The clinical effectiveness and cost effectiveness of clozapine for inpatients with severe borderline personality disorder (CALMED study): a randomised placebo-controlled trial.

Background: Data from case series suggest that clozapine may benefit inpatients with borderline personality disorder (BPD), but randomised trials have not been conducted. Methods: Multicentre, double-blind, placebo-controlled trial. We aimed to recruit 222 inpatients with severe BPD aged 18 or over, who had failed to respond to other antipsychotic medications. We randomly allocated participants on a 1:1 ratio to receive up to 400 mg of clozapine per day or an inert placebo using a remote web-based randomisation service. The primary outcome was total score on the Zanarini Rating scale for Borderline Personality Disorder (ZAN-BPD) at 6 months. Secondary outcomes included self-harm, aggression, resource use and costs, side effects and adverse events. We used a modified intention to treat analysis (mITT) restricted to those who took one or more dose of trial medication, using a general linear model fitted at 6 months adjusted for baseline score, allocation group and site. Results: The study closed early due to poor recruitment and the impact of the COVID-19 pandemic. Of 29 study participants, 24 (83%) were followed up at 6 months, of whom 21 (72%) were included in the mITT analysis. At 6 months, 11 (73%) participants assigned to clozapine and 6 (43%) of those assigned to placebo were still taking trial medication. Adjusted difference in mean total ZAN-BPD score at 6 months was -3.86 (95% Confidence Intervals = -10.04 to 2.32). There were 14 serious adverse events; 6 in the clozapine arm and 8 in the placebo arm of the trial. There was little difference in the cost of care between groups. Interpretation: We recruited insufficient participants to test the primary hypothesis. The study findings highlight problems in conducting placebo-controlled trials of clozapine and in using clozapine for people with BPD, outside specialist inpatient mental health units. Trial registration: ISRCTN18352058. https://doi.org/10.1186/ISRCTN18352058.

Side-effect monitoring of continuing LAI antipsychotic medication in UK adult mental health services.

BACKGROUND: Long-acting injectable (LAI) antipsychotic medications are used to optimise treatment outcomes in schizophrenia. Guaranteed medication delivery increases the responsibility of prescribers to monitor and manage adverse effects. METHODS: In the context of a quality improvement programme conducted by the Prescribing Observatory for Mental Health, a clinical audit addressed documented side-effect monitoring in patients prescribed continuing LAI antipsychotic medication under the care of United Kingdom adult mental health services. RESULTS: A total of 62 mental health services submitted data on 5169 patients prescribed LAI antipsychotic medication for more than a year. An assessment of side effects had been documented in the past year in 2304 (45%) cases. Post hoc analysis showed that extrapyramidal side effects were more likely to have been assessed and found to be present in those patients prescribed LAI haloperidol, flupentixol or zuclopenthixol. There was little other targeting of assessments to the known side effects profiles of individual LAI antipsychotic medications, but when dysphoria had been assessed it was most commonly found with LAI haloperidol treatment and when weight gain, sexual and prolactin-related side effects had been assessed, they were more often identified with LAI paliperidone. CONCLUSION: The data suggest a relatively low frequency of side-effect assessments, largely untargeted. This is likely to result in many adverse effects going unrecognised and unmanaged, thus failing to tackle their potential to confound mental state assessment and adversely affect physical health and adherence. Patients receiving LAI antipsychotic medication have regular contact with a healthcare professional who administers the medication, which provides an opportunity to potentially remedy this situation.

Switching antipsychotic medication to reduce sexual dysfunction in people with psychosis: the REMEDY RCT.

BACKGROUND: Sexual dysfunction is common among people who are prescribed antipsychotic medication for psychosis. Sexual dysfunction can impair quality of life and reduce treatment adherence. Switching antipsychotic medication may help, but the clinical effectiveness and cost-effectiveness of this approach is unclear. OBJECTIVE: To examine whether or not switching antipsychotic medication provides a clinically effective and cost-effective method to reduce sexual dysfunction in people with psychosis. DESIGN: A two-arm, researcher-blind, pilot randomised trial with a parallel qualitative study and an internal pilot phase. Study participants were randomised to enhanced standard care plus a switch of antipsychotic medication or enhanced standard care alone in a 1 : 1 ratio. Randomisation was via an independent and remote web-based service using dynamic adaptive allocation, stratified by age, gender, Trust and relationship status. SETTING: NHS secondary care mental health services in England. PARTICIPANTS: Potential participants had to be aged ≥ 18 years, have schizophrenia or related psychoses and experience sexual dysfunction associated with the use of antipsychotic medication. We recruited only people for whom reduction in medication dosage was ineffective or inappropriate. We excluded those who were acutely unwell, had had a change in antipsychotic medication in the last 6 weeks, were currently prescribed clozapine or whose sexual dysfunction was believed to be due to a coexisting physical or mental disorder. INTERVENTIONS: Switching to an equivalent dose of one of three antipsychotic medications that are considered to have a relatively low propensity for sexual side effects (i.e. quetiapine, aripiprazole or olanzapine). All participants were offered brief psychoeducation and support to discuss their sexual health and functioning. MAIN OUTCOME MEASURES: The primary outcome was patient-reported sexual dysfunction, measured using the Arizona Sexual Experience Scale. Secondary outcomes were researcher-rated sexual functioning, mental health, side effects of medication, health-related quality of life and service utilisation. Outcomes were assessed 3 and 6 months after randomisation. Qualitative data were collected from a purposive sample of patients and clinicians to explore barriers to recruitment. SAMPLE SIZE: Allowing for a 20% loss to follow-up, we needed to recruit 216 participants to have 90% power to detect a 3-point difference in total Arizona Sexual Experience Scale score (standard deviation 6.0 points) using a 0.05 significance level. RESULTS: The internal pilot was discontinued after 12 months because of low recruitment. Ninety-eight patients were referred to the study between 1 July 2018 and 30 June 2019, of whom 10 were randomised. Eight (80%) participants were followed up 3 months later. Barriers to referral and recruitment included staff apprehensions about discussing side effects, reluctance among patients to switch medication and reticence of both staff and patients to talk about sex. LIMITATIONS: Insufficient numbers of participants were recruited to examine the study hypotheses. CONCLUSIONS: It may not be possible to conduct a successful randomised trial of switching antipsychotic medication for sexual functioning in people with psychosis in the NHS at this time. FUTURE WORK: Research examining the acceptability and effectiveness of adjuvant phosphodiesterase inhibitors should be considered. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12307891. 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. 24, No. 44. See the NIHR Journals Library website for further project information.

