1. First-Generation Versus Second- Generation Antipsychotics in Adults: Comparative Effectiveness Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov

2.  Introduction to first-generation and second-generation antipsychotics  Systematic review methods  The clinical questions addressed by the comparative effectiveness review  Results of studies and evidence-based conclusions about the comparative effectiveness and adverse effects of antipsychotics  Gaps in knowledge  What to discuss with patients and their caregivers Outline of Material Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

3.  Antipsychotics can be classified into two categories based on the timeline of their development, pharmacology, and anticipated adverse effects profiles:  First–generation antipsychotics (FGAs), also called conventional or typical antipsychotics  Second–generation antipsychotics, also called atypical antipsychotics  The FGAs were the first successful pharmacological treatments for primary psychotic disorders, such as schizophrenia.  In addition to schizophrenia, antipsychotics have been approved by the U.S. Food and Drug Administration for treating bipolar disorder. Introduction to First-Generation and Second- Generation Antipsychotics (1 of 4) Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

4.  First-generation antipsychotics (FGAs) are associated with side effects that are difficult to manage and, in some cases, are irreversible.  Examples are extrapyramidal symptoms and tardive dyskinesia.  Second-generation antipsychotics (SGAs) were developed with the intent of avoiding these adverse effects.  SGAs are not as strongly associated with neuromotor side effects as are FGAs, but they are associated with elevated risks for dyslipidemia, weight gain, metabolic syndrome, and diabetes mellitus. Introduction to First-Generation and Second- Generation Antipsychotics (2 of 4) Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

5.  Individuals taking antipsychotics of either class (first generation and second generation) may discontinue use because of adverse effects, lack of improvement in symptoms, or both.  A synthesis of the evidence from the clinical literature that directly compares the first-generation and second- generation antipsychotics may inform treatment choices that balance benefits and adverse effects for adults with psychosis, mania, or bipolar disorder. Introduction to First-Generation and Second- Generation Antipsychotics (3 of 4) Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

6. Introduction to First-Generation and Second- Generation Antipsychotics (4 of 4)  The first-generation antipsychotics included in the review are:  Chlorpromazine (Thorazine ® )  Fluphenazine (Permitil ®, Prolixin ® )  Haloperidol (Haldol ® )  Perphenazine (Trilafon ® )  Trifluoperazine (Stelazine ® )  Thioridazine (Mellaril ® )  As of the date of this review, nine second-generation antipsychotics have been approved by the U.S. Food and Drug Administration.  Aripiprazole (Abilify ® )  Asenapine (Saphris ® )  Clozapine (Clozaril ®, FazaClo ® )  Iloperidone (Fanapt ® )  Olanzapine (Zyprexa ® )  Paliperidone (Invega ® )  Quetiapine (Seroquel ® )  Risperidone (Risperdal ® )  Ziprasidone (Geodon ® ) Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

7.  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 Research Summaries and the full report, with references for included and excluded studies, are available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm. Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

8.  The strength of evidence was classified into four broad categories: Rating the Strength of Evidence From the Comparative Effectiveness Review Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm. Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Review. 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. Available at www.cc-ims.net/revman/other-resources/gradepro/gradepro.

9.  The comparative effectiveness review focused on the first-generation (FGAs) and second-generation (SGAs) antipsychotics used to treat adults (ages 18 to 64 years) with schizophrenia, schizophrenia-related psychoses, and bipolar disorder (all are approved indications).  Clinical questions addressed by the comparative effectiveness review include:  What are the comparative efficacy and effectiveness of FGAs versus SGAs for improving core illness symptoms?  What is the comparative effectiveness of FGAs versus SGAs for improving functional outcomes and decreasing utilization of the health care system? Clinical Questions Addressed by the Comparative Effectiveness Review (1 of 2) Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

