Treatment response, safety, and tolerability of paliperidone extended release treatment in patients recently diagnosed with schizophrenia.

OBJECTIVE: This study was designed to explore the efficacy and tolerability of oral paliperidone extended release (ER) in a sample of patients who were switched to flexible doses within the crucial first 5 years after receiving a diagnosis of schizophrenia. METHODS: Patients were recruited from 23 countries. Adults with nonacute but symptomatic schizophrenia, previously unsuccessfully treated with other oral antipsychotics, were transitioned to paliperidone ER (3-12 mg/day) and prospectively treated for up to 6 months. The primary efficacy outcome for patients switching for the main reason of lack of efficacy with their previous antipsychotic was at least 20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores. For patients switching for other main reasons, such as lack of tolerability, compliance or 'other', the primary outcome was non-inferiority in efficacy compared with the previous oral antipsychotic. RESULTS: For patients switching for the main reason of lack of efficacy, 63.1% achieved an improvement of at least 20% in PANSS total scores from baseline to endpoint. For each reason for switching other than lack of efficacy, efficacy maintenance after switching to paliperidone ER was confirmed. Statistically significant improvement in patient functioning from baseline to endpoint, as assessed by the Personal and Social Performance scale, was observed (p < 0.0001). Treatment satisfaction with prior antipsychotic treatment at baseline was rated 'good' to 'very good' by 16.8% of patients, and at endpoint by 66.0% of patients treated with paliperidone ER. Paliperidone ER was generally well tolerated, with frequently reported treatment-emergent adverse events being insomnia, anxiety and somnolence. CONCLUSIONS: Flexibly dosed paliperidone ER was associated with clinically relevant symptomatic and functional improvement in recently diagnosed patients with non-acute schizophrenia previously unsuccessfully treated with other oral antipsychotics.

The Use of Continuous Treatment Versus Placebo or Intermittent Treatment Strategies in Stabilized Patients with Schizophrenia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials with First- and Second-Generation Antipsychotics.

BACKGROUND: Although continuous treatment with antipsychotics is still recommended as the gold standard treatment paradigm for all patients with schizophrenia, some clinicians question whether continuous antipsychotic treatment is necessary, or even justified, for every patient with schizophrenia who has been stabilized on antipsychotics. OBJECTIVE: The primary objectives of this systematic review and meta-analysis were (i) to compare relapse/hospitalization risks of stabilized patients with schizophrenia under active versus intermittent or placebo treatment conditions; (ii) to examine the role of several study characteristics, possibly intervening in the relationship between relapse risk and treatment condition; and (iii) to examine whether time to relapse is associated with antipsychotic treatment duration. METHODS: A systematic literature search, using the MEDLINE database (1950 until November 2014), was conducted for English-language published randomized controlled trials, covering a follow-up time period of at least 6 months, and investigating relapse/rehospitalization and/or time-to-relapse rates with placebo or intermittent treatment strategies versus continuous treatment with oral and long-acting injectable first- or second-generation antipsychotics (FGAs/SGAs) in stabilized patients with schizophrenia. Additional studies were identified through searches of reference lists of other identified systematic reviews and Cochrane reports. Two meta-analyses (placebo versus continuous and intermittent versus continuous treatment) were performed to obtain an optimal estimation of the relapse/hospitalization risks of stabilized patients with schizophrenia under these treatment conditions and to assess the role of study characteristics. For time-to-relapse data, a descriptive analysis was performed. RESULTS: Forty-eight reports were selected as potentially eligible for our meta-analysis. Of these, 21 met the inclusion criteria. Twenty-five records, identified through Cochrane and other systematic reviews and fulfilling the inclusion criteria, were added, resulting in a total of 46 records. Stabilized patients with schizophrenia who have been exposed for at least 6 months to intermittent or placebo strategies, respectively, have a 3 (odds ratio [OR] 3.36; 95% CI 2.36-5.45; p < 0.0001) to 6 (OR 5.64; 95% CI 4.47-7.11; p < 0.0001) times increased risk of relapse, compared with patients on continuous treatment. The availability of rescue medication (p = 0.0102) was the only study characteristic explaining systematic differences in the OR for relapse between placebo versus continuous treatment across studies. Studies reporting time-to-relapse data show that the time to (impending) relapse is always significantly delayed with continuous treatment, compared with placebo or intermittent treatment strategies. Although the interval between treatment discontinuation and symptom recurrence can be highly variable, mean time-to-relapse data seem to indicate a failure of clinical stability before 7-14 months with intermittent and before 5 months with placebo treatment strategies. For all reports included in this systematic review, median time-to-relapse rates in the continuous treatment group were not estimable as <50% of the patients in this treatment condition relapsed before the end of the study. CONCLUSIONS: With continuous treatment, patients have a lower risk of relapse and remain relapse free for a longer period of time compared with placebo and intermittent treatment strategies. Moreover, 'success rates' in the intermittent treatment conditions are expected to be an overestimate of actual outcome rates. Therefore, continuous treatment remains the 'gold standard' for good clinical practice, particularly as, until now, only a few and rather general valid predictors for relapse in schizophrenia are known and subsequent relapses may contribute to functional deterioration as well as treatment resistance in patients with schizophrenia.

