MEASURE Resource Module

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MEASURE Resource Module
 
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Approved/Unapproved Use

• The following presentation may contain
  information concerning a use that has not been
  approved by the US Food and Drug Administration.
  Any unlabeled/investigational discussion of drugs
  will be disclosed during the presentation.

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Safety of Atypical Antipsychotic Pharmacotherapy
for Bipolar Disorder
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Conventional vs Atypical AntipsychoticsSide-Effe
ct Profiles
Key 0 absent ? minimal mild
moderate severe TRZ Thioridazine HAL
haloperidol CLZ clozapine OLZ olanzapine
RIS risperidone QTP quetiapine ZIP
ziprasidone a Minimal weight gain in long-term
treatment.
Tandon R, Jibson MD.Psychoneuroendocrinology.
200328(suppl 1)9-26.
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Epidemiology of Obesity

• The prevalence of adults overweight, obese, or
  extremely obese in the US has increased in the
  last 5 years
• According to the National Heart, Lung, and Blood
  Institute
• Overweight adults have increased from 56 to 65
• Overweight a body mass index (BMI) of ? 25
  kg/m2 but lt 30 kg/m2
• Obese adults have increased from 23 to 31
• Obesity BMI of ? 30 kg/m2
• Extremely obese adults have increased from 3 to
  5
• Extreme obesity BMI of ? 40 kg/m2

Keck PE Jr, McElroy SL. J Clin Psychiatry.
2003641426-1435.
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Obesity Is Correlated WithImportant Clinical
Features in Bipolar I Disorder

• Obese BP I patients
• Experience greater number of lifetime depressive
  and manic episodes
• Present with more severe and difficult-to-treat
  index affective episodes
• Are more likely to develop an affective
  recurrence, in particular, depressive recurrence

Fagiolini A et al. Am J Psychiatry.
2003160112-117.
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Obesity and Bipolar DisorderMore Severe Disease

• Obesity
• Negative impact on general physical well-being
  and functioning
• Quality of life
• Self-esteem
• Psychological well-being
• Sleep apnea
• Disrupts sleep
• Causes or contributes to mood destabilization
• Bipolar disorder
• Increased risk of obesity due to medication
  exposure
• Disease-specific symptoms occur during depressive
  episodes
• Increased appetite
• Reduced energy expenditure

Fagiolini A et al. Am J Psychiatry.
2003160112-117.
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Issues and Considerations Pharmacotherapy-Relate
d Weight Gain in Bipolar Disorder

• Weight gain is an important clinical management
  dilemma
• Societys negative view of obesity
• Psychosocial sequelae
• Physical morbidity/mortality risks
• Cardiovascular and cerebrovascular disease risk
• Diabetes risk
• Comorbid weight-gain risks
• Weight loss is often difficult
• Potential relation to remitted depression

Nemeroff CB. J Clin Psychiatry. 200364532-539.
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Issues and Considerations Pharmacotherapy-Relate
d Weight Gain in Bipolar Disorder (cont.)

• No standard evaluative criteria
• Obesity not fully understood
• Long-term effects often underestimated
• Poor individual predictive value
• Management complacency
• Relationship to regimen adherence
• Need for drugs with more favorable safety
  profiles

Nemeroff CB. J Clin Psychiatry. 200364532-539.
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Olanzapine, Quetiapine, Risperidone, Ziprasidone,
Aripiprazole Mean Change From Baseline Weight
Olanzapine (12.517.5 mg) Olanzapine (117.5 mg)
Ziprasidone Aripiprazole
Quetiapine
Risperidone
14
30
Olanzapine (12.517.5 mg) Olanzapine (117.5
mg) Quetiapine
12
26
22
10
18
8
Change From Baseline Weight (lb)
Change From Baseline Weight (kg)
13
6
9
4
4
2
0
0
52
48
44
40
36
32
28
24
20
16
12
8
0
4
Weeks
Jones M et al. Poster. 2003 Marder SR. J Clin
Psychiatry. 2003641386-1387 Nemeroff CB. J
Clin Psychiatry. 199758(suppl 10)45-49 Sussman
N. J Clin Psychiatry. 2001625-12.
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Risk of TD With Antipsychotic Agents
Reports in previously neuroleptic-naïve patients
Personal Communication RM Trosch, MD. Friedman
JH. Psychoneuroendocrinology. 200328(suppl
1)39-51.
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Dose-Response Curve for Antipsychotic and EPS
Effects for Conventional and Atypical
Antipsychotics
EPS Effect for Different Agents
100
75
Different degrees of separation
Effect ()
Antipsychotic effect
(Normalized for all antipsychotics)
Quetiapine
50
neuroleptics
Olanzapine
Clozapine
Risperidone
25
Various
0
Dose (mg/kg)
Jibson MD, Tandon R. J Psychiatry Res.
199832215-228. Tandon R, et al. J Clin
Psychiatry. 199960(suppl 8)21-28.
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Relative Risk of Drug-Induced EPS From Combined
Data
In order of frequency (greatest to lowest)

