Real-world clinical and cost-effectiveness of community clozapine initiation: mirror cohort study.

BACKGROUND: Clozapine is the only drug licensed for treatment-resistant schizophrenia (TRS) but the real-world clinical and cost-effectiveness of community initiation of clozapine is unclear. AIMS: The aim was to assess the feasibility and cost-effectiveness of community initiation of clozapine. METHOD: This was a naturalistic study of community patients recommended for clozapine treatment. RESULTS: Of 158 patients recommended for clozapine treatment, 88 (56%) patients agreed to clozapine initiation and, of these, 58 (66%) were successfully established on clozapine. The success rate for community initiation was 65.4%; which was not significantly different from that for in-patient initiation (58.82%, χ2(1,88) = 0.47, P = 0.49). Following clozapine initiation, there was a significant reduction in median out-patient visits over 1 year (from 24.00 (interquartile range (IQR) = 14.00-41.00) to 13.00 visits (IQR = 5.00-24.00), P < 0.001), and 2 years (from 47.50 visits (IQR = 24.75-71.00) to 22.00 (IQR = 11.00-42.00), P < 0.001), and a 74.71% decrease in psychiatric hospital bed days (z = -2.50, P = 0.01). Service-use costs decreased (1 year: -£963/patient (P < 0.001); 2 years: -£1598.10/patient (P < 0.001). Subanalyses for community-only initiation also showed significant cost reductions (1 year: -£827.40/patient (P < 0.001); 2 year: -£1668.50/patient (P < 0.001) relative to costs prior to starting clozapine. Relative to before initiation, symptom severity was improved in patients taking clozapine at discharge (median Positive and Negative Syndrome Scale total score: initial visit: 80 (IQR = 71.00-104.00); discharge visit 50.5 (IQR = 44.75-75.00), P < 0.001) and at 2 year follow-up (Health of Nation Outcome Scales total score median initial visit: 13.00 (IQR = 9.00-15.00); 2 year follow-up: 8.00 (IQR = 3.00-13.00), P = 0.023). CONCLUSIONS: These findings indicate that community initiation of clozapine is feasible and is associated with significant reductions in costs, service use and symptom severity.

Evaluation of Intraperitoneal [18F]-FDOPA Administration for Micro-PET Imaging in Mice and Assessment of the Effect of Subchronic Ketamine Dosing on Dopamine Synthesis Capacity.

Positron emission tomography (PET) using the radiotracer [18F]-FDOPA provides a tool for studying brain dopamine synthesis capacity in animals and humans. We have previously standardised a micro-PET methodology in mice by intravenously administering [18F]-FDOPA via jugular vein cannulation and assessment of striatal dopamine synthesis capacity, indexed as the influx rate constant K i Mod of [18F]-FDOPA, using an extended graphical Patlak analysis with the cerebellum as a reference region. This enables a direct comparison between preclinical and clinical output values. However, chronic intravenous catheters are technically difficult to maintain for longitudinal studies. Hence, in this study, intraperitoneal administration of [18F]-FDOPA was evaluated as a less-invasive alternative that facilitates longitudinal imaging. Our experiments comprised the following assessments: (i) comparison of [18F]-FDOPA uptake between intravenous and intraperitoneal radiotracer administration and optimisation of the time window used for extended Patlak analysis, (ii) comparison of Ki Mod in a within-subject design of both administration routes, (iii) test-retest evaluation of Ki Mod in a within-subject design of intraperitoneal radiotracer administration, and (iv) validation of Ki Mod estimates by comparing the two administration routes in a mouse model of hyperdopaminergia induced by subchronic ketamine. Our results demonstrate that intraperitoneal [18F]-FDOPA administration resulted in good brain uptake, with no significant effect of administration route on Ki Mod estimates (intraperitoneal: 0.024 ± 0.0047 min-1, intravenous: 0.022 ± 0.0041 min-1, p = 0.42) and similar coefficient of variation (intraperitoneal: 19.6%; intravenous: 18.4%). The technique had a moderate test-retest validity (intraclass correlation coefficient (ICC) = 0.52, N = 6) and thus supports longitudinal studies. Following subchronic ketamine administration, elevated K i Mod as compared to control condition was measured with a large effect size for both methods (intraperitoneal: Cohen's d = 1.3; intravenous: Cohen's d = 0.9), providing further evidence that ketamine has lasting effects on the dopamine system, which could contribute to its therapeutic actions and/or abuse liability.

A potential biomarker for treatment stratification in psychosis: evaluation of an [18F] FDOPA PET imaging approach.

