Exploring the experiences and responses of siblings living with a brother or sister with obsessive compulsive disorder.

OBJECTIVES: The impact of having a child with diagnosed obsessive-compulsive disorder (OCD) can reportedly cause significant disruption to caregiver routines and negatively affect their mental health. Less is known about the impact to other first-degree relatives such as siblings due to limited research. It should not be assumed that findings in the caregiver literature can simply be applied to siblings. This study, therefore, aimed to explore the experiences and responses of cohabiting siblings of a brother or sister with an OCD diagnosis. METHOD: Eight participant siblings were recruited from a UK specialist OCD NHS clinic and interviewed via telephone about their experiences co-habiting with a brother or sister with OCD. Interviews were transcribed and subjected to interpretative phenomenological analysis (IPA). RESULTS: Two superordinate themes of 'OCD as a dangerous dictator' and the 'unifying/polarising influence of OCD on relationships' were interpreted from the eight participant experiences. Siblings spoke to OCD creating a dictatorial environment characterised by sibling loss, helplessness and adjustment. This fragile domestic environment seemingly pushed non-anxious siblings to the periphery of the family or conversely centralised their position through parentification. CONCLUSIONS: Many of the sibling experiences of frustration, distress avoidance, helplessness and symptom accommodation are mirrored in the burgeoning caregiver literature. Longitudinal studies are required to track sibling experiences over the course of their siblings OCD journey and expand our knowledge in this area. Counselling services, sibling support groups and inclusion in family assessment, formulation and treatment are possible avenues of exploration for siblings of those with an OCD diagnosis.

Therapeutic D2/3 receptor occupancies and response with low amisulpride blood concentrations in very late-onset schizophrenia-like psychosis (VLOSLP).

OBJECTIVE: Antipsychotic drug sensitivity in very late-onset schizophrenia-like psychosis (VLOSLP) is well documented, but poorly understood. This study aimed to investigate blood drug concentration, D2/3 receptor occupancy and outcome in VLOSLP during open amisulpride prescribing, and compare this with Alzheimer's disease (AD). METHODS: Blood drug concentration, prolactin, symptoms and extrapyramidal side-effects (EPS) were serially assessed during dose titration. [18 F]fallypride imaging was used to quantify D2/3 receptor occupancy. Average steady-state amisulpride concentration (Caverage, ng/ml) was estimated by incorporating pharmacokinetic (PK) data into an existing population PK model (25 AD participants, 20 healthy older people). RESULTS: Eight patients (target 20) were recruited (six women; 76 + - 6 years; six treatment compliant; five serially sampled; three with paired imaging data). Mean + - SD symptom reduction was 74 ± 12% (50-100 mg/day; 92.5 + -39.4 ng/ml). Mild EPS emerged at 96 ng/ml (in AD, severe EPS, 50 mg/day, 60 ng/ml). In three participants, imaged during optimal treatment (50 mg/day; 41-70 ng/ml), caudate occupancy was 44-59% (58-74% in AD across a comparable Caverage). CONCLUSIONS: Despite the small sample size, our findings are highly relevant as they suggest that, as in AD, 50 mg/day amisulpride is associated with >40% occupancy and clinically relevant responses in VLOSLP. It was not possible to fully characterise concentration-occupancy relationships in VLOSLP, and it is thus unclear whether the greater susceptibility of those with AD to emergent EPS was accounted for by increased central drug access. Further investigation of age- and diagnosis-specific threshold sensitivities is warranted, to guide amisulpride prescribing in older people, and therapeutic drug monitoring studies offer a potentially informative future approach. Copyright © 2017 John Wiley & Sons, Ltd.

A Population Approach to Guide Amisulpride Dose Adjustments in Older Patients With Alzheimer's Disease.

