Michela Nosè

How often do patients with psychosis fail to adhere to treatment programmes? A systematic review.

BACKGROUND Studies that assess the rates of psychotic patients who fail to adhere to treatment programmes have generated heterogeneous results, with estimates ranging from 24 to 90%. This paper presents findings from a systematic review on adherence to treatment by patients with psychosis. Its purpose is to provide an overall estimate of treatment non-adherence in community psychiatric services, and to analyse and study patient characteristics explaining the between-study heterogeneity in rates of non-adherence. METHOD A systematic review of published studies that report rates of non-adherence with medication and scheduled appointments by psychotic patients in community settings has been undertaken. RESULTS A total of 103 studies were included in this systematic review. Eighty-six of these studies were suitable for data re-analysis. The overall weighted mean rate of non-adherence, calculated in a sample of 23 796 patients, was 25.78%. A linear regression analysis of non-adherence rates on background characteristics showed that sample size was negatively associated with non-adherence rates, while first-contact cases and low-adherence cases, in comparison with ongoing cases, were associated with higher non-adherence rates. Factors associated with poor compliance included: lack of insight; positive symptoms; younger age; male gender; history of substance abuse; unemployment; and low social functioning. CONCLUSIONS Approximately one in four patients with psychosis fails to adhere with treatment programmes. Preventive evidence-based clinical interventions should be routinely implemented in community settings to reduce patient non-adherence.

Investigation of corpus callosum in schizophrenia with diffusion imaging

BACKGROUND Corpus callosum (CC) is the main white matter commissure between the two cerebral hemispheres. Abnormalities of CC have been shown in schizophrenia patients by magnetic resonance imaging (MRI) studies. We here further investigated CC organization with diffusion imaging (DWI) in a sample of schizophrenia patients recruited from the epidemiologically defined catchment area of South Verona, Italy. METHODS Sixty-seven patients with schizophrenia and 70 normal controls were studied. Regions of interests (ROIs), standardized at 5 pixels, were placed in CC on the non-diffusion weighted echoplanar images (b = 0) and were then automatically transferred to the corresponding maps to obtain the apparent diffusion coefficient (ADC) of water molecules. RESULTS ADC measures for all callosal subregions in schizophrenia patients were significantly greater compared to normal controls (ANCOVA, p < 0.05). Positive symptoms significantly correlated with anterior callosal ADC measures (partial correlation analyses, p < 0.05). CONCLUSIONS These findings support the existence of widespread microstructure disruption of CC in schizophrenia, which may ultimately lead to inter-hemispheric misconnection, and also suggest a specific role of anterior transcallosal disconnectivity in underlying positive symptoms. Future longitudinal MRI studies in high risk and first-episode patients together with neurophysiological tests are indicated to further examine CC anatomical abnormalities and inter-hemispheric transmission in schizophrenia.

Sex differences in the subjective tolerability of antipsychotic drugs.

Abstract: In recent years, research efforts have been directed to better characterize the subjective experience of taking psychotropic drugs. This study investigated the sex difference in the subjective tolerability of antipsychotic drugs. Participants were recruited from patients under the care of psychiatric services serving geographical catchment areas in Croydon (UK), Verona (Italy), Amsterdam (Netherlands), and Leipzig (Germany). Clinically unstable patients with a clinical diagnosis of schizophrenia and a research diagnosis of schizophrenia, established using the Item Group Checklist of the Schedule for Clinical Assessment in Neuropsychiatry, were enrolled. Antipsychotic subjective tolerability was rated by means of the Liverpool University Neuroleptic Side Effect Rating Scale. During the recruitment period, 245 men and 164 women with schizophrenia were recruited. In both sexes, the most frequently reported side effects were difficulty in concentrating, tiredness, and weight gain; these side effects occurred in approximately 50% of men and in up to 70% of women. Extrapyramidal and anticholinergic reactions were reported more often by women, whereas men reported sexual problems more often. After background group differences were controlled for, sex was the strongest determinant of the subjective tolerability of antipsychotic drugs. We therefore conclude that sex differences in the subjective tolerability of antipsychotic drugs should be taken into account in the pharmacological management of patients with schizophrenia. Studies should no longer consider men and women as a homogeneous group, given that the subjective tolerability of antipsychotic drugs substantially differs between sexes.

