Long-term Management Of Schizophrenia Research Articles

Lurasidone for the treatment of schizophrenia in adult and paediatric populations.

Schizophrenia is a common debilitating disorder characterized by significant impairments in how reality is perceived, combined with behavioural changes. In this review, we describe the lurasidone development programme for adult and paediatric patients. Both the pharmacokinetic and pharmacodynamic characteristics of lurasidone are revisited. In addition, pivotal clinical studies conducted on both adults and children are summarized. Several clinical cases, which demonstrate the role of lurasidone in real-world practice, are also presented. Current clinical guidelines recommend lurasidone as the first-line treatment in the acute and long-term management of schizophrenia in both adult and paediatric populations.

Dosing Cariprazine Within and Beyond Clinical Trials: Recommendations for the Treatment of Schizophrenia.

Although the optimal dosing of an antipsychotic medication is known to be essential in the long-term management of schizophrenia, in case of novel drugs such as cariprazine, determining the right dosing strategy is not that simple. Without decades of experience with a particular compound, evidence regarding dosing and titration comes primarily from double-blind, placebo controlled clinical trials that are not necessarily mirroring the real-life experiences of doctors. Via summarizing data from both clinical data (n = 3275) and real-world evidence (observational study n = 116, case studies n = 29), this perspective paper aims to shed a light on the appropriate dosing strategies of cariprazine from treatment initiation through switching strategies to concomitant medications.

Clinical relevance of paliperidone palmitate 3-monthly in treating schizophrenia.

Antipsychotics are the mainstay in schizophrenia management, and long-acting injectable (LAI) antipsychotics contribute to the successful maintenance of treatment by improving non-adherence and preventing relapses. Paliperidone palmitate 3-monthly (PP3M) formulation is the only available LAI antipsychotic that offers an extended 3-month window of stable plasma drug concentration, enabling only four injections per year. This paper summarizes clinically relevant endpoints from available evidence for PP3M to bridge translational research gaps and provide measurable outcomes that can be interpreted in clinical practice. Low number-needed-to-treat (NNT) for relapse prevention (NNT [95% CI] 6-month estimate: 4.8 [3.2; 10.0]; 12-month estimate: 3.4 [2.2; 7.0]), and high number-needed-to-harm (NNH [95% CI] akathisia, 27.1 [12.3; −667.1]; tremor, 80.0 [22.5; 67.3]; dyskinesia, −132.6 [44.5; −23.2]; parkinsonism, 160.0 [28.9; −49.8]) quantify the relative benefits and low propensity for adverse events with PP3M. Symptom remission and reductions in positive and negative symptoms indicate treatment stability. Additionally, meaningful functional remission, reduced dosing frequency, and freedom from daily negotiations favorably impact patient preference and attenuate burdensome aspects of caregiving, representing important healthcare determinants that enhance prospects of treatment continuity in schizophrenia. This information can potentially improve clinicians’ judgment of treatment choices, clinical response, and patient selection in routine care. Taken together, PP3M is a valuable antipsychotic treatment option, meriting consideration for a broader role in the long-term management of schizophrenia; its utility should not be limited to patients with poor adherence or when oral antipsychotics have failed.

Cost-effectiveness of long-acting injectable risperidone versus flupentixol decanoate in the treatment of schizophrenia: a Markov model parameterized using administrative data

We use longitudinal patient-level data from a German sickness fund with 7.26 million insured in a Markov-simulation model to assess the cost-effectiveness of long-acting injectable risperidone (LAI-RIS) compared with long-acting injectable flupentixol (LAI-FLX) in the long-term management of schizophrenia. We simulate treatment costs from the payer's perspective, hospitalization, the probability to be prescribed co-medication, and treatment discontinuation over a 2-year time horizon. Model inputs were derived from 935 patients hospitalized with schizophrenia between 2005 and 2008 who received either LAI-RIS or LAI-FLX for at least 1 month. After 2 years, 89.4% (95.8%) of patients who were initiated on LAI-RIS (LAI-FLX) discontinued the initial regimen. The number of days spent in hospital per month and patient was slightly lower with LAI-RIS (1.08 vs. 1.28 days, p<0.001). The proportion of patients receiving side-effect co-medication was lower with LAI-RIS (8.3 vs. 15.0% per month, p<0.001). Mean total costs of treatment per patient and month were 1,015 € under LAI-RIS and 395 € under LAI-FLX, resulting in an ICER of 3,088 € (95% CI [-913 €; 3,551 €]) for an avoided hospital day per patient and month in the base case scenario with a 15.1% probability of LAI-FLX being the dominant treatment strategy. Cost differences were mainly attributable to the higher drug costs of LAI-RIS. The effectiveness of LAI-RIS in preventing hospital days appears to be similar to LAI-FLX, with a slight superiority in side-effect and switching rates. This comes at the cost of substantially higher treatment expenses. From a decision-maker's point of view, the use of health insurance data as a source of input for decision models appears to be a reasonable alternative to models driven by clinical data only.