Antipsychotic medications can improve the mental health of people with psychosis but may also cause side effects. These include sexual side effects, such as reduced desire for sex or less pleasure from having sex. One way to try to tackle this problem is to switch the medicine people take to one that is thought less likely to cause these problems. However, it is unclear if this helps, and switching medication could potentially harm mental health or cause new side effects. We conducted a study to compare the effect of switching with not switching the medication of people with psychosis experiencing sexual side effects. We collected information about sexual functioning, mental health, quality of life and use of services at the start of the study and 6 months later. We also interviewed nurses, doctors and patients to get their views about the study. We recruited 10 patients over a 12-month period and conducted interviews with 51 clinicians and four patients. Many clinicians said that they found it difficult to talk to their patients about sex. Some thought that these problems occurred rarely and that other side effects mattered more to patients. Many patients were concerned about switching their medication, especially when it had improved their mental health. Others felt that these side effects were not very important, and some were not prepared to take part in a trial that could delay a change being made to their medication. We did not collect enough information to be able to find out if switching medication helps people who experience sexual side effects of antipsychotic drugs. It is important that clinicians ask about sexual side effects of antipsychotic medication and that further efforts are made to find ways to help patients who experience them.

The physical health and side-effect monitoring of patients prescribed clozapine: data from a clinical audit conducted in UK mental health services.

BACKGROUND: In addition to mandatory haematological monitoring, treatment guidelines recommend routine monitoring of adverse effects and physical health in patients prescribed clozapine. METHODS: NHS trusts/healthcare organisations participated in a clinical audit in the context of a UK quality improvement programme addressing clozapine-prescribing practice. RESULTS: Data relating to 6948 adult patients prescribed clozapine were submitted by 63 NHS trusts/healthcare organisations. Of 481 patients treated with clozapine for up to 18 weeks, there was documented pretreatment screening of blood pressure, heart rate and ECG in at least 90%, and body weight, plasma lipids, plasma glucose/glycated haemoglobin (HbA1c) and physical examination in approximately 80%. During the first 2 weeks of clozapine treatment there was documented daily measurement of both heart rate and blood pressure in 82% and body temperature in 77%. In a subsample of 411 patients, of the 72% who had weekly side-effect assessments documented in the first month of treatment, a structured assessment tool had been used in 29%. Treatment monitoring up to 18 weeks included an ECG in 90%, C-reactive protein (CRP) or creatine kinase in 42%, and troponin or B-type natriuretic peptide (BNP) in 29%. In the 5908 patients prescribed clozapine for at least 1 year, blood pressure and body weight/body mass index were documented in at least 80%, plasma lipids in 78% and plasma glucose in 73%, with an ECG in 55%. Two-thirds were prescribed medication to manage side effects of clozapine and one third of those with a diagnosis of schizophrenia were prescribed a second antipsychotic medication. CONCLUSION: The findings suggest that for most patients treated with clozapine in UK mental health services, physical health screening and side-effect monitoring follow recommended practice, but there was limited use of structured side-effect assessment tools. Monitoring for clozapine-induced myocarditis during the early risk period using markers of inflammation such as CRP, and cardiac damage such as troponin and BNP, was less consistent. This may partly reflect the variation in guideline recommendations for monitoring for myocarditis and partly the selected use of such tests when prompted by cardiac symptoms. The relatively common coprescription of medications for the majority of people on longer-term clozapine treatment may well further increase side-effect burden and physical health risks, reinforcing the need for continuing systematic monitoring.

Are socioenvironmental factors associated with psychotic symptoms in people with first-episode psychosis? A cross-sectional study of a West London clinical sample.

