment related. One participant in the control group was hospitalised with drug-injection-related sepsis and died. INTERPRETATION: In maintenance opioid agonist therapy, an adjunctive personalised psychosocial intervention in addition to standard therapy was efficacious and cost-effective compared with standard therapy alone at helping treatment-resistant patients abstain from using illicit and non-prescribed opioids and cocaine. FUNDING: Indivior.

Extended-release naltrexone versus standard oral naltrexone versus placebo for opioid use disorder: the NEAT three-arm RCT.

BACKGROUND: People recovering from heroin addiction need better treatments than are currently offered. The chronic relapsing nature of drug dependence means that helping a patient to achieve abstinence is often difficult. Naltrexone blocks the effects of ingested heroin; however, evidence is conflicting regarding the best delivery method. OBJECTIVES: The primary purpose of the trial was to evaluate the clinical effectiveness and cost-effectiveness of extended-release naltrexone versus standard oral naltrexone versus relapse prevention therapy without medication for opioid use disorder (OUD). DESIGN: This was a 3-year, definitive, three-centre, three-arm, parallel group, placebo-controlled, double-blind, double-dummy, randomised controlled trial. SETTING: Two specialist NHS outpatient addiction clinics: one in London and one in Birmingham. PARTICIPANTS: Planned study sample - 300 adult patients with OUD who had completed detoxification. INTERVENTIONS: One iGen/Atral-Cipan Extended Release Naltrexone device (iGen/Atral-Cipan, Castanheira do Ribatejo, Portugal) (765 mg naltrexone or placebo) at day 0 of study week 1. Three weekly directly observed active or placebo oral naltrexone tablets (2 × 50 mg, Monday and Wednesday; 3 × 50 mg, Friday) at day 0 of study week 1 (for 4 weeks) and then an 8-week regimen of patient-administered dosing at the same dosing level. MAIN OUTCOME MEASURE: The primary outcome measure was the proportion of heroin-negative urine drug screen (UDS) results at the end of the 12-week post-randomisation time point. RESULTS: Six patients were recruited and randomised to receive study interventions. Two patients had no positive UDS samples for heroin during the 12-week treatment period, one patient had only one positive UDS sample and the remaining patients had two, six and eight positive UDS results for heroin. All patients had at least one missed clinic visit (range 1-14). CONCLUSIONS: Considerable problems were encountered with (1) the stipulated requirement of a validated 'detoxified' status prior to the initiation of the study naltrexone, (2) the requirement for a consent cooling-off period and (3) delays awaiting the surgical implant procedure. Major upheaval to the organisation and delivery of NHS community treatment services across England led to extremely poor levels of actual entry of patients into the trial. Research-vital clinical and procedural requirements were, therefore, more challenging to implement. The potential therapeutic value of the opioid antagonist naltrexone still needs clear investigation, including comparison of the established oral form with the new ultra-long-acting depot implant formulations (for which no licensed products exist in Europe). Despite the small number of study participants, some tentative conclusions can be reached, relevant to potential future work. The blinding of the active/placebo medications appeared to be good. Self-report was not sufficient to detect instances of heroin use. Self-report plus UDS information provided a fuller picture. Instances of lapsed heroin use were not necessarily followed by full relapse, and future work should consider the lapse-relapse relationship. The prison release setting also warrants special consideration. In future, investigators should consider seeking ethics approval for studies in which clinical procedures to accelerate the treatment process are permitted, even if outside orthodox clinical practice, if they address a clinical need at the time of challenge and clinical risk. In addition, it may be appropriate to seek exemption from the ordinary requirement of a cooling-off period after securing consent because it is often essential to initiate treatment promptly. TRIAL REGISTRATION: Current Controlled Trials ISRCTN95809946. 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. 23, No. 3. See the NIHR Journals Library website for further project information.

Advanced Statistics for Exotic Animal Practitioners.

Correlation and regression assess the association between 2 or more variables. This article reviews the core knowledge needed to understand these analyses, moving from visual analysis in scatter plots through correlation, simple and multiple linear regression, and logistic regression. Correlation estimates the strength and direction of a relationship between 2 variables. Regression can be considered more general and quantifies the numerical relationships between an outcome and 1 or multiple variables in terms of a best-fit line, allowing predictions to be made. Each technique is discussed with examples and the statistical assumptions underlying their correct application.