2966 – Understanding the non-adherence and how to improve it

Schizophrenia is a chronic psychiatric disorder with onset of symptoms typically occurring in early adulthood, and requires lifelong treatment. Treatment goals for the long-term management of this debilitating disorder include sustained symptom remission and control, maintaining or improving patient level of functioning and quality of life, prevention of relapse, and continued monitoring for adverse events, as well as sustained adherence to medication. 1 Poor adherence to medication is multifactorial and presents a major challenge in the long-term management of schizophrenia. In fact, rates of non-adherence and of partial compliance to antipsychotic medication are high and are associated with a significantly increased risk of relapse, hospitalization, and the potential for progressive functional impairment, resulting in increased morbidity and high healthcare costs. 2,3 Thus, recognizing and managing non-adherence with the latest treatment advances has the potential to benefit patients as well as their families. One possible solution to the challenge of non-adherence is the availability of long-acting injectable (LAI) formulations of atypical antipsychotics. The use of LAI antipsychotics may help improve the management of adherence and enhance the therapeutic alliance through regular injection visits. In addition to pharmacotherapy, current clinical practice guidelines recommend the use of psychoeducation to improve treatment outcomes. 4 Psychoeducation, along with other behavioral therapies, can facilitate the improvement of patient insight, prevention of relapse, promotion of adherence, and ultimately improve continuity of care. This presentation will provide an overview of key unmet needs in the long-term management of schizophrenia, and evaluate factors leading to non-adherence. The use of non-pharmacological and pharmacological strategies for improving adherence in routine clinical practice will be discussed in the context of a strong therapeutic alliance.

2967 – Long-acting injectable antipsychotics in the treatment of schizophrenia

The nature of schizophrenia gives rise to a number of unmet needs that go beyond proven efficacy and safety of pharmacotherapy in randomized clinical trials (RCTs). Long-acting injectable (LAI) formulations of new generation antipsychotics offer an alternative treatment choice, and the investigational formulation of aripiprazole once-monthly is under regulatory review in the both the US and EU for maintenance treatment of schizophrenia. The efficacy of aripiprazole tablets in the treatment of schizophrenia has been well established, with consistently low relapse rates, good tolerability, and preservation of function. In the “ASPIRE US” (Aripiprazole-Intramuscular-Depot Program in Schizophrenia) trial, a 52-week, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of aripiprazole once-monthly as maintenance treatment in patients with schizophrenia, aripiprazole oncemonthly significantly delayed the time to impending relapse compared with placebo in the long-term maintenance treatment for schizophrenia. At 52 weeks, 10% of patients in the aripiprazole once-monthly group had relapsed, compared with 39.9% of patients in the placebo group (Hazard ratio, 5.03, p 1 In a second study comparing aripiprazole once-monthly with oral aripiprazole, 2 aripiprazole once-monthly was non-inferior to oral aripiprazole and significantly delayed time to exacerbation of psychotic symptoms/impending relapse compared with aripiprazole once-monthly at a sub-threshold therapeutic dose. The estimated relapse rates at Week 26 were 7.1% for aripiprazole once-monthly and 7.8% for oral aripiprazole. This presentation will review the available evidence from recent RCTs showing the efficacy and safety of aripiprazole once-monthly for the longterm management of schizophrenia, and to explore, the link between low relapse rates and functional preservation.