Extrapyramidal symptoms during treatment of first schizophrenia episode: results from EUFEST.

The European First Episode Schizophrenia Trial (EUFEST) included first-episode schizophrenia patients, assessing the efficacy of five antipsychotic drugs (haloperidol, amisulpride, olanzapine, quetiapine and ziprasidone) over one year. Baseline frequency of extrapyramidal symptoms (EPS) in this group of patients (n=490) was as follows: parkinsonism 10.8%, akathisia 10.0%, dystonia 1.8%, and dyskinesia 0.6%. The frequency of parkinsonism at baseline was greater in patients with a brief prior exposure to antipsychotics (≤2 weeks) compared with antipsychotic-naïve ones, and was positively correlated with the intensity of negative symptoms and negatively with depressive symptoms. After one month of treatment, the increase of parkinsonism was highest in patients receiving haloperidol (+13%), that of akathisia in patients treated with ziprasidone (+14%), and 10.1% of the patients were taking anticholinergic drugs, most frequently in the haloperidol group (24%). In 291 patients remaining on treatment after one year, both parkinsonism and akathisia had decreased: the frequency of parkinsonism was 3%, highest in the haloperidol group (9.1%), that of akathisia was 3%, highest in the quetiapine group (7.5%), and 4% of patients were taking anticholinergic drugs, most frequently those receiving haloperidol (10.5%). The results obtained suggest that in first-episode schizophrenia patients during the first year of antipsychotic treatment (in this case amisulpride, haloperidol in low doses, olanzapine, quetiapine and ziprasidone), EPS were present as manageable clinical problems.

Dosing and switching of paliperidone ER in patients with schizophrenia: recommendations for clinical practice.

Many patients with schizophrenia receive long-term treatment with antipsychotic medication. Switching of antipsychotic medication due to lack of efficacy, tolerability issues, and partial/non-adherence is common. Despite this, consensus strategies for switching between antipsychotics are lacking. This manuscript provides practical recommendations for switching antipsychotic medication to ensure optimal management of patients with schizophrenia, with a particular focus on paliperidone extended release (ER). The authors drew on their clinical experience supported by detailed discussion of literature describing antipsychotic switching techniques and strategies and findings from paliperidone ER clinical trials. Antipsychotic switching strategies should be individualized and take into consideration the pharmacokinetic (PK) and pharmacodynamic (PD) properties of the pre- and post-switch medication. The use of temporary concomitant medications may be appropriate in some scenarios. Abrupt withdrawal of pre-switch medication may be appropriate in some instances but carries a greater risk of rebound and withdrawal symptoms than other strategies. Cross-tapering is the method most widely used in clinical practice. Paliperidone ER can be initiated without dose titration. The EU SmPC recommended dose of paliperidone ER is 6 mg/day; but doses should be individualized within the approved range of 3-12 mg/day. Higher doses may be required due to insufficient efficacy of the previous antipsychotic or in patients with acute symptoms. Recently diagnosed patients, those with renal impairment, or patients who have previously experienced tolerability issues with other antipsychotics may require lower doses. When switching from risperidone, higher doses of paliperidone ER may be required compared with risperidone. When switching from antipsychotics that have sedative and/or significant anticholinergic activity, the pre-switch antipsychotic should be tapered off gradually. Antipsychotics with less sedating and little anticholinergic activity can be tapered off over a shorter period. Temporary concomitant sedative medication may be beneficial when switching from antipsychotics with relatively higher sedative propensities. Switching from another antipsychotic to paliperidone ER requires individualized switching strategies and dosing, dependent on the characteristics of the patient and the PK and PD properties of the pre-switch medication. Cross-tapering strategies should be considered as a means of reducing the risk of rebound and withdrawal symptoms.

Second-generation and newly approved antipsychotics, serum prolactin levels and sexual dysfunctions: a critical literature review.

