Off-Label Use of Atypical Antipsychotics: An Update
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  • Off-Label Use of Atypical Antipsychotics: An Update This slide set is based on a comparative effectiveness review (CER), Off-Label Use of Atypical Antipsychotics: An Update, which was developed by the Southern California RAND Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ) under Contract No. HHSA 290-2007-10062-I and is available online at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm. CERs are comprehensive systematic reviews of the literature that usually compare two or more types of treatment, such as different drugs or adding a second drug to usual care for the same disease. The literature included in this review was identified in searches for trials and studies that explicitly evaluated the use of atypical antipsychotics for off-label indications. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Outline of Material - The material begins with an introduction to atypical antipsychotics and their use off-label. - The systematic review methods used to develop the comparative effectiveness review (CER) are presented. - The clinical questions addressed by the CER are presented, as well as a review of the modes of statistical analysis and results reporting in the CER. - The results of studies and evidence-based conclusions about effectiveness and adverse effects of atypical antipsychotics used off-label are presented. - Gaps in knowledge revealed by the review process are presented. - Some suggestions are made for what to discuss with patients and their caregivers, based on the CER findings. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Introduction to Atypical Antipsychotics (1 of 4) Antipsychotics can be classified into two categories, based on the timeline of their development, pharmacology, and anticipated adverse effects profiles. The groups are the typical antipsychotics, also called conventional or first generation, and the atypical antipsychotics, also called second generation. Typical antipsychotics were the first successful pharmacological treatments for primary psychotic disorders such as schizophrenia. However, they are associated with side effects that are difficult to manage and, in some cases, irreversible. Atypical antipsychotics were developed in response to avoiding these adverse effects. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Introduction to Atypical Antipsychotics (2 of 4) As of the date of this review, nine second-generation, atypical antipsychotic drugs have been approved by the U.S. Food and Drug Administration (FDA). Aripiprazole (Abilify®) Asenapine (Saphris®) Clozapine (Clozaril®, FazaClo®) Iloperidone (Fanapt®) Olanzapine (Zyprexa®) Paliperidone (Invega®) Quetiapine (Seroquel®) Risperidone (Risperdal®) Ziprasidone (Geodon®) Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Introduction to Atypical Antipsychotics (3 of 4) Several atypical antipsychotics are approved for indications in addition to primary psychoses, including autism spectrum disorders, bipolar depression, and major depressive disorder. Prescribing of atypical antipsychotics has expanded beyond these approved indications. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Introduction to Atypical Antipsychotics (4 of 4) Recommendations or advertisements that promote the use of pharmaceuticals for indications that have not been approved by the FDA (i.e., off-label) are illegal. Off-label prescribing by physicians is permitted. Given that antipsychotics are used off label, what is known about the efficacy or comparative effectiveness, benefits, and adverse effects of atypical antipsychotics when prescribed for unapproved (off-label) indications? Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others. A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment. The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The Summaries and the full report, with references for included and excluded studies, are available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Rating the Strength of Evidence From the Comparative Effectiveness Review The Evidence-based Practice Center GRADE approach, based on the standard GRADE approach, was used to assess the quality of the body of evidence for each outcome. The overall strength of evidence was graded as high (further research is very unlikely to change the confidence in the estimate of effect), moderate (further research may change the confidence in the estimate of effect and may change the estimate), low (further research is likely to change the confidence in the estimate of effect and is likely to change the estimate), or insufficient (evidence either is unavailable or does not permit estimation of an effect). The authors also independently evaluated the applicability to real-world practice of the total body of evidence within a given clinical indication by using the PICOTS (population, intervention, comparator, outcome, timing, and setting) framework. References: Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality; March 2011. AHRQ Publication No. 10(11)-EHC063-EF. Chapters available at www.effectivehealthcare.ahrq.gov/methodsguide.cfm. Brozek J, Oxman A, Schünemann H, for the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group. GRADEpro [computer program]. Version 3.2 for Windows. 2008. Available at www.cc-ims.net/revman/other-resources/gradepro/gradepro. Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Clinical Questions Addressed by the Comparative Effectiveness Review (1 of 2) The comparative effectiveness review addressed several key clinical questions, including: What are the leading off-label uses of atypical antipsychotics in utilization studies? How have trends in utilization changed in recent years, including inpatient versus outpatient use? What new uses are being studied in trials? What does the evidence show regarding the efficacy and comparative effectiveness of atypical antipsychotics for off-label indications? How do atypical antipsychotic medications compare with other drugs, including first-generation antipsychotics, for treating off-label indications? Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Clinical Questions Addressed by the Comparative Effectiveness Review (2 of 2) Key questions addressed by the comparative effectiveness review included: What are the potential adverse effects and/or complications involved with off-label prescribing of atypical antipsychotics? How do they compare within the class and with other drugs used for the conditions? What is the effective dose and time limit for atypical antipsychotics used in off-label indications? Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Clinically Significant Outcomes of Interest in the Comparative Effectiveness Review (1 of 2) A variety of validated assessment instruments are used to measure outcomes of treatment with atypical antipsychotics, both in practice and in clinical studies. Remission rates and changes in symptom severity are reported. Response rates are defined as the proportion of participants achieving an a priori-specified degree of improvement on a rating scale. For dementia, outcomes are often assessed with the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD), the Brief Psychiatric Rating Scale (BPRS), and the Neuropsychiatric Inventory Scale (NPI). For major depressive disorder, the Hamilton Depression Rating Scale (HAM-D) and the Montgomery-Asberg Depression Rating Score (MADRS) are common choices. For obsessive-compulsive disorder, the Yale-Brown Obsessive Compulsive Scale (YBOCS) is used. For eating disorders, the body mass index (BMI) is used for treatment monitoring. Generalized anxiety disorder is evaluated with the Hamilton Anxiety Rating Scale (HAM-A). Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Clinically Significant Outcomes of Interest in the Comparative Effectiveness Review (2 of 2) A variety of validated assessment instruments are used to measure outcomes of treatment with atypical antipsychotics. Remission rates and changes in symptom severity are reported. Response rates are defined as the proportion of participants achieving an a priori-specified degree of improvement on a rating scale. For personality disorders, either borderline (BPD) or schizotypal, several tools are used, including the Symptom Checklist 90 Revised (SCL-90-R), Clinical Global Impressions–BPD (CGI-BPD), the Hamilton Anxiety Rating Scale (HAM-A), and the Positive and Negative Symptoms Scale (PANSS). Post-traumatic stress disorder (PTSD) is assessed with the Clinician Administered PTSD Scale (CAPS). Substance abuse outcomes assessment tools include the Cocaine Craving Questionnaire (CCQ) and the Addiction Severity Index (ASI). Tourette’s syndrome evaluation includes the symptom-specific Yale Global Tic Severity (YGTS) scale and Clinical Global Impressions–Improvement (CGI-I) scale. For insomnia, sleep quality and time-to-onset are scored. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Adverse Effects of Interest in the Comparative Effectiveness Review The adverse effect profiles of the atypical antipsychotics are not expected to vary according to indication. An exception is dementia, which is associated with older age. Patient age is expected to influence the adverse effect profiles. Reported adverse events were evaluated according to age groups: (1) adults 18–64 years of age and (2) elderly adults aged 64 and older. The key adverse events of interest were mortality, weight gain, endocrine disorders and diabetes, cardiovascular events, extrapyramidal symptoms, and sedative effects. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Summary of Study Characteristics Evaluated in the Effectiveness Review: PICOTS Framework Development of clinical studies of effectiveness of medical interventions is guided by the PICOTS framework. These items are critical elements that will help to answer important clinical questions. In the comparative effectiveness review, the clinical study literature was reviewed and summarized by using the PICOTS framework as summarized below. The evidence concerning the outcomes identified here was examined in: Population: Adults - All indications for which the intervention does not have formal approval Interventions: Atypical antipsychotics - All formulations, administration routes, and doses Comparators: Other antipsychotics, other active interventions, placebo, or no active intervention Outcomes: - Symptom response and remission, general health and quality of life - Key adverse effects: mortality, weight gain, endocrine disturbance/diabetes, cardiovascular events, extrapyramidal symptoms, and sedation Timing: Any time point, ranging from less than 6 weeks to months/years Setting: All settings, including community-dwelling, nursing home, inpatient, Veterans Administration, and outpatient Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Summary of Studies Included in the Comparative Effectiveness Review (1 of 2) Studies of efficacy, effectiveness, benefits, and adverse effects of atypical antipsychotics as treatment for several off-label indications are reported in the clinical literature. There are no reports of studies of off-label use of the newer atypical antipsychotics asenapine, iloperidone, and paliperidone. The atypical antipsychotic clozapine was not included in the review; clozapine can only be prescribed in a system that provides weekly monitoring for bone marrow-suppression disorders as a condition of receiving the treatment. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Summary of Studies Included in the Comparative Effectiveness Review (2 of 2) Off-label indications of atypical antipsychotics that have been studied and reported in the clinical literature are: - Dementia - Major depressive disorder (MDD) - Obsessive-compulsive disorder (OCD) - Borderline personality disorder (BPD) - Post-traumatic stress disorder (PTSD) - Substance abuse - Eating disorders - Anxiety - Insomnia Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Modes of Results Reporting and Statistical Analysis in the Comparative Effectiveness Review (1 of 2) 95% Confidence Interval : The range of statistically valid results that will include the true population mean in 95 of 100 repeated experiments. Mean Difference (MD) : The difference between treatment and comparison group means. To determine a standardized mean difference (SMD), results from different scales are normalized to a common, “standardized” scale before calculating the mean difference. For MD and SMD, the result is statistically significant ( p < 0.05) when the 95-percent confidence interval does not include 0.0, which is the point of no difference between groups. Relative Risk (RR) : The ratio of the rate (absolute risk, probability) of an event in the treatment group to the rate of the event in the comparison group. For RR, the result is statistically significant at p < 0.05 when the 95-percent confidence interval does not include 1.0, which is the point of equal risk for both groups. References: Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions. Version 5.1.0. London: The Cochrane Collaboration; March 2011. Available at www.cochrane-handbook.org. http://www.cochrane-handbook.org Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Modes of Results Reporting and Statistical Analysis in the Comparative Effectiveness Review (2 of 2) Absolute Risk Difference : The absolute value of the mathematical difference between the rates (risk) of an event in the treatment and comparison groups. ARD = | ARC–ART | Number Needed To Treat or Harm (NNT, NNH) : The number of patients to be treated to observe benefit or harm in one patient more than seen in the comparison group. The number of patients to be treated in order to find a benefit or harm attributable to the intervention. NNT or NNH = | ARC–ART | -1 for a benefit or adverse event, respectively Number of attributable events per 1,000 = 1,000 x | ARC–ART | References: Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions. Version 5.1.0. London: The Cochrane Collaboration; March 2011. Available at www.cochrane handbook.org. Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. London: Routledge Academic; 1988. Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Results: Atypical Antipsychotics for Dementia Combined results are presented from meta-analyses of all atypical antipsychotics that have been studied as treatment for dementia in placebo comparisons. The effect size is the standardized mean difference between the means of treated and control groups after the treatment period. The published study results came from a variety of assessment instruments and, as a procedure of the meta-analysis, they were standardized to a common scale before determining the mean difference across studies. The results are presented together with the 95-percent confidence interval, which is the statistically valid range of results that includes the true population mean in 95 of 100 experiments. For mean differences, the result is statistically significant at p < 0.05 when the 95-percent confidence interval does not cross 0.0. As a class, atypical antipsychotics improved global scores by 0.17 points (statistically valid range from 0.08 to 0.25). Psychosis scores improved by 0.12 points (statistically valid range from 0.04 to 0.19), and agitation scores improved by 0.20 points (valid range from 0.12 to 0.27). The strength of evidence for these findings is high. Among atypical antipsychotics examined individually, the difference in means was an improvement of 0.12 points with olanzapine alone (valid range from 0.00 to 0.25). No statistically significant difference was found for psychosis scores. Agitation scores were reduced by 0.19 points (valid range from 0.07 to 0.31). Risperidone improved global scores by 0.19 points (range from 0.00 to 0.38), psychosis scores by 0.2 points (range from 0.05 to 0.36), and agitation scores by 0.22 points (valid range from 0.09 to 0.35). The strength of evidence for olanzapine is moderate and for risperidone is high. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Summary of Benefits: Dementia Atypical antipsychotics, as a class, improve behavioral symptoms of dementia, although effect sizes are small in magnitude. This conclusion is supported with high strength of evidence. When examined individually, some, but not all, atypical antipsychotics demonstrate statistically significant differences from placebo for some outcomes. Aripiprazole and olanzapine improve scores on agitation subscales but not psychosis scores. The evidence for aripiprazole is low strength and for olanzapine it is moderate strength. Risperidone is superior to placebo on both agitation and psychosis subscales, a conclusion supported by high strength of evidence. The evidence for quetiapine is mixed and insufficient to permit conclusions. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Results: Atypical Antipsychotics for Major Depressive Disorder (1 of 2) Atypical antipsychotics have been studied for treatment of major depressive disorder (MDD), both as augmentation to selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) and as monotherapy. Aripiprazole, quetiapine XR, and combination therapy with olanzapine and fluoxetine are FDA approved for MDD. Remission and response to risperidone were measured with the HAM-D scale. One in every eight patients experience remission attributable to risperidone treatment, defined as a score less than 7 or 8 over two consecutive visits. The strength of evidence for this finding is moderate. One in every seven patients demonstrated response attributable to risperidone treatment, defined as at least a 50-percent reduction in the HAM-D score. The strength of evidence for this finding is moderate. Quetiapine XR was studied as a monotherapy using the MADRS for outcome assessment. Remission was 1.43-fold the rate achieved with placebo (95-percent confidence interval from 1.07 to 1.91). The response rate was 1.49-fold the rate with placebo (from 1.23 to 1.81). The strength of evidence for these findings is moderate. Olanzapine was studied as monotherapy, and the response and remission rates were determined based on the MADRS outcomes. No statistically significant difference between placebo and olanzapine monotherapy was found. The strength of evidence for this finding is moderate. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Summary of Benefits: Atypical Antipsychotics for Major Depressive Disorder Atypical antipsychotics increase the rate of response or remission when used to augment SSRIs and SNRIs. The strength of evidence for risperidone is moderate. In monotherapy, quetiapine XR improves remission and response rates when compared with placebo, but olanzapine does not show efficacy. The strength of evidence in support of these findings is moderate. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Results: Atypical Antipsychotics for Obsessive-Compulsive Disorder Atypical antipsychotics have been used to treat obsessive-compulsive disorder as augmentation of selective serotonin reuptake inhibitors and selective serotonin and norepinephrine reuptake inhibitors. In comparisons with placebo for response rate measured with the YBOCS in 3 trials with a total of 97 subjects, risperidone resulted in 1 of every 5 patients demonstrating an improved YBOCS score. The strength of evidence for this finding is moderate. In head-to-head trials of comparative effectiveness, olanzapine was compared with risperidone in 1 trial of 50 participants by using the YBOCS score. No statistically significant difference between treatments was detected. The strength of evidence for this finding is low. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Summary of Benefits: Atypical Antipsychotics for Obsessive-Compulsive Disorder Risperidone improves symptoms of obsessive-compulsive disorder when used as an adjunct to selective serotonin reuptake inhibitors (SSRIs) for patients whose symptoms are refractory to treatment. The strength of evidence in support of this finding is moderate. Olanzapine and risperidone are similar in effect for augmenting SSRIs. The strength of evidence in support of this finding is low. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Results: Atypical Antipsychotics for Post-traumatic Stress Disorder Atypical antipsychotics have been studied as treatment for post-traumatic stress disorder (PTSD). In the effectiveness review, the outcome analyzed was the difference between CAPS scores when compared with placebo. Risperidone was studied as a treatment for PTSD from all causes in 4 studies with a total of 151 patients. In a meta-analysis, the CAPS score was found to be 6.47 points lower with risperidone than with placebo, with the true effect lying in a range from 0.32 to 12.61 points lower. The strength of evidence for the finding is moderate. Three studies with a total of 124 patients with combat-related PTSD showed in a meta-analysis that the CAPS score was 7.95 points lower with risperidone (from 1.06 to 14.84 points lower). The strength of evidence for the finding is moderate. No summary result was produced for studies of abused women, and the strength of evidence for an effect of risperidone is insufficient for that indication. For olanzapine and quetiapine, no summary result was produced because of heterogeneity in studies, and the evidence is insufficient to permit conclusions. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Summary of Benefits: Post-traumatic Stress Disorder Adjunctive treatment with risperidone reduces the symptoms of combat-related post-traumatic stress disorder (PTSD). The strength of evidence supporting this finding is moderate. As a treatment for abused women with PTSD, the evidence of benefits from risperidone is insufficient to determine an effect. The evidence for olanzapine and quetiapine is insufficient for analysis. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Results and Summary of Benefits: Atypical Antipsychotics for Generalized Anxiety Disorder The effect of quetiapine on response rate, as measured with the HAM-A, was studied in 3 trials with a total of 2,437 patients and used for meta-analysis. Response on the HAM-A was found to be 1.26-fold more likely with quetiapine than with placebo (lying in a range from 1.02- to 1.56-fold). The response rate of one in eight treated patients is attributable to quetiapine. The results from one study each of olanzapine and risperidone were not statistically significantly different from placebo, but the evidence is insufficient to permit conclusions about the effects of these treatments. The conclusion from evidence to date is that quetiapine improves symptoms of generalized anxiety disorder. The strength of evidence in support of this conclusion is moderate. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Results and Summary of Benefits: Atypical Antipsychotics for Bipolar Personality Disorder Of seven studies of bipolar personality disorder (BPD), four showed statistically significant beneficial effects. Two studies showed some efficacy of aripiprazole, but the strength of evidence is low. One study showed that olanzapine is efficacious at 5–10 mg/day but not at 2.5 mg/day. The strength of evidence for the finding is low. In summary, although there is some evidence for benefit from atypical antipsychotics for BPD, it is inadequate for a meta-analysis and conclusions about the statistical or clinical significance of the effect. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Results and Summary of Benefits: Atypical Antipsychotics for Eating Disorders (Anorexia Nervosa) Olanzapine was studied in 3 trials with a total of 84 patients, using body mass index (BMI) at 1 and 3 months as the outcome measure. No statistically significant difference between patients treated with olanzapine and those in the placebo group was detected. The strength of evidence in support of this finding is moderate. Likewise, quetiapine was studied in 1 trial of 27 patients, measuring BMI at 3 months as the outcome. No statistically significant difference between treated and control groups was detected. The strength of evidence for this finding is low. In conclusion, olanzapine and quetiapine do not increase BMI in patients with anorexia nervosa. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Results: Atypical Antipsychotics in Substance Abuse Treatment Atypical antipsychotics were studied for benefits as adjuncts to substance abuse treatment. In alcohol abuse studies, aripiprazole and quetiapine were compared with placebo, using the percentage of patients completely abstinent as the outcome measure. Three trials with a total of 386 patients were reviewed. No statistically significant difference between the treatment and control groups was found. The rate of abstinence with treatment lies between 2.8-fold greater with placebo to 5.7-fold greater with an atypical antipsychotic. The strength of evidence is moderate for aripiprazole and low for quetiapine. In cocaine abuse, olanzapine and risperidone were compared with placebo, using the ASI composite score as the outcome measure in 3 trials with a total of 129 patients. No statistically significant difference between the treatment and control groups was found. The score lies between 0.04 lower with treatment to 0.04 higher with treatment. The strength of evidence is low. For patients with either cocaine or opiate abuse, 1 study of 31 patients examined risperidone given as a 25 mg-per-week injection as an adjunct to methadone treatment. The ASI score was the measured outcome. No statistically significant difference between the treatment and control groups was found. The strength of evidence is low. In summary, atypical antipsychotics are not effective as adjuncts in treating substance abuse. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Results for Other Indications The evidence for efficacy of atypical antipsychotics is insufficient to permit conclusions for Tourette’s syndrome or insomnia. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Adverse Effects of Atypical Antipsychotics The reviewed data were restricted to reports in studies of off-label use of atypical antipsychotics. With the exception of dementia, which is associated with older age, the adverse effects observed were not expected to be influenced by the diagnosis. Evidence was analyzed for two separate groups: elderly patients with dementia and adults aged 18–64. The atypical antipsychotic clozapine was not included in the review; clozapine can only be prescribed in a system that requires weekly monitoring for bone marrow-suppression disorders before providing the drug. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Adverse Effects in Elderly Patients: Placebo Comparisons (1 of 3) A previously published meta-analysis combined the results from 15 placebo comparisons of aripiprazole, olanzapine, quetiapine, and risperidone comprising a total of 5,204 patients. The investigators found that, when compared with placebo, the risk of death in elderly patients (65 and older) with dementia was elevated during treatment with atypical antipsychotics. For every 100 patients, over a 10- to 12-week course of treatment, 1 death is attributable to the atypical antipsychotic. The strength of evidence for this finding is high. Typical antipsychotics are also associated with an increased risk of death among dementia patients, as revealed in a review of the literature reporting observational studies that was performed as part of the comparative effectiveness review. Twelve studies with a total of 310,752 patients were reviewed and found to demonstrate that there is an elevated risk of death with both atypical and typical antipsychotics when used to treat patients with dementia. The strength of evidence for this finding is moderate. References: Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005;294:1934-43. PMID: 16234500. Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Adverse Effects in Elderly Patients: Placebo Comparisons (2 of 3) A meta-analysis performed for the comparative effectiveness review shows that among elderly patients (65 and older), risperidone treatment is associated with an increased risk of cerebrovascular accidents and cardiovascular adverse events and that olanzapine is associated with an increased risk of cardiovascular adverse events. Four studies with a total of 1,852 participants examined cerebrovascular accidents associated with risperidone treatment, finding that when compared with placebo, 1 of every 53 patients treated with risperidone experiences a cerebrovascular accident. The strength of evidence in support of this finding is moderate. Six studies with a total of 2,767 participants examined cardiovascular adverse events associated with risperidone treatment, finding that when compared with placebo, 1 of every 34 patients treated with risperidone experiences a cardiovascular adverse event. The strength of evidence in support of this finding is moderate. Five studies with a total of 1,218 participants examined cardiovascular adverse events associated with olanzapine treatment, finding that when compared with placebo, 1 of every 48 patients treated with olanzapine experiences a cardiovascular adverse event. The strength of evidence in support of this finding is moderate. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Adverse Effects in Elderly Patients: Placebo Comparisons (3 of 3) In summary, a meta-analysis of placebo comparison studies yielded the following results: - Extrapyramidal symptoms are common with risperidone and olanzapine. - Atypical antipsychotics are associated with sedative effects and fatigue. - Atypical antipsychotics elevate the risk of urinary adverse effects in elderly patients (65 or older), but the evidence is too limited to permit conclusions about the degree of risk. No statistically significant difference in the rate of extrapyramidal symptoms was found in a meta-analysis of 4 studies of aripiprazole with a total of 1,080 participants. Extrapyramidal symptoms are found in 1 of 10 patients treated with olanzapine, as determined in 1 study of 242 participants. No statistically significant difference in the rate of extrapyramidal symptoms was found in a meta-analysis of 3 studies of quetiapine with a total of 609 participants. Extrapyramidal symptoms are found in 1 of 20 patients treated with risperidone, as determined in 5 studies with a total of 1,477 participants. The strength of evidence for the finding about extrapyramidal symptoms is moderate. Sedative effects were found in 1 of 16 patients treated with aripiprazole, in a meta-analysis of 4 studies of aripiprazole with a total of 1,080 participants. Sedative effects were found in 1 of 9 patients treated with olanzapine, as determined in 5 studies with a total of 1,218 participants. Sedative effects were found in 1 of 4 patients treated with quetiapine, as determined in 4 studies with a total of 799 participants. Sedative effects were found in 1 of 10 patients treated with risperidone, as determined in 5 studies with a total of 2,182 participants. The strength of evidence for findings about sedative effects is moderate. Fatigue was found in 1 of 22 patients treated with aripiprazole, in a meta-analysis of 3 studies of aripiprazole with a total of 872 participants. Fatigue was found in 1 of 34 patients treated with olanzapine, as determined in 3 studies with a total of 808 participants. Fatigue was found in 1 of 34 patients treated with quetiapine, as determined in 3 studies with a total of 569 participants. Fatigue was found in 1 of 34 patients treated with risperidone, as determined in 2 studies with a total of 517 participants. The strength of evidence for findings about fatigue is moderate. No statistically significant difference in weight gain was found in patients treated with aripiprazole, in a meta-analysis of 2 studies of aripiprazole with a total of 695 participants. Weight gain was found in 1 of 24 patients treated with olanzapine, as determined in 3 studies with a total of 808 participants. The strength of evidence for this finding is moderate. No statistically significant difference in weight gain was found in patients treated with quetiapine, as determined in 1 study of 236 participants. Weight gain was found in 1 of 24 patients treated with risperidone, as determined in 2 studies with a total of 517 participants. The strength of evidence for findings about weight gain is high. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Summary of Adverse Effects in Elderly Patients (1 of 2) Antipsychotics increase the risk of death in elderly patients (65 and older) with dementia. For atypical antipsychotics, the death of 1 in 100 patients can be attributed to the antipsychotic drug. The strength of evidence for this finding is high. Risperidone is associated with an increased risk of cerebrovascular accidents. One in 34 patients will experience a cerebrovascular accident attributable to risperidone. The strength of evidence for this finding is moderate. Both risperidone and olanzapine are associated with increased risk of cardiovascular adverse events. For every 53 patients treated, 1 cardiovascular adverse event will occur due to risperidone. For every 48 patients treated, 1 cardiovascular adverse event will occur due to olanzapine. The strength of evidence for these findings is moderate. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Summary of Adverse Effects in Elderly Patients (2 of 2) In elderly adults (65 and older), extrapyramidal symptoms are most common with risperidone and olanzapine. The strength of evidence for this finding is moderate. Atypical antipsychotics are associated with sedative effects and fatigue. The strength of evidence for this finding is moderate. Atypical antipsychotics elevate the risk of urinary adverse effects in elderly patients, but the evidence is too limited to permit conclusions about the degree of risk. The strength of evidence for this finding is low. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Adverse Effects in Adult Patients: Placebo Comparisons (1 of 2) The number of patients to be treated in order to observe an adverse effect attributable to the intervention is low for olanzapine, being one in every three patients. In contrast, 1 of 35 patients treated with aripiprazole show the adverse effect. The strength of evidence for this finding is high. Endocrine and other lab test abnormalities are not as frequently examined or detected as is weight gain, although statistically significant increases when compared with placebo control groups are measurable. A meta-analysis of 4 studies with a total of 1,387 participants treated with aripiprazole found that 1 of 35 treated patients experienced weight gain or appetite increase attributed to the drug treatment. In 11 studies with a total of 1,637 participants treated with olanzapine, 1 of 3 treated patients experienced weight gain or appetite increase attributed to the drug treatment. In 13 studies with a total of 4,733 participants treated with quetiapine, 1 of 16 treated patients experienced weight gain or appetite increase attributed to the drug treatment. In 4 studies with a total of 434 participants treated with risperidone, 1 of 21 treated patients experienced weight gain or appetite increase attributed to the drug treatment. The strength of evidence for these findings is high. No reports of the effects of ziprasidone on weight or appetite were presented. For the effects of atypical antipsychotics on endocrine and other metabolic lab tests, no reports of the effect of aripiprazole were presented. A meta-analysis of 2 studies with a total of 374 participants treated with olanzapine found that 1 of 12 treated patients demonstrated endocrine or other metabolic abnormalities attributable to treatment with the drug. A meta-analysis of 3 studies with a total of 1,440 participants treated with quetiapine found that 1 of 18 treated patients demonstrated endocrine or other metabolic abnormalities attributable to treatment with the drug. The strength of evidence for these findings is low. No reports for risperidone or ziprasidone were presented. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Adverse Effects in Adult Patients: Placebo Comparisons (2 of 2) In summary, sedation is measurable with the use of all atypical antipsychotics studied, and fatigue may also be found. The strength of evidence for this conclusion is moderate. Extrapyramidal symptoms not found in placebo-treated groups are found with aripiprazole, quetiapine, and ziprasidone. The strength of evidence for this conclusion is low. Extrapyramidal symptoms are found in 1 of 11 patients treated with aripiprazole, as determined from a meta-analysis of 5 studies with a total of 1,215 participants. No statistically significant difference in the rate of extrapyramidal symptoms is found with olanzapine, as determined from a meta-analysis of 3 studies with a total of 136 participants. Extrapyramidal symptoms are found in 1 of 36 patients treated with quetiapine, as determined from a meta-analysis of 7 studies with a total of 2,566 participants. No statistically significant difference in the rate of extrapyramidal symptoms was found with olanzapine, as determined from 1 study with 25 participants. Extrapyramidal symptoms are found in 1 of 24 patients treated with ziprasidone, as determined from a meta-analysis of 3 studies with a total of 482 participants. The strength of evidence for these findings about adverse event rates of extrapyramidal symptoms is low. Sedation is measurable with the use of all atypical antipsychotics studied. From a meta-analysis of 7 studies with a total of 1,630 participants, sedative effects attributable to aripiprazole are found in 1 of 8 patients treated. From a meta-analysis of 14 studies with a total of 1,805 participants, sedative effects attributable to olanzapine are found in 1 of 6 patients treated. From a meta-analysis of 18 studies with a total of 5,816 participants, sedative effects attributable to quetiapine are found in 1 of 3 patients treated. From a meta-analysis of 8 studies with a total of 626 participants, sedative effects attributable to risperidone are found in 1 of 11 patients treated. From a meta-analysis of 5 studies with a total of 604 participants, sedative effects attributable to ziprasidone are found in 1 of 6 patients treated. The strength of evidence for these findings is moderate. Fatigue is attributed to atypical antipsychotics. From a meta-analysis of 4 studies with a total of 1,387 participants, fatigue attributable to aripiprazole is found in 1 of 15 patients treated. From a meta-analysis of 7 studies with a total of 1,457 participants, fatigue attributable to olanzapine is found in 1 of 19 patients treated. From a meta-analysis of 13 studies with a total of 5,082 participants, fatigue attributable to quetiapine is found in 1 of 18 patients treated. From a meta-analysis of 4 studies with a total of 507 participants, no statistically significant difference in the rate of fatigue is observed. From a meta-analysis of 2 studies with a total of 180 participants, fatigue attributable to ziprasidone is found in 1 of 14 patients treated. The strength of evidence for these findings is moderate. In head-to-head comparisons with typical antipsychotics, extrapyramidal symptoms are less likely with aripiprazole or olanzapine than with typical antipsychotics. One study for each of these drugs was reviewed. The odds ratio for extrapyramidal symptoms with aripiprazole is 0.24, with a statistically valid range of 0.18 to 0.32. For olanzapine, the odds ratio for extrapyramidal symptoms is 0.28, with a statistically valid range from 0.23 to 0.33. The strength of evidence for these findings is low. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Summary of Adverse Effects in Adults (1 of 2) Antipsychotics in the atypical class generally promote weight gain in adults (ages 18–64) and in the elderly (ages ≥65), but olanzapine is associated with greater risk than typical or other atypical antipsychotics. For olanzapine, the number needed to harm is 3 versus 16–35 for other atypical antipsychotics. Some atypical antipsychotics (olanzapine in particular) are associated with endocrine and metabolic abnormalities, but the degree of increased risk is not clear. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Summary of Adverse Effects in Adults (2 of 2) The risk of extrapyramidal symptoms is elevated with aripiprazole (NNH = 11; akathisia, NNH =7), quetiapine (NNH = 36), and ziprasidone (NNH = 24) in adults (ages 18–64). The strength of evidence for these findings is low. The risks of extrapyramidal symptoms with olanzapine and aripiprazole are about one-fourth of the risks for adult patients taking typical antipsychotics. The strength of evidence for these findings is low. Atypical antipsychotics are associated with sedative effects and fatigue (sedation NNH = 3 for quetiapine, whereas others range from 6–11; fatigue NNH = 14–19) in adults. The strength of evidence for these findings is moderate. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Trends in Off-Label Use of Atypical Antipsychotics Since the FDA regulatory warning in 2005 about severe adverse events in the elderly (ages ≥65), the use of atypical antipsychotics for treating the elderly has declined. However, the statistical significance of the change is not known. Off-label use of atypical antipsychotics is higher in long-term care settings than in the community. No off-label use of the most recently approved atypical antipsychotics (asenapine, iloperidone, and paliperidone) has been reported in the literature. Risperidone, quetiapine, and olanzapine are the most commonly prescribed atypical antipsychotics for off-label indications. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Gaps in Knowledge The comparative effectiveness review revealed areas where the evidence is inadequate to answer many questions about the benefits and adverse effects of off-label use of atypical antipsychotics. The evidence is insufficient to understand the effects of age (with the exception of adverse effects in patients with dementia), race, ethnicity, and baseline severity of disease on outcomes of treatment for off-label indications. For most drugs and indications, there are too few studies to permit conclusions about dosage and duration of treatment. There are few head-to-head comparisons of atypical and typical antipsychotics, either within or between classes, for treating off-label indications. Adverse event reporting is not standardized, preventing global analysis and understanding of risks. Evidence about the effects of antipsychotics on endocrine function, metabolic, or blood glucose regulation is limited. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Conclusions (1 of 3) Atypical antipsychotics can improve behavioral symptoms of dementia, although the effect sizes are considered to be small in magnitude. Several atypical antipsychotics are approved for treating major depressive disorder, and additional members of the class show evidence of efficacy. - Risperidone (Strength of Evidence = Moderate) - Ziprasidone (Strength of Evidence = Low) - Quetiapine XR monotherapy (Strength of Evidence = Moderate) There is a growing evidence base for the efficacy of individual atypical antipsychotics in treating these disorders: - Obsessive-compulsive disorder: Risperidone (Strength of Evidence = Moderate) - Post-traumatic stress disorder (combat-related): Risperidone (Strength of Evidence = Moderate) - Generalized anxiety disorder: Quetiapine (Strength of Evidence = Moderate) - Borderline personality disorder: Aripiprazole and Olanzapine (Strength of Evidence = Low) Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Conclusions (2 of 3) The evidence for efficacy of atypical antipsychotics in treating borderline personality disorders is too limited to estimate benefits. Evidence is insufficient for treatment of Tourette’s syndrome in adults (ages 18–64). Evidence is stronger that atypical antipsychotics neither increase body weight in patients with anorexia nervosa nor do they reduce substance abuse. There is little evidence about optimal dosages or durations of treatment in off-label use. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • Conclusions (3 of 3) The risk of death in elderly patients (ages ≥65) is increased by both atypical and typical class antipsychotics. Adverse effects in both elderly and adult (ages 18–64) patients, not associated with age, include: - Increased risk of weight gain: more common and severe with olanzapine - Endocrine and metabolic abnormalities: risks are measurable but less certain - Sedative effects, fatigue - Extrapyramidal symptoms The possibility of urinary adverse effects in elderly patients has appeared in studies of the atypical antipsychotics. Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • What To Discuss With Your Patients and Their Caregivers Topics addressed in this summary can be presented in discussions with patients. These include: The potential benefits of antipsychotics for treating disorders that are not psychoses The risks of adverse effects, including irreversible harms, when antipsychotics are used The elevated mortality risk for elderly patients with dementia who take antipsychotics Patient and caregiver preferences and values regarding treatment Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.

Transcript

  • 1. Off-Label Use of Atypical Antipsychotics: An Update Prepared for:Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov
  • 2. Outline of Material  Introduction to atypical antipsychotics and prescribing for other than approved indications (off-label)  Systematic review methods  The clinical questions addressed by the comparative effectiveness review (CER)  Modes of statistical analysis and results reporting in the CER  Results of studies and evidence-based conclusions about effectiveness and adverse effects of atypical antipsychotics used off-label  Gaps in knowledge  What to discuss with patients and their caregiversMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 3. Introduction to Atypical Antipsychotics (1 of 4)  Antipsychotics can be classified into two categories, based on the timeline of their development, pharmacology, and anticipated adverse effects profiles:  Typical antipsychotics, also called conventional or first– generation antipsychotics  Atypical antipsychotics, also called second–generation antipsychotics  Typical antipsychotics were the first successful pharmacological treatments for primary psychotic disorders, such as schizophrenia.  Typical antipsychotics are associated with side effects that are difficult to manage and in some cases irreversible.  Atypical antipsychotics were developed in response to avoid these adverse effects.Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 4. Introduction to Atypical Antipsychotics (2 of 4)  By 2001, 95.9 percent of antipsychotics prescribed to new users were of the atypical class.  As of the date of this review, nine second-generation, atypical antipsychotic drugs have been approved by the U.S. Food and Drug Administration (FDA), some for indications other than primary psychoses.  Aripiprazole (Abilify®)  Asenapine (Saphris®)  Clozapine (Clozaril®, FazaClo®)  Iloperidone (Fanapt®)  Olanzapine (Zyprexa®)  Paliperidone (Invega®)  Quetiapine (Seroquel®)  Risperidone (Risperdal®)  Ziprasidone (Geodon®)Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 5. Introduction to Atypical Antipsychotics (3 of 4)  Several atypical antipsychotics are approved by the FDA for indications in addition to primary psychoses, including autism spectrum disorders, bipolar disorder, and major depressive disorder.  Aripiprazole (Abilify): bipolar mania  Olanzapine (Zyprexa): manic or mixed episodes of bipolar I  Quetiapine (Seroquel): bipolar mania and bipolar depression  Risperidone (Risperdal): manic or mixed episodes of bipolar I; irritability associated with autism  Prescribing of atypical antipsychotics has expanded beyond these approved indications.Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 6. Introduction to Atypical Antipsychotics (4 of 4)  The FDA prohibits manufacturers from advertising or promoting the use of pharmaceuticals for indications that have not been approved by the FDA. To do so is illegal.  Off-label prescribing by physicians is permitted.  What is known about the efficacy or comparative effectiveness, benefits, and adverse effects of atypical antipsychotics when prescribed for unapproved (off- label) indications?Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 7. Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development  Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others.  A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment.  The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The Summaries and the full report, with references for included and excluded studies, are available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 8. Rating the Strength of Evidence From the Comparative Effectiveness Review  The strength of evidence was classified into four broad categories:Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 9. Clinical Questions Addressed by the Comparative Effectiveness Review (1 of 2)  Clinical questions addressed by the comparative effectiveness review include:  What are the leading off-label uses of atypical antipsychotics in utilization studies? How have trends in utilization changed in recent years, including inpatient versus outpatient use? What new uses are being studied in trials?  What does the evidence show regarding the efficacy and comparative effectiveness of atypical antipsychotics for off-label indications?  How do atypical antipsychotic medications compare with other drugs, including first-generation antipsychotics, for off-label indications?Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 10. Clinical Questions Addressed by the Comparative Effectiveness Review (2 of 2)  What are the potential adverse effects and/or complications involved with off-label prescribing of atypical antipsychotics? How do they compare within the class and with other drugs used for the conditions?  