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This study, based on the 'Servizi Territoriali Associati per la Ricerca' (STAR) Network Depot Study nationwide baseline data, explored whether individual symptoms severity and clusters might influence the prescription of paliperidone palmitate 1-month (PP1M) vs. aripiprazole monohydrate. The Brief Psychiatric Rating Scale (BPRS) was used to assess psychopathology and relevant symptoms clusters. Drug Attitude Inventory, 10 items, was used to test attitude towards medications. Adherence to treatments was rated according to the Kemp seven-point scale. We assessed for eligibility 451 individuals and, among them, we included 195 subjects (n = 117 who started PPM1 and n = 78 aripiprazole monohydrate). Individuals were comparable in terms of age, gender, treatment years, recent hospitalizations, previous long-acting injectable antipsychotic treatments, additional oral treatments, attitude toward drugs, medication adherence, and alcohol/substance-related comorbidities. Subjects starting PP1M presented higher BPRS overall (P = 0.009), positive (P = 0.015), and negative (P = 0.010) symptom scores compared to subjects starting aripiprazole monohydrate. Results were confirmed by appropriate regression models and propensity score matching analysis. No differences were found comparing the other BPRS subscale scores: affect, resistance, and activation. Clinicians may be more prone to prescribe PPM1, rather than aripiprazole monohydrate, to subjects showing higher overall symptom severity, including positive and negative symptoms. No additional clinical factors influenced prescribing attitudes in our sample.

To assess the efficacy and acceptability of antidepressants in adults with ischemic heart disease (IHD). We gathered all available randomized-controlled trials comparing antidepressants versus placebo or other antidepressants in adults with IHD. The primary outcome was depressive symptoms at the study endpoint, as measured by validated rating scales. We pooled data in a meta-analysis using a random-effects model. The confidence in the estimates (or certainty of the evidence) was assessed using the GRADE approach. Antidepressants appeared to be more effective than placebo in reducing depressive symptoms (11 comparisons; 1685 participants; standardized mean difference -0.71, 95% confidence interval: -1.11 to -0.30; GRADE quality: moderate). This result was confirmed in the subgroup of serotonin selective reuptake inhibitors, and for the single drugs sertraline and citalopram, with a greater magnitude of effect and a higher quality of evidence for the former. No differences between antidepressants and placebo emerged in terms of acceptability and tolerability, quality of life, mortality, and cardiovascular events. Only two small head-to-head studies were identified. Sertraline is a reasonable first-line choice in patients with IHD and depression, whereas the role of citalopram as the first-line agent should be reconsidered.

To investigate the extent to which exposure to first-generation and second-generation antipsychotics (APs) is associated with an increased risk of fractures, with a particular focus on hip fractures, and to ascertain the risk associated with exposure to individual drugs. We included observational studies that reported data on fractures in individuals exposed to APs compared with unexposed individuals or individuals with previous exposure. We extracted information on study design, source of data, population characteristics, outcomes of interest, matching and confounding factors, and used a modified version of the Newcastle-Ottawa Scale to judge study risk of bias. We pooled adjusted estimates of relative effects to generate pooled odds ratios (ORs) and their 95% confidence interval (CI) using a random-effects model. We rated the quality of evidence using the GRADE approach. Of 36 observational studies, 29 proved to have a low risk of bias and seven were found to have a high risk of bias. The risk of hip fracture (OR: 1.57, 95% CI: 1.42-1.74, low quality of evidence) and of any fracture (OR: 1.17, 95% CI: 1.04-1.31, very low quality of evidence) increased with exposure to APs, with similar increases in risk in the first generation and second generation. The risk was similar among different diagnostic categories. The few studies that provided data were insufficient to allow inferences on individual drugs. AP exposure in unselected populations was associated with a 57% increase in the risk of hip fractures and a 17% increase in the risk of any fractures. Between-study heterogeneity limits the confidence in this estimate.