A multicentre randomiSed controlled TRial of IntraVEnous immunoglobulin compared with standard therapy for the treatment of transverse myelitis in adults and children (STRIVE).

BACKGROUND: Transverse myelitis (TM) is an immune-mediated disorder of the spinal cord that affects adults and children and that causes motor, sensory and autonomic dysfunction. There is a prolonged recovery phase, which may continue for many years. Neuromyelitis optica (NMO) is an uncommon relapsing inflammatory central nervous system condition in which TM can be the first presenting symptom. As TM and NMO affect many patients in the prime of their working life, the disorder can impose a significant demand on health resources. There are currently no robust controlled trials in children or adults to inform the optimal treatment of TM. However, treatment with intravenous immunoglobulin (IVIG) is being effectively used in the management of a range of neurological conditions. Although other interventions such as plasma exchange (PLEX) in addition to intravenous (IV) methylprednisolone therapy can be beneficial in TM, PLEX is costly and technically challenging to deliver in the acute setting. IVIG is more readily accessible and less costly. OBJECTIVE: To evaluate whether additional and early treatment with IVIG is of extra benefit in TM compared with standard therapy with IV steroids. DESIGN: A multicentre, single-blind, parallel-group randomised controlled trial of IVIG compared with standard therapy for the treatment of TM in adults and children. PARTICIPANTS: Patients aged ≥ 1 year diagnosed with either acute first-onset TM or first presentation of NMO. Target recruitment was 170 participants (85 participants per arm). INTERVENTIONS: Participants were randomised 1 : 1 to treatment with IV methylprednisolone only or treatment with IV methylprednisolone plus 2 g/kg of IVIG in divided doses within 5 days of the first commencement of steroid therapy. MAIN OUTCOME MEASURES: Primary outcome measure - American Spinal Injury Association (ASIA) Impairment Scale at 6 months post randomisation, with a good outcome defined by a two-grade change. Secondary and tertiary outcome measures - ASIA motor and sensory scales, Expanded Disability Status Scale, health outcome, quality of life, Client Service Receipt Inventory and International Spinal Cord Injury Pain, Bladder and Bowel Basic Data Sets. RESULTS: In total, 26 participants were screened and two were randomised into the study. With the limited sample size, treatment effect could not be determined. However, we identified barriers to accrual that included strict inclusion criteria, the short enrolment window, challenges associated with the use of the ASIA Impairment Scale as an outcome measure and estimation of the incidence of TM. CONCLUSIONS: The study did not reach the end point and the effect of IVIG in TM/NMO could not be determined. Investigators should be aware of the potential challenges associated with carrying out a rare disease trial with a short enrolment window. The study question is one that still necessitates investigation. Preliminary work to ameliorate the effect of the barriers encountered in this study is vital. TRIAL REGISTRATION: EudraCT 2014-002335-34, ClinicalTrials.gov NCT02398994 and Current Controlled Trials ISRCTN12127581. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 31. See the NIHR Journals Library website for further project information. Funding was also received from Biotest AG, Germany (supply of IVIG) and the Transverse Myelitis Society (excess research cost to facilitate study initiation).

Effectiveness of adjunctive, personalised psychosocial intervention for non-response to opioid agonist treatment: Study protocol for a pragmatic randomised controlled trial.

INTRODUCTION: Opioid use disorder (OUD) is a debilitating and relapsing psychiatric disorder; opioid agonist therapy (OAT) is the front-line, evidence-supported treatment. A substantial number of patients relapse or continue to use heroin or other illicit drugs during OAT. There is considerable heterogeneity in the OAT-resistant sub-population, with many behavioural moderators of treatment response. We have developed a personalised psychosocial intervention (PSI) targeting these individuals. A formulation-guided assessment is linked to a toolkit of motivational, cognitive/behavioural and social support techniques. Change methods have been adapted from evidence-supported psychological therapies and are idiosyncratically tailored to the need and response. METHODS: In this single-centre, 18-week, parallel group, pragmatic randomised clinical trial, we will determine the clinical and cost-effectiveness of the PSI as an adjunctive intervention during OAT, in comparison to opioid agonist treatment-as-usual. We plan to recruit 368 adults. The primary outcome measure is the proportion of participants categorised as 'responders' at the end of the intervention (defined as self-reported abstinence from heroin and cocaine with no positive biological drug tests during the 28days prior to the endpoint). Secondary outcomes include: percentage of days abstinent from heroin and cocaine in the 28days before follow-up; treatment retention; therapy compliance; health and social functioning; exploratory genetic biomarkers; and analyses of treatment moderation and mediation. CONCLUSIONS: This pragmatic controlled trial determines the effectiveness and cost-effectiveness of a personalised PSI for non-responding patients during OAT. Our intervention applies motivational, cognitive/behavioural and social support techniques adapted from evidence-based therapies. Findings will inform stratified delivery of OAT.