INTRODUCTION: Using antipsychotic (AP) medication can increase prolactin (PRL) levels and place the patient at risk of sexual dysfunction (SD). AREAS COVERED: The aim of this review is to describe the PRL propensity of the different second-generation and newly approved APs. It then considers the prevalence rates of SDs associated with these compounds in patients with schizophrenia and treatment strategies for the management of SDs and/or hyperprolactinemia (HPRL). Furthermore, we address the lingering question regarding the association between SDs and PRL. EXPERT OPINION: SD (particularly long-term) data remain scarce for several APs. A wide variety of assessment techniques used in SD research make reliable comparisons between APs impossible. The majority of these reports do not equally allow us to distinguish between treatment (AP and co-medication)-emergent SDs and illness-related SDs. This makes it difficult to assess the degree to which these side effects are associated with 'PRL-raising' APs, and what part of this fraction is directly reducible to serum PRL levels. Also, few evidence-based treatment strategies for HPRL and associated side effects are available. Therefore, longer-term randomized controlled trials, using reliable and valid structured interviews or questionnaires, are necessary to establish the precise relationship between APs, PRL levels and SDs rates and develop valuable treatment options.

Paliperidone extended-release in patients with non-acute schizophrenia previously unsuccessfully treated with other oral antipsychotics.

OBJECTIVE: This study explores relevant outcomes with flexibly dosed paliperidone extended-release (ER) in a real-world design. RESEARCH DESIGN AND METHODS: Patients were recruited from 23 countries. Adults with non-acute schizophrenia (n = 1812), previously unsuccessfully treated with other oral antipsychotics, were transitioned to paliperidone ER and prospectively treated for 6 months. MAIN OUTCOME MEASURES: Primary efficacy outcome for patients switching for the main reason of lack of efficacy was ≥ 20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores. For patients switching for main reasons other than lack of efficacy, primary outcome was non-inferiority in efficacy compared with the previous medication. RESULTS: Among the lack-of-efficacy group, 61% achieved a ≥ 20% improvement in PANSS total scores from baseline to endpoint. For switchers from other than the lack-of-efficacy group, efficacy maintenance after switching to paliperidone ER was confirmed. Clinically relevant and statistically significant symptomatic improvements occurred for each patient group based on main reason for switching. CONCLUSION: Paliperidone ER was well tolerated and associated with a meaningful clinical response in patients who switched from other oral antipsychotics, with insomnia and anxiety as most frequent side-effects.

SMARTS (Systematic Monitoring of Adverse events Related to TreatmentS): The development of a pragmatic patient-completed checklist to assess antipsychotic drug side effects.

OBJECTIVES: Antipsychotic drug side effects are common and can cause stigmatisation, decreased quality of life, poor adherence, and secondary morbidity and mortality. Systematic assessment of anticipated side effects is recommended as part of good clinical care, but is uncommon in practice and patients may not spontaneously report side effects. We aimed to develop a simple patient-completed checklist to screen systematically for potential antipsychotic side effects. METHODS: The SMARTS checklist was developed over a series of group meetings by an international faculty of 12 experts (including psychiatrists, a general physician and a psychopharmacologist) based on their clinical experience and knowledge of the literature. The emphasis is on tolerability (i.e. assessment of side effects that 'trouble' the patient) as subjective impact of side effects is most relevant to medication adherence. The development took account of feedback from practising psychiatrists in Europe, the Middle East and Africa, a process that contributed to face validity. RESULTS: The SMARTS checklist assesses whether patients are currently 'troubled' by 11 well-established potential antipsychotic side effects. Patients provide their responses to these questions by circling relevant side effects. An additional open question enquires about any other possible side effects. The checklist has been translated into Italian and Turkish. CONCLUSIONS: The SMARTS checklist aims to strike a balance between brevity and capturing the most common and important antipsychotic side effects. It is appropriate for completion by patients prior to a clinical consultation, for example, in the waiting room. It can then form the focus for a more detailed clinical discussion about side effects. It can be used alone or form part of a more comprehensive assessment of antipsychotic side effects including blood tests and a physical examination when appropriate. The checklist assesses current problems and can be used longitudinally to assess change.

Clinical outcomes of long-acting risperidone in recent versus long-term diagnosed Belgian schizophrenic patients: results from electronic Schizophrenia Treatment Adherence Registry (e-STAR) and Trial for the Initiation and Maintenance Of REmission in Schizophrenia with risperidone (TIMORES).