Adherence and Long-Acting Injectable Antipsychotics in Schizophrenia: An Update

Adherence and long-acting injectable antipsychotics in schizophrenia: an update Nonadherence to antipsychotics poses a major problem in the long-term management of schizophrenia. Subjective measures of adherence (self-reports, provider reports) are unreliable, more objective methods (e.g., electronic monitoring, plasma levels) are neither available in clinical practice, nor are they infallible. Risk factors include history of nonadherence, substance use, limited insight, treatment with antidepressants, medication-induced cognitive impairment, hostility, and violent behavior. Nonadherence results in partial or no response to antipsychotic treatment with many adverse consequences, including higher mortality. A recent meta-analysis somewhat surprisingly failed to prove higher adherence to long-acting injectable antipsychotics (LAI) than to oral antipsychotics. However, unexpectedly high adherence in the reviewed trials suggests selection bias. This is further supported indirectly by the findings from two large observational studies from Finland. They showed that LAI, as compared to oral formulations of the same drugs, were associated with a significantly lower risk of rehospitalization and drug discontinuation. Prescription data from the Czech Republic indicate that LAI are underutilized. Contrary to traditional assumptions, patients with previous exposure to LAI appraised them favorably and frequently preferred them in the long-term treatment. LAI may be considered not only for nonadherent, relapsing or difficult-to-manage patients, but also for actively participating, well-informed patients with insight.

P-1103 - Patient attitudes, satisfaction, tolerability for conventional depot antipsychotics and risperidone long acting injection: a cross-sectional survey in community patients

Maintenance antipsychotic medication has a key role in the long term management of schizophrenia but in clinical practice its effectiveness is often reduced by poor adherence. Antipsychotic long acting injections (LAIs) can improve clinical outcomes in those who have adhered poorly with oral medication. To compare patients’ attitudes, satisfaction and tolerability to their currently prescribed LAI, either a FGA-LAI or risperidone long-acting injection (RLAI), which was the only SGA-LAI at the time of this research. Cross-sectional survey of a representative sample of patients prescribed a FGA-LAI (n = 39) or RLAI (n = 28) for a minimum of 6 months. Assessments comprised drug attitude inventory (DAI-30), tolerability measured by Liverpool university neuroleptic side effect rating scale (LUNSERS) and satisfaction with antipsychotic medication by the SWAM scale. The DAI-30 score for patients on FGA depots was 16.18 and RLAI was 14.43, which indicated positive attitudes in both the groups. This difference did not reach statistical significance (p = 0.491). Further analysis, based on both the LUNSERS and SWAM scales, did not find any significant difference in tolerability and patient satisfaction. There was no evidence of differences between FGA-LAIs and RLAI in terms of patient rated tolerability, attitudes and satisfaction. Both groups of patients had positive attitudes to their LAI and overall tolerability was good. This data is observational, and not from a randomised design, which may reflect selection bias. Randomised studies are needed to further investigate differences in tolerability and attitudes between specific LAIs.

Transition from Ziprasidone IM to Oral Formulation in Agitated Patients with Acute Exacerbation of Schizophrenia: An Open Trial

A transition from IM to oral formulation of an antipsychotic agent is often required during the long-term management of schizophrenia. This multicenter trial evaluates the IM/oral sequential administration of ziprasidone in agitated subjects with an exacerbation of schizophrenia. Adult patients requiring IM therapy for schizophrenic symptoms were assigned to IM ziprasidone 10 mg for 3 days, followed by oral ziprasidone (initial dose: 80 mg/day) for 8 weeks. The primary efficacy outcomes were the change in the total PANSS and in the CGI-S scores vs. baseline values. In total, 150 patients were included in the study. A decline in the PANSS and CGI-S scores was observed throughout the study (p < 0.0001 vs. baseline): these reductions became significant at the point of transition from IM to oral formulation (p < 0.0001 vs. baseline). Even with the limitations of any non-comparative study, these results suggest that the IM/oral sequential administration of ziprasidone is an effective and well tolerated therapeutic option in the management of acute exacerbations of schizophrenia in agitated patients.

Risperidone long-acting injection: safety and efficacy in elderly patients with schizophrenia.

