Combinations of QT-prolonging drugs: towards disentangling pharmacokinetic and pharmaco-dynamic effects in their potentially additive nature.

Background: Whether arrhythmia risks will increase if drugs with electrocardiographic (ECG) QT-prolonging properties are combined is generally supposed but not well studied. Based on available evidence, the Arizona Center for Education and Research on Therapeutics (AZCERT) classification defines the risk of QT prolongation for exposure to single drugs. We aimed to investigate how combining AZCERT drug categories impacts QT duration and how relative drug exposure affects the extent of pharmacodynamic drug–drug interactions. Methods: In a cohort of 2558 psychiatric inpatients and outpatients, we modeled whether AZCERT class and number of coprescribed QT-prolonging drugs correlates with observed rate-corrected QT duration (QTc) while also considering age, sex, inpatient status, and other QTc-prolonging risk factors. We concurrently considered administered drug doses and pharmacokinetic interactions modulating drug clearance to calculate individual weights of relative exposure with AZCERT drugs. Because QTc duration is concentration-dependent, we estimated individual drug exposure with these drugs and included this information as weights in weighted regression analyses. Results: Drugs attributing a ‘known’ risk for clinical consequences were associated with the largest QTc prolongations. However, the presence of at least two versus one QTc-prolonging drug yielded nonsignificant prolongations [exposure-weighted parameter estimates with 95% confidence intervals for ‘known’ risk drugs + 0.93 ms (–8.88;10.75)]. Estimates for the ‘conditional’ risk class increased upon refinement with relative drug exposure and coadministration of a ‘known’ risk drug as a further risk factor. Conclusions: These observations indicate that indiscriminate combinations of QTc-prolonging drugs do not necessarily result in additive QTc prolongation and suggest that QT prolongation caused by drug combinations strongly depends on the nature of the combination partners and individual drug exposure. Concurrently, it stresses the value of the AZCERT classification also for the risk prediction of combination therapies with QT-prolonging drugs

Off–label long acting injectable antipsychotics in real–world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction: Information on the off–label use of Long–Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on– vs off–label LAIs and predictors of off–label First– or Second–Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method: In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off– or on–label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off–label group. Results: SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on– and off–label use. Approximately 1 in 4 patients received an off–label prescription. In the off–label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion: Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off–label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co–morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns

Comparing Long-Acting Antipsychotic Discontinuation Rates Under Ordinary Clinical Circumstances: A Survival Analysis from an Observational, Pragmatic Study

Background: Recent guidelines suggested a wider use of long-acting injectable antipsychotics (LAI) than previously, but naturalistic data on the consequences of LAI use in terms of discontinuation rates and associated factors are still sparse, making it hard for clinicians to be informed on plausible treatment courses. Objective: Our objective was to assess, under real-world clinical circumstances, LAI discontinuation rates over a period of 12 months after a first prescription, reasons for discontinuation, and associated factors. Methods: The STAR Network ‘Depot Study’ was a naturalistic, multicentre, observational prospective study that enrolled subjects initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centres were assessed at baseline and at 6 and 12 months of follow-up. Psychopathology, drug attitude and treatment adherence were measured using the Brief Psychiatric Rating Scale, the Drug Attitude Inventory and the Kemp scale, respectively. Results: The study followed 394 participants for 12 months. The overall discontinuation rate at 12 months was 39.3% (95% confidence interval [CI] 34.4–44.3), with paliperidone LAI being the least discontinued LAI (33.9%; 95% CI 25.3–43.5) and olanzapine LAI the most discontinued (62.5%; 95% CI 35.4–84.8). The most frequent reason for discontinuation was onset of adverse events (32.9%; 95% CI 25.6–40.9) followed by participant refusal of the medication (20.6%; 95% CI 14.6–27.9). Medication adherence at baseline was negatively associated with discontinuation risk (hazard ratio [HR] 0.853; 95% CI 0.742–0.981; p = 0.026), whereas being prescribed olanzapine LAI was associated with increased discontinuation risk compared with being prescribed paliperidone LAI (HR 2.156; 95% CI 1.003–4.634; p = 0.049). Conclusions: Clinicians should be aware that LAI discontinuation is a frequent occurrence. LAI choice should be carefully discussed with the patient, taking into account individual characteristics and possible obstacles related to the practicalities of each formulation

Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment-resistant schizophrenia

<p>Abstract</p> <p>Background</p> <p>One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study.</p> <p>Methods/Design</p> <p>The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome.</p> <p>Discussion</p> <p>The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia.</p> <p>Trial Registration</p> <p><b>Clincaltrials.gov Identifier</b>: NCT00395915</p

A multi-element psychosocial intervention for early psychosis (GET UP PIANO TRIAL) conducted in a catchment area of 10 million inhabitants: study protocol for a pragmatic cluster randomized controlled trial

Multi-element interventions for first-episode psychosis (FEP) are promising, but have mostly been conducted in non-epidemiologically representative samples, thereby raising the risk of underestimating the complexities involved in treating FEP in 'real-world' services

Hypoxic-ischemia-related obstetric complications and risk of anorexia nervosa and bulimia nervosa