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 Spearman's 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 (Spearman's rho=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 (Spearman's rho=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.

The persistent use of doses in excess of recommended levels is associated with increased risks of adverse reactions without evidence of additional benefits. Such treatment modality was evaluated in hospitalized psychiatric patients. During a 6-year recruitment period, a consecutive series of psychiatric inpatients receiving antipsychotic therapy were included. At admission, sociodemographic and clinical data, including antipsychotic drug use, were collected, and the 18-item version of the Brief Psychiatric Rating Scale was administered. At discharge, data on antipsychotic drug therapy were collected. Prescribed daily doses were converted into multiples of the defined daily doses. Using a cut-off score of a prescribed daily dose/defined daily dose as a ratio of more than 1.5 both at admission and at discharge assessments, a total of 62 (15.4%) patients persistently received high antipsychotic dose. With less stringent criteria (prescribed daily dose/defined daily dose as a ratio of more than 2), however, only 4.4% of the entire sample was persistently exposed to high antipsychotic doses. Bootstrapped linear regression analysis revealed that positive symptoms were positively associated with high antipsychotic dose, whereas negative symptoms were negatively associated with high antipsychotic dose. Antipsychotic polypharmacy at admission was the strongest predictor of persistently receiving antipsychotic doses in excess of recommended levels. This study showed that the use of high antipsychotic dosing is not an occasional event. Clinicians should consider that concurrent prescribing of two or more antipsychotic agents increases the probability of administering excessive dosing in the long-term.

The purpose of this study was to calculate the proportion of patients with schizophrenia receiving persistent antipsychotic polypharmacy and excessive dosing in four European countries; to test the hypothesis that excessive dosing and/or antipsychotic polypharmacy is associated with higher levels of psychopathology; and to establish whether use of second-generation antipsychotics is a protective or a risk factor for polypharmacy and excessive dosing. Participants with schizophrenia were recruited from patients under the care of psychiatric services serving geographical catchment areas in Croydon (UK), Verona (Italy), Amsterdam (Netherlands), and Leipzig (Germany). We defined patients persistently receiving high antipsychotic dose (i.e. excessive dosing) as those with a prescribed daily dose/defined daily dose ratio of >1.5 both at initial assessment and after 1 year of follow-up. Similarly, we defined patients persistently receiving polypharmacy as those being prescribed two or more antipsychotic drugs both at baseline and at follow-up. A sample of 375 participants with schizophrenia was analyzed. A proportion of 28% of patients persistently received high-dose antipsychotic drugs, and a proportion of 13% of patients persistently received antipsychotic polypharmacy. In the multivariate analysis, psychopathology was not a predictor of persistent polypharmacy and excessive dosing; similarly, use of second-generation antipsychotics was not associated with polypharmacy and excessive dosing; however, persistence with high antipsychotic doses was predicted by baseline use of first-generation antipsychotics and second-generation antipsychotics concurrently. Antipsychotic drug use for patients with schizophrenia is only sometimes satisfactory and offers the opportunity of improvement. Clinicians should consider that dose reduction strategies have been shown to be a feasible intervention in patients with schizophrenia.

We conducted a meta-analysis of published randomized, placebo-controlled clinical trials that evaluated the effect of pharmacotherapy in patients with borderline personality disorder. Comprehensive searches of the MEDLINE, EMBASE, PsychLIT and Cochrane Central Register of Controlled Trials databases were performed using web-based search engines. Twenty articles, reporting 22 placebo-controlled comparisons, were included in the meta-analysis: eight involved antipsychotics, seven antidepressants and seven mood stabilizers. Antidepressants (four studies, standardized mean difference -0.55, 95% confidence interval -0.92, -0.17) and mood stabilizers (six studies, standardized mean difference -1.74, 95% confidence interval -2.76, -0.73) were effective against affective instability and anger, but did not produce significant benefits against impulsivity and aggression, unstable relationships, suicidality and global functioning. Antipsychotics as a class had a positive effect in terms of impulsivity and aggression (three studies, standardized mean difference -0.31, 95% confidence interval -0.63, -0.003), interpersonal relationships (three studies, standardized mean difference -0.52, 95% confidence interval -0.87, -0.17) and global functioning (seven studies, standardized mean difference -0.56, 95% confidence interval -1.00, -0.11). No difference was observed between pharmacotherapy and placebo in terms of participants leaving the study early. Pharmacotherapy can exert a modest beneficial effect on some core traits of borderline personality disorder.