Antipsychotic medication is considered the cornerstone of the treatment in elderly patients with schizophrenia. Long acting risperidone injection was the first antipsychotic available for use in this group of patients. Current scientific literature revealed that long-acting risperidone is effective in treating the positive and negative symptoms of schizophrenia and some improvements in cognition and functioning have also been found. In terms of efficacy, there is a paucity of randomized trials but the studies suggest that long-acting risperidone is efficient in the long-term management of schizophrenia, with a safety profile similar to that of oral risperidone. It seems that patient acceptance of treatment is greater when patients are switched from a traditional oral medication to depot risperidone and some improvements in cognition and functioning might be related. Further long-term comparisons with other oral and long-acting antipsychotic medications are needed. These studies should include cost-effectiveness data. Research into metabolic side effects is also needed.

Personal and social functioning in schizophrenia: defining a clinically meaningful measure of maintenance in relapse prevention

Background:Relapse prevention and maintenance of social functioning are important treatment objectives in the long-term management of schizophrenia. However, relatively little is known about measuring maintenance of social functioning to assess treatment benefit in relapse prevention clinical trials or as a tool to predict relapse in clinical practice. This study aims (1) to define a clinically meaningful decrease in the Personal and Social Performance scale (PSP) to assess antipsychotic treatment benefit in terms of maintenance of functioning and (2) to explore the threshold value of PSP decline as a useful tool to predict relapse in clinical practice.Methods:This post hoc analysis of two similar placebo-controlled relapse prevention clinical trials consisted of an exploration of change in PSP that would represent a clinically important decrement to measure treatment benefit in terms of time to PSP decrement (ITT analysis set; Study 1: n = 205) and an assessment of predictive value of PSP decrement and relapse status (ITT analysis set; Study 2: n = 408).Results:A 10-point decrement in PSP score was the threshold value for a clinically meaningful decline in personal and social functioning in a relapse prevention trial (Study 1). A strong association was found with relapse status: 61% of subjects with at least a 10-point decrease in PSP experienced the decrement prior to (between start of double-blind phase and before day of relapse) or on the day of relapse (Study 2). Kaplan–Meier survival analysis of time to at least a 10-point decrement in PSP showed that the proportion of subjects who did not experience at least a 10-point PSP decrease was statistically significantly greater in the paliperidone palmitate group than in the placebo group (p = 0.0014) (Study 2).Conclusions:Findings suggest a 10-point PSP decrement is a clinically relevant measure of maintenance of functioning in patients stabilized with antipsychotic therapy. Paliperidone palmitate demonstrated a statistically significant treatment benefit in terms of maintenance of functioning versus placebo. Furthermore, measuring a clinically relevant PSP decrement may be useful as an early functional indicator of relapse in clinical practice.Limitations:The exploration and validation of the threshold value of change in the PSP was designed and conducted post hoc. Predictive value is limited by the frequency in which PSP assessments were carried out in these trials, underscoring the importance of regular assessment.

Time to ‘Get Real’: Preliminary Insights into the Long-Term Management of Schizophrenia

A brief file and medication chart review was undertaken to examine the 'real world' treatment of schizophrenia, with a particular focus on long-term treatment strategies that extend beyond existing evidence-based guidelines. Treatment strategies were identified through an audit of patient files and their medication charts for patients admitted 2-5 years in a non-acute psychiatric hospital. Twenty-nine file reviews and 20 medication chart audits were conducted. High levels of diagnostic heterogeneity were identified with the presence of psychosis and mood-related diagnoses (primarily schizophrenia and schizoaffective disorder) and high rates of comorbidity (86%). Functional impairment, poor insight and high levels of risk were present in most patients. Treatments largely consisted of combination strategies with 75% of patients prescribed two or more antipsychotics and an average of 3.4 psychotropic medications in total. While clozapine was commonly prescribed (65%), this was often in combination with, on average, two other psychotropic agents. Notwithstanding the limited sample, these findings provide a valuable glimpse into the management strategies employed in the long-term management of schizophrenia. Evidence-based guidelines are largely of limited value for this cohort that often has complex presentations and further research is urgently needed to provide guidance into management strategies that extend beyond 5 years, with particular emphasis on the utility of medication combinations.