[18F]FDOPA PET imaging has shown dopaminergic function indexed as Kicer differs between antipsychotic treatment responders and non-responders. However, the theragnostic potential of this biomarker to identify non-responders has yet to be evaluated. In view of this, we aimed to evaluate this as a theragnostic test using linear and non-linear machine-learning (i.e., Bernoulli, support vector, random forest and Gaussian processes) analyses and to develop and evaluate a simplified approach, standardised uptake value ratio (SUVRc). Both [18F]FDOPA PET approaches had good test-rest reproducibility across striatal regions (Kicer ICC: 0.68-0.94, SUVRc ICC: 0.76-0.91). Both our linear and non-linear classification models showed good predictive power to distinguish responders from non-responders (receiver operating curve area under the curve for region-of-interest approach: Kicer = 0.80, SUVRc = 0.79; for voxel-wise approach using a linear support vector machine: 0.88) and similar sensitivity for identifying treatment non-responders with 100% specificity (Kicer: ~50%, SUVRc: 40-60%). Although the findings were replicated in two independent datasets, given the total sample size (n = 84) and single setting, they warrant testing in other samples and settings. Preliminary economic analysis of [18F]FDOPA PET to fast-track treatment-resistant patients with schizophrenia to clozapine indicated a potential healthcare cost saving of ~£3400 (equivalent to $4232 USD) per patient. These findings indicate [18F]FDOPA PET dopamine imaging has potential as biomarker to guide treatment choice.

A Meta-analysis of Immune Parameters, Variability, and Assessment of Modal Distribution in Psychosis and Test of the Immune Subgroup Hypothesis.

Immune parameters are elevated in psychosis, but it is unclear whether alterations are homogenous across patients or heterogeneity exists, consistent with the hypothesis that immune alterations are specific to a subgroup of patients. To address this, we examine whether antipsychotic-naïve first-episode psychosis patients exhibit greater variability in blood cytokines, C-reactive protein, and white cell counts compared with controls, and if group mean differences persist after adjusting for skewed data and potential confounds. Databases were searched for studies reporting levels of peripheral immune parameters. Means and variances were extracted and analyzed using multivariate meta-analysis of mean and variability of differences. Outcomes were (1) variability in patients relative to controls, indexed by variability ratio (VR) and coefficient of variation ratio (CVR); (2) mean differences indexed by Hedges g; (3) Modal distribution of raw immune parameter data using Hartigan's unimodality dip test. Thirty-five studies reporting on 1263 patients and 1470 controls were included. Variability of interleukin-6 (IL6) (VR = 0.19), tumor necrosis factor-α (TNFα) (VR = 0.36), interleukin-1ß (VR = 0.35), interleukin-4 (VR = 0.55), and interleukin-8 (VR = 0.28) was reduced in patients. Results persisted for IL6 and IL8 after mean-scaling. Ninety-four percent and one hundred percent of raw data were unimodally distributed in psychosis and controls, respectively. Mean levels of IL6 (g = 0.62), TNFα (g = 0.56), interferon-γ (IFNγ) (g = 0.32), transforming growth factor-ß (g = 0.53), and interleukin-17 (IL17) (g = 0.48) were elevated in psychosis. Sensitivity analyses indicated this is unlikely explained by confounders for IL6, IFNγ, and IL17. These findings show elevated cytokines in psychosis after accounting for confounds, and that the hypothesis of an immune subgroup is not supported by the variability or modal distribution.

Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology.

An expert review of the aetiology, assessment, and treatment of autism spectrum disorder, and recommendations for diagnosis, management and service provision was coordinated by the British Association for Psychopharmacology, and evidence graded. The aetiology of autism spectrum disorder involves genetic and environmental contributions, and implicates a number of brain systems, in particular the gamma-aminobutyric acid, serotonergic and glutamatergic systems. The presentation of autism spectrum disorder varies widely and co-occurring health problems (in particular epilepsy, sleep disorders, anxiety, depression, attention deficit/hyperactivity disorder and irritability) are common. We did not recommend the routine use of any pharmacological treatment for the core symptoms of autism spectrum disorder. In children, melatonin may be useful to treat sleep problems, dopamine blockers for irritability, and methylphenidate, atomoxetine and guanfacine for attention deficit/hyperactivity disorder. The evidence for use of medication in adults is limited and recommendations are largely based on extrapolations from studies in children and patients without autism spectrum disorder. We discuss the conditions for considering and evaluating a trial of medication treatment, when non-pharmacological interventions should be considered, and make recommendations on service delivery. Finally, we identify key gaps and limitations in the current evidence base and make recommendations for future research and the design of clinical trials.

Translation and cross-cultural adaptation of the Sexual Function Questionnaire (SFQ) into Brazilian Portuguese.

INTRODUCTION: Sexual dysfunction is common in patients with psychotic illness. This article describes the translation and cross-cultural adaptation of the Sexual Function Questionnaire (SFQ) into Brazilian Portuguese. METHODS: The translation and cross-cultural adaptation followed the guidelines for adapting self-report instruments proposed by the Task Force of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Briefly, ISPOR steps include: preparation, forward translation, reconciliation, back-translation, back-translation review, harmonization, cognitive debriefing, review of cognitive debriefing and finalization, before proofreading and final version. The original authors authorized the translation and participated in the study. RESULTS: There was good agreement between translations and between the back-translation and the original English version of the SFQ. The final version was prepared with certificated evaluators in the original language and in Portuguese. Few changes were necessary to the new version in Portuguese. CONCLUSION: The translated and adapted Brazilian Portuguese version of the SFQ is reliable and semantically equivalent to the original version. Studies on psychotropic-related sexual dysfunction may now test the validity of the instrument and can investigate sexual dysfunction in Portuguese-speaking patients.

