First-Generation Versus Second-Generation Antipsychotics in Adults: Comparative Effectiveness

1
First-Generation Versus Second-Generation
Antipsychotics in Adults Comparative
Effectiveness

• Prepared for
• Agency for Healthcare Research and Quality (AHRQ)
  
• www.ahrq.gov

2
Outline of Material

• 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

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

3
Introduction to First-Generation and
Second-Generation Antipsychotics (1 of 4)

• Antipsychotics can be classified into two
  categories based on the timeline of their
  development, pharmacology, and anticipated
  adverse effects profiles
• Firstgeneration antipsychotics (FGAs), also
  called conventional or typical antipsychotics
• Secondgeneration 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.

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

4
Introduction to First-Generation and
Second-Generation Antipsychotics (2 of 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.

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

5
Introduction to First-Generation and
Second-Generation Antipsychotics (3 of 4)

• 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.

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-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/anti
  psychotics-adult.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 Research
  Summaries and the full report, with references
  for included and excluded studies, are available
  at www.effectivehealthcare.ahrq.gov/antipsychotics
  -adult.cfm.

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

8
Rating the Strength of Evidence From the
Comparative Effectiveness Review

• The strength of evidence was classified into four
  broad categories

High ??? High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.
Moderate ??? Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate.
Low ??? Low confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of effect and is likely to change the estimate.
Insufficient ??? Evidence either is unavailable or does not permit a conclusion.

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-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
Clinical Questions Addressed by theComparative
Effectiveness Review (1 of 2)

• 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?

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

10
Clinical Questions Addressed by theComparative
Effectiveness Review (2 of 2)

• 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

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

11
Clinically Important Outcomes of Interestin the
Comparative Effectiveness Review (1 of 3)

• 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.

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

12
Clinically Important Outcomes of Interest in the
Comparative Effectiveness Review (2 of 3)
Indication Outcome Category Outcome Assessment Instruments for Schizophrenia
Schizophrenia Positive symptoms PANSS Positive and Negative Syndrome Scale SAPS Scale for the Assessment of Positive Symptoms
Schizophrenia Negative symptoms PANSS Positive and Negative Syndrome Scale SANS Scale for the Assessment of Negative Symptoms
Schizophrenia 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
Schizophrenia Global ratings and total scores BPRS Brief Psychiatric Rating Scale CGI-I Clinical Global ImpressionsImprovement Subscale CGI-S Clinical Global ImpressionsSeverity 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/anti
  psychotics-adult.cfm.

13
Clinically Important Outcomes of Interest in the
Comparative Effectiveness Review (3 of 3)
Indication Outcome Category Outcome Assessment Instruments for Bipolar Disorder
Bipolar Disorder Mood (mania) CARS-M Clinician-Administered Rating Scale for Mania YMRS Young Mania Rating Scale
Bipolar Disorder Mood (depression) CDS-S Calgary Depression Scale for Schizophrenia HAM-D Hamilton Depression Scale MADRS Montgomery-Asberg Depression Rating Scale
Bipolar Disorder Positive/negative symptoms PANSS Positive and Negative Syndrome Scale
Bipolar Disorder Sleep Number of awakenings, sleep efficiency (), time in rapid eye movement (REM) stage (min), total REM activity, and total sleep time (min)
Bipolar Disorder 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/anti
  psychotics-adult.cfm.

14
Adverse Effects of Interest in theComparative
Effectiveness Review

• Key adverse events of interest are
• Mortality
• Weight gain
• Endocrine disorders and diabetes
• Cardiovascular events
• Extrapyramidal symptoms
• Sedation

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

15
Summary of Study Characteristics Evaluated in the
Comparative Effectiveness Review PICOTS

• Population Adults 1864 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

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

16
Modes of Results Reporting and Statistical
Analysis in the Comparative Effectiveness Review

• 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 lt 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 lt 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.

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-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 First-Generation Antipsychotics (FGAs) in head-to-Head Comparison With Second-Generation Antipsychotics (SGAs) for Treating Schizophrenia Number of Studies First-Generation Antipsychotics (FGAs) in head-to-Head Comparison With Second-Generation Antipsychotics (SGAs) for Treating Schizophrenia Number of Studies First-Generation Antipsychotics (FGAs) in head-to-Head Comparison With Second-Generation Antipsychotics (SGAs) for Treating Schizophrenia Number of Studies First-Generation Antipsychotics (FGAs) in head-to-Head Comparison With Second-Generation Antipsychotics (SGAs) for Treating Schizophrenia Number of Studies First-Generation Antipsychotics (FGAs) in head-to-Head Comparison With Second-Generation Antipsychotics (SGAs) for Treating Schizophrenia Number of Studies First-Generation Antipsychotics (FGAs) in head-to-Head Comparison With Second-Generation Antipsychotics (SGAs) for Treating Schizophrenia Number of Studies
SGAs FGAs FGAs FGAs FGAs FGAs FGAs
SGAs Chlorpromazine Fluphenazine Haloperidol Perphenazine Trifluoperazine Thioridazine
Aripiprazole 8 1
Asenapine 1
Clozapine 12 11 1 1
Olanzapine 1 2 35 2
Quetiapine 1 1 11 1
Risperidone 1 39 2 1
Ziprasidone 1 9 1

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-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 SGAs PANSS 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 NSD no statistically significant difference in effect RCT randomized controlled trial SOE strength of evidence 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/anti
  psychotics-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) NSD ??? (2 RCTs)
95 CI 95-percent confidence interval MD mean difference RCT randomized controlled trial SOE strength of evidence 95 CI 95-percent confidence interval MD mean difference RCT randomized controlled trial SOE strength of evidence 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/anti
  psychotics-adult.cfm.