Functional SNPs in Genes Encoding the 5-HT2AReceptor Modify the Affinity and Potency of Several Atypical Antipsychotic Drugs

Atypical antipsychotic drugs (AADs) are the standard treatment for both the acute and long-term management of schizophrenia and an augmentation to mood stabilizers for bipolar disorder (BD). Yet many individuals who take AADs do not fully respond to them, while others experience side effects that include weight gain and metabolic disorder. This in vitro pharmacogenetic study examined whether allelic variants in the 5-hydroxytryptamine (HT)(2A) receptor alter the in vitro pharmacology of six AADs (clozapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole). We selected 4 functional single-nucleotide polymorphisms (SNPs) for investigation (Thr25Asn, Ile197Val, Ala447Val, and His452Tyr), conducted site-directed mutagenesis studies to induce variants into human HEK-293 cell lines, and screened allelic variants for their effects on 5-HT( 2A) receptors in the cell lines. We conducted numerous binding assays and fluorescence-based assay system (FLEX station) experiments using the six AADs. Our results indicated that three polymorphic 5-HT(2A) receptors (Ile197Val, Ala447Val, and His452Tyr) exhibited statistically significant, though modest, changes in atypical antipsychotic affinity. In addition, three polymorphic receptors (Thr25Asn, Ile197Val, and His452Try) altered AAD potency. Our findings support in vivo evidence that functional SNPs in genes encoding neuroreceptor drug targets could explain interindividual differences in AAD drug response and tolerability. We suggest that more in vivo pharmacogenetic studies of well-characterized patients who are prescribed AADs be indicated. Future pharmacogenetic studies of well-characterized patients will likely involve tagging SNPs and the use of haplotypes related to other genes encoding neuroreceptor drug targets.

Second-generation antipsychotic long-acting injections: Systematic review

Second-generation antipsychotics (SGAs) represent an advance in the long-term management of schizophrenia. To review the available evidence concerning SGA long-acting injections (LAIs). A systematic review of the literature was conducted using PubMed. Risperidone long-acting injection was the first licensed SGA-LAI compound and is effective in the long-term management of schizophrenia, with a safety profile similar to that of oral risperidone. Olanzapine pamoate has recently been approved in Europe. In terms of efficacy, at injection intervals of up to 4 weeks it appears comparable to oral olanzapine, although the potential for ;post-injection syndrome' (delirium) calls for additional safety considerations. Paliperidone palmitate is currently under review with the licensing authorities. It also affords the potential advantage of monthly dosing. More long-term comparisons of SGA-LAIs with oral SGAs as well as with first-generation antipsychotic LAIs are needed. These studies should include cost-effectiveness data.

Experience with injectable long-acting risperidone in long-term therapy after an acute episode of schizophrenia: the SPHERE Study

Background: Risperidone long-acting injectable (RLAI) is the first long-acting formulation of an atypical antipsychotic introduced into clinical practice. RLAI combines the benefits of atypical antipsychotic agents with an extended duration of activity and is intended for long-term management of schizophrenia. This study evaluated the use of RLAI as part of a long-term management strategy in patients with an acute episode of schizophrenia. Objectives: The primary objective was to determine clinicians’ approaches to the use of RLAI in patients with an acute exacerbation of schizophrenia by examining the prescribing patterns of antipsychotic and other psychotropic medications. Other objectives were to evaluate the overall safety of switching patients to RLAI from previous antipsychotic therapy and to determine patients’, caregivers’ and relatives’ attitudes towards RLAI treatment. Methods: The Safety and Profile of Handling and Employing of Risperdal® Consta® in Emergency/Acute Care Settings (SPHERE) study was an observational, non-interventional, multicenter, retrospective study involving a large cohort of patients with acute psychotic exacerbation who attended Spanish emergency/acute care facilities (between August and December 2003) and were treated with RLAI during hospitalization. Results: A total of 1232 patients (70% men; mean age 37 years; median of 8 months since most recent admission) were included in the analyses; 79% had been receiving antipsychotic therapy prior to admission. All patients received RLAI post-stabilization. The main reasons for initiating RLAI were the need for long-term treatment (76%) and a low adherence to previous treatment (71%). RLAI doses administered during hospitalization were: 25 (26%), 37.5 (29%), 50 (42%) and 75–100 mg (3%). The mean number of injections per patient (2 ± 1) and mean hospitalization time (25 ± 16 days) indicated that RLAI was administered every 2 weeks as per the manufacturer’s recommendations. All patients were discharged on RLAI treatment; 62% were prescribed concomitant therapy, mainly oral risperidone (39%), anxiolytics (25%), antiparkinsonians (15%), hypnotics (11%) and anticonvulsants (11%). Only 5.7% of patients reported adverse events, most commonly extrapyramidal symptoms (1.1%) and somnolence (0.9%). Conclusions: As part of a long-term management strategy aimed at improving treatment adherence in schizophrenic patients, RLAI was prescribed to a wide spectrum of patients with an acute episode of schizophrenia during hospitalization and at the time of discharge from emergency/acute care facilities. RLAI was well tolerated in the study population and the overall impression of patients, primary caregivers and relatives to RLAI therapy was positive.