OBJECTIVES: To determine whether neighbourhood-level socioenvironmental factors including deprivation and inequality predict variance in psychotic symptoms after controlling for individual-level demographics. DESIGN: A cross-sectional design was employed. SETTING: Data were originally collected from secondary care services within the UK boroughs of Ealing, Hammersmith and Fulham, Wandsworth, Kingston, Richmond, Merton, Sutton and Hounslow as part of the West London First-Episode Psychosis study. PARTICIPANTS: Complete case analyses were undertaken on 319 participants who met the following inclusion criteria: aged 16 years or over, resident in the study's catchment area, experiencing a first psychotic episode, with fewer than 12 weeks' exposure to antipsychotic medication and sufficient command of English to facilitate assessment. OUTCOME MEASURES: Symptom dimension scores, derived from principal component analyses of the Scale for the Assessment of Positive Symptoms and Scale for the Assessment of Negative Symptoms, were regressed on neighbourhood-level predictors, including population density, income deprivation, income inequality, social fragmentation, social cohesion, ethnic density and ethnic fragmentation, using multilevel regression. While age, gender and socioeconomic status were included as individual-level covariates, data on participant ethnicity were not available. RESULTS: Higher income inequality was associated with lower negative symptom scores (coefficient=-1.66, 95% CI -2.86 to -0.46, p<0.01) and higher levels of ethnic segregation were associated with lower positive symptom scores (coefficient=-2.32, 95% CI -4.17 to -0.48, p=0.01) after adjustment for covariates. CONCLUSIONS: These findings provide further evidence that particular characteristics of the environment may be linked to specific symptom clusters in psychosis. Longitudinal studies are required to begin to tease apart the underlying mechanisms involved as well as the causal direction of such associations.

Cognitive-behavioural therapy for clozapine-resistant schizophrenia: the FOCUS RCT.

BACKGROUND: Clozapine (clozaril, Mylan Products Ltd) is a first-choice treatment for people with schizophrenia who have a poor response to standard antipsychotic medication. However, a significant number of patients who trial clozapine have an inadequate response and experience persistent symptoms, called clozapine-resistant schizophrenia (CRS). There is little evidence regarding the clinical effectiveness of pharmacological or psychological interventions for this population. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of cognitive-behavioural therapy (CBT) for people with CRS and to identify factors predicting outcome. DESIGN: The Focusing on Clozapine Unresponsive Symptoms (FOCUS) trial was a parallel-group, randomised, outcome-blinded evaluation trial. Randomisation was undertaken using permuted blocks of random size via a web-based platform. Data were analysed on an intention-to-treat (ITT) basis, using random-effects regression adjusted for site, age, sex and baseline symptoms. Cost-effectiveness analyses were carried out to determine whether or not CBT was associated with a greater number of quality-adjusted life-years (QALYs) and higher costs than treatment as usual (TAU). SETTING: Secondary care mental health services in five cities in the UK. PARTICIPANTS: People with CRS aged ≥ 16 years, with an International Classification of Diseases, Tenth Revision (ICD-10) schizophrenia spectrum diagnoses and who are experiencing psychotic symptoms. INTERVENTIONS: Individual CBT included up to 30 hours of therapy delivered over 9 months. The comparator was TAU, which included care co-ordination from secondary care mental health services. MAIN OUTCOME MEASURES: The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months and the primary secondary outcome was PANSS total score at the end of treatment (9 months post randomisation). The health benefit measure for the economic evaluation was the QALY, estimated from the EuroQol-5 Dimensions, five-level version (EQ-5D-5L), health status measure. Service use was measured to estimate costs. RESULTS: Participants were allocated to CBT (n = 242) or TAU (n = 245). There was no significant difference between groups on the prespecified primary outcome [PANSS total score at 21 months was 0.89 points lower in the CBT arm than in the TAU arm, 95% confidence interval (CI) -3.32 to 1.55 points; p = 0.475], although PANSS total score at the end of treatment (9 months) was significantly lower in the CBT arm (-2.40 points, 95% CI -4.79 to -0.02 points; p = 0.049). CBT was associated with a net cost of £5378 (95% CI -£13,010 to £23,766) and a net QALY gain of 0.052 (95% CI 0.003 to 0.103 QALYs) compared with TAU. The cost-effectiveness acceptability analysis indicated a low likelihood that CBT was cost-effective, in the primary and sensitivity analyses (probability < 50%). In the CBT arm, 107 participants reported at least one adverse event (AE), whereas 104 participants in the TAU arm reported at least one AE (odds ratio 1.09, 95% CI 0.81 to 1.46; p = 0.58). CONCLUSIONS: Cognitive-behavioural therapy for CRS was not superior to TAU on the primary outcome of total PANSS symptoms at 21 months, but was superior on total PANSS symptoms at 9 months (end of treatment). CBT was not found to be cost-effective in comparison with TAU. There was no suggestion that the addition of CBT to TAU caused adverse effects. Future work could investigate whether or not specific therapeutic techniques of CBT have value for some CRS individuals, how to identify those who may benefit and how to ensure that effects on symptoms can be sustained. TRIAL REGISTRATION: Current Controlled Trials ISRCTN99672552. 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. 7. See the NIHR Journals Library website for further project information.

Physical health monitoring after rapid tranquillisation: clinical practice in UK mental health services.