20
Comparative Effectiveness of Haloperidol and SGAs
for Treating Schizophrenia General
Psychopathology

• 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.

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 ???
Olanzapine NSD ??? (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)
Quetiapine NSD ??? (4 RCTs) CDS-S NSD ??? (2 RCTs)
Risperidone NSD ??? (20 RCTs) NSD ??? (2 RCTs) CDS-S NSD ??? (3 RCTs) YMRS NSD ??? (2 RCTs)
Ziprasidone ??? MADRS ??? Covi Anxiety Scale ???
Clozapine NSD ??? (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 95 CI 95-percent confidence interval NSD no statistically significant difference in effect MD mean difference RCT randomized controlled trial SOE strength of evidence 95 CI 95-percent confidence interval NSD no statistically significant difference in effect MD mean difference RCT randomized controlled trial SOE strength of evidence 95 CI 95-percent confidence interval NSD no statistically significant difference in effect MD mean difference RCT randomized controlled trial SOE strength of evidence 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/anti
  psychotics-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) NSD ??? (4 RCTs) Not available NSD ??? (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 95 CI 95-percent confidence interval NSD no statistically significant difference in effect MD mean difference RCT randomized controlled trial SOE strength of evidence 95 CI 95-percent confidence interval NSD no statistically significant difference in effect MD mean difference RCT randomized controlled trial SOE strength of evidence 95 CI 95-percent confidence interval NSD no statistically significant difference in effect MD mean difference RCT randomized controlled trial SOE strength of evidence 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/anti
  psychotics-adult.cfm.

22
Comparative Effectiveness of FGAs and SGAs for
Treating Schizophrenia Other Comparisons (1 of 2)

• 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.

• Lieberman JA, Stroup TS, McEVoy JP, et al. N Engl
  J Med 2005 Sep 22353(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/anti
  psychotics-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  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 ImpressionsImprovement Subscale MD mean difference PANSS Positive and Negative Syndrome Scale RCT randomized controlled trial SANS Scale for the Assessment of Negative Symptoms 95 CI 95-percent confidence interval BPRS Brief Psychiatric Rating Scale CGI-I Clinical Global ImpressionsImprovement 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/anti
  psychotics-adult.cfm.

24
Comparative Effectiveness of FGAs and SGAs for
Treating Schizophrenia Response and Remission
Rates

• 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.

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

25
Summary of Results FGAs Versus SGAs for Treating
Schizophrenia

• 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

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-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 First-Generation Antipsychotics in Head-to-Head Comparisons With Second-Generation Antipsychotics in Treatment of Bipolar Disorder First-Generation Antipsychotics in Head-to-Head Comparisons With Second-Generation Antipsychotics in Treatment of Bipolar Disorder First-Generation Antipsychotics in Head-to-Head Comparisons With Second-Generation Antipsychotics in Treatment of Bipolar Disorder First-Generation Antipsychotics in Head-to-Head Comparisons With Second-Generation Antipsychotics in Treatment of Bipolar Disorder First-Generation Antipsychotics in Head-to-Head Comparisons With Second-Generation Antipsychotics in Treatment of Bipolar Disorder
FGAs SGAs SGAs SGAs SGAs SGAs
FGAs Aripiprazole Olanzapine Quetiapine Risperidone Ziprasidone
Haloperidol 2 2 1 5 1

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

27
Results of Comparative Effectiveness Studies of
Antipsychotics as Treatment for Bipolar Disorder

• 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

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

28
Other Report Findings Functional Outcomes

• 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).

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

29
Other Report Findings Outcome Modifiers

• 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).

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

30
Comparative Adverse Effects

• 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.

• Abou-Setta AM, Mousavi SS, Spooner C, et al.
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

31
Gaps in Knowledge

• ?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.

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

32
Conclusions (1 of 3)

• 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).

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

33
Conclusions (2 of 3)

• 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

• Abou-Setta AM, Mousavi SS, Spooner C, et al. AHRQ
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/anti
  psychotics-adult.cfm.

34
Conclusions (3 of 3)

• 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.

• Abou-Setta AM, Mousavi SS, Spooner C, et al.
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/adul
  tantipsych.cfm.

35
What To Discuss With Patientsand Their Caregivers

• 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

• Abou-Setta AM, Mousavi SS, Spooner C, et al.
  Comparative Effectiveness Review No. 63.
  Available at www.effectivehealthcare.ahrq.gov/adul
  tantipsych.cfm.