What is the effective dose and time limit for atypical antipsychotics used in off-label indications?Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 11. Clinically Significant Outcomes of Interest in the Comparative Effectiveness Review (1 of 2)  A variety of validated assessment instruments are used to measure outcomes of treatment with atypical antipsychotics, both in practice and in clinical studies. Remission rates and changes in symptom severity are reported. Response rate is defined as the proportion of participants achieving a degree of improvement on a rating scale that was specified a priori. Indication Outcome Assessment Instruments Dementia BEHAVE-AD: Behavioral Pathology in Alzheimer’s Disease Rating Scale BPRS: Brief Psychiatric Rating Scale NPI: Neuropsychiatric Inventory Scale Major Depressive HAM-D: Hamilton Depression Rating Scale Disorder MADRS: Montgomery-Asberg Depression Rating Score Obsessive- YBOCS: Yale-Brown Obsessive Compulsive Scale Compulsive Disorder Eating Disorders BMI: body mass index Generalized Anxiety HAM-A: Hamilton Anxiety Rating Scale DisorderMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 12. Clinically Significant Outcomes of Interest in the Comparative Effectiveness Review (2 of 2)  A variety of validated assessment instruments are used to measure outcomes of treatment with atypical antipsychotics, both in practice and in clinical studies. Remission rates and changes in symptom severity are reported. Response rate is defined as the proportion of participants achieving an a priori-specified degree of improvement on a rating scale. Indication Outcome Assessment Instruments Personality Disorder SCL-90-R: Symptom Checklist 90 Revised (Borderline or Schizotypal) CGI-BPD: Clinical Global Impressions–BPD HAM-A HAM-D MADRS BPRS PANSS: Positive and Negative Symptoms Scale Post-traumatic Stress Disorder (PTSD) CAPS: Clinician Administered PTSD Scale Substance Abuse CCQ: Cocaine Craving Questionnaire ASI: Addiction Severity Index Tourette’s Syndrome YGTS: Yale Global Tic Severity CGI-I: Clinical Global Impressions–Improvement Insomnia Sleep quality and onsetMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 13. Adverse Effects of Interest in the Comparative Effectiveness Review  The adverse effect profiles of the atypical antipsychotics are not expected to vary according to indication (with the exception of dementia, which is associated with older age).  Patient age is expected to influence the adverse effect profiles.  Reported adverse events were evaluated according to age groups:  Adults 18–64 years of age  Elderly adults with dementia, aged 65 and older  Key adverse events of interest are:  Mortality  Weight gain  Endocrine disorders and diabetes  Cardiovascular events  Extrapyramidal symptoms  SedationMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 14. Summary of Study Characteristics Evaluated in the Effectiveness Review: PICOTS Framework  Population: adults  All indications for which the intervention does not have formal approval  Interventions: atypical antipsychotics  All formulations, routes of administration, and doses  Comparators: Other antipsychotics, other active interventions, placebo, or no active intervention  Outcomes:  Symptom response and remission, general health and quality of life  Key adverse effects: mortality, weight gain, endocrine abnormalities/ diabetes, cardiovascular events, extrapyramidal symptoms, and sedation  Timing: any time point, ranging from <6 weeks to months/years  Setting: All settings, including community-dwelling, nursing home, inpatient, Veterans Administration, and outpatientMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 15. Summary of Studies Included in the Comparative Effectiveness Review (1 of 2)  Studies of efficacy, effectiveness, benefits, and adverse effects of atypical antipsychotics as treatment for several off-label indications are reported in the clinical literature.  There are no reports of studies of off-label use of the newer atypical antipsychotics: asenapine, iloperidone, and paliperidone.  The atypical antipsychotic clozapine was not included in the review; clozapine can only be prescribed in a system that provides weekly monitoring for bone marrow- suppression disorders as a condition of receiving the treatment.Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 16. Summary of Studies Included in the Comparative Effectiveness Review (2 of 2)  Off-label indications of atypical antipsychotics that have been studied and reported in the clinical literature are:  Dementia  Major depressive disorder (MDD)  Obsessive-compulsive disorder (OCD)  Borderline personality disorder (BPD)  Post-traumatic stress disorder (PTSD)  Substance abuse  Eating disorders  Anxiety  InsomniaMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 17. Modes of Results Reporting and Statistical Analysis in the Comparative Effectiveness Review (1 of 2)  95% Confidence Interval: The range of statistically valid results that will include the true population mean in 95 of 100 repeated experiments.  Mean Difference (MD): The difference between treatment and comparison group means.  Standardized mean difference (SMD) is the mean difference expressed in units of standard deviations. It is a method for normalizing results to a uniform scale for pooled analysis, when different scales are used in trials.  For MD and SMD, the result is statistically significant (p < 0.05) when the 95% confidence interval does not include 0.0, which is the point of no difference between groups.  Relative Risk (RR): The ratio of the rate (absolute risk, probability) of an event in the treatment group to the rate of the event in the comparison group.  For RR, the result is statistically significant at p < 0.05 when the 95% confidence interval does not include 1.0, which is the point of equal risk for both groups.Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 18. Modes of Results Reporting and Statistical Analysis in the Comparative Effectiveness Review (2 of 2)  Absolute Risk Difference: The absolute value of the mathematical difference between the rates (risk) of an event in the treatment and comparison groups.  ARD = | ARC–ART |  Number Needed To Treat or Harm (NNT, NNH): The number of patients to be treated to observe benefit or harm in one patient more than seen in the comparison group. The number of patients to be treated in order to find a benefit or harm attributable to the intervention.  NNT or NNH = |ARC–ART|-1 for a benefit or adverse event, respectively  Number of attributable events per 1,000 = 1,000 x |ARC–ART|  Effect sizes of 0.20 or smaller were considered small, sizes of 0.50 and greater were considered large, and those between were considered moderate.Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 19. Results: Atypical Antipsychotics for Dementia Effect Size/Meta-analytic Result: SMD and 95% CI, With Strength of Evidence Total Score/ Strength Atypical Antipsychotics in Global of Placebo Comparisons Impressions Psychosis Agitation Evidence Atypicals as a Class High Combined result 0.17 (0.08, 0.25) 0.12 (0.04. 0.19) 0.20 (0.12, 0.27)  (18 studies, >4,578 patientsa) Olanzapine Moderate 0.12 (0.00, 0.25) NSD 0.19 (0.07, 0.31) (4 studies, > 840 patientsa)  Risperidone High 0.19 (0.00, 0.38) 0.20 (0.05, 0.36) 0.22 (0.09, 0.35) (6 studies, ≈2,213 patientsb)  SMD = Standardized mean difference: the difference between the post-treatment mean scores of treatment and control groups. The scores from a variety of assessment instruments were standardized to a common scale (standard deviations) for meta-analysis. 95% CI = 95-percent confidence interval: the range of statistically valid results; p ≥ 0.05 when the confidence interval crosses 0 (mean difference measures) or 1 (relative risk and odds ratios). NSD = no statistically significant difference ; a Estimated: One study of olanzapine did not report the number of patients. b Estimated: The exact number of patients receiving either risperidone or placebo was not provided for three multiple treatment comparisons .Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available atwww.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 20. Summary of Benefits: Dementia  Atypical antipsychotics, as a class, improve behavioral symptoms of dementia, although effect sizes are small.  Strength of Evidence = High  When examined individually, some, but not all, atypical antipsychotics demonstrate statistically significant differences from placebo for some outcomes.  Risperidone is superior to placebo on both agitation and psychosis subscales.  Strength of Evidence = High  Olanzapine improves scores on agitation subscales but not psychosis scores.  Strength of Evidence = ModerateMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 21. Results: Atypical Antipsychotics for Major Depressive Disorder (1 of 2) Atypical Outcome Result: NNT, SMD, and 95% CI SOE Augmentation of SSRIs/SNRIs Risperidone HAM-D One in every eight patients experienced remission attributable to Moderate remission rate risperidone treatment (score less than 7 or 8 over two visits).  (3 studies, 645 patients) HAM-D One in every seven patients responded with at least a 50% reduction Moderate response rate in score attributable to risperidone.  Monotherapy MADRS One in every 13 patients experienced remission attributable to Moderate Quetiapine XR remission rate olanzapine treatment (score less than 7 or 8 over two visits).  (5 studies, 2,454 patients) MADRS One in every six patients responded with at least a 50% reduction in Moderate response rate score attributable to quetiapine XR.  