Hyperprolactinaemia in first episode psychosis - A longitudinal assessment.

Little is known about hyperprolactinaemia (HPL) in first episode psychosis (FEP) patients. We investigated longitudinal changes in serum prolactin in FEP, and the relationship between HPL, and antipsychotic medication and stress. Serum prolactin was recorded in FEP patients at recruitment and again, 3 and 12months later. HPL was defined as a serum prolactin level >410mIU/L (~19.3ng/ml) for males, and a serum prolactin level >510mIU/L (~24.1ng/ml) for females. From a total of 174 people with serum prolactin measurements at study recruitment, 43% (n=74) had HPL, whilst 27% (n=21/78) and 27% (n=26/95) had HPL at 3 and 12months respectively. We observed higher serum prolactin levels in females versus males (p<0.001), and in antipsychotic treated (n=68) versus antipsychotic naïve patients (p<0.0001). Prolactin levels were consistently raised in FEP patients taking risperidone, amisulpride and FGAs compared to other antipsychotics. No significant relationship was observed between perceived stress scores (ß=7.13, t=0.21, df=11, p=0.0.84 95% CI -72.91-87.16), or objective life stressors (ß=-21.74, t=-0.31, df=8, p=0.77 95% CI -218.57-175.09) and serum prolactin. Our study found elevated rates of HPL over the course of the first 12months of illness. We found no evidence to support the notion that stress is related to elevated serum prolactin at the onset of psychosis.

Translation and cross-cultural adaptation of the Sexual Function Questionnaire (SFQ) into Brazilian Portuguese / Tradução e adaptação transcultural do Questionário de Função Sexual (SFQ) para o português do Brasil

Abstract Introduction Sexual dysfunction is common in patients with psychotic illness. This article describes the translation and cross-cultural adaptation of the Sexual Function Questionnaire (SFQ) into Brazilian Portuguese. Methods The translation and cross-cultural adaptation followed the guidelines for adapting self-report instruments proposed by the Task Force of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Briefly, ISPOR steps include: preparation, forward translation, reconciliation, back-translation, back-translation review, harmonization, cognitive debriefing, review of cognitive debriefing and finalization, before proofreading and final version. The original authors authorized the translation and participated in the study. Results There was good agreement between translations and between the back-translation and the original English version of the SFQ. The final version was prepared with certificated evaluators in the original language and in Portuguese. Few changes were necessary to the new version in Portuguese. Conclusion The translated and adapted Brazilian Portuguese version of the SFQ is reliable and semantically equivalent to the original version. Studies on psychotropic-related sexual dysfunction may now test the validity of the instrument and can investigate sexual dysfunction in Portuguese-speaking patients.

Resumo Introdução A disfunção sexual é comum em pacientes com doença psicótica. Este artigo descreve a tradução e adaptação transcultural do Questionário de Função Sexual (SFQ) para o português do Brasil. Métodos A tradução e a adaptação transcultural seguiram as diretrizes para a adaptação de instrumentos de autorrelato propostas pela Força-Tarefa da Sociedade Internacional de Pesquisa Farmacológica e de Resultados (International Society for Pharmacoeconomics and Outcomes Research, ISPOR). As etapas da ISPOR incluem: preparação, primeiras traduções, reconciliação, retrotradução, revisão da retrotradução, harmonização, interrogatório cognitivo, revisão do interrogatório cognitivo e finalização, antes da revisão e versão final. Os autores originais autorizaram a tradução e participaram do estudo. Resultados Houve boa concordância entre as traduções e entre a retrotradução e a versão original em inglês do SFQ. A versão final foi preparada com avaliadores certificados na língua original e em português. Poucas mudanças foram necessárias para a nova versão em português. Conclusão A versão brasileira traduzida e adaptada do SFQ é confiável e semanticamente equivalente à versão original. Estudos sobre disfunção sexual relacionada a psicotrópicos podem agora testar a validade do instrumento e investigar a disfunção sexual em pacientes brasileiros.

Economic impact of early detection and early intervention of psychosis.

BACKGROUND: Whilst there is a growing body of evidence relating to the effectiveness of early detection and early intervention services there have been relatively few studies which have provided information on whether they are cost-effective. AIM: The aim of this paper is to review the cost-effectiveness evidence for early detection and early intervention in psychosis. METHODS: Full economic evaluations, cost studies, and studies which do not report costs but do provide important resource use information were included in the review. RESULTS: All cost effectiveness analysis to date suggest that it is possible to offer help early in the development of psychosis in a cost effective manner. CONCLUSIONS: The potential longer term economic benefits of early detection and early intervention are required.