Irene Bighelli

Psychosocial interventions for post-traumatic stress disorder in refugees and asylum seekers resettled in high-income countries: Systematic review and meta-analysis.

Treatment of post-traumatic stress disorder (PTSD) in refugees and asylum seekers resettled in high-income countries presents specific challenges. This systematic review examined the effectiveness of psychosocial interventions for this group. We searched the Cochrane Central Register of randomised trials, CINAHL, EMBASE, PILOTS, PsycINFO, PubMed and Web of Science up to July 2016. Studies included randomised and controlled clinical trials comparing psychosocial interventions with waiting list or treatment as usual in adult refugees and asylum seekers with PTSD resettled in high-income countries. PTSD symptoms post-intervention was the primary outcome. We computed standardized mean differences (SMD) with 95% confidence intervals (CI). This study is registered with PROSPERO: CRD42015027843. Twelve studies were included in the meta-analysis. Psychosocial interventions were effective in decreasing PTSD symptoms relative to control groups (SMD -1·03, 95% CI -1·55 to -0·51; number needed to treat 4·4; I2 86%; 95% CI 77 to 91). Narrative exposure therapy, a manualized short-term variant of cognitive behavioural therapy with a trauma focus, was the best-supported intervention (5 RCTs, 187 participants, SMD -0·78, 95% CI -1·18 to -0·38, I2 37%; 95% CI 0 to 77). Methodological quality of the included studies was limited. Overall, psychosocial interventions for asylum seekers and refugees with PTSD resettled in high-income countries were found to provide significant benefits in reducing PTSD symptoms. Yet, the number of studies is small and their methodological quality limited, so that more rigorous trials should be conducted in the future.

Effectiveness of lithium in subjects with treatment-resistant depression and suicide risk: a protocol for a randomised, independent, pragmatic, multicentre, parallel-group, superiority clinical trial.

BackgroundData on therapeutic interventions following deliberate self harm (DSH) in patients with treatment-resistant depression (TRD) are very scant and there is no unanimous consensus on the best pharmacological option for these patients. There is some evidence that lithium treatment might be effective in reducing the risk of completed suicide in adult patients with unipolar affective disorders, however no clear cut results have been found so far. The primary aim of the present study is to assess whether adding lithium to standard therapy is an effective treatment strategy to reduce the risk of suicidal behaviour in long term treatment of people with TRD and previous history of DSH.Methods/DesignWe will carry out a randomised, parallel group, assessor-blinded superiority clinical trial. Adults with a diagnosis of major depression, an episode of DSH in the previous 12 months and inadequate response to at least two antidepressants given sequentially at an adequate dose for an adequate time for the current depressive episode will be allocated to add lithium to current therapy (intervention arm) or not (control arm). Following randomisation, treatment is to be taken daily for 1 year unless some clear reason to stop develops. Suicide completion and acts of DSH during the 12 months of follow-up will constitute the composite primary outcome. To preserve outcome assessor blindness, an independent adjudicating committee, blind to treatment allocation, will anonymously review all outcome events.DiscussionThe results of this study should indicate whether lithium treatment is associated with lower risk of completed suicide and DSH in adult patients with treatment resistant unipolar depression, who recently attempted suicide.Trial registrationClinicalTrials.gov identifier: NCT00927550

Prevalence and correlates of QTc prolongation in Italian psychiatric care: Cross-sectional multicentre study

AIMS In recent years several warnings have been issued by regulatory authorities on the risk of electrocardiogram abnormalities in individuals exposed to psychotropic drugs. As a consequence of these warnings, monitoring of the QT interval corrected for heart rate (QTc) has become increasingly common. This study was conducted to measure the frequency of QTc prolongation in unselected psychiatric patients, and to document the associated factors using a cross-sectional approach. METHOD The study was carried out in 35 Italian psychiatric services that are part of the STAR (Servizi Territoriali Associati per la Ricerca) Network, a research group established to produce scientific knowledge by collecting data under ordinary circumstances. During a three-month period, a consecutive unselected series of both in- and out-patients were enrolled if they performed an ECG during the recruitment period and were receiving psychotropic drugs on the day ECG was recorded. RESULTS During the recruitment period a total of 2411 patients were included in the study. The prevalence of QTc prolongation ranged from 14.7% (men) and 18.6% (women) for the cut-off of 450 ms, to 1.26% (men) and 1.01% (women) for the cut-off of 500 ms. In the multivariate model conducted in the whole sample of patients exposed to psychotropic drugs, female sex, age, heart rate, alcohol and/or substance abuse, cardiovascular diseases and cardiovascular drug treatment, and drug overdose were significantly associated with QTc prolongation. In patients exposed to antipsychotic drugs, polypharmacy was positively associated with QTc prolongation, whereas use of aripiprazole decreased the risk. In patients exposed to antidepressant drugs, use of citalopram, citalopram dose and use of haloperidol in addition to antidepressant drugs, were all positively associated with QTc prolongation. CONCLUSIONS The confirmation of a link between antipsychotic polypharmacy and QTc prolongation supports the current guidelines that recommend avoiding the concurrent use of two or more antipsychotic drugs, and the confirmation of a link between citalopram and QTc prolongation supports the need for routine QTc monitoring. The relatively low proportion of patients with QTc prolongation not only suggests compliance with current safety warnings issued by regulatory authorities, but also casts some doubts on the clinical relevance of QTc prolongation related to some psychotropic drugs.