Olanzapine MADRS No statistically significant difference from placebo. Moderate (3 studies, >98 response and  patients)a remission rates 95% CI = 95-percent confidence interval; NNT = number needed to treat; SMD = standard mean difference; SNRI = selective serotonin and norepinephrine reuptake inhibitor; SOE = strength of evidence; SSRI = selective serotonin reuptake inhibitor; XR = extended release a The number of patients was not reported in one study. Aripiprazole, quetiapine XR, and combination therapy with olanzapine and fluoxetine are FDA approved for major depressive disorder.Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available atwww.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 22. Summary of Benefits: Atypical Antipsychotics for Major Depressive Disorder  Atypical antipsychotics increase the rate of response or remission when used as augmentation to SSRIs and SNRIs.  Risperidone: Strength of Evidence = Moderate  In monotherapy, quetiapine XR improves remission and response rates when compared with placebo, but olanzapine does not show efficacy.  Strength of Evidence = ModerateMDD = major depressive disorder; SNRI = selective serotonin and norepinephrine reuptake inhibitor; SSRIselective serotonin reuptake inhibitor; XR = extended releaseMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 23. Results: Atypical Antipsychotics for Obsessive-Compulsive Disorder  Atypical antipsychotics are studied as augmentation of SSRIs and SNRIs in treating obsessive-compulsive disorder. N Studies; Strength of Atypical Outcome N Participants Effect Size/Meta-analysis Result Evidence Augmentation of SSRIs/SNRIs, Placebo Comparisons One in every five patients demonstrated a YBOCS Moderate Risperidone 3; 97 response (improved YBOCS score) response rate  attributable to risperidone. Comparative Effectiveness for Augmentation Olanzapine Low No statistically significant difference Versus YBOCS score 1; 50  between olanzapine and risperidone. Risperidone SNRI = selective serotonin and norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitorMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 24. Summary of Benefits: Atypical Antipsychotics for Obsessive-Compulsive Disorder Risperidone improves symptoms of obsessive-compulsive  One in every five patients treated will show some benefit.  Strength of Evidence = Moderate Olanzapine and risperidone are similar in effect for  Strength of Evidence = LowMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 25. Results: Atypical Antipsychotics for Post- traumatic Stress Disorder Atypical Versus N Studies; Effect Size/Meta-analytic Result Strength of Placebo Outcome N Participants (95% Confidence Interval) Evidence 4; 151 Score is 6.47 points lower with risperidone Moderate (all causes) (from 0.32 to 12.61 lower)  Difference in 3; 124 Score is 7.95 points lower with risperidone Moderate Risperidone CAPS score (combat-related) (from 1.06 to 14.84 lower)  Insufficient (abused women) No summary result  Difference in Insufficient Olanzapine CAPS score (all causes) No summary result  Difference in Insufficient Quetiapine CAPS score (all causes) No summary result  PTSD = post-traumatic stress disorderMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 26. Summary of Benefits: Post-traumatic Stress Disorder  Adjunctive treatment with risperidone reduces the symptoms of combat-related post-traumatic stress disorder (PTSD).  Strength of Evidence = Moderate  The evidence for benefits of risperidone as treatment of abused women with PTSD is insufficient to determine an effect.  Strength of Evidence = Insufficient  The evidence for olanzapine and quetiapine is insufficient for analysis.  Strength of Evidence = InsufficientMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 27. Results and Summary of Benefits: Atypical Antipsychotics for Generalized Anxiety Disorder Quetiapine improves symptoms of generalized anxiety disorder. N Studies; Strength of Atypical Outcome N Participants Result (95% CI) Evidence • Response is 1.26-fold more likely HAM-A with quetiapine than with placebo Moderate Quetiapine percent 3; 2,437 (from 1.02- to 1.56-fold).  responding • Response in 1 in 8 treated patients is attributable to quetiapine. HAM-A Insufficient Olanzapine percent 1; 24 NSD responding  Risperidone HAM-A NSD Insufficient percent 1; 417  responding 95% CI = 95-percent confidence interval; NSD = no statistically significant differenceMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 28. Results and Summary of Benefits: Atypical Antipsychotics for Bipolar Personality Disorder  Of seven studies of bipolar personality disorder (BPD), four showed statistically significant beneficial effects.  Aripiprazole:  Two studies: Strength of Evidence = Low  Olanzapine:  One study: Efficacious at 5–10 mg/day but not at 2.5 mg/day.  Strength of Evidence = Low  Quetiapine:  One study: Strength of Evidence = Insufficient  In summary, although there is some evidence for benefit from atypical antipsychotics for BPD, it is inadequate for a meta- analysis and conclusions about the statistical or clinical significance of the effect.Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 29. Results and Summary of Benefits: Atypical Antipsychotics for Eating Disorders (Anorexia Nervosa) Olanzapine and quetiapine do not increase BMI in patients with anorexia nervosa. N Studies; Strength of Atypical Outcome N Participants Result and 95% CI Evidence NSD BMI at 1 3; 84 (BMI may lie in a range from 0.56 month Olanzapine kg lower to 0.57 kg higher) Moderate  NSD BMI at 3 3; 84 (BMI may lie in a range from 0.34 months kg lower to 0.84 kg higher) BMI at 3 NSD Low Quetiapine 1; 27 (BMI may lie in a range from 1.74  months kg lower to 1.54 kg higher) 95% CI = 95-percent confidence interval; BMI = body mass index; NSD = no statistically significant differenceMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 30. Results: Atypical Antipsychotics in Substance Abuse Treatment Atypical antipsychotics are not effective as adjuncts in treating substance abuse. No. Studies; Effect Size/Meta-analysis Summary Strength of Atypical Outcome No. Participants Result and 95% CI Evidence Alcohol Abuse Aripiprazole NSD: The rate of abstinence with Moderate Percentage  treatment lies between 2.8-fold more completely 3; 386 Quetiapine with placebo to 5.7-fold more with an Low abstinent atypical antipsychotic.  Cocaine Abuse ASI NSD: The score lies between 0.04 Low Olanzapine, composite 3; 129 lower with treatment to 0.04 higher  Risperidone score with treatment. Cocaine or Opiate Abuse Risperidone NSD: The rate of reports of cocaine ASI Low (with and opiate use did not differ composite 1; 31  methadone between risperidone at 2 or 4 mg score treatment) and placebo. 95% CI = 95-percent confidence interval; BMI = body mass index; NSD = no statistically significant differenceMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 31. Results for Other Indications  The evidence for efficacy of atypical antipsychotics is insufficient to permit conclusions for:  Tourette’s syndrome  InsomniaMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 32. Adverse Effects of Atypical Antipsychotics  The reviewed data were restricted to reports in studies of off-label use of atypical antipsychotics.  With the exception of dementia, which is associated with older age, the adverse effects observed were not expected to be influenced by the diagnosis.  Evidence was analyzed for two separate groups:  Elderly patients with dementia  Adults aged 18–64  The atypical antipsychotic clozapine was not included in the review; clozapine can only be prescribed in a system that requires weekly monitoring for bone marrow- suppression disorders before providing the drug.Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 33. Adverse Effects in Elderly Patients: Placebo Comparisons (1 of 3)  A previously published meta-analysis combined the results from 15 placebo comparisons of aripiprazole, olanzapine, quetiapine, and risperidone. The investigators found that, when compared with placebo, the risk of death in elderly patients (65 and older) with dementia was elevated during treatment with atypical antipsychotics.*  Typical antipsychotics are also associated with an increased risk of death among dementia patients, as revealed in a review of the literature reporting observational studies that was performed as part of the comparative effectiveness review. N Studies; Strength of Comparison N Participants Effect Size/Meta-analytic Result: NNH Evidence Death of 1 in every 100 patients (over a 10- Atypical Antipsychotics to 12-week course of treatment) is High 15; 5,204  vs. Placebo* attributable to treatment with an atypical antipsychotic. Typical and Atypical Moderate Elevated risk of death with both atypical Antipsychotics: 12; 310,752  and typical antipsychotics. Cohort Studies * Schneider LS, Dagerman KS, Insel P. JAMA 2005;294:1934-43. PMID:16234500. NNH = number needed to harm (the number of patients that need to be treated in order to find an adverse event attributable to the drug)Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 34. Adverse Effects in Elderly Patients: Placebo Comparisons (2 of 3)  A meta-analysis for the comparative effectiveness review shows that among elderly patients (65 and older):  Risperidone is associated with an increased risk of cerebrovascular accidents and cardiovascular adverse events.  Olanzapine is associated with increased risk of cardiovascular adverse events. N Studies; Strength of Comparison N Participants Outcome Effect Size/Meta-analytic Result: NNH Evidence Risperidone vs. Cerebrovascular One in every 53 patients treated with Moderate 4; 1,852  Placebo accidents risperidone will experience CVAs. Risperidone vs. One in every 34 patients treated with Moderate 6; 2,767 Cardiovascular AE  Placebo risperidone will experience a cardiovascular AE. Olanzapine vs. One in every 48 patients treated with olanzapine Moderate 5; 1,218 Cardiovascular AE  Placebo will experience a cardiovascular AE. AE = adverse events; CVA = cerebrovascular accident; NNH = number needed to harm (the number of patients that need to be treated in order to find an adverse event attributable to the drug)Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 35. Adverse Effects in Elderly Patients: Placebo Comparisons (3 of 3) Meta-analytic Result: NNH (N Studies; N Participants) Adverse Event Aripiprazole Olanzapine Quetiapine Risperidone SOE NSD (4; EPSs 10 (1; 242) NSD (3; 609) 20 (5; 1,477) Moderate  1,080) Sedation 16 (4; 1,080) 9 (5; 1,218) 4 (4; 799) 10 (5; 2,182) Moderate  Fatigue 22 (3; 872) 34 (3; 808) 34 (2; 569) 34 (2; 517) Moderate  Weight Gain NSD (2; 695) 24 (3; 808) NSD (1; 236) 24 (2; 517) High  EPSs = extrapyramidal symptoms; NSD = no statistically significant difference; SOE = strength of evidence  In summary, a meta-analysis of placebo comparison studies yielded the following results:  In elderly adults, extrapyramidal symptoms are common with risperidone and olanzapine.  