Prenatal anxiety, maternal stroking in infancy, and symptoms of emotional and behavioral disorders at 3.5 years.

Animal findings of long-term effects of maternal behaviors mediated via altered GR gene expression will, if translated into humans, have far reaching implications for our understanding of child and adolescent psychopathology. We have previously shown that mothers' self-reported stroking of their infants modifies associations between prenatal depression and anxiety and child outcomes at 29 weeks and 2.5 years. Here, we examine whether the effect of early maternal stroking is evident at 3.5 years, and in a much larger sample than in previous publications. A general population sample of 1233 first-time mothers completed anxiety measures at 20 weeks gestation, 865 reported on infant stroking at 9 weeks, and 813 on child symptoms at 3.5 years. Maternal stroking moderated the association between pregnancy-specific anxiety and internalizing (p = 0.010) and externalizing (p = 0.004) scores, such that an effect of PSA to increase symptoms was markedly reduced for mothers who reported high levels of stroking. There was no effect of maternal stroking on general anxiety. The findings confirm the previously reported effect of maternal stroking, and in a much larger sample. They indicate that there are long-term effects of early maternal stroking, modifying associations between prenatal anxiety and child emotional and behavioral symptoms.

The NOURISHED randomised controlled trial comparing mentalisation-based treatment for eating disorders (MBT-ED) with specialist supportive clinical management (SSCM-ED) for patients with eating disorders and symptoms of borderline personality disorder.

BACKGROUND: In this multi-centre randomized controlled trial (RCT) we compared modified mentalisation-based treatment (MBT-ED) to specialist supportive clinical management (SSCM-ED) in patients with eating disorders (EDs) and borderline personality disorder symptoms (BPD). This group of patients presents complex challenges to clinical services, and a treatment which addresses their multiple problems has the potential to improve outcome. MBT has been shown to be effective in improving outcome in patients with BPD, but its use has not been reported in ED. METHODS: Sixty-eight eligible participants were randomised to MBT-ED or SSCM-ED. The primary outcome measure was the global score on the Eating Disorder Examination. Secondary outcomes included measures of BPD symptoms (the Zanarini Rating Scale for Borderline Personality Disorder), general psychiatric state, quality of life and service utilisation. Participants were assessed at baseline and at 6, 12 and 18 months after randomisation. Analysis was performed using linear mixed models. RESULTS: Only 15 participants (22 %) completed the 18 month follow-up. Early drop-out occurred significantly more in the SSCM-ED group. Drop-out did not vary with treatment model later in therapy and was sometimes attributed to participants moving away. There was higher drop--out amongst smokers and those with higher neuroticism scores. 47.1 % of participants in the MBT-ED arm and 37.1 % in the SSCM-ED arm attended at least 50 % of therapy sessions offered. Amongst those remaining in the trial, at 12 and 18 months MBT-ED was associated with a greater reduction in Shape Concern and Weight Concern in the Eating Disorder Examination compared to SSCM-ED. At 6, 12 and 18 months there was a decline of ED and BPD symptoms in both groups combined. Ten participants were reported as having had adverse events during the trial, mostly self-harm, and there was one death, attributed as 'unexplained' by the coroner. CONCLUSIONS: The high drop-out rate made interpretation of the results difficult. Greater involvement of research staff in clinical management might have improved compliance with both therapy and research assessment. MBT-ED may have had an impact on core body image psychopathology. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN51304415 . Registered on 19 April 2011.

An economic evaluation of contingency management for completion of hepatitis B vaccination in those on treatment for opiate dependence.