Antipsychotic Dose Mediates the Association between Polypharmacy and Corrected QT Interval

Antipsychotic (AP) drugs have the potential to cause prolongation of the QT interval corrected for heart rate (QTc). As this risk is dose-dependent, it may be associated with the number of AP drugs concurrently prescribed, which is known to be associated with increased cumulative equivalent AP dosage. This study analysed whether AP dose mediates the relationship between polypharmacy and QTc interval. We used data from a cross-sectional survey that investigated the prevalence of QTc lengthening among people with psychiatric illnesses in Italy. AP polypharmacy was tested for evidence of association with AP dose and QTc interval using the Baron and Kenny mediational model. A total of 725 patients were included in this analysis. Of these, 186 (26%) were treated with two or more AP drugs (AP polypharmacy). The mean cumulative AP dose was significantly higher in those receiving AP polypharmacy (prescribed daily dose/defined daily dose = 2.93, standard deviation 1.31) than monotherapy (prescribed daily dose/defined daily dose = 0.82, standard deviation 0.77) (z = −12.62, p < 0.001). Similarly, the mean QTc interval was significantly longer in those receiving AP polypharmacy (mean = 420.86 milliseconds, standard deviation 27.16) than monotherapy (mean = 413.42 milliseconds, standard deviation 31.54) (z = −2.70, p = 0.006). The Baron and Kenny mediational analysis showed that, after adjustment for confounding variables, AP dose mediates the association between polypharmacy and QTc interval. The present study found that AP polypharmacy is associated with QTc interval, and this effect is mediated by AP dose. Given the high prevalence of AP polypharmacy in real-world clinical practice, clinicians should consider not only the myriad risk factors for QTc prolongation in their patients, but also that adding a second AP drug may further increase risk as compared with monotherapy.

INvolvement of breast CAncer patients during oncological consultations: A multicentre randomised controlled trial-the INCA study protocol

Introduction Studies on patient involvement show that physicians make few attempts to involve their patients who ask few questions if not facilitated. On the other hand, the patients who participate in the decision-making process show greater treatment adherence and have better health outcomes. Different methods to encourage the active participation during oncological consultation have been described; however, similar studies in Italy are lacking. The aims of the present study are to (1) assess the effects of a preconsultation intervention to increase the involvement of breast cancer patients during the consultation, and (2) explore the role of the attending companions in the information exchange during consultation. Methods and analysis All female patients with breast cancer who attend the Oncology Out-patient Services for the first time will provide an informed consent to participate in the study. They are randomly assigned to the intervention or to the control group. The intervention consists of the presentation of a list of relevant illness-related questions, called a question prompt sheet. The primary outcome measure of the efficacy of the intervention is the number of questions asked by patients during the consultation. Secondary outcomes are the involvement of the patient by the oncologist; the patients perceived achievement of her information needs; the patients satisfaction and ability to cope; the quality of the doctor–patient relationship in terms of patient-centeredness; and the number of questions asked by the patients companions and their involvement during the consultation. All outcome measures are supposed to significantly increase in the intervention group. Ethics and dissemination The study was approved by the local Ethics Committee of the Hospital Trust of Verona. Study findings will be disseminated through peer-reviewed publications and conference presentations. Trial registration ClinicalTrials.gov identifier: NCT01510964

Does formulation matter? A systematic review and meta-analysis of oral versus long-acting antipsychotic studies