10.  Clinical questions addressed by the comparative effectiveness review include:  Do first-generation (FGAs) and second-generation (SGAs) antipsychotics differ in medication-associated adverse effects and safety?  What is the comparative effectiveness of FGAs versus SGAs for outcomes other than core illness symptoms, such as:  Relapse and remission rates  Medication adherence  Patient insight  Health-related quality of life  Patient satisfaction Clinical Questions Addressed by the Comparative Effectiveness Review (2 of 2) Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

11.  A variety of validated assessment instruments are used to measure outcomes of treating schizophrenia and bipolar disorder with antipsychotics.  Assessment instruments are used 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 (specified a priori) on a rating scale.  The primary instruments used in the included studies and analyzed in the comparative effectiveness review are presented in the tables in the following slides. Clinically Important Outcomes of Interest in the Comparative Effectiveness Review (1 of 3) Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

12. Clinically Important Outcomes of Interest in the Comparative Effectiveness Review (2 of 3) Indication Outcome CategoryOutcome Assessment Instruments for Schizophrenia Schizophrenia Positive symptoms PANSS: Positive and Negative Syndrome Scale SAPS: Scale for the Assessment of Positive Symptoms Negative symptoms PANSS: Positive and Negative Syndrome Scale SANS: Scale for the Assessment of Negative Symptoms General psychopathology ABS: Agitated Behavior Scale ACES: Agitation-Calmness Evaluation Scale CDS-S: Calgary Depression Scale for Schizophrenia HAM-A: Hamilton Anxiety Scale HAM-D: Hamilton Depression Scale MADRS: Montgomery-Asberg Depression Rating Scale PANSS: Positive and Negative Syndrome Scale Global ratings and total scores BPRS: Brief Psychiatric Rating Scale CGI-I: Clinical Global Impressions – Improvement Subscale CGI-S: Clinical Global Impressions – Severity Subscale PANSS: Positive and Negative Syndrome Scale Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

13. Clinically Important Outcomes of Interest in the Comparative Effectiveness Review (3 of 3) IndicationOutcome CategoryOutcome Assessment Instruments for Bipolar Disorder Bipolar Disorder Mood (mania)CARS-M: Clinician-Administered Rating Scale for Mania YMRS: Young Mania Rating Scale Mood (depression)CDS-S: Calgary Depression Scale for Schizophrenia HAM-D: Hamilton Depression Scale MADRS: Montgomery-Asberg Depression Rating Scale Positive/negative symptoms PANSS: Positive and Negative Syndrome Scale SleepNumber of awakenings, sleep efficiency (%), time in rapid eye movement (REM) stage (min), total REM activity, and total sleep time (min) Global ratings and total scores BPRS: Brief Psychiatric Rating Scale CGI-BP: Clinical Global Impression-Bipolar Scale CGI-I: Clinical Global Impressions: Improvement Subscale PANSS: Positive and Negative Syndrome Scale Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

14.  Key adverse events of interest are:  Mortality  Weight gain  Endocrine disorders and diabetes  Cardiovascular events  Extrapyramidal symptoms  Sedation Adverse Effects of Interest in the Comparative Effectiveness Review Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

15.  Population: Adults 18 – 64 years of age with schizophrenia or related psychoses or with bipolar disorder  Interventions: Any currently available FDA-approved first-generation antipsychotic  Comparators: Any currently available FDA-approved second-generation antipsychotic  Outcomes:  Core illness symptom severity, remission, relapse, and response rates  Functional outcomes (e.g., employment, social functioning, legal system encounters)  Utilization of the health care system (e.g., length of hospitalization due to mental illness, rates of emergency department visits)  Adverse events  Timing: All follow-up periods; the last time point was assessed if multiple points were provided  Setting: All settings, including hospital and outpatient Summary of Study Characteristics Evaluated in the Comparative Effectiveness Review: PICOTS Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

16.  95-Percent Confidence Interval (95% CI): 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  For MD, the result is statistically significant (p < 0.05) when the 95% CI 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% CI does not include 1.0, which is the point of equal risk for both groups.  Clinically Significant Difference: At least a 20-percent difference between treatments on an individual assessment scale. Modes of Results Reporting and Statistical Analysis in the Comparative Effectiveness Review Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