AIMS: To determine whether the provision of contingency management using financial incentives to improve hepatitis B vaccine completion in people who inject drugs entering community treatment represents a cost-effective use of health-care resources. DESIGN: A probabilistic cost-effectiveness analysis was conducted, using a decision-tree to estimate the short-term clinical and health-care cost impact of the vaccination strategies, followed by a Markov process to evaluate the long-term clinical consequences and costs associated with hepatitis B infection. SETTINGS AND PARTICIPANTS: Data on attendance to vaccination from a UK cluster randomized trial. INTERVENTION: Two contingency management options were examined in the trial: fixed versus escalating schedule financial incentives. MEASUREMENT: Life-time health-care costs and quality-adjusted life years discounted at 3.5% annually; incremental cost-effectiveness ratios. FINDINGS: The resulting estimate for the incremental life-time health-care cost of the contingency management strategy versus usual care was £21.86 [95% confidence interval (CI) = -£12.20 to 39.86] per person offered the incentive. For 1000 people offered the incentive, the incremental reduction in numbers of hepatitis B infections avoided over their lifetime was estimated at 19 (95% CI = 8-30). The probabilistic incremental cost per quality adjusted life-year gained of the contingency management programme was estimated to be £6738 (95% CI = £6297-7172), with an 89% probability of being considered cost-effective at a threshold of £20 000 per quality-adjusted life years gained (97.60% at £30 000). CONCLUSIONS: Using financial incentives to increase hepatitis B vaccination completion in people who inject drugs could be a cost-effective use of health-care resources in the UK as long as the incidence remains above 1.2%.

Drug use, health and social outcomes of hard-to-treat heroin addicts receiving supervised injectable opiate treatment: secondary outcomes from the Randomized Injectable Opioid Treatment Trial (RIOTT).

AIMS: The Randomized Injectable Opioid Treatment Trial (RIOTT) compared supervised injectable heroin (SIH) and supervised injectable methadone (SIM) with optimized oral methadone (OOM) (ISRCTN0133807). Heroin addicts (previously unresponsive to treatment) made significant reductions in street heroin use at 6 months when treated with SIH. We now examine secondary outcomes. DESIGN: Multi-site randomized controlled trial (RCT) comparing SIH versus OOM and SIM versus OOM. SETTING: Three supervised injectable opiate clinics in England. PARTICIPANTS: Chronic refractory heroin addicts continuing to inject street heroin virtually daily despite oral substitution treatment (n = 127), randomized to either SIH(n = 43), SIM(n = 42) or OOM(n = 42). All received high levels of medical and psychosocial support. SECONDARY OUTCOMES: wider drug use, crime, health and social functioning at 6 months. FINDINGS: At 6 months, no significant differences were found between treatment groups in wider drug use (crack/cocaine, benzodiazepines, alcohol), physical and mental health (SF-36) or social functioning. Within each treatment group, significant reductions were observed in crime [SIH = odds ratio (OR) 0.05; P < 0.001; SIM = OR 0.11; P = 0.002; OOM = OR 0.11; P = 0.003] and money spent per week on illicit drugs (SIH = mean change £-289.43; P < 0.001; SIM = mean change £-183.41; P < 0.001; OOM = mean change £-162.80; P < 0.001), with SIH significantly more likely to have reduced money spent on illicit drugs versus OOM (mean difference £-92.04; P < 0.001). Significant improvements were seen in physical health for SIH and SIM (SIH = mean change 3.97; P = 0.008; SIM = mean change 4.73; P = 0.002) and mental health for OOM (mean change 6.04; P = 0.013). CONCLUSIONS: Supervised injectable heroin treatment and supervised injectable methadone treatment showed no clearly identified benefit over optimized oral methadone in terms of wider drug use, crime, physical and mental health within a 6-month period, despite reducing street heroin use to a greater extent. However, all interventions were associated with improvements in these outcomes.

Use of contingency management incentives to improve completion of hepatitis B vaccination in people undergoing treatment for heroin dependence: a cluster randomised trial.

