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

Medium and long-term efficacy of psychoeducational family intervention for bipolar I disorder: Results from a real-world, multicentric study

Objectives: This study aims to explore the long-term efficacy of a psychoeducational family intervention (PFI) in bipolar I disorder at one and five years post-intervention in terms of improvement of: (1) patients’ symptoms and global functioning and (2) relatives’ objective and subjective burden and coping strategies. Methods: This is a multicentre, real-world, controlled, outpatient trial. Recruited patients and key-relatives were consecutively allocated to the experimental intervention or treatment as usual. Patients were assessed at baseline, and after one and five years. Results: One hundred and thirty-seventh number families have been recruited; 70 have been allocated to the experimental intervention, and 67 have been allocated to the control group. We observed an increasing positive effect of the PFI on patients’ clinical status, global functioning and objective and subjective burden after one year. We also found a reduction in the levels of relatives’ objective and subjective burden and a significant improvement in the levels of perceived professional support and of coping strategies. The efficacy of PFI on patients’ clinical status was maintained at five years from the end of the intervention, in terms of relapses, hospitalizations and suicide attempts. Conclusions: The study showed that the provision of PFI in real-world settings is associated with a significant improvement of patients’ and relatives’ mental health and psychosocial functioning in the long term. We found that the clinical efficacy of the intervention, in terms of reduction of patients’ relapses, hospitalization and suicide attempts, persists after 5 years. It is advisable that PFI is provided to patients with BD I in routine practice

The effects of psychoeducational family intervention on coping strategies of relatives of patients with bipolar I disorder: results from a controlled, real-world, multicentric study

Gaia Sampogna,1 Mario Luciano,1 Valeria Del Vecchio,1 Claudio Malangone,1,2 Corrado De Rosa,1 Vincenzo Giallonardo,1 Giuseppina Borriello,1 Benedetta Pocai,1 Micaela Savorani,1 Luca Steardo Jr,1 Debora Lampis,3 Franco Veltro,4 Francesco Bartoli,5 Francesco Bardicchia,6 Anna Maria Moroni,7 Giusy Ciampini,8 Emanuele Orlandi,9 Silvia Ferrari,10 Silvia Biondi,11 Sonia Iapichino,11,12 Enrico Pompili,13 Massimiliano Piselli,14 Alfonso Tortorella,15 Giuseppe Carrà,5,16 Andrea Fiorillo1 1Department of Psychiatry, University of Campania “Luigi Vanvitelli”, Naples, 2Mental Health Centre of Ravello, Mental Health Unit, Ravello, 3Mental Health Centre of Lanusei, Mental Health Unit, Lanusei, 4Mental Health Department of Campobasso, Campobasso, 5Department of Medicine and Surgery, University of Milano Bicocca, Monza, 6Mental Health Centre of Grosseto, Mental Health Unit, Grosseto, 7Niguarda Hospital, Department of Psychiatry, Milan, 8Mental Health Centre of Lanciano, Mental Health Unit, Lanciano, 9Mental Health Centre of Sassuolo, Mental Health Unit, Sassuolo, 10University of Modena and Reggio Emilia, Department of Psychiatry, Reggio Emilia, 11Mental Health Centre of Montecatini, Mental Health Unit, Montecatini, 12Auditor Psychiatrist, for the activities of Clinical Risk Management and safety of treatments, Tuscany Region, 13Mental Health Centre of Rome, Mental Health Unit, Rome, 14Mental Health Centre of Foligno, Mental Health Unit, Foligno, 15Department of Medicine, Section of Psychiatry, University of Perugia, Perugia, Italy; 16Division of Psychiatry, University College of London, London, UK Background: Psychoeducational family intervention (PFI) has been proven to be effective in improving the levels of family burden and patients’ personal functioning in schizophrenia and bipolar disorders (BDs). Less is known about the impact of PFI on relatives’ coping strategies in BD. Methods: A multicenter, controlled, outpatient trial funded by the Italian Ministry of Health and coordinated by the Department of Psychiatry of the University of Campania “Luigi Vanvitelli” has been conducted in patients with bipolar I disorder (BD-I) and their key relatives consecutively recruited in 11 randomly selected Italian community mental health centers. We aim to test the hypothesis that PFI improves problem-oriented coping strategies in relatives of BD-I patients compared to the Treatment As Usual (TAU) group. Results: The final sample was constituted of 123 patients and 139 relatives. At baseline assessment (T0), the vast majority of relatives already adopted problem-oriented coping strategies more frequently than the emotion-focused ones. At the end of the intervention, relatives receiving PFI reported a higher endorsement of adaptive coping strategies, such as “maintenance of social interests” (odds ratio [OR]=0.309, CI=0.04–0.57; p=0.023), “positive communication with the patient” (OR=0.295, CI=0.13–0.46; p=0.001), and “searching for information” (OR=0.443, CI=0.12–0.76; p=0.007), compared to TAU relatives, after controlling for several confounders. As regards the emotion-focused coping strategies, relatives receiving the experimental intervention less frequently reported to adopt “resignation” (OR=-0.380, CI=-0.68 to -0.08; p=0.014) and “coercion” (OR=-0.268, CI=-0.46 to -0.08; p=0.006) strategies, compared to TAU relatives. Conclusion: PFI is effective in improving the adaptive coping strategies of relatives of BD-I patients, but further studies are needed for evaluating the long-term benefits of this intervention. Keywords: coping strategies, family burden, psychoeducation family intervention, bipolar disorder, social functionin

Pathways to mental health care in Italy: Results from a multicenter study.

In Italy, the reform of the mental health system in 1978 should have drastically changed the provision of care and pathways of patients seeking to obtain it. The aim of this article is to examine the current pathways to psychiatric care in Italy