BACKGROUND: We aimed to assess the quality of physical health monitoring following rapid tranquillisation (RT) for acute behavioural disturbance in UK mental health services. METHODS: The Prescribing Observatory for Mental Health (POMH-UK) initiated an audit-based quality improvement programme addressing the pharmacological treatment of acute behavioural disturbance in mental health services in the UK. RESULTS: Data relating to a total of 2454 episodes of RT were submitted by 66 mental health services. Post-RT physical health monitoring did not reach the minimum recommended level in 1933 (79%) episodes. Patients were more likely to be monitored (OR 1.78, 95% CI 1.39-2.29, p < 0.001) if there was actual or threatened self-harm, and less likely to be monitored if the episode occurred in the evening (OR 0.79, 95% CI 0.62-1.0, p < 0.001) or overnight (OR 0.57, 95% CI 0.44-0.75, p < 0.001). Risk factors such as recent substance use, RT resulting in the patient falling asleep, or receiving high-dose antipsychotic medication on the day of the episode, did not predict whether or not the minimum recommended level of post-RT monitoring was documented. CONCLUSIONS: The minimum recommended level of physical health monitoring was reported for only one in five RT episodes. The findings also suggest a lack of targeting of at-risk patients for post-RT monitoring. Possible explanations are that clinicians consider such monitoring too demanding to implement in routine clinical practice or not appropriate in every clinical situation. For example, physical health measures requiring direct contact with a patient may be difficult to undertake, or counter-productive, if RT has failed. These findings prompt speculation that post-RT monitoring practice would be improved by the implementation of guidance that integrated and refined the currently separate systems for undertaking and recording physical health observations post-RT, determining nursing observation schedules and detecting acute deterioration in physical health. The effectiveness and clinical utility of such an approach would be worth testing.

The pharmacological management of acute behavioural disturbance: Data from a clinical audit conducted in UK mental health services.

BACKGROUND: A quality improvement programme addressing prescribing practice for acutely disturbed behaviour was initiated by the Prescribing Observatory for Mental Health. METHOD: This study analysed data from a baseline clinical audit conducted in inpatient mental health services in member trusts. RESULTS: Fifty-eight mental health services submitted data on 2172 episodes of acutely disturbed behaviour. A benzodiazepine alone was administered in 60% of the 1091 episodes where oral medication only was used and in 39% of the 1081 episodes where parenteral medication (rapid tranquillisation) was used. Haloperidol was combined with lorazepam in 22% of rapid tranquillisation episodes and with promethazine in 3%. Physical violence towards others was strongly associated with receiving rapid tranquillisation in men (odds ratio 1.74, 1.25-2.44; p<0.001) as was actual or attempted self-harm in women (odds ratio 1.87, 1.19-2.94; p=0.007). Where physical violence towards others was exhibited, a benzodiazepine and antipsychotic was more likely to be prescribed than a benzodiazepine alone (odds ratio 1.39, 1.00-1.92; p=0.05). The data suggested that 25% of patients were at least 'extremely or continuously active' in the hour after rapid tranquillisation was administered. CONCLUSION: The current management of acutely disturbed behaviour with parenteral medication may fail to achieve a calming effect in up to a quarter of episodes. The most common rapid tranquillisation combination used was lorazepam and haloperidol, for which the randomised controlled trial evidence is very limited. Rapid tranquillisation prescribing practice was not wholly consistent with the relevant National Institute for Health and Care Excellence guideline, which recommends intramuscular lorazepam on its own or intramuscular haloperidol combined with intramuscular promethazine. Clinical factors prompting the use of rapid tranquillisation rather than oral medication may differ between the genders.

The component structure of the scales for the assessment of positive and negative symptoms in first-episode psychosis and its dependence on variations in analytic methods.

A secondary analysis was undertaken on Scales for the Assessment of Positive and Negative Symptoms (SAPS/SANS) data from 345 first-episode psychosis (FEP) patients gathered in the West London FEP study. The purpose of this study was to determine: (i) the component structure of these measures in FEP (primary analyses), and (ii) the dependence of any findings in these primary analyses on variations in analytic methods. Symptom ratings were exposed to data reduction methods and the effects of the following manipulations ascertained: (i) level of analysis (individual symptom vs. global symptom severity ratings), (ii) extraction method (principal component vs. exploratory factor analysis) and (iii) retention method (scree test vs. Kaiser criterion). Whilst global ratings level analysis rendered the classic triad of psychotic syndromes (positive, negative and disorganisation), symptom level analyses revealed a hierarchical structure, with 11 first-order components subsumed by three second-order components, which also mapped on to this syndrome triad. These results were robust across data reduction but not component retention methods, suggesting that discrepancies in the literature regarding the component structure of the SAPS/SANS partly reflect the level of analysis and component retention method used. Further, they support a hierarchical symptom model, the implications of which are discussed.

Development and clinimetric assessment of a nurse-administered screening tool for movement disorders in psychosis.