17. Summary of Studies of Schizophrenia Included in the Comparative Effectiveness Review Studies of efficacy, effectiveness, and adverse effects of antipsychotics for the approved indication of schizophrenia were evaluated in the systematic comparative effectiveness review. Many different scales were used to assess outcomes, thus limiting the quantitative pooling of data in the comparative effectiveness review. First-Generation Antipsychotics (FGAs) in head-to-Head Comparison With Second-Generation Antipsychotics (SGAs) for Treating Schizophrenia: Number of Studies SGAs FGAs ChlorpromazineFluphenazineHaloperidolPerphenazine Trifluoperazin eThioridazine Aripiprazole 81 Asenapine 1 Clozapine 121111 Olanzapine 12352 Quetiapine 11111 Risperidone 13921 Ziprasidone 1 91 Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

18. Comparative Effectiveness of Haloperidol and SGAs for Treating Schizophrenia: Positive Symptoms Haloperidol and second-generation antipsychotics were compared for effectiveness in treating positive symptoms of schizophrenia. The assessment instruments commonly used were the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessment of Positive Symptoms (SAPS). No statistically significant difference in effect was noted in the studies that were evaluated. Haloperidol Compared With SGAsPANSS: SOE (N Studies)SAPS: SOE (N Studies) Aripiprazole NSD   (2 RCTs)  (1 RCT) Olanzapine NSD   (14 RCTs)NSD   (2 RCTs) Quetiapine NSD   (4 RCTs) Risperidone NSD   (20 RCTs)NSD   (2 RCTs) Clozapine NSD   (2 RCTs) NSD = no statistically significant difference in effect; RCT = randomized controlled trial; SOE = strength of evidence Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

19. Comparative Effectiveness of Haloperidol and SGAs for Treating Schizophrenia: Negative Symptoms Haloperidol and second-generation antipsychotics (SGAs) were compared for effectiveness in treating negative symptoms of schizophrenia. The assessment instruments that were commonly used are the Scale for the Assessment of Negative Symptoms (SANS) and the Positive and Negative Syndrome Scale (PANSS). When a statistically significant difference in effect was noted, the SGAs had a greater beneficial effect than haloperidol. Olanzapine specifically demonstrated a clinically significant greater benefit than haloperidol. Haloperidol Compared With SGAs PANSS: MD (95% CI) SOE (N Studies)SANS: MD (95% CI) SOE (N Studies) Aripiprazole MD = 0.8 (0.14, 1.46)   (3 RCTs)  Olanzapine MD = 1.06 (0.46, 1.67)   (14 RCTs)MD = 1.79 (1.57, 2.02)   (5 RCTs) Quetiapine NSD   (4 RCTs)  Risperidone MD = 0.60 (0.01, 1.20)   (20 RCTs)MD = 0.58 (0.37, 0.80)   (4 RCTs) Ziprasidone NSD   (3 RCTs) Clozapine NSD   (2 RCTs) 95% CI = 95-percent confidence interval; MD = mean difference; RCT = randomized controlled trial; SOE = strength of evidence Abou-Setta AM, Mousavi SS, Spooner C, et al. Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