BACKGROUND: Poor adherence to treatment diminishes its individual and public health benefit. Financial incentives, provided on the condition of treatment attendance, could address this problem. Injecting drug users are a high-risk group for hepatitis B virus (HBV) infection and transmission, but adherence to vaccination programmes is poor. We aimed to assess whether contingency management delivered in routine clinical practice increased the completion of HBV vaccination in individuals receiving opioid substitution therapy. METHODS: In our cluster randomised controlled trial, we enrolled participants at 12 National Health Service drug treatment services in the UK that provided opioid substitution therapy and nurse-led HBV vaccination with a super-accelerated schedule (vaccination days 0, 7, and 21). Clusters were randomly allocated 1:1:1 to provide vaccination without incentive (treatment as usual), with fixed value contingency management (three £10 vouchers), or escalating value contingency management (£5, £10, and £15 vouchers). Both contingency management schedules rewarded on-time attendance at appointments. The primary outcome was completion of clinically appropriate HBV vaccination within 28 days. We also did sensitivity analyses that examined vaccination completion with full adherence to appointment times and within a 3 month window. The trial is registered with Current Controlled Trials, number ISRCTN72794493. FINDINGS: Between March 16, 2011, and April 26, 2012, we enrolled 210 eligible participants. Compared with six (9%) of 67 participants treated as usual, 35 (45%) of 78 participants in the fixed value contingency management group met the primary outcome measure (odds ratio 12·1, 95% CI 3·7-39·9; p<0·0001), as did 32 (49%) of 65 participants in the escalating value contingency management group (14·0, 4·2-46·2; p<0·0001). These differences remained significant with sensitivity analyses. INTERPRETATION: Modest financial incentives delivered in routine clinical practice significantly improve adherence to, and completion of, HBV vaccination programmes in patients receiving opioid substitution therapy. Achievement of this improvement in routine clinical practice should now prompt actual implementation. Drug treatment providers should employ contingency management to promote adherence to vaccination programmes. The effectiveness of routine use of contingency management to achieve long-term behaviour change remains unknown. FUNDING: National Institute for Health Research (RP-PG-0707-10149).

Study Protocol for a randomized controlled trial of mentalization based therapy against specialist supportive clinical management in patients with both eating disorders and symptoms of borderline personality disorder.

BACKGROUND: The NOURISHED study: Nice OUtcomes for Referrals with Impulsivity, Self Harm and Eating Disorders.Eating Disorders (ED) and Borderline Personality Disorder (BPD) are both difficult to treat and the combination presents particular challenges. Both are associated with vulnerability to loss of mentalization (awareness of one's own and others' emotional state). In BPD, Mentalization Based therapy (MBT) has been found effective in reducing symptoms. In this trial we investigate the effectiveness and cost-effectiveness of MBT adapted for Eating disorders (Mentalization Based Therapy for Eating Disorders (MBT-ED)) compared to a standard comparison treatment, Specialist Supportive Clinical Management (SSCM-ED) in patients with a combination of an Eating Disorder and either a diagnosis of BPD or a history of self-harm and impulsivity in the previous 12 months. METHODS/DESIGN: We will complete a multi-site single-blind randomized controlled trial (RCT) of MBT-ED vs SSCM-ED. Participants will be recruited from three Eating Disorder Services and two Borderline Personality Disorder Services in London. Participants allocated to MBT-ED will receive one year of weekly group and individual therapy and participants allocated to SSCM-ED will receive 20 sessions of individual therapy over 1 year. In addition, participants in both groups will have access to up to 5 hours of dietetic advice. The primary outcome measure is the global score on the Eating Disorders Examination. Secondary outcome measures include total score on the Zanarini BPD scale, the Object Relations Inventory, the Depression Anxiety Stress Scales, quality of life and cost-effectiveness. Measures are taken at recruitment and at 6 month intervals up to 18 months. DISCUSSION: This is the first Randomised Controlled Trial of MBT-ED in patients with eating disorders and symptoms of BPD and will provide evidence to inform therapy decisions in this group of patients. During MBT-ED mentalization is encouraged, while in SSCM-ED it is not overtly addressed. This study will help elucidate mechanisms of change in the two therapies and analysis of therapy and interview transcripts will provide qualitative information about the conduct of therapy and changes in mentalization and object relations. TRIAL REGISTRATION: ISRCTN51304415.

Complex metabolically demanding sensory processing in the olfactory system: implications for epilepsy.