BACKGROUND: Movement disorders associated with exposure to antipsychotic drugs are common and stigmatising but underdiagnosed. AIMS: To develop and evaluate a new clinical procedure, the ScanMove instrument, for the screening of antipsychotic-associated movement disorders for use by mental health nurses. METHOD: Item selection and content validity assessment for the ScanMove instrument were conducted by a panel of neurologists, psychiatrists and a mental health nurse, who operationalised a 31-item screening procedure. Interrater reliability was measured on ratings for 30 patients with psychosis from ten mental health nurses evaluating video recordings of the procedure. Criterion and concurrent validity were tested comparing the ScanMove instrument-based rating of 13 mental health nurses for 635 community patients from mental health services with diagnostic judgement of a movement disorder neurologist based on the ScanMove instrument and a reference procedure comprising a selection of commonly used rating scales. RESULTS: Interreliability analysis showed no systematic difference between raters in their prediction of any antipsychotic-associated movement disorders category. On criterion validity testing, the ScanMove instrument showed good sensitivity for parkinsonism (90%) and hyperkinesia (89%), but not for akathisia (38%), whereas specificity was low for parkinsonism and hyperkinesia, and moderate for akathisia. CONCLUSIONS: The ScanMove instrument demonstrated good feasibility and interrater reliability, and acceptable sensitivity as a mental health nurse-administered screening tool for parkinsonism and hyperkinesia. DECLARATION OF INTEREST: None.

Cognitive behavioural therapy in clozapine-resistant schizophrenia (FOCUS): an assessor-blinded, randomised controlled trial.

BACKGROUND: Although clozapine is the treatment of choice for treatment-refractory schizophrenia, 30-40% of patients have an insufficient response, and others are unable to tolerate it. Evidence for any augmentation strategies is scarce. We aimed to determine whether cognitive behavioural therapy (CBT) is an effective treatment for clozapine-resistant schizophrenia. METHODS: We did a pragmatic, parallel group, assessor-blinded, randomised controlled trial in community-based and inpatient mental health services in five sites in the UK. Patients with schizophrenia who were unable to tolerate clozapine, or whose symptoms did not respond to the drug, were randomly assigned 1:1 by use of randomised-permuted blocks of size four or six, stratified by centre, to either CBT plus treatment as usual or treatment as usual alone. Research assistants were masked to allocation to protect against rater bias and allegiance bias. The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months, which provides a continuous measure of symptoms of schizophrenia; PANSS total was also assessed at the end of treatment (9 months). The primary analysis was by randomised treatment based on intention to treat, for all patients for whom data were available. This study was prospectively registered, number ISRCTN99672552. The trial is closed to accrual. FINDINGS: From Jan 1, 2013, to May 31, 2015, we randomly assigned 487 participants to either CBT and treatment as usual (n=242) or treatment as usual alone (n=245). Analysis included 209 in the CBT group and 216 in the treatment as usual group. No difference occurred in the primary outcome (PANSS total at 21 months, mean difference -0·89, 95% CI -3·32 to 1·55; p=0·48), although the CBT group improved at the end of treatment (PANSS total at 9 months, mean difference -2·40, -4·79 to -0·02; p=0·049). During the trial, 107 (44%) of 242 participants in the CBT arm and 104 (42%) of 245 in the treatment as usual arm had at least one adverse event (odds ratio 1·09, 95% CI 0·81 to 1·46; p=0·58). Only two (1%) of 242 participants in the CBT arm and one (<1%) of 245 in the treatment as usual arm had a trial-related serious adverse event. INTERPRETATION: At 21-month follow-up, CBT did not have a lasting effect on total symptoms of schizophrenia compared with treatment as usual; however, CBT produced statistically, though not clinically, significant improvements on total symptoms by the end of treatment. There was no indication that the addition of CBT to treatment as usual caused adverse effects. The results of this trial do not support a recommendation to routinely offer CBT to all people who meet criteria for clozapine-resistant schizophrenia; however, a pragmatic individual trial might be indicated for some. FUNDING: National Institute for Health Research Technology Assessment programme.

The Assessment and Treatment of Antipsychotic-Induced Akathisia.

BACKGROUND: Akathisia is a common and distressing neuropsychiatric syndrome associated with antipsychotic medication, characterised by subjective and objective psychomotor restlessness. The goal of this guideline is to provide clinicians with recommendations on the assessment and treatment of akathisia. METHODS: We performed a systematic review of therapeutic studies assessing the treatment of antipsychotic-induced extrapyramidal symptoms. Forty studies on akathisia and 4 systematic reviews evaluating the adverse effects of antipsychotics were used in the formulation of recommendations. Studies were rated for methodological quality using the American Academy of Neurology Risk of Bias Classification system. The overall level of evidence classifications and grades of recommendation were made using the Scottish Intercollegiate Guidelines Network framework. RESULTS: As a good practice point, clinicians should systematically assess akathisia with a validated scale before starting antipsychotics and during antipsychotic dosage titration. For the management of akathisia, there was adequate evidence to allow recommendations regarding antipsychotic dose reduction, antipsychotic polypharmacy, switching antipsychotic medication, and the use of adjuvant medications including beta-blockers, anticholinergics, 5HT2A antagonists, benzodiazepines, and vitamin B6. CONCLUSION: The treatment of antipsychotic-induced akathisia should be personalised, with consideration of antipsychotic dose reduction, cessation of antipsychotic polypharmacy, and switching to an antipsychotic with a perceived lower liability for akathisia, before the use of adjuvant medications. The choice of adjuvant medications should favour the more established treatments, with careful consideration of contraindications and side effects. Limitations in the evidence should be acknowledged and prompt cautious prescribing, particularly with respect to the duration of use of adjuvant medications, is warranted.

Clinical and cost-effectiveness of an intervention for reducing cholesterol and cardiovascular risk for people with severe mental illness in English primary care: a cluster randomised controlled trial.