Recently, many authors highlighted the potential advantages of a broader prescription of long-acting injectable antipsychotics (LAIs) based on various assumptions, including favorable pharmacokinetic features. In this systematic review, data from randomized controlled trials comparing LAIs versus the oral formulation of the same antipsychotic were meta-analyzed in order to ascertain whether the route of administration may be associated with a different efficacy and tolerability profile. Of 21 included studies, 18 contributed to the meta-analysis, providing data for risperidone, olanzapine, aripiprazole, zuclopenthixol, fluphenazine and haloperidol. For all drugs, the number of dropouts for any reason (primary outcome) did not differ between the two formulations, except for a small effect in favor of LAI aripiprazole (2 comparisons; 986 patients; relative risk (RR) 0.78; 95% confidence interval (CI) 0.64 to 0.95). Similarly, no differences emerged in terms of dropouts for adverse events, extrapyramidal symptoms, prolactin increase (except for a small advantage for LAI risperidone), weight gain, non-response rate, relapse rate, and dropouts for inefficacy (except for a small advantage for oral olanzapine). Data on aripiprazole proved to be of high quality according to the GRADE approach (Grading of Recommendations, Assessment, Development and Evaluation), therefore we are confident that the effect estimate is close to the true effect. Data on risperidone were of moderate quality, while data on olanzapine, fluphenazine, zuclopenthixol and haloperidol were of low quality. In conclusion, there is no robust evidence to support doctors in choosing LAI instead of oral formulations in order to obtain better tolerability and efficacy.

How well do patients with a first episode of schizophrenia respond to antipsychotics: A systematic review and meta-analysis

It is often stated that first-episode patients tend to respond better to antipsychotics than chronic patients, but the exact numbers and moderators of response in this population are unclear. We, therefore, present the first systematic review on response rates of first episode patients with schizophrenia in randomized trials. We searched multiple databases for randomized-controlled trials of antipsychotics in acutely ill patients with a first episode of schizophrenia (last search: November 17, 2016). The outcomes were response rate based on two criteria, at least 50% PANSS or BPRS total score reduction from baseline and at least 20% reduction. Data were pooled in a single-group summary meta-analysis using Comprehensive Meta-Analysis software. Moreover, several potential moderators of response to antipsychotics were examined by meta-regression. We included 17 studies with a total of 3156 participants. On the average, 81.3%/51.9% of the first-episode patients reached an at least 20%/50% PANSS or BPRS reduction from baseline, respectively. Meta-regressions revealed a better treatment response in female patients, in more severely ill patients at baseline, in antipsychotic naïve patients, in patients with a shorter illness duration and in open studies. Study duration and dosage were no significant moderators of response. Our finding suggest that more than 80% of first-episode patients achieved 20% PANSS/BPRS reduction from baseline and around 50% achieved a 50% PANSS/BPRS reduction. Several patient characteristics moderated response rates.

Regulatory science in Europe: the case of schizophrenia trials

1234 www.thelancet.com Vol 382 October 12, 2013 In April, 2013, new guidance for phase 3 clinical trials in patients with schizophrenia came into eff ect. The guidance, issued by the European Medicines Agency (EMA), is intended to guide the design of regulatory studies of new antipsychotic drugs requiring a marketing authorisation for schizophrenia in Europe. Here, we report some aspects of this offi cial document that could negatively aff ect assessment of drugs for schizophrenia, together with some possible solutions. Schizophrenia is a particularly challenging area, because several active treatments are already available, placebo response is high, and treatment response can be erratic and variable. The fi rst issue is that the EMA does not require drug companies to provide information about all clinical studies that have concluded when they submit a drug for approval, meaning that they can select what data to present. Therefore, regulators have to base the crucial decision about whether a new drug should obtain a marketing authorisation on only a sample of studies, without consideration of all available evidence. The EMA does not stipulate that studies submitted for regulation are registered in an international repository of study protocols. This issue is related to the fi rst, because regulators cannot know how many trials have been done and how many of these have been included in the submission package if the trials have not been registered. Additionally, the EMA recommends that studies of the acute treatment of schizophrenia have three groups, comparing the new product with both placebo and an active comparator. Superiority to placebo is explicitly required, but non-inferiority to an active comparator is not mentioned as a compulsory requirement. This policy may not be relevant when no standard treatments are available, but might be problematic when eff ective agents are available, such as those for schizophrenia. It could allow approval of drugs that might have a less favourable profi le than those already on the market. Additionally, stipulation of placebo groups for comparison could systematically exclude patients with severe symptoms of schizophrenia, because physicians might be reluctant to enrol severely ill patients into a random procedure that could result in placebo treatment for several weeks. The EMA does accept two-arm studies comparing a new drug with an active comparator as an alternative, provided superiority is shown. According to regulatory scientists, a placebo group should not be used when eff ective agents are available; instead, demonstration of superiority to an active comparator should be compulsory. This position, how ever, Regulatory science in Europe: the case of schizophrenia trials AO has received consultancy fees, honoraria, and speakers’ fees from Sanofi , Genzyme, Fresenius Medical Care, and Amgen; research funding or funding for equipment or drugs from Fresenius Medical Care; and travel or accommodation payments from Genzyme, Fresenius Medical Care, Shire, Amgen, Baxter, Rubió, and Abbott. MDS-N has received consultancy fees, honoraria, and speakers’ fees from Genzyme.