The present study investigated the use of antipsychotics in a sample of clinically unstable patients with schizophrenia who were recruited in four European sites. The study aimed: (i) to test whether the length of previous antipsychotic exposure was associated with the choice of antipsychotic medication; (ii) to test whether the severity of illness was associated with the use of second-generation antipsychotic agents (SGAs) or with the concomitant use of both first-generation antipsychotics (FGAs) and SGAs; and (iii) to investigate differences between study sites. Participants were recruited from patients under the care of psychiatric services serving geographical catchment areas in Croydon (UK), Verona (Italy), Amsterdam (The 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. Sociodemographic and clinical data, including current antipsychotic drug therapy, psychopathology, adherence, insight, side-effects, attitudes towards medication and quality of life, were gathered. Three hundred and ninety patients were analysed in total. Almost 60% received SGAs, less than one-third FGAs, and less than 15% received both drug classes. Those receiving SGAs were younger and with a shorter length of antipsychotic drug therapy, whereas those receiving both drug classes were more often separated or widowed, unemployed and with a long history of antipsychotic drug therapy. The distribution of patients receiving FGAs, SGAs and both drug classes by illness-related variables showed that patients receiving both drug classes were more severely ill and complained of more side-effects. Using patients receiving FGAs as the reference category, multinomial logistic regression analysis showed that the length of antipsychotic treatment was negatively correlated with receiving SGAs, and that the severity of illness and being separated/widowed were positively correlated with receiving both drug classes. Compared with patients in Leipzig, patients in Amsterdam, Croydon and Verona were less frequently treated with SGAs and with combinations of both drug classes. Consistent with current clinical uncertainty with respect to what pharmacological treatment should be provided, patients with a long history of antipsychotic exposure were receiving FGAs, SGAs and combinations of both drug classes. Physicians tended to reserve polypharmacy for difficult-to-treat patients (i.e. for managing situations where, despite the lack of an evidence base, there is a pressing need to provide clinical answers).

A recent survey of clinicians' opinions suggested that antipsychotic polypharmacy is reserved for particularly severe cases, and that it is intended to avoid high doses of a single drug. In the present study, we tested these clinicians' reasons for antipsychotic polypharmacy in a sample of Italian psychiatric inpatients. During a 6-year recruitment period, all psychiatric patients receiving antipsychotic therapy at discharge from an inpatient facility were included. Sociodemographic and clinical data were collected, and the 18-item version of the Brief Psychiatric Rating Scale was administered on admission and before discharge. At discharge, data on length of inpatient stay, psychotropic drug therapy and treatment adherence were collected. Prescribed daily doses were converted into multiples of the defined daily doses. A total of 354 inpatients receiving antipsychotic treatment at discharge were included. Of these, 100 (28%) were discharged with two or more antipsychotic drugs. After background group differences were controlled for, positive symptoms, manic/hostility symptoms and polypharmacy on admission were predictors of polypharmacy at discharge. The risk of high-dose antipsychotics in patients receiving polypharmacy at discharge was 10-fold higher than that in patients receiving one antipsychotic (odds ratio 10.70, 95% confidence interval 4.78-23.97, P<0.001). The perception of clinicians is to reserve antipsychotic polypharmacy for severe, persistent and difficult-to-treat cases, and this was confirmed by the finding that patients discharged on two or more antipsychotic agents were more severely ill on admission. Conversely, the theoretical advantage of avoiding a high dose of a single drug is counterbalanced by the documented disadvantage of administering high total doses.