OBJECTIVE: We have previously reported high dopamine D2/3 receptor occupancies at low amisulpride concentrations in older people with Alzheimer's disease (AD), during off-label treatment of AD-related psychosis. This post hoc analysis explored pharmacokinetic (concentration) and pharmacodynamic (prolactin, D2/3 occupancy) contributions to symptom reduction and extrapyramidal side effects (EPS) to inform AD-specific dose adjustments. METHODS: Population pharmacokinetic-pharmacodynamic models were developed by combining pharmacokinetic data from a phase 1 study in 20 healthy older people with pharmacokinetic prolactin, [¹8F]fallypride D2/3 receptor imaging, and clinical outcome data from 28 older patients prescribed open amisulpride (25-75 mg/d) to treat AD-related psychosis. Model predictions were used to simulate dose-response and dose-EPS. RESULTS: Symptom reduction (delusions) was associated with amisulpride concentration (P = 1.3e-05) and D2/3 occupancy (P < .01, caudate, putamen, thalamus). Model predictions suggested that across concentrations of 40-100 ng/mL, and occupancies of 40% to 70% in the caudate and thalamus and 30% to 60% in the putamen, there was a 50% to 90% probability of response and < 30% probability of EPS. Simulations, based on concentration-delusions and concentration-EPS model outputs, showed that 50 mg/d of amisulpride was the appropriate dose to achieve this target range in those aged > 75 years; increasing the dose to 75 mg/d increased the risk of EPS, particularly in those aged > 85 years of low body weight. CONCLUSIONS: These findings argue strongly for the consideration of age- and weight-based dose adjustments in older patients with AD-related psychosis and indicate that 50 mg/d of amisulpride may be both the minimal clinically effective dose and, in those aged > 75 years, the maximally tolerated dose.

Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer's disease.

See Caravaggio and Graff-Guerrero (doi:10.1093/awx023) for a scientific commentary on this article.Antipsychotic drugs, originally developed to treat schizophrenia, are used to treat psychosis, agitation and aggression in Alzheimer's disease. In the absence of dopamine D2/3 receptor occupancy data to inform antipsychotic prescribing for psychosis in Alzheimer's disease, the mechanisms underpinning antipsychotic efficacy and side effects are poorly understood. This study used a population approach to investigate the relationship between amisulpride blood concentration and central D2/3 occupancy in older people with Alzheimer's disease by combining: (i) pharmacokinetic data (280 venous samples) from a phase I single (50 mg) dose study in healthy older people (n = 20, 65-79 years); (ii) pharmacokinetic, 18F-fallypride D2/3 receptor imaging and clinical outcome data on patients with Alzheimer's disease who were prescribed amisulpride (25-75 mg daily) to treat psychosis as part of an open study (n = 28; 69-92 years; 41 blood samples, five pretreatment scans, 19 post-treatment scans); and (iii) 18F-fallypride imaging of an antipsychotic free Alzheimer's disease control group (n = 10, 78-92 years), to provide additional pretreatment data. Non-linear mixed effects modelling was used to describe pharmacokinetic-occupancy curves in caudate, putamen and thalamus. Model outputs were used to estimate threshold steady state blood concentration and occupancy required to elicit a clinically relevant response (>25% reduction in scores on delusions, hallucinations and agitation domains of the Neuropsychiatric Inventory) and extrapyramidal side effects (Simpson Angus Scale scores > 3). Average steady state blood levels were low (71 ± 30 ng/ml), and associated with high D2/3 occupancies (65 ± 8%, caudate; 67 ± 11%, thalamus; 52 ± 11%, putamen). Antipsychotic clinical response occurred at a threshold concentration of 20 ng/ml and D2/3 occupancies of 43% (caudate), 25% (putamen), 43% (thalamus). Extrapyramidal side effects (n = 7) emerged at a threshold concentration of 60 ng/ml, and D2/3 occupancies of 61% (caudate), 49% (putamen) and 69% (thalamus). This study has established that, as in schizophrenia, there is a therapeutic window of D2/3 receptor occupancy for optimal treatment of psychosis in Alzheimer's disease. We have also shown that occupancies within and beyond this window are achieved at very low amisulpride doses in Alzheimer's disease due to higher than anticipated occupancies for a given blood drug concentration. Our findings support a central pharmacokinetic contribution to antipsychotic sensitivity in Alzheimer's disease and implicate the blood-brain barrier, which controls central drug access. Whether high D2/3 receptor occupancies are primarily accounted for by age- or disease-specific blood-brain barrier disruption is unclear, and this is an important future area of future investigation, as it has implications beyond antipsychotic prescribing.

Smoking Cessation Intervention for Severe Mental Ill Health Trial (SCIMITAR+): study protocol for a randomised controlled trial.

