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Depot Atypical Antipsychotics: a Review of the Clinical Effectiveness and Safety

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Depot Atypical Antipsychotics: a Review of the Clinical Effectiveness and Safety TITLE: Depot Atypical Antipsychotics: A Review of the Clinical Effectiveness and Safety DATE: 8 December 2010 CONTEXT AND POLICY ISSUES Medication adherence in patients with psychiatric disorders such as schizophrenia and bipolar disorder is often suboptimal and can be a major barrier to treatment success.1,2 One means of increasing medication adherence is through the use of depot injections of antipsychotic medications, which can be administered at extended intervals (for example, every four weeks).1 Long-acting formulations may be beneficial to those patients who have recurrent relapses that can be attributed to failure to adhere to treatment or patients who prefer this route of administration.1,3 Antipsychotic medications can be categorized as typical or first generation and atypical or second-generation.4 Atypical antipsychotics have some advantages over the typical antipsychotics. In terms of efficacy in schizophrenia, for example, atypical antipsychotics have a more favourable impact on negative symptoms, such as flattened affect, reduced thought and speech productivity, inability to experience pleasure, and decreased initiation of goal-directed behavior, and cognitive impairment, than typical agents.3 Further, atypical antipsychotics tend to have more favourable side effect profiles in that they carry a lower risk of extrapyramidal side effects and tardive dyskinesia than the typical agents.3,4 Both typical (for example, haloperidol, zuclopenthixol, flupenthixol and fluphenazine) and atypical antipsychotic agents (risperidone and paliperidone) are available in Canada as long- acting or depot formulations that are injected intramuscularly (IM).5-9 Long-acting risperidone (LAR) injection is approved for use in Canada in schizophrenia and bipolar disorder,6 whereas long-acting paliperidone injection is approved for use in schizophrenia.5 This report reviews the evidence of comparative clinical effectiveness and harms associated with the use of atypical and typical antipsychotics in schizophrenia and bipolar disorder. As well, evidence of the risks and benefits of depot atypical antipsychotic use in different age groups is reviewed. This information could be helpful in informing formulary decisions with regards to antipsychotic depot injections and in individual patient management. Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners’ own terms and conditions. RESEARCH QUESTIONS 1. What is the comparative clinical effectiveness and safety of depot atypical antipsychotics compared with depot typical antipsychotics for patients with schizophrenia or bipolar disorder? 2. What is the evidence for varying clinical effectiveness and safety of depot atypical antipsychotics in patients with schizophrenia or bipolar disorder of varying ages? KEY MESSAGE In patients with schizophrenia, limited evidence, mainly from non-randomized studies, was inconclusive with regard to the comparative clinical effectiveness and safety of 1) atypical and typical depot antipsychotics and 2) atypical depot antipsychotics in older and younger adults. No evidence was identified for patients with bipolar disorder, so no conclusions can be made with respect to this population. METHODS A limited peer reviewed literature search was conducted using the following bibliographic databases: PubMed and the Cochrane Library (2010, Issue 11). Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, and non-randomized studies. Where possible, retrieval was limited to the human population. The search was limited to English language documents published between January 01, 2005 and November 11, 2010. Grey literature was obtained through health technology agency websites and a focused Internet search. Internet links were provided, where available. HTIS reports are organized so that the higher quality evidence is presented first. Therefore, health technology assessments, systematic reviews and meta-analyses are presented first. These are followed by randomized controlled trials (RCTs) and non-randomized studies. SUMMARY OF FINDINGS No relevant health technology assessments, systematic reviews and meta-analyses were identified. One relevant RCT10 and four relevant non-randomized studies11-14 in patients with schizophrenia were identified by the literature search. Three studies involved comparisons between typical and atypical antipsychotic depot injections,10-12 while two studies compared outcomes of treatment with an atypical antipsychotic in different age groups.13,14 No relevant comparative studies in bipolar disordered were identified. A description of scales used to measure outcomes can be found in the appendix. Health technology assessments No literature identified Systematic reviews and meta-analyses No literature identified Depot Atypical Antipsychotics 2 Randomized controlled trials Comparison of Typical and Atypical Antipsychotic Depot Injections A 2006 open-label RCT compared the efficacy of long-acting risperidone (LAR) injection (n=57) and zuclopenthixol IM depot injection (n=58) in individuals with schizophrenia and a comorbid substance use disorder.10 Individuals between the ages of 18 and 65 years old, with schizophrenia and comorbid substance use disorders were eligible for inclusion in the study. Individuals with organic, neurologic or other psychotic disorders were excluded, as well as those with clinically relevant abnormalities in baseline laboratory tests. Patients were recruited while in hospital, and allocated alternately to the two treatment arms, a method of randomization that is considered inappropriate.15,16 No information was provided about initial dosages or dosage titration. It was stated, however, that the risperidone group received an average of 47.2 mg per 15 days of (LAR) and 3.4 mg daily of oral risperidone, while the zuclopenthixol group received 200 mg of zuclopenthixol-depot every 21 days and 15 mg per day orally. It was not clear if all patients were on combinations of injectable and oral antipsychotics. Patients also participated in a psychotherapeutic program, and were followed for a total of six months. Outcomes included substance use based upon urine screening results, symptoms of schizophrenia (Positive and Negative Syndrome Scale – PANSS) and extrapyramidal symptoms (Extrapyramidal Symptom Rating Scale – ESRS). The clinical global impression (CGI) scale and the Udvaig for klinisike (UKU) Side Effect Rating Scale were also described as outcome measures; however, data for these outcomes were not reported. Outcome assessors were blinded to treatment status. Baseline characteristics were similar between groups and no statistically significant differences were observed.10 In total nine participants dropped out of the study, six treated with zuclopenthixol depot and three treated with LAR. Only those patients with complete data were included in the analysis. After six months of follow-up, the average number of urine tests that were positive for substances of abuse was 8.67 ± 3.0 in the LAR injection group and 10.36 ± 3.1 in the zuclopenthixol depot group (p=0.005). For the PANSS, positive and general symptoms did not differ between treatments; however, negative symptoms were lower in the LAR injection group (18.80 ± 8.71) than in the zuclopenthixol depot group (23.81 ± 7.40; p=0.008). The total PANSS score was also lower in the LAR injection group (64.93 ± 19.9 versus 74.03 ± 20.9; p=0.02), as were scores on the ESRS (1.24 ± 0.3 versus 2.85 ± 1.1; p=0.05). The authors of the study concluded that LAR injection was more effective than zuclopenthixol depot injection for the management of symptoms related to schizophrenia and in reducing substance use. Limitations to this study10 include the open-label design and questionable method of randomization. Selective outcome reporting may have been an issue as results were not presented for all outcomes described
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