Making the use of psychotropic drugs more rational through the development of GRADE recommendations in specialist mental healthcare

IntroductionIn recent years the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology has often been used by international or national health authorities, or scientific societies, for developing evidence-based treatment recommendations. However, the GRADE approach has never been used by practicing physicians who aim at harmonizing their prescribing behaviours paying due attention to the best available evidence. This paper describes the experience of a working group of psychiatrists who adopted the GRADE approach to develop clinical recommendations on the use of psychotropic drugs in specialist mental healthcare.Case descriptionThe project was conducted in the Department of Mental Health of Verona, Italy, a city located in the north of Italy. At the beginning of 2012, psychiatrists with a specific interest in the rational use of psychotropic drugs were identified and appointed as members of a Guideline Development Group (GDG). The first task of the GDG was the identification of controversial areas in the use of psychotropic drugs, the definition of scoping questions, and the identification of outcomes of interest. The GDG was supported by a scientific secretariat, who searched the evidence, identified one or more systematic reviews matching the scoping questions, and drafted GRADE tables.Discussion and evaluationOn the basis of efficacy, acceptability, tolerability and safety data, considering the risk of bias and confidence in estimates, and taking also into consideration preferences, values and practical aspects in favour and against the intervention under scrutiny, a draft recommendation with its strength was formulated and agreed by GDG members. Recommendations were submitted for consideration to all specialists of the Department, discussed in two plenary sessions open to the whole staff, and finally approved at the end of 2012.ConclusionThe present project of guideline development raised several challenging and innovating aspects, including a “bottom-up” approach, as it was motivated by reasons that found agreement among specialists, those who developed the recommendations were those who were supposed to follow them, and values, preferences and feasibility issues were considered paying due attention to local context variables.

Effectiveness of lithium in subjects with treatment-resistant depression and suicide risk: results and lessons of an underpowered randomised clinical trial

BackgroundAs lithium treatment might be effective in reducing the risk of deliberate self-harm (DSH) in adult patients with unipolar affective disorders, we designed a pragmatic randomised trial to assess its efficacy in more than 200 patients with treatment-resistant depression. However, we randomised 56 patients only. The aim of this report is therefore twofold: first, to disseminate the results of this underpowered study which may be incorporated into future meta-analytical reviews; second, to analyse some critical aspects of the study which might explain failure to reach the target sample size.MethodsWe carried out a randomised, parallel group, assessor-blinded superiority clinical trial. Adults with a diagnosis of major depression, an episode of DSH in the previous 12 months and inadequate response to at least two antidepressants given sequentially at an adequate dose for an adequate time for the current depressive episode were allocated to add lithium to usual care (intervention arm) versus usual care alone (control arm). Suicide completion and acts of DSH during the 12 months of follow-up constituted the composite primary outcome.ResultsOf 58 patients screened for inclusion, 29 were allocated to lithium plus usual care and 27 were assigned to usual care without lithium. Six patients in the lithium plus usual care group and seven in the usual care group committed acts of DSH during the follow-up phase. The survival probability did not differ between the two treatment arms (Chi2 = 0.17, p =0.676). With regard to changes in the severity of depressive symptomatology from baseline to endpoint, no significant differences were detected.ConclusionsThe present study failed to achieve the minimum sample size needed to detect a clinically meaningful difference between the two treatment arms. Consequently, the finding that lithium, in addition to usual care, did not exert a positive effect in terms of reduction of DSH after 12 months of follow-up is likely due to the lack of sufficient statistical power to detect a difference, if a difference existed. The dissemination of the results of this underpowered study will inform future meta-analytical reviews on lithium and suicide-related outcomes.Trial registrationClinicalTrials.gov identifier: NCT00927550