20. Comparative Effectiveness of Haloperidol and SGAs for Treating Schizophrenia: General Psychopathology Haloperidol Compared With SGAs PANSS: MD (95% CI) SOE (N Studies) HAM-D: MD (95% CI) SOE (N studies) Other Tools: MD (95% CI) SOE (N Studies) Other Tools: MD (95% CI) SOE (N studies) Aripiprazole  OlanzapineNSD   (10 RCTs) 1.69 (1.41, 1.96)   (3 RCTs) MADRS: 2.46 (1.78, 3.14)   (6 RCTs) NSD   ABS (2 RCTs), ACES (2 RCTs), CDS-S (3 RCTs), HAM-A (2 RCTs) QuetiapineNSD   (4 RCTs) CDS-S: NSD   (2 RCTs) RisperidoneNSD   (20 RCTs)NSD   (2 RCTs) CDS-S: NSD   (3 RCTs) YMRS: NSD   (2 RCTs) Ziprasidone  MADRS  Covi Anxiety Scale  ClozapineNSD   (2 RCTs) 95% CI = 95-percent confidence interval; NSD = no statistically significant difference in effect; MD = mean difference; RCT = randomized controlled trial; SOE = strength of evidence Haloperidol and second-generation antipsychotics were compared for effectiveness in improving the general psychopathology of schizophrenia. The assessment instruments commonly used were the PANSS, the HAM-D, the HAM-A, the MADRS, the YMRS, the CDS-S, the ABS, and the ACES. Olanzapine demonstrated a clinically significant greater benefit than haloperidol. Abou-Setta AM, Mousavi SS, Spooner C, et al. Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics- adult.cfm.

21. Comparative Effectiveness of Haloperidol and SGAs for Treating Schizophrenia: Global Ratings/Total Scores Haloperidol and second-generation antipsychotics were compared for effectiveness in treating positive symptoms of schizophrenia. The assessment instruments commonly used were the PANSS, the BPRS, the CGI-I, and the CGI-S. Olanzapine demonstrated a clinically significant greater benefit than haloperidol. Haloperidol Compared With SGAs PANSS: MD (95% CI) SOE (N Studies) BPRS: MD (95% CI) SOE (N Studies) CGI-I: MD (95% CI) SOE (N Studies) CGI-S: MD (95% CI) SOE (N Studies) Aripiprazole NSD   (3 RCTs)NSD   (5 RCTs) Olanzapine MD = 2.31 (0.44, 4.18)   (14 RCTs) NSD   (13 RCTs)NSD   (2 RCTs)MD = 0.20 (0.07, 0.32)   (7 RCTs) Quetiapine NSD   (6 RCTs)NSD   (4 RCTs)NSD   (3 RCTs)Haloperidol: MD = 0.23 (0. 04, 0. 42)   (4 RCTs) Risperidone NSD   (20 RCTs)NSD   (13 RCTs)NSD   (3 RCTs)NSD   (8 RCTs) Ziprasidone NSD   (4 RCTs) Not availableNSD   (4 RCTs) Clozapine NSD   (3 RCTs)NSD   (4 RCTs)  95% CI = 95-percent confidence interval; NSD = no statistically significant difference in effect; MD = mean difference; RCT = randomized controlled trial; SOE = strength of evidence Abou-Setta AM, Mousavi SS, Spooner C, et al. Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

22.  The evidence is insufficient to permit conclusions from comparisons of fluphenazine with the second-generation antipsychotics (SGAs) and from the comparison of chlorpromazine with olanzapine, quetiapine, and ziprasidone.  The first-generation antipsychotic (FGA) perphenazine was compared to several SGAs in the well-known National Institute of Mental Health-sponsored CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) trial, which found no statistically significant differences in effectiveness between perphenazine and the SGAs. However, the evidence remains insufficient to permit conclusions about comparative effectiveness. Comparative Effectiveness of FGAs and SGAs for Treating Schizophrenia: Other Comparisons (1 of 2) Lieberman JA, Stroup TS, McEVoy JP, et al. N Engl J Med 2005 Sep 22;353(12):1209-23. PMID: 16172203. Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

