Comparative Effectiveness Review Number 43 Effective Health Care Program
Off-Label Use of Atypical Antipsychotics: An Update Executive Summary
Background Effective Health Care Program Antipsychotics medications are approved The Effective Health Care Program by the U.S. Food and Drug Administration was initiated in 2005 to provide valid (FDA) for treatment of schizophrenia and evidence about the comparative bipolar disorder. These medications are effectiveness of different medical commonly divided into two classes, interventions. The object is to help reflecting two waves of historical consumers, health care providers, and development: the conventional others in making informed choices antipsychotics and the atypical. The among treatment alternatives. Through conventional antipsychotics served as the its Comparative Effectiveness Reviews, first successful pharmacologic treatment the program supports systematic for primary psychotic disorders such as appraisals of existing scientific schizophrenia. Having been widely used evidence regarding treatments for for decades, the conventional high-priority health conditions. It also antipsychotics also produced various side promotes and generates new scientific effects requiring additional medications, evidence by identifying gaps in which spurred the development of the existing scientific evidence and atypical antipsychotics. supporting new research. The program Currently, nine atypical antipsychotic drugs puts special emphasis on translating have been approved by FDA: aripiprazole, findings into a variety of useful asenapine, clozapine, iloperidone, formats for different stakeholders, olanzapine, paliperidone, quetiapine, including consumers. risperidone, and ziprasidone. These drugs The full report and this summary are have been used off-label (i.e., for available at www.effectivehealthcare. indications not approved by FDA) for the ahrq.gov/reports/final.cfm. treatment of various psychiatric conditions. While it is legal for a physician to prescribe drugs in such a manner, it is effectiveness for off-label uses. (Clozapine illegal for the manufacturer to actively was excluded because of its association promote such use. with a potentially fatal blood disorder of A 2006 study on Efficacy and Comparative bone marrow suppression, and it requires Effectiveness of Off-label Use of Atypical frequent blood tests for safety monitoring.) Antipsychotics reviewed the scientific The 2006 study examined 84 published evidence on the safety, efficacy, and studies on atypicals and found that the
Effective Health Care most common off-label uses of the drugs were for benefit most from atypical antipsychotics, appropriate treatment of depression, obsessive-compulsive disorder dose, and time needed to see clinical improvement. This (OCD), post-traumatic stress disorder (PTSD), update will try to address these issues. personality disorders, Tourette’s syndrome, autism, and This report covers the following off-label uses of atypical agitation in dementia. It concluded that with few antipsychotic medications: anxiety, ADHD, dementia and exceptions, there was insufficient high-strength evidence severe geriatric agitation, major depressive disorder to reach conclusions about the efficacy of any off-label (MDD), eating disorders, insomnia, OCD, PTSD, uses of these medications. It also found strong evidence personality disorders, substance abuse, and Tourette’s that atypicals are associated with increased risk of syndrome. Autism, included in the original systematic adverse events such as significant weight gain, sedation, review, is now reviewed in a study on the comparative and, among the elderly, increased mortality. Future effectiveness of typical and atypical antipsychotics for research areas suggested by the report include safe on-label indications, conducted by another organization. treatment for agitation in dementia, association between the increased risk of death and antipsychotics drugs, and This report addresses the following Key Questions: comparison of the development of adverse effects between patients taking atypical antipsychotics and those Key Question 1: What are the leading off-label uses of taking conventional antipsychotics. atypical antipsychotics in utilization studies? How have trends in utilization changed in recent years, including Since publication of that report, important changes have inpatient versus outpatient use? What new uses are being occurred that make the report out of date. Studies have studied in trials? been published on new off-label uses, such as treatment of eating disorders, insomnia, attention-deficit Key Question 2: What does the evidence show regarding hyperactivity disorder (ADHD), anxiety, and substance the efficacy and comparative effectiveness of atypical abuse. New or increased adverse effects of off-label antipsychotics for off-label indications? indications have been observed and new atypicals Sub-Key Question 2: How do atypical antipsychotic (asenapine, iloperidone, and paliperidone) have been medications compare with other drugs, including first- approved by FDA for the treatment of schizophrenia and generation antipsychotics, for treating off-label bipolar disorder. In addition, the following previously indications? off-label uses have been approved for on-label use by the FDA: Key Question 3: What subset of the population would potentially benefit from off-label uses? Do effectiveness - Quetiapine and quetiapine ER (extended release) as and harms differ by race/ethnicity, gender, and age monotherapy in bipolar depression group? By severity of condition and clinical subtype? - Quetiapine ER as augmentation for major Key Question 4: What are the potential adverse effects depressive disorder (MDD) and/or complications involved with off-label prescribing - Aripiprazole as augmentation for MDD of atypical antipsychotics? How do they compare within the class and with other drugs used for the conditions? - Olanzapine/fluoxetine combination for MDD Key Question 5: What is the effective dose and time - Olanzapine/fluoxetine combination for bipolar limit for off-label indications? depression - Risperidone and aripiprazole for autism spectrum Conclusions disorders Key Question 1: What are the leading off-label uses of An update is needed to better understand the trends in atypical antipsychotics in utilization studies? How have off-label use and the associated risks and benefits. trends in utilization changed in recent years, including Further, a number of issues remain unclear due to inpatient versus outpatient use? What new uses are being insufficient information in the previous report: studied in trials? subpopulations (i.e., race/ethnicity, gender) that would
2 Atypicals have been studied as off-label treatment Key Question 2: What does the evidence show for the following conditions: ADHD, anxiety, regarding the efficacy and comparative effectiveness of dementia in elderly patients, depression, eating atypical antipsychotics, for off-label indications? Sub- disorders, insomnia, OCD, personality disorder, Key Question 2: How do atypical antipsychotic PTSD, substance use disorders, and Tourette’s medications compare with other drugs, including first- syndrome. generation antipsychotics, for treating off-label indications? Off-label use of atypical antipsychotics in various settings has increased rapidly since their The efficacy results are summarized in Table A below. introduction in the 1990s; risperidone, quetiapine, It is important to note that no trials of the three most and olanzapine are the most common atypicals recently FDA-approved atypicals (asenapine, prescribed for off-label use. iloperidone, and paliperidone) were found for off-label use. Cells shaded in dark blue indicate areas with the One recent study indicated that the 2005 strongest evidence of efficacy, followed by the areas in regulatory warning from the FDA and Health orange. Areas containing circles indicate areas where Canada was associated with decreases in the no clinical trials exist. Light orange and light blue areas overall use of atypical antipsychotics, especially indicate areas where evidence of inefficacy exists. among elderly dementia patients. Areas in medium blue indicate mixed results. Use of atypicals in the elderly is much higher in long-term care settings than in the community. Atypicals are frequently prescribed to treat PTSD in the U.S. Department of Veterans Affairs health system. At least 90 percent of antipsychotics prescribed to children are atypical, rather than conventional antipsychotics. The majority of use is off-label. No off-label use of the newly approved atypicals (asenapine, iloperidone, and paliperidone) was reported in the utilization literature.