AIM: Potential differences in psychiatric clinical outcomes and hospitalization rates before and after the initiation of long-acting risperidone among recently and long-term diagnosed schizophrenia patients were studied. METHODS: Data from two observational studies (Trial for the Initiation and Maintenance Of REmission in Schizophrenia with risperidone (TIMORES) and electronic Schizophrenia Treatment Adherence Registry (e-STAR)) were categorized by the recency of their diagnose and compared in several post hoc analyses. Clinical Global Impression of illness Severity (CGI-S) and Global Assessment of Functioning (GAF) scores, as well as symptoms of clinical deterioration (including hospitalization data) at baseline, 12-month (for TIMORES and e-STAR) and 24-month (for e-STAR) follow-up were analysed. Other outcome measures included discontinuation rate, employment status and remission attainment. RESULTS: Statistically significantly differences between recent and long-term diagnosed schizophrenic patients at 12- and 24-month follow-up were found for CGI-S (between P < 0.01 and P ≤ 0.001) and GAF (P < 0.05) scores. Other differences between both schizophrenic patient groups were found for measures of clinical deterioration, employment status and full symptomatic remission rates at 1 year. Although no consistent difference was found between recent and long-term patient groups for hospitalization parameters, the difference in length of full hospitalization days was statistically significantly different (P < 0.01) between e-STAR 'Early' and 'Late' patient groups at both 12- and 24-month endpoints: the mean change from baseline was significantly greater for e-STAR 'Early' at 12 months, but greater for e-STAR 'Late' at 24 months. CONCLUSIONS: The findings of the post hoc analyses support the significance of pharmacological interventions, such as long-acting risperidone, in addressing discontinuity issues, especially in recently diagnosed patients.

Subjective well-being in schizophrenia: a randomised controlled open-label 12-month non-inferiority study comparing quetiapine XR with risperidone (RECOVER).

UNLABELLED: This randomised 12-month open study analysed the effectiveness of quetiapine XR (400-800 mg) versus risperidone (2-6 mg) on subjective well-being in schizophrenia (NCT00600756). Primary objective was to demonstrate non-inferiority of quetiapine XR to risperidone in 6-month responder rate using the Subjective Well-Being under Neuroleptics scale (SWN-K) (per-protocol at Month 6 [PP 6] population). Non-inferiority was defined as the lower limit of the 95% confidence interval (CI) greater than -9.7% for the adjusted difference between quetiapine XR and risperidone. Secondary objectives included non-inferiority of quetiapine XR versus risperidone (lower limit of 95% CI greater than -7.5 points) for SWN-K change from baseline to Month 12 (PP 12). 798 patients were randomised (quetiapine XR, n=395; risperidone, n=403); at Month 12, 212 (54%) and 227 (56%) patients, respectively, completed the study. At Month 6, SWN-K responder rate in the PP 6 population was 65% (136/210) with quetiapine XR and 68% (158/232) with risperidone (adjusted treatment difference: -5.7%; 95% CI: -15.1, 3.7); thus, non-inferiority could not be established. SWN-K change from baseline to Month 12 was 23.2 points for quetiapine XR and 21.1 points for the risperidone group; treatment difference was 2.1 (95% CI: -0.8; 5.0); non-inferiority was established (PP 12). CONCLUSION: SWN-K response at 6 months was comparable between the two antipsychotics. However, with a lower than expected responder rate and a lower than expected number of evaluable patients in the PP 6 population, non-inferiority was not demonstrated. A secondary objective (SWN-K total score) established non-inferiority of quetiapine XR to risperidone at Month 12.

Increased ventral striatal CB1 receptor binding is related to negative symptoms in drug-free patients with schizophrenia.

Increasing animal genetic, post-mortem and pharmacological evidence supports a role for the cerebral type 1 cannabinoid (CB1) receptor in the pathogenesis of schizophrenia (SCZ) and/or neural circuit dysfunctions responsible for its symptomatology. Moreover, since important interspecies differences are present in CB1 receptor expression, in vivo human data are of direct interest. We investigated an in vivo CB1 receptor expression in SCZ patients compared to healthy controls (CON), and in relation with psychopathological symptom severity using positron emission tomography (PET) and the selective high-affinity radioligand [(18)F]MK-9470. A total of sixty-seven patients with SCZ, with (SCZ-T, n=51) and without (SCZ-F, n=16) antipsychotic treatment, and 12 age and gender-matched CON were investigated with [(18)F]MK-9470 PET. Parametric modified standardized uptake value (mSUV) images, reflecting CB1 receptor binding, were compared and related to psychopathological symptoms. Compared to CON, there was a significant increase of CB1 receptor binding in SCZ patients in the nucleus accumbens, insula, cingulate cortex, inferior frontal cortex, parietal and mediotemporal lobe. Furthermore, in the SCZ-F group only, CB1 receptor binding was negatively correlated to negative symptoms and to depression scores, especially in the nucleus accumbens. Present findings strongly support that CB1 receptor binding is altered in the mesocorticolimbic circuitry of both SCZ-T and SCZ-F patients, especially in the nucleus accumbens. In SCZ-F patients, it is associated with negative symptoms and depression scores.