BACKGROUND: People with severe mental illnesses, including psychosis, have an increased risk of cardiovascular disease. We aimed to evaluate the effects of a primary care intervention on decreasing total cholesterol concentrations and cardiovascular disease risk in people with severe mental illnesses. METHODS: We did this cluster randomised trial in general practices across England, with general practices as the cluster unit. We randomly assigned general practices (1:1) with 40 or more patients with severe mental illnesses using a computer-generated random sequence with a block size of four. Researchers were masked to allocation, but patients and general practice staff were not. We included participants aged 30-75 years with severe mental illnesses (schizophrenia, bipolar disorder, or psychosis), who had raised cholesterol concentrations (5·0 mmol/L) or a total:HDL cholesterol ratio of 4·0 mmol/L or more and one or more modifiable cardiovascular disease risk factors. Eligible participants were recruited within each practice before randomisation. The Primrose intervention consisted of appointments (≤12) with a trained primary care professional involving manualised interventions for cardiovascular disease prevention (ie, adhering to statins, improving diet or physical activity levels, reducing alcohol, or quitting smoking). Treatment as usual involved feedback of screening results only. The primary outcome was total cholesterol at 12 months and the primary economic analysis outcome was health-care costs. We used intention-to-treat analysis. The trial is registered with Current Controlled Trials, number ISRCTN13762819. FINDINGS: Between Dec 10, 2013, and Sept 30, 2015, we recruited general practices and between May 9, 2014, and Feb 10, 2016, we recruited participants and randomly assigned 76 general practices with 327 participants to the Primrose intervention (n=38 with 155 patients) or treatment as usual (n=38 with 172 patients). Total cholesterol concentration data were available at 12 months for 137 (88%) participants in the Primrose intervention group and 152 (88%) participants in the treatment-as-usual group. The mean total cholesterol concentration did not differ at 12 months between the two groups (5·4 mmol/L [SD 1·1] for Primrose vs 5·5 mmol/L [1·1] for treatment as usual; mean difference estimate 0·03, 95% CI -0·22 to 0·29; p=0·788). This result was unchanged by pre-agreed supportive analyses. Mean cholesterol decreased over 12 months (-0·22 mmol/L [1·1] for Primrose vs -0·36 mmol/L [1·1] for treatment as usual). Total health-care costs (£1286 [SE 178] in the Primrose intervention group vs £2182 [328] in the treatment-as-usual group; mean difference -£895, 95% CI -1631 to -160; p=0·012) and psychiatric inpatient costs (£157 [135] vs £956 [313]; -£799, -1480 to -117; p=0·018) were lower in the Primrose intervention group than the treatment-as-usual group. Six serious adverse events of hospital admission and one death occurred in the Primrose group (n=7) and 23, including three deaths, occurred in the treatment-as-usual group (n=18). INTERPRETATION: Total cholesterol concentration at 12 months did not differ between the Primrose and treatment-as-usual groups, possibly because of the cluster design, good care in the treatment-as-usual group, short duration of the intervention, or suboptimal focus on statin prescribing. The association between the Primrose intervention and fewer psychiatric admissions, with potential cost-effectiveness, might be important. FUNDING: National Institute of Health Research Programme Grants for Applied Research.

Amisulpride augmentation in clozapine-unresponsive schizophrenia (AMICUS): a double-blind, placebo-controlled, randomised trial of clinical effectiveness and cost-effectiveness.

BACKGROUND: When treatment-refractory schizophrenia shows an insufficient response to a trial of clozapine, clinicians commonly add a second antipsychotic, despite the lack of robust evidence to justify this practice. OBJECTIVES: The main objectives of the study were to establish the clinical effectiveness and cost-effectiveness of augmentation of clozapine medication with a second antipsychotic, amisulpride, for the management of treatment-resistant schizophrenia. DESIGN: The study was a multicentre, double-blind, individually randomised, placebo-controlled trial with follow-up at 12 weeks. SETTINGS: The study was set in NHS multidisciplinary teams in adult psychiatry. PARTICIPANTS: Eligible participants were people aged 18-65 years with treatment-resistant schizophrenia unresponsive, at a criterion level of persistent symptom severity and impaired social function, to an adequate trial of clozapine monotherapy. INTERVENTIONS: Interventions comprised clozapine augmentation over 12 weeks with amisulpride or placebo. Participants received 400 mg of amisulpride or two matching placebo capsules for the first 4 weeks, after which there was a clinical option to titrate the dosage of amisulpride up to 800 mg or four matching placebo capsules for the remaining 8 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was the proportion of 'responders', using a criterion response threshold of a 20% reduction in total score on the Positive and Negative Syndrome Scale. RESULTS: A total of 68 participants were randomised. Compared with the participants assigned to placebo, those receiving amisulpride had a greater chance of being a responder by the 12-week follow-up (odds ratio 1.17, 95% confidence interval 0.40 to 3.42) and a greater improvement in negative symptoms, although neither finding had been present at 6-week follow-up and neither was statistically significant. Amisulpride was associated with a greater side effect burden, including cardiac side effects. Economic analyses indicated that amisulpride augmentation has the potential to be cost-effective in the short term [net saving of between £329 and £2011; no difference in quality-adjusted life-years (QALYs)] and possibly in the longer term. LIMITATIONS: The trial under-recruited and, therefore, the power of statistical analysis to detect significant differences between the active and placebo groups was limited. The economic analyses indicated high uncertainty because of the short duration and relatively small number of participants. CONCLUSIONS: The risk-benefit of amisulpride augmentation of clozapine for schizophrenia that has shown an insufficient response to a trial of clozapine monotherapy is worthy of further investigation in larger studies. The size and extent of the side effect burden identified for the amisulpride-clozapine combination may partly reflect the comprehensive assessment of side effects in this study. The design of future trials of such a treatment strategy should take into account that a clinical response may be not be evident within the 4- to 6-week follow-up period usually considered adequate in studies of antipsychotic treatment of acute psychotic episodes. Economic evaluation indicated the need for larger, longer-term studies to address uncertainty about the extent of savings because of amisulpride and impact on QALYs. The extent and nature of the side effect burden identified for the amisulpride-clozapine combination has implications for the nature and frequency of safety and tolerability monitoring of clozapine augmentation with a second antipsychotic in both clinical and research settings. TRIAL REGISTRATION: EudraCT number 2010-018963-40 and Current Controlled Trials ISRCTN68824876. 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. 21, No. 49. See the NIHR Journals Library website for further project information.

