A head-to-head comparison of aripiprazole and risperidone for safety and treating autistic disorders, a randomized double blind clinical trial

Aripiprazole and risperidone are the only FDA approved medications for treating irritability in autistic disorder, however there are no head-to-head data comparing these agents. This is the first prospective randomized clinical trial comparing the safety and efficacy of these two medications in patients with autism spectrum disorders. Fifty nine children and adolescents with autism spectrum disorders were randomized to receive either aripiprazole or risperidone for 2 months. The primary outcome measure was change in Aberrant Behavior Checklist (ABC) scores. Adverse events were assessed. Aripiprazole as well as risperidone lowered ABC scores during 2 months. The rates of adverse effects were not significantly different between the two groups. The safety and efficacy of aripiprazole (mean dose 5.5 mg/day) and risperidone (mean dose 1.12 mg/day) were comparable. The choice between these two medications should be on the basis of clinical equipoise considering the patient's preference and clinical profile.

Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial.

Case reports and studies of other neuroleptics suggest the efficacy of risperidone in the treatment of mania. Forty-five inpatients with DSM-IV mania were studied in a 28-day randomized, controlled, double-blind trial of either 6 mg daily of risperidone, 10 mg daily of haloperidol, or 800 to 1200 mg daily of lithium. The patients in all three groups showed a similar improvement on the total score for all rating scales at day 28 (Brief Psychiatric rating scale; lithium 9.1, haloperidol 4.9, risperidone 6.5, F = 1.01, df = 2, p = 0.37; Mania rating scale; lithium 15.7, haloperidol 10.2, risperidone 12.4, F = 1.07, df = 2, p = 0.35 [analysis of variance]). The Global Assessment of Functioning and Clinical Global Impression data showed a similar pattern of improvement. This study suggests that risperidone is of equivalent efficacy to lithium and haloperidol in the management of acute mania. The extrapyramidal side effects of risperidone and haloperidol were not significantly different.

Assessing cost-effectiveness of drug interventions for schizophrenia

Objective: To assess from a health sector perspective the incremental cost-effectiveness of eight drug treatment scenarios for established schizophrenia.

Method: Using a standardized methodology, costs and outcomes are modelled over the lifetime of prevalent cases of schizophrenia in Australia in 2000. A two-stage approach to assessment of health benefit is used. The first stage involves a quantitative analysis based on disability-adjusted life years (DALYs) averted, using best available evidence. The robustness of results is tested using probabilistic uncertainty analysis. The second stage involves application of 'second filter' criteria (equity, strength of evidence, feasibility and acceptability) to allow broader concepts of benefit to be considered.

Results: Replacing oral typicals with risperidone or olanzapine has an incremental costeffectiveness ratio (ICER) of A$48 000 and A$92 000/DALY respectively. Switching from low-dose typicals to risperidone has an ICER of A$80 000. Giving risperidone to people experiencing side-effects on typicals is more cost-effective at A$20 000. Giving clozapine to people taking typicals, with the worst course of the disorder and either little or clear deterioration, is cost-effective at A$42 000 or A$23 000/DALY respectively. The least costeffective intervention is to replace risperidone with olanzapine at A$160 000/DALY.

Conclusions: Based on an A$50 000/DALY threshold, low-dose typical neuroleptics are indicated as the treatment of choice for established schizophrenia, with risperidone being reserved for those experiencing moderate to severe side-effects on typicals. The more expensive olanzapine should only be prescribed when risperidone is not clinically indicated. The high cost of risperidone and olanzapine relative to modest health gains underlie this conclusion. Earlier introduction of clozapine however, would be cost-effective. This work is limited by weaknesses in trials (lack of long-term efficacy data, quality of life and consumer satisfaction evidence) and the translation of effect size into a DALY change. Some stakeholders, including SANE Australia, argue the modest health gains reported in the literature do not adequately reflect perceptions by patients, clinicians and carers, of improved quality of life with these atypicals.

Assessing cost-effectiveness in mental health: helping policy-makers prioritize and plan health services

Objective: We assessed, from a health sector perspective, options for change that could improve the efficiency of Australia's current mental health services by directing available resources toward 'best practice' cost-effective services.

Method: We summarize cost-effectiveness results of a range of interventions for depression, schizophrenia, attention deficit hyperactivity disorder and anxiety disorders that have been presented in previous papers in this journal. Recommendations for change are formulated after taking into account 'second-filter criteria' of equity, feasibility of implementing change, acceptability to stakeholders and the strength of the evidence. In addition, we estimate the impact on total expenditure if the recommended mental health interventions for depression and schizophrenia are to be implemented in Australia.