Eating Disorders Research Society Annual Meeting, Amsterdam, October 7-9, 200

Giovani, salute e comportamenti a rischio: politiche di prevenzione autogestite

Il progetto di ricerca \u2013 coordinato dall\u2019unit\ue0 di Macerata, in collaborazione con le unit\ue0 di Udine, Bologna e Cassino \u2013 si propone si realizzare una ricerca-intervento rivolta agli studenti delle scuole e finalizzata alla prevenzione dei comportamenti a rischio e alla promozione della salute bio-psico-sociale. L\u2019obiettivo \ue8 quello di potenziare nei giovani le capacit\ue0 di comunicazione tra pari sulla salute, sul rischio e su stili di vita sani. Sar\ue0 interesse delle unit\ue0 di ricerca comprendere il punto di vista giovanile e coinvolgere i ragazzi come interlocutori dal ruolo attivo nella costruzione di strumenti comunicativi efficaci e messaggi corretti rivolti a coetanei. Le unit\ue0 di ricerca di Bologna, Macerata e Udine saranno impegnate in una ricerca azione rivolta ad alcune specifiche condotte giovanili, quali l\u2019uso di alcol e di droghe, i comportamenti sessuali a rischio, il bullismo e i comportamenti a rischio che possono diffondersi attraverso Internet. Mentre, l\u2019unit\ue0 di Cassino esaminer\ue0 specifici comportamenti a rischio che possono interessare gli studenti stranieri. Svilupper\ue0, dunque, un progetto di intervento mirato alla promozione della salute tra gli studenti stranieri e alla prevenzione di comportamenti di discriminazione etnica e di bullismo tra studenti italiani e stranieri. Durante il primo anno del progetto, circa 1000 studenti di scuole superiori saranno coinvolti in un\u2019inchiesta campionaria online. Si costituir\ue0, pertanto, un campione rappresentativo nazionale di studenti del primo e del secondo anno di scuola superiore. Lo scopo della web survey \ue8 di rilevare tre aspetti in particolare: gli atteggiamenti sociali dei giovani verso i comportamenti a rischio; le conoscenze dei giovani sui rischi correlati a certe condotte; la valutazione degli interventi di prevenzione. La ricerca sar\ue0 promossa sia attraverso gli enti istituzionali, ma anche grazie all\u2019utilizzo dei principali social network, al fine di creare una rete di istituti e di studenti cui rivolgere le azioni successive del progetto. Parallelamente le unit\ue0 di ricerca compiranno una revisione sistematica della letteratura scientifica sui comportamenti a rischio tra i giovani e degli studi sull\u2019efficacia delle strategie di prevenzione. Sul tema delle prevenzione del rischio e delle campagne pubbliche di promozione della salute, saranno prese in esame le principali campagne di comunicazione (nazionali, regionali, locali) e sar\uf2 condotta un\u2019analisi del contenuto. Nel secondo anno, sar\ue0 selezionato un sotto-campione di scuole dove svolgere una ricerca-azione sui temi di pertinenza delle quattro unit\ue0. Obiettivo della ricerca sar\ue0 quello di impostare una campagna di comunicazione online rivolta alla rete di scuole costituita nella prima fase della ricerca. La ricerca azione \ue8 una tecnica finalizzata a stimolare cambiamenti negli atteggiamenti e nei comportamenti delle persone coinvolte nella ricerca, attraverso la loro partecipazione diretta al processo. Pertanto, i giovani saranno condotti in un percorso di attivazione di tre capacit\ue0: capacit\ue0 di riconoscere i propri pregiudizi e le false credenze; capacit\ue0 di individuare informazioni corrette; capacit\ue0 di comunicare tra pari informazioni corrette in modo efficace. Strategia comune delle unit\ue0 di ricerca sar\ue0 quella di ottenere tale attivazione coinvolgendo gli studenti nella progettazione di un portale online di informazione sulla salute e sul benessere dei giovani. I contenuti del portale dovranno essere prodotti dagli stessi studenti e rivolti ai propri coetanei. Contenuti, stili comunicativi e mezzi di diffusione del massaggio saranno discussi e concordati all\u2019interno dei gruppi. Nel terzo anno, si arriver\ue0 all\u2019implementazione del portale web, cui saranno collegate tutte le scuole della rete, ma potenzialmente aperto all\u2019adesione di tutti gli istituti scolastici presenti sul territorio nazionale. Per accrescere la visibilit\ue0 e incentivare la partecipazione degli studenti sar\ue0 lanciato un concorso nazionale che premier\ue0 la migliore produzione di una campagna di comunicazione rivolta ai giovani sulla prevenzione del rischio e la promozione di stili di vita sani. La votazione si svolger\ue0 online e sar\ue0 aperta a tutti i visitatori. Al fine di valutare l\u2019impatto e l\u2019efficacia della ricerca-intervento, saranno svolti localmente focus group con studenti e altri soggetti interessati. A livello nazionale, sar\ue0 riproposta la web survey, al fine di valutare attraverso opportuni test statistici l\u2019effetto della ricerca in termini di sviluppo delle conoscenze e cambiamento di atteggiamenti sociali