Schizophrenia symptoms and functioning in patients receiving long-term treatment with olanzapine long-acting injection formulation: a pooled analysis.

BACKGROUND: This analysis of pooled data evaluates treatment outcomes of patients with schizophrenia receiving maintenance treatment with olanzapine long-acting injection (OLAI) by means of a categorical approach addressing the symptomatic and functional status of patients at different times. METHODS: Patients were grouped into 5 categories at baseline, 6 months, and 12 months. Shifts between categories were assessed for individual patients and factors associated with improvement were analyzed. 1182 patients from 3 clinical trials were included in the current analysis. RESULTS: At baseline, 434 (36.8%) patients had minimal Positive and Negative Syndrome Scale (PANSS) symptoms but seriously impaired Heinrich Carpenter's Quality of Life Scale (QLS) functioning; 303 (25.6%) had moderate to severe symptoms and seriously impaired function; 208 (17.6%) had mild to moderate symptoms but good functioning, and 162 (13.7%) had minimal symptoms and good functioning. Baseline category was significantly associated with Clinical Global Impression--Severity (CGI-S), extrapyramidal symptoms, working status, age, and number of previous episodes. The majority of all patients starting OLAI treatment maintained or improved (62% at 6 months and 52% at 12 months) their symptom and functioning levels on OLAI maintenance treatment. Less than 8% of the patients showed worsening of symptoms or functioning. An improvement in category was associated with high PANSS positive and low CGI-S scores at baseline. CONCLUSIONS: We present evidence that a composite assessment of schizophrenic patients including symptom severity and functioning is helpful in the evaluation of maintenance treatment outcomes. This approach could also be useful for the assessment of treatment options in clinical practice.The trials from which data are reported here were registered on clinicaltrials.gov as NCT00088491, NCT00088465, and NCT00320489.

Effect of aripiprazole on verbal memory and fluency in schizophrenic patients : results from the ESCAPE study.

BACKGROUND: Second-generation antipsychotics have gradually replaced first-generation antipsychotics as first-line treatment for patients with schizophrenia. Some positive effects on verbal cognition have been shown for the second-generation antipsychotics, but most studies are based on relatively small numbers of patients. OBJECTIVE: In the frame of the prospective, multi-centre, open-label study ESCAPE (A Prospective, Multicenter, Open-Label Study to Evaluate the Effectiveness and the Effect on Cognitive Function of a Treatment With Aripiprazole in a Broad Range of Schizophrenic Patients; clinicaltrials.gov identifier NCT00329810) evaluating the effectiveness and effect on cognitive functioning of aripiprazole in schizophrenic patients, we conducted a post hoc analysis to examine changes in verbal cognition and investigate the predictive value of a cognitive improvement on quality of life. STUDY DESIGN: This was a prospective, multi-centre, non-comparative, open-label study of aripiprazole in schizophrenic patients. At study enrolment, these patients were being treated with various first- or second-generation antipsychotics or were without previous antipsychotic treatment. On entering the study, all patients were treated with aripiprazole (Abilify(®); Otsuka, Tokyo, Japan) monotherapy; those patients who had received prior treatment with antipsychotics had their current drug(s) tapered off over a 2-week period. A post hoc analysis of the effect of aripiprazole on two verbal cognitive measures and their correlation with efficacy measures and quality of life was conducted. SETTING: Patients with schizophrenia were recruited in 56 psychiatric hospitals. PATIENTS: A total of 361 patients with schizophrenia, ranging from 18 to 65 years, entered the study. INTERVENTION: Patients were treated with aripiprazole monotherapy at a dosage of 10-30 mg/day. Those who were receiving first- or second-generation antipsychotics at enrolment were switched to aripiprazole monotherapy by tapering off their current drug(s) over a 2-week period. MAIN OUTCOME MEASURE: Physician- and patient-rated parameters were measured to gain a complete view of the effectiveness of aripiprazole on the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) at baseline and at weeks 4, 8 and 12 and on the Clinical Global Impression-Severity of Illness (CGI-S) scale at baseline and at weeks 1, 2, 4, 8 and 12. A secondary endpoint of verbal cognitive function was measured by the California Verbal Learning Test (CVLT) and the Verbal Fluency (VF) test at baseline and at weeks 4 and 12. The hypothesis of an improvement in verbal cognition and its predictive value on the quality of life was formulated during data collection. RESULTS: 238 patients completed the study. A significant improvement in verbal cognition was observed from week 4 with the long term free recall (LTFR) in the CVLT over the scheduled visits in the trial (F(2,519) = 29.67, p < 0.0001). For the phonemic (letter) subtest of the VF test, patients scored significantly better at week 12 in comparison with baseline (F(2,519) = 3.57, p = 0.0289). There was no significant effect on the semantic (categories) subtest of the VF test (F(2,518) = 0.57, p = 0.5614). Improvement in CGI-S scores at a particular moment in time predicted improvement in LTFR scores at that same moment (F(1,519) = 38.38, p < 0.0001) and in the phonemic (F(1,519) = 42.77, p < 0.0001) and semantic (F(1,518) = 67.43, p < 0.0001) subtests of the VF test. Similarly, CGI-S score improvement globally predicted quality-of-life improvement over visits. The Q-LES-Q scales leisure (F(1,144) = 14.03, p < 0.0001) and social relations (F(1,469) = 5.28, p = 0.0220) also directly correlated with verbal cognition. CONCLUSION: The findings suggest that switching to, or initiating aripiprazole in schizophrenic patients results in improvement in verbal cognitive functioning. The observed improvement on quality of life is explained by the effect of aripiprazole on the CGI-S score, though the leisure and social relations scales of the Q-LES-Q also independently correlated with verbal fluency. Randomized, controlled, clinical trials of this effect of aripiprazole for selected patients are needed.