BACKGROUND: Smoking is highly prevalent among people who have experience of severe mental ill health, contributing to their poor physical health. Despite the 'culture' of smoking in mental health services, people with severe mental ill health often express a desire to quit smoking; however, the services currently available to aid quitting are those which are widely available to the general population and may not be suitable or effective for people with severe mental ill health. The aim of this study is to explore the effectiveness and cost-effectiveness of a bespoke smoking-cessation intervention specifically targeted at people with severe mental ill health. METHODS/DESIGN: SCIMITAR+ is a multicentre, pragmatic, two-arm, parallel-group, individually randomised controlled trial. We aim to recruit 400 participants aged 18 years and above with a documented diagnosis of bipolar disorder, schizophrenia or schizoaffective disorder who smoke. Potentially eligible participants identified in primary or secondary care will be screened, and baseline data collected. Eligible, consenting participants will be randomly allocated to one of two groups. In the intervention arm, the participant will be assigned a mental health professional trained to deliver smoking-cessation interventions who will work with the participant and participant's GP or mental health specialist to provide an individually tailored smoking-cessation service. The comparator arm will be usual care - following current NICE guidelines for smoking cessation, in line with general guidance that is offered to all smokers, with no specific adaptation or enhancement in relation to severe mental ill health. The primary outcome will be self-reported smoking cessation at 12 months verified by expired carbon monoxide (CO) measurement. Secondary outcome measures include Body Mass Index at 12 months, the Fagerström Test for Nicotine Dependence, Motivation to Quit questionnaire, SF-12, PHQ-9, GAD-7, EQ-5D-5 L, and health service utilisation at 6 and 12 months. The economic evaluation at 12 months will be conducted in the form of an incremental cost-effectiveness analysis. DISCUSSION: SCIMITAR+ trial is the largest trial to our knowledge to investigate the effectiveness of a bespoke smoking-cessation service for people with severe mental ill health. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number, ISRCTN72955454 . Registered on 16 January 2015.

A population approach to characterise amisulpride pharmacokinetics in older people and Alzheimer's disease.

INTRODUCTION: Current prescribing guidelines for the antipsychotic amisulpride are based largely on pharmacokinetic (PK) studies in young adults, and there is a relative absence of data on older patients, who are at greatest risk of developing adverse events. METHODS: This study aimed to develop a population PK model for amisulpride specifically in older people, by combining data from a richly sampled phase 1, single (50 mg) dose study in healthy older people (n = 20, 65-79 years), with a clinical dataset obtained during off label, low-dose (25-75 mg daily) amisulpride prescribing in older people with Alzheimer's disease (AD) (n = 25, 69-92 years), as part of an observational study. RESULTS: After introducing a scaling factor based on body weight, age accounted for 20 % of the inter-individual variability in drug clearance (CL), resulting in a 54 % difference in CL between those aged 65 and those aged 85 years, and higher blood concentrations in older patients. DISCUSSION: These findings argue for the consideration of age and weight-based dose stratification to optimise amisulpride prescribing in older people, particularly in those aged 85 years and above.

Towards a therapeutic window of D2/3 occupancy for treatment of psychosis in Alzheimer's disease, with [18F]fallypride positron emission tomography.

OBJECTIVE: Dopamine D2/3 receptor positron emission tomography tracers have guided antipsychotic prescribing in young people with schizophrenia by establishing a 'therapeutic window' of striatal D2/3 receptor occupancy. Older people, particularly those with dementia, are highly susceptible to motor side effects and may benefit from the appropriate application of imaging techniques. The study aimed to adapt [18F]fallypride imaging for use in occupancy studies in Alzheimer's disease (AD) and to investigate whether data acquisition could be made more tolerable by piloting the protocol in a small sample. METHODS: Six participants with AD (three men; 85.0 ± 5.6 years old; MMSE = 16.0 ± 2.4) were recruited prior to commencing amisulpride for the treatment of psychosis and associated agitation. [18F]fallypride binding potential (BPND ) was determined using an interrupted scanning protocol at baseline (n = 6) and after 27.0 ± 6.1 days of amisulpride (25-50 mg) treatment (n = 4). D2/3 occupancy was calculated by percentage reduction in BPND between scanning sessions. Image data were re-analysed after reducing individual sampling times to 20 min. RESULTS: The protocol was tolerated well, apart from the final (40 min) session of the post-treatment scan in one participant. Higher occupancies were achieved in the striatum (caudate 47-70%, putamen 31-58%) and thalamus (54-76%) than in the inferior temporal gyrus (27-43%). There was high agreement between occupancy values derived using longer and shorter sampling times (mean absolute difference 6.1% in the inferior temporal gyrus; <2% all other regions). CONCLUSIONS: The protocol is feasible for use in AD and represents the first step towards establishing dose-occupancy relationships across older clinical populations.