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16 Key Question 5 : What is the effective dose and time There is almost no evidence about how treatment limit for off-label indications? efficacy may vary within populations, including variations due to gender, race, ethnicity, or medical There are too few studies comparing doses of atypical comorbidities. In addition, existing evidence about the antipsychotic medications to draw a conclusion about a role of baseline severity of disease is too heterogeneous minimum dose needed. Most trials used flexible dosing, to allow us to draw conclusions. In future research, resulting in patients taking a wide range of doses. standardized measures of disease severity might allow According to a meta-analysis we were able to conduct for greater knowledge of the patient populations who using the percentage of remitters and responders would benefit from treatment with atypical agents. according to the MADRS as outcome, 150 mg quetiapine daily augmentation has equal efficacy as Regarding adverse effects of the atypical augmentation with 300 mg for patients with MDD who antipsychotics, existing evidence varies by drug and by respond inadequately to SSRIs. More trials examining description of the adverse event. It would facilitate different doses of other atypicals for MDD would help assessments of comparative effectiveness if future guide clinicians in treating this population. In addition, studies contained a standardized list of assessed side more dosage trials for treating conditions such as OCD, effects. As many trials report only those side effects PTSD, and anxiety disorder would allow for pooling observed, we are unable to compare between trials for and comparison of results. many of the side effects. Though there is some trial data regarding duration of Another area where clinical guidance is needed is in the treatment in PTSD, eating disorders, and borderline dosages required to achieve effects in off-label personality disorder, the outcome of treatment appears indications. The dosages used in off-label indications to be the same regardless of reported followup time. varied from those used in on-label indications. There were few trials that compared effects by dose. Most Remaining Issues studies used “flexible” dosing, where a patients dosage can be adjusted during the trial. Thus, a dosage The overarching finding of this review is that although comparison across trials was generally not possible. atypical antipsychotic medications are used for a large More research, examining differing dosages within the number of off-label indications, there is moderate to same population, is required in order to guide clinicians strong evidence of efficacy for only a few of the drugs in the appropriate doses to prescribe. A similar issue is and for only a few of the off-label indications. Most of that of treatment length. More research reporting the evidence is for the drugs risperidone, olanzapine, responses at various time points would be helpful in and quetiapine, for the off-label indications of determining how long treatment is required. Given the dementia, depression, and OCD. For the newly risk of side effects when using these agents, clinicians approved atypicals (asenapine, iloperidone, and need to know when a result is expected to prevent paliperidone), we found no clinical trials assessing their continuing an inefficacious agent, unnecessarily. use for any off-label condition, and for some off-label Newer agents, such as asenapine, iloperidone, and uses, we found no or only a small number of trials. paliperidone, cannot be assumed to have efficacy and Head-to-head comparisons of atypical antipsychotic harms similar to the older atypical antipsychotics, since drugs for off-label uses are few, and evidence from the evidence to date does not support that there is a placebo-controlled trials for off-label use suggests that general “class effect” in terms of either efficacy or efficacy differs between drugs, meaning that the harm for most off-label indications. Trials assessing the assumption of a “class effect” for atypical newer agents’ efficacy and safety are necessary if they antipsychotics may be unwarranted. This means that are to be used off-label for any of the above treatment each drug requires its own evaluation of efficacy for areas. each off-label indication, which is a large task; drugs demonstrated to be efficacious will need to be compared in head-to-head in trials.
17 Full Report For More Copies
This executive summary is part of the following For more copies of Off-Label Use of Atypical document: Maglione M, Ruelaz Maher A, Hu J, Wang Antipsychotics: An Update: Executive Summary No. 43 Z, Shanman R, Shekelle PG, Roth B, Hilton L, Suttorp (AHRQ Pub. No 11-EHC087-1), please call the AHRQ MJ, Ewing BA, Motala A, Perry T. Off-Label Use of Clearinghouse at 1–800–358–9295 or email Atypical Antipsychotics: An Update. Comparative [email protected]. Effectiveness Review No. 43. (Prepared by the Southern California/RAND Evidence-based Practice Center under Contract No. HHSA290-2007-10062-1.) AHRQ Publication No. 11-EHC087-EF. Rockville, MD: Agency for Healthcare Research and Quality. September 2011. www.effectivehealthcare.ahrq.gov/reports/final.cfm.
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AHRQ Pub. No. 11-EHC087-1 September 2011