Is the Defined Daily Dose system a reliable tool for standardizing antipsychotic dosages

The present study was carried out to establish whether the Defined Daily Doses (DDDs) system could be reliably applied to standardize antipsychotic dosages. Initially, the relationship between antipsychotic doses expressed as DDDs, chlorpromazine equivalents (CPZEs) and percentages of the British National Formulary (BNF) maximum recommended daily dose were investigated by calculating Spearmans rank correlation coefficients. Second, factors associated with antipsychotic dose, expressed as DDDs, CPZEs and percentages of the BNF maximum recommended daily dose, were investigated by means of linear regression analysis. The study sample consisted of 277 patients with schizophrenia. The relationship between antipsychotic daily doses expressed as multiples of DDDs and CPZEs revealed a significant correlation (Spearmans ρ=0.779, P<0.001). Similarly, the relationship between antipsychotic daily doses expressed as multiples of DDDs and percentages of the BNF maximum recommended daily dose revealed a significant correlation (Spearmans ρ=0.869, P<0.001). Linear regression analyses highlighted a high degree of coherence between antipsychotic doses expressed as DDDs, CPZEs and percentages of the BNF maximum recommended daily dose. In conclusion, this study found that the DDD system is a reliable tool for standardizing antipsychotic doses in drug utilization research.

Off-label and non-classical prescriptions of antipsychotic agents in ordinary in-patient practice

Objective:  To estimate the proportion of off‐label prescriptions of antipsychotics (APs) in ordinary in‐patient practice.

Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia in routine clinical care: a randomized, controlled trial

This multisite study was conducted to compare the efficacy and tolerability of combination treatment with clozapine plus aripiprazole versus combination treatment with clozapine plus haloperidol in patients with schizophrenia who do not have an optimal response to clozapine. Patients continued to take clozapine and were randomly assigned to receive daily augmentation with aripiprazole or haloperidol. Physicians prescribed the allocated treatments according to usual clinical care. Withdrawal from allocated treatment within 3 months was the primary outcome. Secondary outcomes included severity of symptoms on the Brief Psychiatric Rating Scale and antipsychotic subjective tolerability on the Liverpool University Neuroleptic Side Effect Rating Scale. A total of 106 patients with schizophrenia were randomly assigned to treatment. After 3 months, we found no difference in the proportion of patients who discontinued treatment between the aripiprazole and haloperidol groups (13.2% vs 15.1%, P = 0.780). The 3-month change of the Brief Psychiatric Rating Scale total score was similar in the aripiprazole and haloperidol groups (−5.9 vs −4.4 points, P = 0.523), whereas the 3-month decrease of the Liverpool University Neuroleptic Side Effect Rating Scale total score was significantly higher in the aripiprazole group than in the haloperidol group (−7.4 vs −2.0 points, P = 0.006). These results suggest that augmentation of clozapine with aripiprazole offers no benefit with regard to treatment withdrawal and overall symptoms in schizophrenia compared with augmentation with haloperidol. However, an advantage in the perception of adverse effects with aripiprazole treatment may be meaningful for patients.

Comparison of Patient and Clinician Perspectives in the Assessment of Antipsychotic Medication Adherence

Background: Factors influencing patient and clinician perspectives in the assessment of medication adherence have never been compared. Method: This study used baseline and 12-month follow-up data from the QUATRO study, an international multicentre study. At baseline, information on patient sociodemographic characteristics, treatment factors, psychopathology, functioning and experience of antipsychotic side effects was gathered. After 12 months of follow-up, psychopathology, functioning and patient experience of antipsychotic side effects were measured once more, and a patient and clinician rating of adherence was obtained by means of the Medication Adherence Rating Scale (MARS) and the Compliance Rating Scale (CRS). Results: During the recruitment period, 409 subjects with a diagnosis of schizophrenia were recruited. Patients were more often men and single. Mean age was 41.5 years. At the time of the assessment, more than 40% were unemployed and on average had been on antipsychotic treatment for more than 10 years. Nearly 70% were receiving second-generation antipsychotics, and 50% received adherence therapy during the 12 months after enrolment. The relationship between the MARS and the CRS scores showed only a small overlap (correlation coefficient = 0.26). In the multivariate model, the only factor significantly associated with both patient and clinician ratings of adherence was psychopathology. Unemployment and poor subjective tolerability of antipsychotics were significantly associated with low levels of patient ratings of adherence. Conversely, length of treatments and use of newer antipsychotics were significantly associated with better clinician ratings of adherence. Conclusion: Patient and clinician ratings of adherence do not measure the same dimension. Factors that may positively affect adherence in terms of compliance with prescribed medication regimens may not affect patients’ views on adherence, and this should be taken into consideration when planning and negotiating treatment modalities with each individual patient suffering from schizophrenia.

Antipsychotic drug exposure and risk of pneumonia: a systematic review and meta‐analysis of observational studies

Pneumonia is one of the major leading causes of morbidity and mortality among persons aged 65 years or older. Recently, several studies suggested an association between antipsychotic (AP) use and risk of pneumonia in elderly patients. The aim of the present systematic review and meta‐analysis of observational studies was to investigate if first‐generation and second‐generation AP drugs increase the risk of pneumonia in the elderly and also in the younger population, and to ascertain the risk associated with exposure to individual drugs.

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.

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

BackgroundOne 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.Methods/DesignThe 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.DiscussionThe 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.Trial RegistrationClincaltrials.gov Identifier: NCT00395915