Evidenced Based Pharmacotherapy for Schizophrenia

1
Evidenced Based Pharmacotherapy for Schizophrenia

• Stephen R. Marder, M.D.
• Director, VA Desert Pacific Mental Illness
  Research, Education, and Clinical Center
• Professor and Vice Chair
• Department of Psychiatry, UCLA

2
Evidence Based Treatment of Schizophrenia

• Definition of Evidence Based Medicine
• Levels of Evidence
• Guidelines, Algorithms, etc
• Choice of Antipsychotics
• High doses of Second Generation Drugs
• Side Effect Monitoring

3
Evidence-based practices

• Interventions for which there is consistent
  scientific evidence demonstrating that they
  improve outcomes

4
Evidence Based Medicine Why?

• Clinical experience is unable to differentiate
  small yet important differences between
  interventions
• Example Differences in death rates on
  thrombolytic agents for MI measured in the
  life/thousands
• Clinical experience
• Extremely influential and valuable when
  differences in interventions are great and
  differences are easily detected
• Can bias treatment selection towards a
  sub-optimal choice when differences in
  interventions are small and differences are not
  easily detected

5
Evidence Based Treatment of Schizophrenia

• Definition of Evidence Based Medicine
• Levels of Evidence
• Guidelines, Algorithms, etc
• Choice of Antipsychotics
• High doses of Second Generation Drugs
• Side Effect Monitoring

6
Levels of Evidence Therapies
1. Canadian Task Force on the Periodic Health
Examination The periodic health examination.
CMAJ 19791211193-1254. 2. Sackett DL. Rules of
evidence and clinical recommendations on use of
antithrombotic agents. Chest 1986 Feb 89 (2
suppl.)2S-3S. 3. Cook DJ, Guyatt GH, Laupacis A,
Sackett DL, Goldberg RJ. Clinical recommendations
using levels of evidence for antithrombotic
agents. Chest 1995 Oct 108(4 Suppl)227S-230S.
4. Yusuf S, Cairns JA, Camm AJ, Fallen EL, Gersh
BJ. Evidence-Based Cardiology. London BMJ
Publishing Group, 1998.
7
Levels of Evidence Therapies
1. Canadian Task Force on the Periodic Health
Examination The periodic health examination.
CMAJ 19791211193-1254. 2. Sackett DL. Rules of
evidence and clinical recommendations on use of
antithrombotic agents. Chest 1986 Feb 89 (2
suppl.)2S-3S. 3. Cook DJ, Guyatt GH, Laupacis A,
Sackett DL, Goldberg RJ. Clinical recommendations
using levels of evidence for antithrombotic
agents. Chest 1995 Oct 108(4 Suppl)227S-230S.
4. Yusuf S, Cairns JA, Camm AJ, Fallen EL, Gersh
BJ. Evidence-Based Cardiology. London BMJ
Publishing Group, 1998.
8
Evidence Based Treatment of Schizophrenia

• Definition of Evidence Based Medicine
• Levels of Evidence
• Guidelines, Algorithms, etc
• Choice of Antipsychotics
• High doses of Second Generation Drugs
• Side Effect Monitoring

9
Implementing evidence-based practice

• Practice guidelines - include expert opinion and
  literature reviews
• Recommendations (eg Schizophrenia Port) - lit
  reviews with recommendations based on evidence
• Algorithms (eg TMAP) - a set of rules for making
  clinical decisions
• Expert consensus guidelines - based on a survey
  of experts

10
Schizophrenia PORTSelected Recommendations (1995)

• Antipsychotics other than clozapine as first-line
  treatments for acute schizophrenia
• Dosage for acute symptoms should be 300-1000 cpz
  equivalents
• Maintenance therapy for at least 1 year after an
  episode
• Depot drugs for compliance problems
• Clozapine after failing 2 drugs from different
  classes

11
Schizophrenia PORTSelected Recommendations (cont)

• Adjunctive medications for persistent and
  significant anxiety, depression, manic-like
  symptoms
• Family interventions with education for pts with
  ongoing contact
• Voc Rehab and Assertive Community Treatment for
  appropriate pts

12
Conformance with PORT Recommendations
13
Quality of Care for Schizophrenia

• In patients at 2 public health settings, 38
  received poor quality medication management and
  52 had inadequate psychosocial care (Young et
  al, 1998).
• Surveys have found that PORT recommendations are
  frequently not followed in clinical settings.