23. Comparative Effectiveness of FGAs and SGAs for Treating Schizophrenia: Other Comparisons (2 of 2) The first-generation antipsychotic (FGA) chlorpromazine has been compared to the second-generation antipsychotic (SGA) clozapine in head-to-head trials. Clozapine yields better total scores than chlorpromazine when using the BPRS. All other comparisons of chlorpromazine and SGAs are insufficient to permit conclusions about comparative effectiveness. Chlorpromazine Versus Clozapine Total score Clozapine results in more improvement in BPRS scores (6 RCTs) MD = 8.4 (95% CI, 5.92 to 10.88)   CGI-I, PANSS, and SANS  Positive symptoms PANSS (1 RCT)  Negative symptoms SANS (1 RCT)  General psychopathology PANSS (1 RCT)  95% CI = 95-percent confidence interval; BPRS = Brief Psychiatric Rating Scale; CGI-I = Clinical Global Impressions – Improvement Subscale; MD = mean difference; PANSS = Positive and Negative Syndrome Scale; RCT = randomized controlled trial; SANS = Scale for the Assessment of Negative Symptoms Abou-Setta AM, Mousavi SS, Spooner C, et al. Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

24.  Few statistically significant differences in other outcomes (e.g., response and remission rates, health care system utilization) were found in comparisons of first-generation (FGAs) and second-generation (SGAs) antipsychotics.  In treating schizophrenia, risperidone yields better relapse rates and olanzapine provides better response and relapse rates when both antipsychotics are compared with haloperidol.  Strength of Evidence was not rated. Comparative Effectiveness of FGAs and SGAs for Treating Schizophrenia: Response and Remission Rates Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

25.  Few differences were found in comparisons of the first- generation antipsychotic haloperidol with the second- generation antipsychotics. Clinical significance, defined as at least a 20-percent difference between interventions on an individual scale, was rarely found.  When compared with haloperidol, olanzapine may provide clinically significant, greater improvement in negative symptoms (PANSS, SANS), total scores (PANSS), and measures of general psychopathology (HAM-D, MADRS).  Strength of Evidence = Moderate Summary of Results: FGAs Versus SGAs for Treating Schizophrenia Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

26. Summary of Studies of Bipolar Disorder Included in the Comparative Effectiveness Review Studies of efficacy, effectiveness, benefits, and adverse effects of antipsychotics for the approved indication of bipolar disorder were evaluated in the systematic comparative effectiveness review. Many different scales were used to assess outcomes, so the quantitative pooling of data in the comparative effectiveness review was limited. No trials compared the effectiveness of the first-generation antipsychotics (FGAs) fluphenazine, perphenazine, trifluoperazine and thioridazine with second-generation antipsychotics (SGAs). One trial compared chlorpromazine with clozapine. No trials compared the SGAs asenapine or clozapine with any FGA. First-Generation Antipsychotics in Head-to-Head Comparisons With Second-Generation Antipsychotics in Treatment of Bipolar Disorder FGAs SGAs AripiprazoleOlanzapineQuetiapineRisperidoneZiprasidone Haloperidol22151 Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

27.  No statistically significant difference in the assessment of mania, depression, or global impressions of bipolar disorder is noted in comparisons of haloperidol and aripiprazole.  Strength of Evidence = Low  No statistically significant difference in total score for mania assessment is found in comparisons of haloperidol with olanzapine or risperidone.  Strength of Evidence = Low  In bipolar disorder, haloperidol produces lower relapse rates than aripiprazole and provides better response rates than ziprasidone.  Strength of Evidence Not Rated Results of Comparative Effectiveness Studies of Antipsychotics as Treatment for Bipolar Disorder Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

28.  The variety of functional measures assessed across the studies prevents analysis and firm conclusions about comparative effectiveness for patient functioning (e.g., sleep characteristics, memory, verbal fluency, attention, neurocognitive testing). Other Report Findings: Functional Outcomes Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

29.  In treatment of schizophrenia, the most commonly performed subgroup analysis was for the effect of race on treatment resistance. No notable differences from the overall findings were found for subgroups.  For bipolar disorder, subgroup analysis was by disorder subtype. For bipolar 1 disorder, haloperidol was found to be more effective than ziprasidone for core illness symptoms (Young Mania Rating Scale and total score). Other Report Findings: Outcome Modifiers Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