Design and protocol for the Focusing on Clozapine Unresponsive Symptoms (FOCUS) trial: a randomised controlled trial.

BACKGROUND: For around a third of people with a diagnosis of schizophrenia, the condition proves to respond poorly to treatment with many typical and atypical antipsychotics. This is commonly referred to as treatment-resistant schizophrenia. Clozapine is the only antipsychotic with convincing efficacy for people whose symptoms are considered treatment-resistant to antipsychotic medication. However, 30-40 % of such conditions will have an insufficient response to the drug. Cognitive behavioural therapy has been shown to be an effective treatment for schizophrenia when delivered in combination with antipsychotic medication, with several meta-analyses showing robust support for this approach. However, the evidence for the effectiveness of cognitive behavioural therapy for people with a schizophrenia diagnosis whose symptoms are treatment-resistant to antipsychotic medication is limited. There is a clinical and economic need to evaluate treatments to improve outcomes for people with such conditions. METHODS/DESIGN: A parallel group, prospective randomised, open, blinded evaluation of outcomes design will be used to compare a standardised cognitive behavioural therapy intervention added to treatment as usual versus treatment as usual alone (the comparator group) for individuals with a diagnosis of schizophrenia for whom an adequate trial of clozapine has either not been possible due to tolerability problems or was not associated with a sufficient therapeutic response. The trial will be conducted across five sites in the United Kingdom. DISCUSSION: The recruitment target of 485 was achieved, with a final recruitment total of 487. This trial is the largest definitive, pragmatic clinical and cost-effectiveness trial of cognitive behavioural therapy for people with schizophrenia whose symptoms have failed to show an adequate response to clozapine treatment. Using a prognostic risk model, baseline information will be used to explore whether there are identifiable subgroups for which the treatment effect is greatest. TRIAL REGISTRATION: Current Controlled Trials ISRCTN99672552 . Registered 29(th) November 2012.

Antidepressant Controlled Trial For Negative Symptoms In Schizophrenia (ACTIONS): a double-blind, placebo-controlled, randomised clinical trial.

BACKGROUND: Negative symptoms of schizophrenia represent deficiencies in emotional responsiveness, motivation, socialisation, speech and movement. When persistent, they are held to account for much of the poor functional outcomes associated with schizophrenia. There are currently no approved pharmacological treatments. While the available evidence suggests that a combination of antipsychotic and antidepressant medication may be effective in treating negative symptoms, it is too limited to allow any firm conclusions. OBJECTIVE: To establish the clinical effectiveness and cost-effectiveness of augmentation of antipsychotic medication with the antidepressant citalopram for the management of negative symptoms in schizophrenia. DESIGN: A multicentre, double-blind, individually randomised, placebo-controlled trial with 12-month follow-up. SETTING: Adult psychiatric services, treating people with schizophrenia. PARTICIPANTS: Inpatients or outpatients with schizophrenia, on continuing, stable antipsychotic medication, with persistent negative symptoms at a criterion level of severity. INTERVENTIONS: Eligible participants were randomised 1 : 1 to treatment with either placebo (one capsule) or 20 mg of citalopram per day for 48 weeks, with the clinical option at 4 weeks to increase the daily dosage to 40 mg of citalopram or two placebo capsules for the remainder of the study. MAIN OUTCOME MEASURES: The primary outcomes were quality of life measured at 12 and 48 weeks assessed using the Heinrich's Quality of Life Scale, and negative symptoms at 12 weeks measured on the negative symptom subscale of the Positive and Negative Syndrome Scale. RESULTS: No therapeutic benefit in terms of improvement in quality of life or negative symptoms was detected for citalopram over 12 weeks or at 48 weeks, but secondary analysis suggested modest improvement in the negative symptom domain, avolition/amotivation, at 12 weeks (mean difference -1.3, 95% confidence interval -2.5 to -0.09). There were no statistically significant differences between the two treatment arms over 48-week follow-up in either the health economics outcomes or costs, and no differences in the frequency or severity of adverse effects, including corrected QT interval prolongation. LIMITATIONS: The trial under-recruited, partly because cardiac safety concerns about citalopram were raised, with the 62 participants recruited falling well short of the target recruitment of 358. Although this was the largest sample randomised to citalopram in a randomised controlled trial of antidepressant augmentation for negative symptoms of schizophrenia and had the longest follow-up, the power of statistical analysis to detect significant differences between the active and placebo groups was limited. CONCLUSION: Although adjunctive citalopram did not improve negative symptoms overall, there was evidence of some positive effect on avolition/amotivation, recognised as a critical barrier to psychosocial rehabilitation and achieving better social and community functional outcomes. Comprehensive assessment of side-effect burden did not identify any serious safety or tolerability issues. The addition of citalopram as a long-term prescribing strategy for the treatment of negative symptoms may merit further investigation in larger studies. FUTURE WORK: Further studies of the viability of adjunctive antidepressant treatment for negative symptoms in schizophrenia should include appropriate safety monitoring and use rating scales that allow for evaluation of avolition/amotivation as a discrete negative symptom domain. Overcoming the barriers to recruiting an adequate sample size will remain a challenge. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2009-009235-30 and Current Controlled Trials ISRCTN42305247. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 29. See the NIHR Journals Library website for further project information.