14
Evidence Based Treatment of Schizophrenia

• Definition of Evidence Based Medicine
• Levels of Evidence
• Guidelines, Algorithms, etc
• Choice of Antipsychotics
• High doses of Second Generation Drugs
• Side Effect Monitoring

15
Important Unresolved Issues

• Is there a role for Conventional Antipsychotics?
• Are Second Generation Antipsychotics less likely
  to cause TD?
• How many failed trials before clozapine?
• How high a dose of newer drugs should be
  prescribed for refractory patients?
• Should antipsychotics be combined?

16
U.S. Anti-Psychotic Market1995 - 2000 Total
Sales
Million US
Source IMS Data MAT March 2000
17
Hopes for Second Generation Antpsychotics

• Greater efficacy
• Positive
• Negative
• Mood Symptoms
• More effective for refractory patients
• Lower risk of Extrapyramidal Side Effects and
  Tardive Dyskinesia
• Reduced risk of other side effects

18
Atypical Antipsychotics in the Treatment of
Schizophrenia Systematic Overview and
Meta-regression Analysis

• John Geddes, Senior Clinical Research Fellow
• Nick Freemantle, Reader in Epidemiology and
  Biostatistics
• Paul Harrison, Professor
• Paul Bebbington, Professor of Social and
  Community Psychiatry for the National
  Schizophrenia Guideline Development Group
• Geddes J, et al. BMJ. 20003211371-1376.

19
ConclusionsGeddes J, et al. BMJ.
20003211371-1376.

• Atypical antipsychotics have a similar effect on
  symptoms to conventional antipsychotics at an
  average haloperidol dose of 12 mg or equivalent.
• Atypical antipsychotics cause fewer EPS, but
  overall tolerability is similar to conventional
  drugs.
• Conventional agents should be first treatments
  except when EPS is a problem.

20
New Antipsychotics and Haloperidol vs Placebo
Pooled DataMean BPRS Changes

• -0.4 -0.3 0.2 0.1 0 0.1 0.2 0.3
  0.4 0.5 r (95 CI)

Statistically significant. Data from Leucht S,
et al. Schizophr Res. 19993551-68.
21
New Antipsychotics vs Haloperidol Pooled
DataMean BPRS Changes

• -0.4 -0.3 0.2 0.1 0 0.1 0.2 0.3
  0.4 0.5 r (95 CI)

Statistically significant. Data from Leucht S,
et al. Schizophr Res. 19993551-68.
22
New Antipsychotics and Haloperidol vs Placebo
Pooled DataMean Change in Negative Symptoms

• -0.4 -0.3 0.2 -0.1 0 0.1 0.2 0.3
  0.4 0.5 r (95 CI)

Statistically significant. Data from Leucht S,
et al. Schizophr Res. 19993551-68.
23
New Antipsychotics vs Haloperidol Pooled
DataMean Change in Negative Symptoms

• -0.4 -0.3 0.2 -0.1 0 0.1 0.2 0.3
  0.4 0.5 r (95 CI)

Statistically significant. Data from Leucht S,
et al. Schizophr Res. 19993551-68.
24
New Antipsychotics vs HaloperidolPooled
DataUse of Anticholinergic Medication

• -0.4 -0.3 0.2 -0.1 0 0.1 0.2 0.3
  0.4 0.5 r (95 CI)

Statistically significant. Data from Leucht S,
et al. Schizophr Res. 19993551-68.
25
Negative and Neurocognitive Symptoms

• Long-term functional outcome in schizophrenia is
  related to negative and neurocognitive symptoms.
• Although large studies have found statistically
  significant advantages for 2nd Generation
  Antipsychotics on negative symptoms, the effect
  sizes are very small.
• Patients with schizophrenia often perform 1 to 3
  standard deviations below the mean on
  neuropsychological tests. However, 2nd
  Generation Antipsychotics may improve performance
  by one-third to one-half a standard deviation

26
Haloperidol vs RisperidoneBPRS Scores
Between-group significance
Marder SR, et al. Presented at the Annual Meeting
of the ACNP, 1999.
27
Haloperidol vs Risperidone BPRS

Thinking disturbance


Anxiety/Depression

Withdrawal-Retardation


Hostile/Suspicious


Total

Within-group significance. Between-group
significance.
28
Haloperidol vs RisperidoneSCL-90 Ratings