• Typical antipsychotics
• High potency
• Mid-range potency
• Low potency
• Atypical antipsychotics
• Risperidone
• Ziprasidone
• Olanzapine
• Quetiapine
• Clozapine

Most Likely
Least Likely
Adapted from Caroff SN et al. J Clin Psychiatry.
200263(suppl 4)12-19.
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Food and Drug Administration Letter Requesting
Updated Product Labeling for All
AtypicalAntipsychotics (9/15/03)

• ...Hyperglycemia, in some cases extreme and
  associated with ketoacidosis or hyperosmolar coma
  or death, has been reported in patients treated
  with atypical antipsychotics.
• ...Increased attention to the signs and symptoms
  of diabetes mellitus may lead to earlier
  detection and appropriate treatment, and thus may
  reduce the risk for the most serious outcomes.
• Some differences in wording have been agreed to
  by the FDA and individual pharmaceutical
  manufacturers of atypical antipsychotics

Rosack J. Psychiatric News. 2003381-4.
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ADA Consensus on Antipsychotic Drugs

• Atypicals and Metabolic Abnormalities

increase effect no effect D
discrepant results.Newer drugs with limited
long-term data
American Diabetes Association. Diabetes Care.
200427596-601.
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ADA Consensus Monitoring Protocol

• (adapt to clinical status)

American Diabetes Association. Diabetes Care.
200427596-601.
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Cerebrovascular Adverse EventsRisperidone and
Olanzapine Warnings

• Cerebrovascular Adverse Events, Including Stroke,
  in Elderly Patients With DementiaCerebrovascular
  adverse events (eg, stroke, transient ischemic
  attack), including fatalities, were reported in
  patients (mean age 85 years range 7397) in
  trials of risperidone in elderly patients with
  dementia-related psychosis. In placebo-controlled
  trials, there was a significantly higher
  incidence of cerebrovascular adverse events in
  patients treated with risperidone compared to
  patients treated with placebo. Risperdal has not
  been shown to be safe or effective in the
  treatment of patients with dementia-related
  psychosis.
• Cerebrovascular Adverse Events, Including Stroke,
  in Elderly Patients With DementiaCerebrovascular
  adverse events (eg, stroke, transient ischemic
  attack), including fatalities, were reported in
  patients in trials of olanzapine in elderly
  patients with dementia-related psychosis. In
  placebo-controlled trials, there was a
  significantly higher incidence of cerebrovascular
  adverse events in patients treated with
  olanzapine compared to patients treated with
  placebo. Olanzapine is not approved for the
  treatment of patients with dementia-related
  psychosis.

Risperdal package insert. 2003.Zyprexa
package insert. 2004.
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Potential Health Disturbances With
Prolactin-Elevating Antipsychotic Agents
Men
Women

• Short-Term
• Loss of libido
• Erectile dysfunction
• Ejaculatory dysfunction
• Reduced spermatogenesis
• Gynecomastia
• Long-Term
• Decreased bone density
• Mediated by relative or absolute deficiency of
  testosterone
• Cardiovascular disease?
• Depression?

• Short-Term
• Menstrual disturbances
• Galactorrhea
• Breast engorgement
• Sexual dysfunction
• Infertility
• Long-Term
• Decreased bone density
• Mediated by relative or absolute deficiency of
  estrogen
• Cardiovascular disease?
• Cancer (breast, endometrial)?
• Depression?

? few data available
Maguire GA. J Clin Psychiatry. 200263(suppl
4)56-62.
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Antipsychotics and Prolactin
? few data available
Maguire GA. J Clin Psychiatry. 2002 63(suppl 4)
56-62.
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Prolactin Levels in Men Treated WithClozapine,
Olanzapine, Risperidone, orHaloperidola
50
Baseline


8 week period
40
14 week period
30
Mean Prolactin Level (ng/mL)
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10
0
n 22
n 15
n 12
n 22
n 18
n 14
n 25
n 19
n 16
n 23
n 21
n 20
Clozapine
Olanzapine
Risperidone
Haloperidol
aBars indicate standard deviations
P lt 0.05 vs baseline
Volavka J et al. J Clin Psychiatry.
20046557-61.
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Revised Nomenclature of Antipsychotic Agents
? few data available
Maguire GA et al. CNS News. 2003519-22.
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Management of Side Effects of Antipsychotic Drugs
Adapted from Zarate CA Jr. J Clin Psychiatry.
200061(suppl 8)52-61.