Evaluation of subjective treatment satisfaction with antipsychotics in schizophrenia patients

Adherence to antipsychotic treatment is particularly important in the long-term management of schizophrenia and other related psychotic disorders since poor adherence to medication is associated with poor health outcomes. Although the patients’ subjective satisfaction with the medication is crucial for adherence to medication, few studies have examined the relationship between subjective satisfaction with antipsychotics and adherence. In this study, we investigated subjective satisfaction with antipsychotics in patients with schizophrenia by using the Treatment Satisfaction Questionnaire for Medication (TSQM), a self-reporting instrument to assess the major dimensions of patients’ satisfaction with their medication. The subjects included 121 clinically stabilized outpatients who met the following criteria: 1) patients between 20 and 65 years of age, diagnosed with schizophrenia or other psychotic disorders as defined by DSM-IV, 2) patients undergoing oral antipsychotic monotherapy or taking only an antiparkinsonian agent as an adjuvant remedy, and 3) patients who had received a stable dose of an antipsychotic for more than four weeks. Patients were asked to answer the TSQM questions, and their clinical symptoms were also evaluated by the Brief Psychiatric Rating Scale (BPRS). Satisfaction with regard to side-effects ( p = 0.015) and global satisfaction ( p = 0.035) were significantly higher in patients taking second-generation antipsychotics (SGAs, n = 111) than those taking first-generation antipsychotics (FGAs, n = 10), whereas no significant difference was found between the two groups in clinical symptoms according to BPRS ( p = 0.637) or the Drug-induced Extrapyramidal Symptoms Scale (DIEPSS, p = 0.209). In addition, correlations were not significant between the subjective satisfactions and clinician-rated objective measures of the symptoms. These findings suggest that SGAs have more favorable subjective satisfaction profiles than FGAs in the treatment of schizophrenia. Since it is often difficult to detect the difference by a traditional objective assessment of the patients, it is desirable that physicians pay attention to the patients’ subjective satisfaction in conjunction with their own objective clinical assessment.