Somatization

Obsessive-compulsive

Interpersonal sensitivity

Depression

Anxiety

Anger-hostility

Phobic anxiety

Paranoid ideation

Psychoticism

Global severity index
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
Haloperidol
Risperidone
Within-group significance. Between-group
significance. SCL-90 Symptom
Checklist-90. Marder SR et al. Presented at
Annual Meeting of ACNP, 1999.
29
Comparison of Patients Assigned toClozapine or
Haloperidol Treatment WithParticipation in
Psychosocial Treatment
60
50
40
Patients Participatingat Level 2 or Higher ()
30
20
Clozapine-treated patients
Haloperidol-treated patients
10
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Length of Treatment (months)
Rosenheck et al 1998
30
Olanzapine and quality of life results

F-test for treatment group from regression
model containing the terms treatment and
geographic region, p lt 0.05 vs. haloperidol
31
Risperidone vs HaloperidolRelapse Prevention in
Stable Patients
100
P0.001
80
Risperidone
60
Survival probability
Haloperidol
40
20
0
100
0
800
700
600
500
400
300
200
Days
Csernansky et al. N Engl J Med. 200234616.
32
Mount Sinai Consensus Conference on Antipsychotic
PrescribingSeptember 6, 2001

• Organizers
• Susan Essock
• Alexander Miller
• Steve Marder
• Participants
• Jeffrey Lieberman
• John Davis
• Bob Buchanan
• Nina Schooler
• John Kane

33
SHOULD CONVENTIONALS BE FIRST LINE?

• Second Generation Agents are preferred due to
  reduced EPS and TD risk
• Exceptions
• History of favorable response w/o EPS
• Need for long-acting med
• Failure on newer agents

34
Should antipsychotics be combined in poor
responders

• Level 1 1 RCT of adding sulpiride to clozapine.
• Level 2 Case series of adding risperidone or
  olanzapine to clozapine Case series of adding
  sulpiride to olanzapine
• Level 3 Case reports of success high rates of
  use

35
Is there sufficient evidence to conclude that
second generation antipsychotics are associated
with a lower risk of tardive dyskinesia?

• Mt Sinai consensus is yes!
• Clozapines low TD risk is well-established
• Good evidence that TD risk is lower with
  risperidone, olanzapine, and quetiapine
• This supports second line use of conventionals,
  particularly in elderly patients

36
What is the relative effectiveness of clozapine
and other second generation antipsychotics in
refractory patients?

• Meta-analysis indicates that effect sizes are
  larger for clozapine than other agents.
• Conley found that severely refractory inpatients
  who did poorly in an olanzapine trial had good
  response rates with clozapine
• Second generation antipsychotics were more
  effective than conventionals in most studies

37
Recommendations

• There is value in a trial of one or two second
  generation agents prior to clozapine
• Patients should not be considered poor responders
  or partial responders until they have received a
  clozapine trial.
• Clozapine is probably underutilized

38
Patient characteristics that should influence
drug choice

• The only established efficacy difference is
  clozapine for treatment refractory patients.
• There is suggestive evidence of newer drugs for
  negative symptoms and neurocognitive impairments.
• Patient preference should be considered.
• Other factors are all related to side effects

39
Department of Veterans Affairs Pharmacy Benefits
Management, Medical Advisory Panel and Mental
Health Strategic Healthcare GroupGuideline for
Atypical Antipsychotic Use

• Selection of therapy for individual patients is
  ultimately based on physicians assessment of
  clinical circumstances and patient needs. At the
  same time, prudent policy requires appropriate
  husbanding of resources to VA to meet the needs
  of all our veteran patients. These guidelines
  are not intended to interfere with clinical
  judgment. Rather, they are intended to assist
  practitioners in providing cost effective,
  consistent, high quality care. The following
  recommendations are dynamic and will be revised,
  as new clinical data become available.

40
Consensus Goals

• Prioritize the use of atypical antipsychotic
  medication for new antipsychotic medication
  starts and for patients not responding to or
  having problematic side effects on typical
  antipsychotic medication.
• Though differences in the clinical effectiveness
  and pharmacoeconomic profile of the atypicals
  have been suggested by some studies, there is no
  consensus in the literature to support one being
  globally superior to another therefore, once the
  physician determines there are no patient
  specific issues, begin therapy with an effective,
  less expensive agent. At the present time, this
  would lead to the preference of Quetiapine and
  Risperidone over Olanzapine.