Results: There are cost-effective treatment options for mental disorders that are currently underutilized (e.g. cognitive–behavioural therapy (CBT) for depression and anxiety, bibliotherapy for depression, family interventions for schizophrenia and clozapine for the worst course of schizophrenia). There are also less cost-effective treatments in current practice (e.g. widespread use of olanzapine and risperidone in the treatment of established schizophrenia and, within those atypicals, a preference for olanzapine over risperidone). Feasibility of funding mechanisms and training of staff are the main second-filter issues for CBT and family interventions. Acceptability to various stakeholders is the main barrier to implementation of more cost-effective drug treatment regimens. More efficient drug intervention options identified for schizophrenia would cost A$68 million less than current practice. These savings would more than cover the estimated A$36M annual cost of delivering family interventions to the 51% of people with schizophrenia whom we estimated to be eligible and this would lead to an estimated 12% improvement in their health status. Implementing recommended strategies for depression would cost A$121M annually for the 24% of people with depression who seek care currently, but do not receive an evidence-based treatment.

Conclusions: Despite considerable methodological problems, a range of cost-effective and less cost-effective interventions for major mental disorders can be discerned. The biggest hurdle to implementation of more efficient mental health services is that this change would require reallocation of funds between interventions, between disorders and between service providers with different funding mechanisms.

Restless leg syndrome caused by olanzapine: a case series

Restless leg syndrome (RLS) is a common disorder associated with significant distress. We report three cases of drug induced RLS caused by olanzapine. In each case, RLS commenced after initiation of treatment with olanzapine and resolved after ceasing olanzapine. All three patients were subsequently treated with other atypical antipsychotics, risperidone, quetiapine or aripiprazole, without re-emergence of RLS. RLS is associated with central dopaminergic dysfunction. Dopamine agonists and l-dopa reduce the symptoms of RLS, and some agents that block the dopaminergic system aggravate RLS. Greater awareness of potential causes of RLS, and its differentiation from akathisia and illness related agitation might help in reducing the distress associated with it and improving patient compliance.

Lovastatin for the adjunctive treatment of schizophrenia: a preliminary randomized double-blind placebo-controlled trial.

While statins target many of the pathways to neuroprogression in schizophrenia, the safety and efficacy of statins for treating schizophrenia has never been examined. This is an 8-week randomized double blind controlled clinical trial examining the efficacy and safety of adjunctive lovastatin (20 mg/day) treatment or placebo for people with schizophrenia. The baseline characteristics of the two groups were not different. Endpoint changes in Positive and Negative Syndrome Scale (PANSS) total and subscale scores did not differ between the two groups. However there was a significant difference between the doses of risperidone used in the two groups. The mean dose in the lovastatin and placebo groups were 4.8(1.8) and 3.4(1.4) mg/day, respectively (P<.03). No serious adverse events were reported. Slowness of movements, muscle rigidity, increased appetite, and decreased energy were the most common adverse effects, and these rates did not differ between the two groups. This study failed to demonstrate a benefit of lovastatin on symptoms of schizophrenia. This combination was well tolerated. However, a higher dosage of risperidone was used for treating the disorder in those taking concomitant lovastatin compared to placebo.

Atypical antipsychotic agents; peas in a pod or chalk and cheese?

With escalating health expenditure and a shrinking purse, there is increased focus on the cost efficacy of still patented versus generic medications in general, and for atypical antipsychotics in particular. In a recent BMC Medicine article, Godman and colleagues presented data indicating poor uptake of the off patent atypical antipsychotic risperidone, arguing for authorities to mandate its greater use. This is under the assumption of clinical equivalence of atypical antipsychotics. This commentary argues that there are clinically meaningful differences between atypical antipsychotics and important inter-individual heterogeneity in clinical response and tolerability. Access to a broad range of atypical antipsychotics enables clinicians to tailor care, taking consideration of differential efficacy and adverse effects profile in order to meet the needs of individual patients with improved real world effectiveness of treatment. Restriction of agent choice risks detracting from optimal clinical care, with possible poorer outcomes and greater costs of care. A balance between encouraging use of cheapest in class agent and allowing access to various atypical agents for tailored care is likely to produce optimal health outcomes.Please see related article: http://www.biomedcentral.com/1741-7015/12/98.

Pharmacotherapy of bipolar disorder: the role of atypical antipsychotics and experimental strategies.

Bipolar disorder, despite being a common and debilitating illness, has remarkably few pharmacological therapeutic options, the majority of which, with the exception of lithium, have been borrowed from other medical indications. Furthermore the quantity and quality of controlled clinical data are considerably smaller than in conditions of comparable severity and frequency. Not surprisingly, the clinical outcome of bipolar disorder is frequently suboptimal. Fortunately there are a growing number of novel therapeutic options for its treatment such as atypical antipsychotics, calcium channel blockers and omega-3 fatty acids. This paper summarizes some of the data regarding these "experimental" therapeutic options, focusing principally on atypical antipsychotics as these are now widely prescribed in the management of bipolar disorder.

Olanzapine compared to lithium in mania: a double-blind randomized controlled trial.