Evaluating the clinical and cost effectiveness of a behaviour change intervention for lowering cardiovascular disease risk for people with severe mental illnesses in primary care (PRIMROSE study): study protocol for a cluster randomised controlled trial.

BACKGROUND: People with severe mental illnesses die up to 20 years earlier than the general population, with cardiovascular disease being the leading cause of death. National guidelines recommend that the physical care of people with severe mental illnesses should be the responsibility of primary care; however, little is known about effective interventions to lower cardiovascular disease risk in this population and setting. Following extensive peer review, funding was secured from the United Kingdom National Institute for Health Research (NIHR) to deliver the proposed study. The aim of the trial is to test the effectiveness of a behavioural intervention to lower cardiovascular disease risk in people with severe mental illnesses in United Kingdom General Practices. METHODS/DESIGN: The study is a cluster randomised controlled trial in 70 GP practices for people with severe mental illnesses, aged 30 to 75 years old, with elevated cardiovascular disease risk factors. The trial will compare the effectiveness of a behavioural intervention designed to lower cardiovascular disease risk and delivered by a practice nurse or healthcare assistant, with standard care offered in General Practice. A total of 350 people will be recruited and followed up at 6 and 12 months. The primary outcome is total cholesterol level at the 12-month follow-up and secondary outcomes include blood pressure, body mass index, waist circumference, smoking status, quality of life, adherence to treatments and services and behavioural measures for diet, physical activity and alcohol use. An economic evaluation will be carried out to determine the cost effectiveness of the intervention compared with standard care. DISCUSSION: The results of this pragmatic trial will provide evidence on the clinical and cost effectiveness of the intervention on lowering total cholesterol and addressing multiple cardiovascular disease risk factors in people with severe mental illnesses in GP Practices. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13762819. Date of Registration: 25 February 2013. Date and Version Number: 27 August 2014 Version 5.

Undertaking clinical audit, with reference to a Prescribing Observatory for Mental Health audit of lithium monitoring.

Audit is an important tool for quality improvement. The collection of data on clinical performance against evidence-based and clinically relevant standards, which are considered by clinicians to be realistic in routine practice, can usefully prompt reflective practice and the implementation of change. Evidence of participation in clinical audit is required to achieve intended learning outcomes for trainees in psychiatry and revalidation for those who are members of the Royal College of Psychiatrists. This article addresses some of the practical steps involved in conducting an audit project, and, to illustrate key points, draws on lessons learnt from a national, audit-based, quality improvement programme of lithium prescribing and monitoring conducted through the Prescribing Observatory for Mental Health.

Monitoring lithium therapy: the impact of a quality improvement programme in the UK.

OBJECTIVES: The study was designed to test an audit-based quality improvement programme (QIP) addressing lithium prescribing and monitoring in UK mental health services. METHODS: A baseline clinical audit was conducted against the following standards: (i) measurement of renal and thyroid function before initiating treatment with lithium and (ii) recommended monitoring of serum lithium and renal and thyroid function during maintenance treatment. A re-audit was conducted at 18 months and a supplementary audit at three years. RESULTS: Data were submitted for patients at baseline (n = 3,373), re-audit (n = 3,647), and supplementary audit (n = 5,683), 57% of whom had bipolar disorder. The baseline findings prompted a patient safety alert issued by the National Patient Safety Agency. By supplementary audit, the proportion of patients having four serum lithium tests over the previous year had increased from 30% at baseline to 48%, and the respective proportions that had two tests of renal function from 55% to 70% and thyroid function from 49% to 66%. Elderly patients and those prescribed a drug known to interact with lithium were not more likely to be monitored in line with the audit standards. Between baseline and supplementary audit, the proportion of patients with a diagnosis of bipolar disorder prescribed an antidepressant increased from 36% to 41%. CONCLUSIONS: Improvements in biochemical monitoring of lithium treatment were achieved over time with participation in a QIP that included benchmarking of performance against clinical standards and customized change interventions. Nevertheless, gaps remain between the standard and current practice. Antidepressants are frequently prescribed in patients with bipolar disorder despite a paucity of evidence supporting their efficacy.