41
Consensus Goals (cont.)

• Utilize current local approaches of clinical
  assessment to determine response to medication
  and whether medication changes are indicated.
  Such assessments should include the presence and
  severity of positive and negative symptoms, AIMS
  score, tremor, weight and GAF.
• For patients currently on Olanzapine, consider a
  trial of Risperidone or Quetiapine in the face of
  relapse or significant/problematic weight gain or
  other side effects.

42
Suggested Dosage Range for Treating Psychosis1

• Risperidone 2-8mg
• Quetiapine 200-800mg
• Olanzapine 5-25mg2
• Ziprasidone 40-160mg
• Clozapine 150-600mg
• 1May need to adjust for age, co-morbidities and
  other factors
• 2Based on anecdotal evidence, dosages at this
  upper level may be appropriate for some patients

43
First episode of psychosis or chronic psychosis
in relapse clinician assessment

• First line
• Risperidone OR
• Quetiapine
• (minimum trial of 6-8 weeks)

Maintain on medication
Response?
Yes
Response?
No

• Switch to
• Quetiapine OR
• Risperidone
• (minimum trial of 6-8 weeks)

44
Response?1
Maintain on medication
Yes
No

• Switch to
• Ziprasidone (minimum trial of 6-8 weeks)2
• Olanzapine (minimum trial of 6-8 weeks)
• Clozapine (minimum trial of 6-8 weeks)3

Maintain on medication
Response?1
Yes
No
1 Consider a trial of Haloperidol or
fluphenazine decanoate for patients
non-adherent to therapy. 2 Ziprasidone may be
considered in patients with significant
intolerance or poor response while taking another
atypical antipsychotic. See Ziprasidone criteria
for use at www.vapbm.org for contraindications to
using this drug. 3 Patient eligible for
Clozapine trial suboptimal response or adverse
events to 2 or more antipsychotics.
Switch to Typical antipsychotic if never
tried (minimum trial of 6-8 weeks)
OR Clozapine if never tried (trial for
6 months)
45
Evidence Based Treatment of Schizophrenia

• Definition of Evidence Based Medicine
• Levels of Evidence
• Guidelines, Algorithms, etc
• Choice of Antipsychotics
• High doses of Second Generation Drugs
• Side Effect Monitoring

46
High Dosing of the Atypicals
Percent of patients receiving high doses of
atypical agents in the New York Department of MHS
High Dose Threshold
April 1 June 30, 2000. Report by the Nathan
Kline Research Institute
47
High Dose Issues Risperidone

• Although originally approved up to 16 mg/day,
  current dosage recommendations are to rarely if
  ever dose above 6 mg, and best doses for
  psychosis may be around 4 mg
• Doses above 6 mg can increase risk of EPS without
  necessarily increasing antipsychotic efficacy

48
High Dose Issues Olanzapine

• Clinical experience suggests increasing efficacy
  without much increase in EPS within the dosing
  range (10 to 20 mg) in some patients
• Clinical experience also suggests that efficacy
  may increase in some patients when doses
  increased from 20 up to 40 60 mg/day, especially
  in patients with only partial responses but no
  side effects at 20 mg/day
• However, costs may increase to over 40 per day
  in high dose range

49
High Dose Issues Quetiapine

• Trends are towards progressive increase in doses
  within approved range (up to 800 mg/day) with
  corresponding improvement in antipsychotic
  efficacy without significant increase in side
  effects
• No known literature reports of safety or efficacy
  above 800 mg/day
• Anecdotal cases of improved efficacy and adequate
  safety in several cases up to 1600 mg/day

50
SUMMARY Where do high doses fit?

• Give adequate trials at therapeutic doses prior
  to switching or dosing beyond the therapeutic
  range
• Maximal therapeutic benefit may not occur until
  many weeks treatment
• If there is a partial response without side
  effects, high doses could be used after
  considering trials of another atypical
  antipsychotic at therapeutic doses
• Using high doses of olanzapine and quetiapine
  might be preferable to using high doses of
  risperidone and ziprasidone
• High doses with side effects and marginal
  therapeutic effects should consider other options
  including conventional or clozapine monotherapy

51
Evidence Based Treatment of Schizophrenia

• Definition of Evidence Based Medicine
• Levels of Evidence
• Guidelines, Algorithms, etc
• Choice of Antipsychotics
• High doses of Second Generation Drugs
• Side Effect Monitoring

52
Side effects of Second Generation Antipsychotics

• Weight gain
• - Glucose metabolism
• - Lipid metabolism
• Prolactin
• - Sexual dysfunction
• Sedation
• - Cognitive dysfunction
• Cardiovascular
• - QTc prolongation