Treatment with selective serotonin reuptake inhibitors (SSRIs) has been associated with intracranial bleeding abnormalities. We investigated the relationship between past exposure to SSRIs and occurrence of cerebrovascular accidents in the elderly. From the regional database of hospital admissions of Lombardy, Italy, we extracted all patients aged 65 years or above with cerebrovascular-related outcomes for the year 2002. From the regional database of prescriptions reimbursed by the National Health Service, we extracted all patients aged 65 years or above who received antidepressant prescriptions during 2001. The two databases were linked anonymously using the individual patient code. The analysis showed that the proportion of cerebrovascular events in those exposed to SSRIs was 135/66 335 [0.20%, 95% confidence interval (CI) 0.17-0.24], whereas the proportion of cerebrovascular accidents in those exposed to tricyclic antidepressants (TCAs) was 28/18 620 (0.15%, 95% CI 0.09-0.21). After background group differences were controlled for, exposure to SSRIs did not increase the risk of accidents (adjusted odds ratio 1.31, 95% CI 0.87-1.97). Although the risk of cerebrovascular accidents is a rare but serious event that should carefully be monitored during antidepressant therapy, this study indicated an absence of difference between TCAs and SSRIs.

The principle of intention-to-treat analysis must be strictly applied to both individual randomized controlled trial and meta-analysis but, in doing so, would involve imputation of some missing data. There is little literature on how to perform this in the case of meta-analysis. For dichotomous outcome measures, one possible strategy is to carry out a sensitivity analysis based on the so-called best case/worst case analyses. For continuous outcomes, it may be possible to achieve this if we can dichotomise the continuous outcomes. Here, we empirically examined the appropriateness of converting continuous outcomes (expressed as mean+/-SD) into dichotomous outcomes (expressed as response rates) in four completed meta-analyses of depression and anxiety, assuming normal distribution of the continuous outcome measures. The agreement between the actually observed versus the imputed raw numbers of responders was indicated by an intraclass correlation coefficient of 0.97 (95% confidence interval 0.95-0.98). The pooled relative risks of the four meta-analyses based on the imputed values were virtually identical to those based on the actually observed values. When individual trials report the means+/-SDs of their outcome measures but fail to report response rates, it may therefore be possible to impute the response rates based on the means+/-SDs, and then submit the meta-analysis to worst case/best case analyses. This would allow a more robust and clinically interpretable estimation of the true, underlying treatment effect to be made.

Despite most studies of antipsychotic efficacy and safety having been conducted in young patients with schizophrenia, antipsychotic agents are often prescribed in elderly subjects with psychotic symptoms. The aim of this study was to document and describe the level of antipsychotic exposure among elderly subjects. We used the Regional Administrative Database of Lombardy, a region of northern Italy with more than 1.6 million elderly inhabitants, to extract all antipsychotic prescriptions dispensed during 2001 to subjects aged 65 years or above. Prevalence data were calculated by dividing antipsychotic users by the total number of male and female residents in each age group. During the 12 months surveyed 35 363 subjects received at least one antipsychotic prescription, yielding a prevalence of use of 2.18 subjects per 100 inhabitants (95% confidence interval 2.16-2.20). Almost two-thirds were prescribed first-generation agents only, and thioridazine, a first-generation agent associated with prolonged QTC interval, and which is restricted in most European countries, was the most prescribed agent. However, risperidone and olanzapine accounted for 30% of antipsychotic use for all subjects. The majority of patients were also prescribed agents for medical disorders. Because the population of Lombardy is approximately one-sixth of the entire Italian population, it can be assumed that there are over 200 000 elderly subjects annually exposed to these agents in Italy. This generates particular concern because elderly patients are vulnerable to the adverse effects of antipsychotics, and recent warnings have indicated that there are cerebrovascular risks associated with risperidone and olanzapine therapy.