Although the olfactory system is not generally associated with seizures, sharp application of odor eliciting activity in a large number of olfactory sensory neurons (OSNs) has been shown to elicit seizures. This is most likely due to increased ictal activity in the anterior piriform cortex-an area of the olfactory system that has limited GABAergic interneuron inhibition of pyramidal output cell activity. Such hyperexcitability in a well-characterized and highly accessible system makes olfaction a potentially powerful model system to examine epileptogenesis.

Diphenytoin, riluzole and lidocaine: three sodium channel blockers, with different mechanisms of action, decrease hippocampal epileptiform activity.

Epilepsy is a condition affecting 1-2% of the population, characterized by the presence of spontaneous, recurrent seizures. The most common type of acquired epilepsy is temporal lobe epilepsy (TLE). Up to 30% of patients with TLE are refractory to currently available compounds, and there is an urgent need to identify novel targets for therapy. Here, we utilized the in-vitro CA3 burst preparation to examine alterations in network excitability, characterized by changes in interburst interval. Specifically, we show that bath application of three different sodium channel blockers-diphenytoin, riluzole, and lidocaine-slow spontaneous CA3 bursts. This in turn, decreased the epileptiform activity. These compounds work at different sites on voltage-gated sodium channels, but produce a similar network phenotype of decreased excitability. In the case of diphenytoin and riluzole, the change in network activity (i.e., increased interburst intervals) was persistent following drug washout. Lidocaine application, however, only increased the CA3 interburst interval when it was in the bath solution. Thus, its action was not permanent and resulted in returning CA3 bursting to baseline levels. These data demonstrate that the CA3 burst preparation provides a relatively easy and quick platform for identifying compounds that can decrease network excitability, providing the initial screen for further and more complex in-vivo, freely-behaving animal studies.

Joint crisis plans for people with borderline personality disorder: feasibility and outcomes in a randomised controlled trial.

BACKGROUND: People with borderline personality disorder frequently experience crises. To date, no randomised controlled trials (RCTs) of crisis interventions for this population have been published. AIMS: To examine the feasibility of recruiting and retaining adults with borderline personality disorder to a pilot RCT investigating the potential efficacy and cost-effectiveness of using a joint crisis plan. METHOD: An RCT of joint crisis plans for community-dwelling adults with borderline personality disorder (trial registration: ISRCTN12440268). The primary outcome measure was the occurrence of self-harming behaviour over the 6-month period following randomisation. Secondary outcomes included depression, anxiety, engagement and satisfaction with services, quality of life, well-being and cost-effectiveness. RESULTS: In total, 88 adults out of the 133 referred were eligible and were randomised to receive a joint crisis plan in addition to treatment as usual (TAU; n = 46) or TAU alone (n = 42). This represented approximately 75% of our target sample size and follow-up data were collected on 73 (83.0%) participants. Intention-to-treat analysis revealed no significant differences in the proportion of participants who reported self-harming (odds ratio (OR) = 1.9, 95% CI 0.53-6.5, P = 0.33) or the frequency of self-harming behaviour (rate ratio (RR) = 0.74, 95% CI 0.34-1.63, P = 0.46) between the two groups at follow-up. No significant differences were observed between the two groups on any of the secondary outcome measures or costs. CONCLUSIONS: It is feasible to recruit and retain people with borderline personality disorder to a trial of joint crisis plans and the intervention appears to have high face validity with this population. However, we found no evidence of clinical efficacy in this feasibility study.

Cost-effectiveness analyses for mirtazapine and sertraline in dementia: randomised controlled trial.