30.  For most comparisons of first-generation antipsychotics (FGAs) with second- generation antipsychotics (SGAs), the evidence about the adverse events of greatest clinical importance (diabetes mellitus, tardive dyskinesia, metabolic syndrome, and mortality) is insufficient to permit conclusions about risk differences.  Diabetes Mellitus and Metabolic Syndrome  No statistically significant difference in risk of metabolic syndrome was found in comparisons of olanzapine and haloperidol.  Strength of Evidence = Low  Mortality  There are no significant differences in risk of mortality in comparisons of chlorpromazine and clozapine or between haloperidol and aripiprazole.  Strength of Evidence = Low  Antipsychotics have been shown to elevate mortality risk for elderly patients; however, the evidence examined for this report was insufficient to permit conclusions about differences in mortality risks between SGAs and FGAs in patient subgroups, including the elderly. Comparative Adverse Effects Abou-Setta AM, Mousavi SS, Spooner C, et al. Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics- adult.cfm.

31.  „Older adults, minorities, and the most seriously ill patients were under- represented in the studies, which were highly selective in patient enrollment. Thus, the studies reported here are more likely to show consistency of benefit and reduced risk of adverse effects.  The evidence about the influence of drug dose, formulation (e.g., long- acting injectable forms), polypharmacy, patient age, and comorbidities is inadequate for fully informed decisionmaking.  „„A consensus is needed on outcomes that demonstrate patient functioning and well-being using treatment goals that are important to patients.  More head-to-head trials are needed to compare currently approved first- generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) for treating bipolar disorder.  „„More studies are needed to evaluate long-term effectiveness and adverse effects of SGAs and FGAs. Gaps in Knowledge Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

32.  Few clinically important differences are found between first- generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) in core illness symptoms or response and remission rates in treating schizophrenia or bipolar disorder.  No class effects for either benefits or adverse effects of antipsychotics can be assumed based on the evidence to date.  The evidence base about comparative effectiveness and safety is inadequate for informed decisionmaking because of sparse data, imprecise effect estimates, and concerns about study usefulness (high risk of bias, wide variety of outcome measures). Conclusions (1 of 3) Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

33.  For treatment of schizophrenia, most head-to-head evaluations compared haloperidol with the second-generation antipsychotics and found no statistically or clinically significant differences.  Only olanzapine demonstrated a clinically significant advantage over haloperidol in improving negative symptoms, total scores, and the general psychopathology of schizophrenia.  Strength of Evidence = Moderate  For mania and mixed episodes of bipolar disorder, limited evidence suggests similar benefits from haloperidol and aripiprazole for mania, depression, and global scores, and olanzapine and risperidone are similar to haloperidol in effect on mania symptoms.  Strength of Evidence = Low Conclusions (2 of 3) Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/antipsychotics-adult.cfm.

34.  There is little evidence from head-to-head comparisons of first-generation antipsychotics and second-generation antipsychotics to estimate differences in risk for the most clinically important adverse effects: mortality, diabetes mellitus, tardive dyskinesia, and metabolic syndrome.  Clinical studies are still lacking to describe comparative long-term efficacy and safety, optimal dosage and duration of treatment, and risks and benefits in patient subpopulations. Conclusions (3 of 3) Abou-Setta AM, Mousavi SS, Spooner C, et al. Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/adultantipsych.cfm.

35.  The potential benefits of antipsychotics  The risks of adverse effects, including irreversible extrapyramidal symptoms, when antipsychotics are used  The effect of medications on other medical conditions and possible interactions with other medications  The trade-offs between benefits and adverse effects  „The roles antipsychotics may play as part of a broader treatment regimen  The importance of taking their medicine consistently and not discontinuing it without medical advice  Patient and caregiver preferences and values regarding treatment What To Discuss With Patients and Their Caregivers Abou-Setta AM, Mousavi SS, Spooner C, et al. Comparative Effectiveness Review No. 63. Available at www.effectivehealthcare.ahrq.gov/adultantipsych.cfm.