Issues in Psychopharmacology

Although pharmacologic treatment remains a critical element in the short- and long-term management of schizophrenia, the past decade has been a challenging time in terms of real progress. Despite the introduction of several new medications as well as the conduct of larger and more diverse clinical trials, there remains considerable debate as to how far we have progressed in addressing some of the fundamental unmet needs in treating this disorder. A theme in this issue of Schizophrenia Bulletin addresses a number of topics in this context. Although the notion of careful, systematic, and critical summaries of all relevant randomized controlled trials is not a new one, the Cochrane Schizophrenia Group is relatively young. Clive Adams, one of its founders, and colleagues provide the rationale and history of the group as well as reviewing its methods and contributions. The Bulletin also carries a “Cochrane Corner” in each issue to alert the field to schizophrenia-related reviews. Systematic meta-analyses are playing an increasingly important role in informing both the research agenda and clinical practice. The work of the Cochrane collaboration has been enormously valuable in this process. In recent years, the field of schizophrenia research has benefited from the application of various clinical trial methodologies to enhance the study of treatment outcomes and determine generalizability. Large effectiveness trials have provided data to expand our knowledge base beyond that which is provided by traditional efficacy trials. Stroup and Geddes provide examples of each type of trial to illustrate their relative advantages and disadvantages. Within the context of different trial designs, Leucht et al provide an overview addressing critical aspects of trial design, potential population sampling bias, endpoint choices and definitions, quality of assessments, data analysis and reporting, as well as, other potential sources of bias or confounds relevant to the interpretation of clinical trials data in schizophrenia. One of the most difficult challenges in the design, conduct, analysis, and interpretation of clinical trials is the problem of dropouts—those individuals who do not complete the trial, often for unknown reasons. A variety of statistical techniques have been developed and applied in order to address this issue; however, none is entirely satisfactory. Rabinowitz and Davidov discuss the association of dropout and outcome in trials of antipsychotic medication and its implications for strategies to address missing data. Another strategy to minimize dropouts in acute treatment trials would be to shorten the length of the trial, particularly when placebo control groups are included. Addressing this issue and drawing on recent meta-analysis suggesting that a substantial proportion of antipsychotic drug response occurs within the first 2 weeks, McMahon and colleagues present an exploratory analysis from short-term placebo controlled clinical trial data suggesting the potential feasibility of reducing the duration of such trials. Much more work needs to be done to determine the benefits and risks of such an approach, but this is a very valuable first step. In the final article, we provide a review of unanswered questions in the pharmacologic treatment of schizophrenia. Despite numerous trials being conducted with antipsychotic medication, there are many clinical decisions that must be made on a day-to-day basis for which sufficient data are not available to provide an adequate evidence base. We hope that these articles will provide a snapshot of current challenges and opportunities for further progress in the design, conduct, and interpretation of psychopharmacologic trials in schizophrenia.

Aripiprazole in the Treatment??of Schizophrenia

Schizophrenia is generally a chronic and disabling mental illness. Pharmacological therapy, which is used for relief of acute psychotic episodes and prevention of subsequent relapse, is essential for the effective management of schizophrenia. In order to alleviate the positive symptoms of schizophrenia, all antipsychotic agents act on the dopaminergic system. However, strong, high-affinity dopamine D(2)-receptor blockade may also be responsible for debilitating extrapyramidal symptoms (EPS) and hyperprolactinaemia. Unlike conventional antipsychotic agents, atypical antipsychotics also exert activity at other receptors, and it is generally acknowledged that, compared with conventional antipsychotics, atypical agents are associated with a broader spectrum of clinical efficacy and are better tolerated. However, other adverse effects such as weight gain and metabolic changes are cause for concern with some atypical antipsychotics. The novel atypical antipsychotic agent aripiprazole is a partial agonist at D(2) receptors that has been shown in clinical trials to be effective in treating both the positive and the negative symptoms of schizophrenia, and to be well tolerated, with a low propensity for EPS and no clinically significant weight gain, hyperprolactinaemia or corrected QT-interval prolongation. Aripiprazole thus provides clinicians with another treatment option, and in October 2005, schizophrenia experts participated in an expert consensus meeting that aimed to agree on a set of guidelines for best-practice use of aripiprazole in the acute and long-term management of schizophrenia in Italy. This report describes the outcome of the meeting. Our recommendations for dosage and administration of aripiprazole are in agreement with the manufacturer's prescribing information. Ideally, optimal dosing should be evaluated on an individual basis, taking into account patients' characteristics such as the presence or absence of agitation. Overall, in our experience, aripiprazole is generally a well accepted, well tolerated, safe and broadly effective first-line antipsychotic agent. Switching to aripiprazole from maintenance therapy with another antipsychotic also works well, provided the change is made gradually, involving tapering of the original medication.