BACKGROUND: Depression is a common and costly comorbidity in dementia. There are very few data on the cost-effectiveness of antidepressants for depression in dementia and their effects on carer outcomes. AIMS: To evaluate the cost-effectiveness of sertraline and mirtazapine compared with placebo for depression in dementia. METHOD: A pragmatic, multicentre, randomised placebo-controlled trial with a parallel cost-effectiveness analysis (trial registration: ISRCTN88882979 and EudraCT 2006-000105-38). The primary cost-effectiveness analysis compared differences in treatment costs for patients receiving sertraline, mirtazapine or placebo with differences in effectiveness measured by the primary outcome, total Cornell Scale for Depression in Dementia (CSDD) score, over two time periods: 0-13 weeks and 0-39 weeks. The secondary evaluation was a cost-utility analysis using quality-adjusted life years (QALYs) computed from the Euro-Qual (EQ-5D) and societal weights over those same periods. RESULTS: There were 339 participants randomised and 326 with costs data (111 placebo, 107 sertraline, 108 mirtazapine). For the primary outcome, decrease in depression, mirtazapine and sertraline were not cost-effective compared with placebo. However, examining secondary outcomes, the time spent by unpaid carers caring for participants in the mirtazapine group was almost half that for patients receiving placebo (6.74 v. 12.27 hours per week) or sertraline (6.74 v. 12.32 hours per week). Informal care costs over 39 weeks were £1510 and £1522 less for the mirtazapine group compared with placebo and sertraline respectively. CONCLUSIONS: In terms of reducing depression, mirtazapine and sertraline were not cost-effective for treating depression in dementia. However, mirtazapine does appear likely to have been cost-effective if costing includes the impact on unpaid carers and with quality of life included in the outcome. Unpaid (family) carer costs were lower with mirtazapine than sertraline or placebo. This may have been mediated via the putative ability of mirtazapine to ameliorate sleep disturbances and anxiety. Given the priority and the potential value of supporting family carers of people with dementia, further research is warranted to investigate the potential of mirtazapine to help with behavioural and psychological symptoms in dementia and in supporting carers.

α7-Nicotinic acetylcholine receptor: role in early odor learning preference in mice.

Recently, we have shown that mice with decreased expression of α7-nicotinic acetylcholine receptors (α7) in the olfactory bulb were associated with a deficit in odor discrimination compared to wild-type mice. However, it is unknown if mice with decreased α7-receptor expression also show a deficit in early odor learning preference (ELP), an enhanced behavioral response to odors with attractive value observed in rats. In this study, we modified ELP methods performed in rats and implemented similar conditions in mice. From post-natal days 5-18, wild-type mice were stroked simultaneously with an odor presentation (conditioned odor) for 90 s daily. Control mice were only stroked, exposed to odor, or neither. On the day of testing (P21), mice that were stroked in concert with a conditioned odor significantly investigated the conditioned odor compared to a novel odor, as observed similarly in rats. However, mice with a decrease in α7-receptor expression that were stroked during a conditioned odor did not show a behavioral response to that odorant. These results suggest that decreased α7-receptor expression has a role in associative learning, olfactory preference, and/or sensory processing deficits.

Effectiveness of group and self-help cognitive behavior therapy in reducing problematic menopausal hot flushes and night sweats (MENOS 2): a randomized controlled trial.

OBJECTIVE: The aim of this study was to examine the effectiveness of group cognitive behavioral therapy (CBT) and guided self-help CBT in reducing hot flush and night sweat (HF/NS) problem rating at 6 and 26 weeks after randomization. METHODS: This was a randomized control trial of 140 women having 10 or more problematic HF/NS a week for at least a month. The primary outcome was HF/NS problem rating (1-10) at 6 weeks after randomization. Secondary outcomes were physiologically measured HF/NS at 6 weeks; HF/NS problem rating at 6 weeks; and frequency, mood (Women's Health Questionnaire), and health-related quality of life (General Health Survey Short Form-36) at 6 and 26 weeks. Intention-to-treat analysis was used, and between-group differences were estimated using linear mixed models. RESULTS: Baseline mean (SD) HF/NS weekly frequency was 63.15 (49.24), and problem rating was 5.87 (2.28). Group and self-help CBT both significantly reduced HF/NS problem rating at 6 weeks-group CBT versus no treatment control (NTC; adjusted mean difference, 2.12; 95% CI, 1.36-2.88; P < 0.001) and self-help CBT versus NTC (adjusted mean difference, 2.08; 95% CI, 1.29-2.86; P < 0.001)-and at 26 weeks-group CBT versus NTC (adjusted mean difference, 1.33; 95% CI, 0.54-2.13; P = 0.001) and self-help CBT versus NTC (adjusted mean difference, 1.19; 95% CI, 0.36-2.02; P = 0.005). Group and self-help CBT significantly reduced night sweat frequency at 6 and 26 weeks. There were improvements in mood and quality of life at 6 weeks and improved emotional and physical functioning for group CBT at 26 weeks. CONCLUSIONS: These results suggest that CBT delivered in group or self-help format is an effective treatment option for women during the menopause transition and postmenopause with problematic HF/NS.