Neuroleptics are of established efficacy in mania. Controlled data on the use of olanzapine in mania is however, absent. In this study, 30 patients meeting DSM-IV criteria for mania were randomly allocated to receive either olanzapine or lithium in a 4 week double-blind randomized controlled design. There were no significant outcome differences between the two groups on any of the primary outcome measures, the Brief Psychiatric Rating Scale (lithium 28.2; olanzapine 28.0; P = 0.44); Clinical Global Impression (CGI) improvement scale (lithium 2.75, olanzapine 2.36; P = 0.163) or the Mania Scale (lithium 13.2, olanzapine 10.2; P = 0.315). Olanzapine was however, significantly superior to lithium on the CGI-severity scale at week 4 (lithium 2.83, olanzapine 2.29; P = 0.025). Olanzapine did not differ from lithium in terms of treatment emergent extrapyramidal side-effects as measured by the Simpson-Angus Scale. Olanzapine appears to be at least as effective as lithium in the treatment of mania.

Associations of obsessive-compulsive symptoms with clinical and neurocognitive features in schizophrenia according to stage of illness

This study aimed to investigate the association of obsessive-compulsive symptoms with clinical and neurocognitive features in patients with schizophrenia. This study enrolled 163 people with schizophrenia who were receiving risperidone monotherapy. Comorbid obsessive-compulsive symptoms were assessed using the Yale-Brown Obsessive-Compulsive Scale, and subjects with a score≥10 constituted the obsessive-compulsive symptom group (n=30, 18.4%). The learning index was significantly higher in patients with obsessive-compulsive symptoms than in those without such symptoms after adjusting for age, stage (early and chronic), duration of illness, and CDSS score. However, there was no significant interaction between obsessive-compulsive symptoms and stage of illness. Scores on Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, and Beck Depression Inventory were significantly higher in the obsessive-compulsive symptom group. In addition, the Subjective Well-being under Neuroleptic Treatment score was significantly lower in the obsessive-compulsive symptom group. In conclusion, comorbid obsessive-compulsive symptoms in patients with schizophrenia were associated with a higher learning ability without a significant interaction with stage of illness. However, schizophrenia patients with obsessive-compulsive symptoms had more severe psychotic and depressive symptoms and poorer quality of life.

Associations of obsessive-compulsive symptoms with clinical and neurocognitive features in schizophrenia according to stage of illness

This study aimed to investigate the association of obsessive-compulsive symptoms with clinical and neurocognitive features in patients with schizophrenia. This study enrolled 163 people with schizophrenia who were receiving risperidone monotherapy. Comorbid obsessive-compulsive symptoms were assessed using the Yale-Brown Obsessive-Compulsive Scale, and subjects with a score ≥ 10 constituted the obsessive-compulsive symptom group (n=30, 18.4%). The learning index was significantly higher in patients with obsessive-compulsive symptoms than in those without such symptoms after adjusting for age, stage (early and chronic), duration of illness, and CDSS score. However, there was no significant interaction between obsessive-compulsive symptoms and stage of illness. Scores on Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, and Beck Depression Inventory were significantly higher in the obsessive-compulsive symptom group. In addition, the Subjective Well-being under Neuroleptic Treatment score was significantly lower in the obsessive-compulsive symptom group. In conclusion, comorbid obsessive-compulsive symptoms in patients with schizophrenia were associated with a higher learning ability without a significant interaction with stage of illness. However, schizophrenia patients with obsessive-compulsive symptoms had more severe psychotic and depressive symptoms and poorer quality of life.

N-acetylcysteine (NAC) in schizophrenia resistant to clozapine: a double blind randomised placebo controlled trial targeting negative symptoms

BACKGROUND: Clozapine is an effective treatment for a proportion of people with schizophrenia (SZ) who are resistant to the beneficial effects of other antipsychotic drugs. However, anything from 40-60 % of people on clozapine experience residual symptoms even on adequate doses of the medication, and thus could be considered 'clozapine resistant'. Agents that could work alongside clozapine to improve efficacy whilst not increasing the adverse effect burden are both desired and necessary to improve the lives of individuals with clozapine-resistant SZ. N-Acetylcysteine (NAC) is one such possible agent. Previous research from our research group provided promising pilot data suggesting the efficacy of NAC in this patient population. The aim of the study reported here is to expand this work by conducting a large scale clinical trial of NAC in the treatment of clozapine-resistant SZ.

METHODS: This study is an investigator initiated, multi-site, randomised, placebo-controlled trial. It aims to include 168 patients with clozapine-resistant SZ, divided into an intervention group (NAC) and a control group (placebo). Participants in the intervention group will receive 2 g daily of NAC. The primary outcome measures will be the negative symptom scores of the Positive and Negative Syndrome Scale (PANSS). Secondary outcome measures will include: changes in quality of life (QoL) as measured by the Lancashire Quality of Life Profile (LQoLP) and cognitive functioning as measured by the total score on the MATRICS. Additionally we will examine peripheral and cortical glutathione (GSH) concentrations as process outcomes.

DISCUSSION: This large scale clinical trial will investigate the efficacy of NAC as an adjunctive medication to clozapine. This trial, if successful, will establish a cheap, safe and easy-to-use agent (NAC) as a 'go to' adjunct in patients that are only partly responsive to clozapine.