Treatment of depression in first episode of schizophrenia: results from EUFEST.

Depressive symptomatology is an important target of treatment in first episode schizophrenia. This reanalysis of the European First Episode Schizophrenia Trial (EUFEST) describes the depressive symptomatology and the effect of antipsychotic treatment in patients suffering from first episode schizophrenia and schizophreniform disorder randomized to treatment with low dose haloperidol (n=103), amisulpride (n=104), olanzapine (n=105), quetiapine (n=104) or ziprasidone (n=82) for one year. At baseline, the mean score on the Calgary Depression Scale for Schizophrenia (CDSS) was 5.1 (±4.9) with 38.3% of patients having a CDSS score≥6, i.e. clinically relevant depressive symptom severity. During treatment depression scores decreased, the mean CDSS score being 1.1 (±2.1) and 3.0% of patients having a CDSS≥6 at 52 weeks. The proportion of patients using antidepressants during the complete trial was 18.5% in the haloperidol group, 28.6% in the olanzapine group compared to 5.8% in the quetiapine group, 12.5% in the amisulpride group, and 9.8% in the ziprasidone group. There were no differences over time in the probability of being depressed (CDSS≥6) between the 5 treatment groups after adjustment for antidepressant use, nor in a sub analysis of patients who did not take any antidepressant. Depression scores at baseline or during the trial had no effect on treatment discontinuation or on the reduction of positive symptoms. In summary, the results of EUFEST did not demonstrate a differential effect of the antipsychotics studied on depressive symptomatology in patients with first episode schizophrenia.

Differential effects of olanzapine and risperidone on plasma adiponectin levels over time: results from a 3-month prospective open-label study.

Second-generation antipsychotics (SGA), especially clozapine and olanzapine, are associated with an increased metabolic risk. Recent research showed that plasma adiponectin levels, an adipocyte-derived hormone that increases insulin sensitivity, vary in the same way in schizophrenic patients as in the general population according to gender, adiposity and metabolic syndrome (MetS). The aim of the present study was to investigate whether different SGAs differentially affect plasma adiponectin levels independent of body mass index (BMI) and MetS status. 113 patients with schizophrenia (65.5% males, 32.3years old) who were free of antipsychotic medication were enrolled in this open-label prospective single-center study and received either risperidone (n=54) or olanzapine (n=59). They were followed prospectively for 12weeks. Average daily dose was 4.4mg/day for risperidone and 17.4mg/day for olanzapine. Plasma adiponectin levels as well as fasting metabolic parameters were measured at baseline, 6weeks and 12weeks. The two groups had similar baseline demographic and metabolic characteristics. A significant increase in body weight was observed over time. This increase was significantly larger in the olanzapine group than in the risperidone group (+7.0kg versus +3.1kg, p<0.0002). Changes in fasting glucose and insulin levels and in HOMA-IR, an index of insulin resistance, were not significantly different in both treatment groups. MetS prevalence increased significantly more in the olanzapine group as compared to the risperidone groups where the prevalence did not change over time. We observed a significant (p=0.0015) treatment by time interaction showing an adiponectin increase in the risperidone-treated patients (from 10,154 to 11,124ng/ml) whereas adiponectin levels decreased in olanzapine treated patients (from 11,280 to 8988ng/ml). This effect was independent of BMI and the presence/absence of MetS. The differential effect of antipsychotic treatment (risperidone versus olanzapine) on plasma adiponectin levels over time, independent of changes in waist circumference and antipsychotic dosing, suggests a specific effect on adipose tissues, similar to what has been observed in animal models. The observed olanzapine-associated reduction in plasma adiponectin levels may at least partially contribute to the increased metabolic risk of olanzapine compared to risperidone.