Study Questions Superiority Of Newer Antipsychotics

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessStudy Questions Superiority Of Newer AntipsychoticsJim RosackJim RosackSearch for more papers by this authorPublished Online:3 Nov 2006https://doi.org/10.1176/pn.41.21.0023Research funded by the United Kingdom's National Health Service suggests that when patients with schizophrenia need to change their medication, either because of ineffectiveness or intolerable side effects, the newer, nonclozapine second-generation antipsychotics (SGAs) do not appear to offer significant benefits over the first-generation antipsychotics (FGAs).The study's findings, reported in the October Archives of General Psychiatry, have generated significant discussion (see article below).The study, known as the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1), is the second over the last year to challenge the widely held perception that SGAs are safer and more effective in treating patients with schizophrenia than are the FGAs. In April, results from the National Institute of Mental Health's CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study indicated that in general patients were likely to do as well on the FGA perphenazine as on newer SGAs (Psychiatric News, April 21).For nearly 50 years, patients taking the older medications would often relapse or develop severe side effects, including sedation and involuntary muscle movements. The development of SGAs was thought to be a major advance primarily because the medications reduced the risk of extrapyramidal symptoms and the potential for development of tardive dyskinesia over the long term. Claims that the SGAs are more effective than the FGAs resulted in significant shifting of prescribing patterns away from the older drugs, even though research comparing the old and the new has produced mixed results.In the Archives report, Peter Jones, M.D., Ph.D., a professor of psychiatry at the University of Cambridge and Cambridgeshire and Peterborough Mental Health NHS Trust, and colleagues studied 227 people with schizophrenia aged 18 to 65 from 14 community psychiatric services in the English National Health Service.“The key question was whether the additional acquisition costs of second-generation antipsychotics over first-generation antipsychotics would be offset by improvements in health-related quality of life or savings in the use of other health and social care services in people with schizophrenia for whom a change in drug treatment was being considered for clinical reasons, most commonly suboptimal efficacy or adverse effects,” Jones and his coauthors wrote.The participants were randomly assigned to receive one class of drug or the other. (Clozapine was not included in the study; see Original article: box) However, their treating physicians determined which of the first- or second-generation medications would be best for them. In the FGA group, 49.15 percent of the patients were started on sulpiride, which is not available in the United States. In the SGA group, 46 percent were started on olanzapine.Participants were assessed at baseline and at 12, 26, and 52 weeks after the change in treatment with the Quality of Life Scale, where higher scores reflect a better quality of life.The researchers hypothesized that the SGAs would produce a five-point improvement in quality-of-life scores compared with the FGAs. Symptoms, side effects, treatment costs, and satisfaction with the drug also were measured.The researchers expressed surprise in finding their hypothesis was not validated (see chart).“Participants in the first-generation antipsychotic arm showed a trend toward greater improvements in Quality of Life Scale and symptom scores,” the authors noted. “Participants reported no clear preference for either drug group; and lastly, costs were similar.”Over the course of the 52 weeks of the trial, mean total costs per patient in the FGA arm were $34,750, compared with $37,185 per patient in the SGA arm. Antipsychotic drug costs accounted for only a small portion of the total costs encountered (2.1 percent for FGAs, and 3.8 percent for SGAs). There was a greater difference in hospitalization costs: inpatient admissions accounted for 93.2 percent of total costs in the FGA arm and 81.5 percent in the SGA arm. Overall the authors concluded that costs were similar between the FGA and SGA arms though they noted that there was a trend toward greater costs in the SGA arm.“All the data suggest that careful prescribing of first-generation antipsychotics, at least in the context of a trial, is not associated with poorer efficacy or a greater adverse-effect burden, both of which would translate into lower quality of life in the medium term,” Jones and his coauthors concluded. “This suggests that despite recent policy statements and prescribing patterns, further randomized and other evaluations of second-generation antipsychotics would still be useful in establishing their role in the long-term management of schizophrenia and, likewise, the continued role of older drugs.”An abstract of “Randomized Controlled Trial of the Effect on Quality of Life of Second- vs. First-Generation Antipsychotic Drugs in Schizophrenia” is posted at<http://archpsyc.ama-assn.org/cgi/content/full/63/10/1079>.▪ ISSUES NewArchived

Quetiapine: efficacy, tolerability and safety in schizophrenia

Quetiapine, a dibenzothiazepine derivative, is an atypical antipsychotic, multireceptor antagonist that has a preclinical profile similar to clozapine. Randomized studies have demonstrated the efficacy of quetiapine relative to placebo in the treatment of acute relapse and the long-term management of schizophrenia. Quetiapine is generally well tolerated relative to other antipsychotic medications, although side effects include sedation, orthostatic hypotension, anticholinergic and metabolic side effects. The purpose of this article is to critically review the current literature on quetiapine with an emphasis on emergent themes and key findings in the use of this agent for the treatment of schizophrenia. There are also continued efforts to understand, predict and manage the side-effect risk with quetiapine.