53
Potential Consequences of QTcInterval
Prolongation
QTc prolongation
Torsade de Pointes arrhythmia
Syncope
Ventricular fibrillation
Sudden Death
54
Mean QTc Change at Steady-State Cmax
QTc (msec)
50
40
30
Mean Change (95 CI)
20
10
0
Hal 15 mg/day
Zip 160 mg/day
Olz 20 mg/day
Ris 68 mg/day
Que 750 mg/day
Thior 300 mg/day
Ris 16 mg/day
-10
Bazett correction used Metabolic inhibition did
not prolong the QTc interval with any drug
studied FDA Committee Recommends Approval for
Zeldox (Ziprasidone) for Schizophrenia. Press
release, Pfizer Inc., July 20, 2000
55
Estimated Weight Gain at 10 Weeks on Standard
Dose
15
10
5
Weight Gain (lbs)
0
-5
-10
Placebo
Sertindole
Molindone
Ziprasidone
Clozapine
Fluphenazine
Olanzapine
Haloperidol
Polypharmacy
Risperidone
Thioridazine
Chlorpromazine
Nonpharmacy control
D. B. Allison et al. American J of Psych 1999
56
Side Effects of Newer Antipsychotic Drugs
ZIP
QTP
OLZ
RIS
CLZ
DAs
?
?
? to ??
?
???
? to ???
Anticholinergic
? to ?
0 to ?
? to ?
? to ??
0 to ?
? to ???
Extrapyramidal
?
??
?
??
???
? to ???
Orthostatic hypotension
QTc prolongation
??
?
?
?
???
? to ???
57
Side Effects of Newer Antipsychotic Drugs
(Contd)
0
?
?
?
??
?? to ???

??
??
?
???
? to ???
? ?
?
?
???
0
0

??
??
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? to ??
???
58
What should a clinician monitor?

• For efficacy?
• Side effects
• EPS for each visit except for quetiapine and
  clozapine.
• TD with AIMS or other instruments at baseline and
  yearly
• Weight and BP every visit for 3 mos
• Blood glucose, cholesterol, triglycerides
  baseline and yearly

59
What should a clinician monitor? (cont)

• For patients with cardiac risk factors, EKG at
  baseline and steady state for ziprasidone
• Sexual side effects every 3 months
• Lens exam for quetiapine?
• Patients at risk for diabetes fasting glucose
  and hemoglobin A1C every 3 mos after starting a
  second generation agent (except ziprasidone)

60
Interventions supported by evidence

• Drug choice
• Second generation drugs for first episode and
  elderly
• Clozapine after failure of two agents
• Differences between older and newer drugs may be
  in negative symptoms, cognition, subjective
  responses

61
Interventions supported by evidence (cont)

• There is very little evidence supporting
  combinations of antipsychotics
• Depending upon the antipsychotic prescribed,
  clinicians should be prepared to monitor TD, EPS,
  weight, blood pressure, EKG, sexual side effects,
  prolactin side effects, glucose control,
  cholesterol, triglycerides

62
Promising pharmacological treatments

• Augmentation strategies
• Long-acting second generation drugs
• Newer antipsychotics

63
Change in Negative and Cognitive Symptoms, During
Treatment with Glycine (60 g per day) Added to
Conventional or Atypical Antipsychotic Drugs
Javitt et al., 2001
64
RISPERDAL CONSTAMean Active Moiety
Concentrations
Focused sampling Oral (n 21)

Focused sampling Consta (n 21)
ng/ml
Day
Consta 25 mg every 2 weeks
RIS-INT-32 Data on file, Janssen Pharmaceutica
Products, L.P.
65
IloperidoneProposed Mechanism of Action

• Mixed 5-HT2A/D2 antagonist
• High affinity for 5-HT6 and 5-HT7 receptors
• Higher affinity for 5-HT2A than for 5-HT2C
  receptor
• High affinity for alpha-1 receptors
• Balance of activity at dopaminergic and
  serotonergic receptors

Szewczak MR et al. J Pharmacol Exp Ther. 1995
Sep274(3)1404-1413.
66
Aripiprazole Pharmacology Summary

• Potent partial agonist of D2 dopamine receptors
• Antagonist under conditions of high dopaminergic
  activity (eg, psychotic symptoms)
• Agonist when too little dopamine is present (low
  EPS)
• Potent antagonist of 5-HT2A serotonin receptors
• Potent partial agonist at 5-HT1A serotonin
  receptors

67
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