Strength of Evidence = Moderate  Atypical antipsychotics are associated with sedative effects and fatigue.  Strength of Evidence = Moderate  Data not shown: Atypical antipsychotics elevate the risk of urinary adverse effects in elderly patients (≥65), but the evidence is too limited to permit conclusions about the degree of risk.Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 36. Summary of Adverse Effects in Elderly Patients (1 of 2)  Antipsychotics increase the risk of death in elderly patients (65 and older) with dementia.  For atypical antipsychotics, the death of 1 in 100 patients can be attributed to the antipsychotic drug.  Strength of Evidence = High  Risperidone is associated with an increased risk of cerebrovascular accidents.  One in 34 patients will experience a cerebrovascular accident attributable to risperidone.  Strength of Evidence = Moderate  Both risperidone and olanzapine are associated with increased risk of cardiovascular adverse events.  For every 53 patients treated, 1 cardiovascular adverse event will occur due to risperidone.  For every 48 patients treated, 1 cardiovascular adverse event will occur due to olanzapine.  Strength of Evidence = ModerateMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 37. Summary of Adverse Effects in Elderly Patients (2 of 2)  In elderly adults (65 and older), extrapyramidal symptoms are most common with risperidone and olanzapine.  Strength of Evidence = Moderate  Atypical antipsychotics are associated with sedative effects and fatigue.  Strength of Evidence = Moderate  Atypical antipsychotics elevate the risk of urinary adverse effects (infections, incontinence) in elderly patients, but the evidence is too limited to permit conclusions about the degree of risk.  Strength of Evidence = LowMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 38. Adverse Effects in Adult Patients: Placebo Comparisons (1 of 2)  The number of patients to be treated in order to observe an adverse effect on weight or appetite that is attributable to the intervention is lowest for olanzapine, being one in every three patients. In contrast, 1 of 35 patients treated with aripiprazole show the adverse effect. The strength of evidence for this finding is high.  Endocrine and other lab test abnormalities are not as frequently examined or detected as is weight gain, although statistically significant increases when compared with placebo control groups are measurable. NNH (N Studies; N Participants*) Aripiprazole Olanzapine Quetiapine Risperidone Ziprasidone SOE Weight gain or 35 3 16 21 Insufficient High appetite (4; 1,387) (11; 1,637) (13; 4, 733) (4; 434)  increase Endocrine and Not 12 18 Not Not Low other metabolic Reported (2; 374) (3; 1,440) Reported Reported  lab test abnormalities * Adults 18–64 years of age. NNH = number needed to harm; SOE = strength of evidenceMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 39. Adverse Effects in Adult Patients: Placebo Comparisons (2 of 2)  As shown below, sedation is measurable with the use of all atypical antipsychotics studied, and fatigue may also be found.  Strength of Evidence = Moderate  Extrapyramidal symptoms not found in placebo-treated groups are found with aripiprazole, quetiapine, and ziprasidone.  Strength of Evidence = Low NNH (N Studies; N Participants*) Adverse Strength of Effect Aripiprazole Olanzapine Quetiapine Risperidone Ziprasidone Evidence EPSs 11 (5; 1,215) NSD (3; 136) 36 (7; 2,566) NSD (1; 25) 24 (3; 482) Low (Akathisia,  NNH = 7) Sedation 8 (7; 1,630) 6 (14; 1,805) 3 (18; 5,816) 11 (8; 626) 6 (5; 604) Moderate  Fatigue 15 (4; 1,387) 19 (7; 1,457) 18 (13; 5,082) NSD (4; 507) 14 (2; 180) Moderate * Adults 18–64 years of age. EPSs = extrapyramidal symptoms; NNH = number needed to harm; NSD = no statisticallysignificant differenceMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 40. Summary of Adverse Effects in Adults (1 of 2)  Antipsychotics in the atypical class generally promote weight gain in adults (ages 18–64) and in the elderly (ages ≥65), but olanzapine is associated with greater risk than other atypicals.  Olanzapine NNH = 3 versus NNH = 16–35 for other atypical antipsychotics  Strength of Evidence = High  Some atypical antipsychotics (olanzapine in particular) are associated with endocrine and metabolic abnormalities, but the degree of increased risk is not clear.  Strength of Evidence = LowMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 41. Summary of Adverse Effects in Adults (2 of 2)  The risk of extrapyramidal symptoms in adults (ages 18–64) is elevated with aripiprazole (NNH = 11; akathisia, NNH = 7), quetiapine (NNH = 36), and ziprasidone (NNH = 24)  Strength of Evidence = Low  The risks of extrapyramidal symptoms with olanzapine and aripiprazole are about one-fourth of the risks for adult patients taking typical antipsychotics.  Strength of Evidence = Low  In adults, atypical antipsychotics are associated with sedative effects and fatigue (sedation NNH = 3 for quetiapine, whereas others range from 6–11; fatigue NNH = 14–19).  Strength of Evidence = ModerateMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 42. Trends in Off-Label Use of Atypical Antipsychotics  Since the FDA regulatory warning in 2005 about severe adverse events in the elderly (ages ≥65), the use of atypical antipsychotics for treating the elderly has declined. However, the statistical significance of the change is not known.  Off-label use of atypical antipsychotics is higher in long- term care settings than in the community.  No off-label use of the most recently approved atypical antipsychotics (asenapine, iloperidone, and paliperidone) has been reported in the literature.  Risperidone, quetiapine, and olanzapine are the most commonly prescribed atypical antipsychotics for off-label indications.Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 43. Gaps in Knowledge  The evidence is insufficient to understand the effects of age (with the exception of adverse effects in patients with dementia), race, ethnicity, and baseline severity of disease on outcomes of treatment for off-label indications.  For most drugs and indications, there are too few studies to permit conclusions about dosage and duration of treatment.  There are few head-to-head comparisons of atypical and typical antipsychotics, either within or between classes, for treating off-label indications.  Adverse event reporting is not standardized, which prevents global analysis and understanding of risks.  Evidence about the effects of antipsychotics on endocrine function, metabolism, and blood glucose regulation is limited.Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 44. Conclusions (1 of 3)  Overall, a class effect of the atypical antipsychotics for each disorder cannot be assumed, and for most of these drugs, adequate supporting evidence for either efficacy or comparative effectiveness is still lacking for many indications.  Atypical antipsychotics can improve behavioral symptoms of dementia, although the effect sizes are considered to be small in magnitude.  Several atypical antipsychotics are approved for treating major depressive disorder, and additional members of the class show evidence of efficacy.  There is a growing evidence base for the efficacy of individual atypical antipsychotics in treating these disorders:  Obsessive-compulsive disorder  Post-traumatic stress disorder (combat-related)  Generalized anxiety disorderMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 45. Conclusions (2 of 3)  The evidence for efficacy of atypical antipsychotics in treating borderline personality disorders is too limited to estimate benefits.  Evidence is insufficient for treatment of Tourette’s syndrome in adults (ages 18–64).  Evidence is stronger that atypical antipsychotics neither increase body weight in patients with anorexia nervosa nor do they reduce substance abuse.  There is little evidence about optimal dosages or durations of treatment in off-label use.Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 46. Conclusions (3 of 3)  The risk of death in elderly patients (ages ≥65) is increased by both atypical and typical class antipsychotics.  Adverse effects in both elderly and adult (ages 18–64) patients, not associated with age, include:  Increased risk of weight gain: more common and severe with olanzapine  Endocrine and metabolic abnormalities: risks are measurable but less certain  Sedative effects, fatigue  Extrapyramidal symptoms  The possibility of urinary adverse effects in elderly patients has appeared in studies of the atypical antipsychotics.Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.
  • 47. What To Discuss With Your Patients and Their Caregivers  The potential benefits of antipsychotics for treating disorders that are not psychoses  The risks of adverse effects, including irreversible extrapyramidal symptoms, when antipsychotics are used  The trade-offs between benefits and risks for death and stroke for elderly patients (ages ≥65) with dementia, and considerations of nonpharmaceutical interventions that might be undertaken before instituting drug treatment  The likelihood of weight gain with these medicines and the implications for lifestyle changes that may be necessary  Patient and caregiver preferences and values regarding treatmentMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.