The management of schizophrenia: focus on extended-release quetiapine fumarate.

Effective management of schizophrenia remains a significant clinical challenge. While antipsychotic medications have proven efficacy in this disease, there remains an opportunity to further improve symptom control and long-term relapse prevention. Also, a number of factors, including tolerability and complex dosing regimens, can result in nonadherence to medication. Quetiapine is an atypical antipsychotic with proven efficacy and an established tolerability profile in schizophrenia. The once-daily extended-release formulation (quetiapine XR) offers a simplified dosing regimen and titration schedule. Short-term clinical studies have shown that quetiapine XR (400-800 mg/d) is efficacious in the acute treatment of schizophrenia, while a long-term study has shown that quetiapine XR was significantly more effective than placebo at preventing relapse. Furthermore, an investigation in which stable patients switched from the immediate-release formulation (quetiapine IR) to quetiapine XR showed that quetiapine XR is generally well tolerated and has no loss of efficacy compared with quetiapine IR. In patients who experienced insufficient efficacy or poor tolerability on their previous antipsychotic, switching to quetiapine XR significantly improved efficacy compared with the previous treatment. In conclusion, quetiapine XR is an effective and generally well tolerated treatment for schizophrenia. Furthermore, once-daily dosing may improve patient adherence, which may impact positively on patient outcomes.

Knowledge about HIV in people with schizophrenia: a general population comparison.

BACKGROUND: Patients with schizophrenia are at higher risk for human immunodeficiency virus infection (HIV) positivity compared to the general population. Only a limited number of studies have evaluated the knowledge about HIV in people with schizophrenia. OBJECTIVES: To compare the knowledge about HIV between people with schizophrenia and the general population. METHODS: The knowledge about HIV was assessed with a questionnaire used in the general health survey of the Belgian population in 2004. RESULTS: Patients with schizophrenia had a significantly better knowledge about nontransmissible contacts compared to the general population (43.2% vs. 32.6%, df=1, chi-square=11.0; p=0.0009). There was no difference regarding the knowledge about protective methods (50.7% vs. 55.9%, df=1, chi-square=2.45; p=0.12). Patients had a better appreciation about the severity and treatment options for acquired immunodeficiency syndrome (AIDS) (54.6% vs. 37.9%, df=1, chi-square=25.91; p<0.0001). CONCLUSIONS: Although the overall knowledge about HIV in patients with schizophrenia is better than that of the general population, it is far from optimal. There is a need for systematic educational programs to improve knowledge.

Effectiveness of injectable risperidone long-acting therapy for schizophrenia: data from the US, Spain, Australia, and Belgium.

BACKGROUND: Because wide variations in mental health care utilization exist throughout the world, determining long-term effectiveness of psychotropic medications in a real-world setting would be beneficial to physicians and patients. The purpose of this analysis was to describe the effectiveness of injectable risperidone long-acting therapy (RLAT) for schizophrenia across countries. METHODS: This was a pragmatic analysis of data from two prospective observational studies conducted in the US (Schizophrenia Outcomes Utilization Relapse and Clinical Evaluation [SOURCE]; ClinicalTrials.gov registration number for the SOURCE study: NCT00246194) and Spain, Australia, and Belgium (electronic Schizophrenia Treatment Adherence Registry [eSTAR]). Two separate analyses were performed to assess clinical improvement during the study and estimate psychiatric hospitalization rates before and after RLAT initiation. Clinical improvement was evaluated using the Clinical Global Impressions-Severity (CGI-S) and Global Assessment of Functioning (GAF) scales, and change from baseline was evaluated using paired t tests. Psychiatric hospitalization rates were analyzed using incidence densities, and the bootstrap resampling method was used to examine differences between the pre-baseline and post-baseline periods. RESULTS: The initial sample comprised 3,069 patients (US, n = 532; Spain, n = 1,345; Australia, n = 784; and Belgium, n = 408). In all, 24 months of study participation, completed by 39.3% (n = 209), 62.7% (n = 843), 45.8% (n = 359), and 64.2% (n = 262) of patients from the US, Spain, Australia, and Belgium, respectively, were included in the clinical analysis. Improvements compared with baseline were observed on both clinical assessments across countries (P < 0.001 at all post-baseline visits). The mean improvement was approximately 1 point on the CGI-S and 15 points on the GAF. A total of 435 (81.8%), 1,339 (99.6%), 734 (93.6%), and 393 (96.3%) patients from the US, Spain, Australia, and Belgium, respectively, had ≥1 post-baseline visit and were included in the analysis of psychiatric hospitalization rates. Hospitalization rates decreased significantly in all countries regardless of hospitalization status at RLAT initiation (P < 0.0001) and decreased significantly in the US and Spain (P < 0.0001) when the analysis was limited to outpatients only. CONCLUSIONS: RLAT in patients with schizophrenia was associated with improvements in clinical and functional outcomes and decreased hospitalization rates in the US, Spain, Australia, and Belgium, despite differences in health care delivery systems.

Prevalence and severity of antipsychotic related constipation in patients with schizophrenia: a retrospective descriptive study.

BACKGROUND: Antipsychotic are the cornerstone in the treatment of schizophrenia. They also have a number of side-effects. Constipation is thought to be common, and a potential serious side-effect, which has received little attention in recent literature. METHOD: We performed a retrospective study in consecutively admitted patients, between 2007 and 2009 and treated with antipsychotic medication, linking different electronic patient data to evaluate the prevalence and severity of constipation in patients with schizophrenia under routine treatment conditions. RESULTS: Over a period of 22 months 36.3% of patients (99) received at least once a pharmacological treatment for constipation. On average medication for constipation was prescribed for 273 days. Severe cases (N = 50), non-responsive to initial treatment, got a plain x-ray of the abdomen. In 68.4% fecal impaction was found. CONCLUSION: A high prevalence of constipation, often severe and needing medical interventions, was confirmed during the study period. Early detection, monitoring over treatment and early intervention of constipation could prevent serious consequences such as ileus.

Age at onset of psychotic disorder: cannabis, BDNF Val66Met, and sex-specific models of gene-environment interaction.

Discovering modifiable predictors for age at onset may help to identify predictors of transition to psychotic disorder in the "at-risk mental state." Inconsistent effects of sex, BDNF Val66Met (rs6265), and cannabis use on age of onset were previously reported. BDNF Val66Met and cannabis use before illness onset were retrospectively assessed in a sample of 585 patients with schizophrenia and their association with age at onset was evaluated. Cannabis use was significantly associated with earlier age at onset of psychotic disorder (AOP; average difference 2.7 years, P < 0.001), showing dose-response effects with higher frequency and earlier age at first use. There was a weak association between BDNF Val66Met genotype and AOP (difference 1.2 years; P = 0.050). No evidence was found for BDNF × cannabis interaction (interaction χ(2) (1) = 0.65, P = 0.420). However, a significant BDNF × cannabis × sex interaction was found (interaction χ(2) (1) = 4.99, P = 0.026). In female patients, cannabis use was associated with earlier AOP in BDNF Met-carriers (difference 7 years), but not in Val/Val-genotypes. In male patients, cannabis use was associated with earlier AOP irrespective of BDNF Val66Met genotype (difference 1.3 years). BDNF Val66Met genotype in the absence of cannabis use did not influence AOP, neither in female or male patients with psychotic disorder. Complex interactions between cannabis and BDNF may shape age at onset in female individuals at risk of psychotic disorder. No compelling evidence was found that BDNF genotype is associated with age at onset of psychotic disorder in the absence of cannabis use.

Metabolic parameters in the short- and long-term treatment of schizophrenia with sertindole or risperidone.

The presence of the metabolic syndrome is an important risk factor for cardiovascular disease and diabetes. The short- and long-term metabolic safety of sertindole was compared to that of risperidone in a subset of patients enrolled in the sertindole cohort prospective (SCoP) study, an open randomized study. In 261 randomized patients, there were moderate increases in mean weight, BMI, and waist circumference during treatment with either sertindole or risperidone; after 12 weeks, the increase in weight was 1.3 and 1.1 kg, respectively, and after 36 weeks, it was 2.2 and 2.0 kg, respectively. From baseline to last assessment (up to 60 weeks), weight gains of 1.8 and 1.7 kg for sertindole and risperidone, respectively, were observed. Similar proportions of patients (sertindole: 17% versus risperidone: 16%) had weight increases ≥7% from baseline to last assessment. The mean changes from baseline in triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol, plasma glucose and blood pressure were small and not clinically relevant in both treatment groups. No patient in either of the groups developed type 2 diabetes during the study. At last assessment, the prevalence of metabolic syndrome (International Diabetes Federation) was 17% in the sertindole group and 26% in the risperidone group and the incidence of metabolic syndrome was 7% in the sertindole group and 10% in the risperidone group. Treatment with either sertindole or risperidone did not appear to be associated with an increased comparative risk of developing metabolic syndrome. In general, the metabolic effects of sertindole and risperidone were similar.