Atypical Antipsychotics:
Limited Benefit, Sizable Risk
Erika Pierce, PA-C, MMS
Elisabeth Fowlie Mock, MD, MPH
Learning Objectives
Upon completion of this activity, participants will be able to:
 Describe comparative effectiveness of antipsychotic
medications (APMs) for several conditions;
 Demonstrate knowledge of the risks associated with APM
use;
 Consider treatment alternatives for APMs;
 Safely initiate APM therapy for targeted indications;
 Screen and monitor for side effects of APMs.
Disclosures


Speakers
MICIS has no commercial ties with
manufacturers of the products discussed
– Co-author of the Maine Pediatric Supplement, Jeffrey Barkin, MD, had a financial interest with
pharmaceutical companies producing antipsychotic medications, terminated in May 2010.

Off-label use
– This presentation contains information about nonFDA approved uses of medications
Materials
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“Un-ad” (summary)
Evidence document
Pocket card
Patient brochures (2)
Pediatric supplement
Resource article available
Uses of Atypical Antipsychotics
Benefit > Risk
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Schizophrenia
Bipolar disorder
Aggression associated
with Autism
Risk > Benefit
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Depression
Behavior management
in dementia
PTSD
OCD
Aggression in nonautistic youth
Antipsychotic Prescription Trends,
1995-2008
Atypical Antipsychotic Drugs
(2nd Generation)
aripiprazole
clozapine
olanzapine
quetiapine
risperidone
ziprasidone
=
=
=
=
=
=
Abilify
Clozaril
Zyprexa
Seroquel
Risperadal
Geodon
asenapine*
iloperidone*
paliperidone*
=
=
=
Saphris
Fanapt
Invega
* Not yet studied adequately
in primary care associated
conditions
Antipsychotic Prescription Trends

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Aggressive promotion has caused the atypical
APMs to be widely used for common conditions.
Primary care providers prescribe 20% of all APMs
in the U.S.
Prescriptions of APMs increased by more than
50% between 2001 and 2008
Antipsychotic Prescriptions
in Primary Care
U.S. Medication Expenditure
Antipsychotics Rank:
#5
2010 Spending
$10 billion (FDA
indicated use)
$6 billion
(off label use)
Adverse Effects of Antipsychotics
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weight gain
adverse metabolic effects (*independent of weight gain)
extra pyramidal symptoms (EPS)
QTc prolongation
sedation
Refer to pocket card
or “un-ad” pg 3
orthostasis
anticholinergic toxicity
prolactin elevation
neuroleptic malignant syndrome
mortality
Side Effects of Atypical Antipsychotics:
Shift in Risk Perception
Prior Safety Concerns
Current Safety Concerns
Diabetes
Neurologic Side Effects
Weight
Gain
EPS + TD
Weight
Gain
Dyslipidemia
Insulin
Dependence
CVD
QTc
Hyperglycemia
Hyperglycemia
CVD
Insulin
Resistance
EPS
QTc
Dyslipidemia
Depression
Depression


APMs FDA approved for augmentation
APMs effective in studies
BUT risk > benefit
and
multiple safer alternatives available
Source: American Psychiatric Association, 2010
Depression Treatment Reality
(≥50% ↓ in sxs)
Data Source: Archives of General Psychiatry, 1998.
Depression and APM Augmentation
31%
(≥50% ↓ in sxs)
17%
(≥50% ↓ in sxs)
Data Source: American Journal of Psychiatry, 2009.
Depression
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1st establish diagnosis
Then use
– Non-pharmacologic therapy
(psychotherapy, cognitive behavioral therapy)
– first line antidepressants
– second & third line antidepressants
– augmentation, combinations or ECT
Depression Treatment Algorithm “STAR-D”
Depression and APMs
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Consider after multiple other options attempted
Use as augmentation (not monotherapy)
Balanced assessment of risks and benefits
Consider psychiatry referral for treatment resistant
depression
Augmentation doses should be significantly LOWER
than doses for other serious psychiatric disease
Consider finite time-frame for use (6 months)
Dementia
Dementia Syndromes: Behavioral Management
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OFF-LABEL USE
Prescribed in up to 15% of nursing home
patients
Ongoing use likely related to:
– High level promotion by Pharma
– Growing number of patients dx’d with dementia
– Increasing need for behavioral management
– Lack of safe & effective alternatives
Nursing Home Patients Rx’d an APM
23%
51%
w/ aggressive
behavioral
problems
40%
w/ non-aggressive
behavioral problems
w/ NO
behavioral
problems
Evidence of Inappropriate Marketing
Company
Drug
Settlement
Date
Eli Lilly
Zyprexa
$1.4 billion
1/15/09
Pfizer
Geodon
$300 million
9/2/09
Astra-Zeneca
Seroquel
$68 million
3/10/11
J&J/Janssen
Risperdal
$1.8 billion *not finalized 3/12/12
Abbott
Depakote**
$100 million
**not an APM
5/7/12
Black Box – APM + Dementia
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APMs increase relative risk of death by 70%
(4.5% vs 2.6% in placebo)

Risk of death higher for 1st generation APMs

.
100
patients rx’d APM
9-25
2
benefit
die
Strategies for (New) Undesirable Behaviors
Evaluate for
 Acute infection
 Hypoxia/other vital sign abnormality
 Pain (difficult if non-verbal)
 Medication side effect
 Hearing loss
 Vision loss
 Environmental upset (temperature, noise, routine)
Non-pharmacologic
Behavioral Treatments
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Re-Orientation Strategies
24 Hour Supervision
Calming Techniques
– Exercise therapy
– Music therapy
– Massage therapy
– “Person-centered” bathing
– Aromatherapy
RCT shown
effectiveness
Sources: Multiple, see evidence document, page 24.
Pharmacologic Management
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SSRIs
Trazodone
Prazosin
Memantine
Benzodiazepines (emergency use only)
To Treat or Not to Treat
If not
disruptive
dangerous
distressing
Rx
Efficacy of APMs in Behavioral Tx of Dementia
35
Improvement in Sx Scale
30
25
20
15
10
5
0
olanzapine
quietapine
risperadone
PLACEBO
If APM Rx Must Be Used for
Agitation or Aggressive Behavior
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Identify target behaviors being rx’d
Start at LOW DOSE
Reassess regularly
– gauge response of targeted sxs
– monitor for side effects
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Use for shortest time possible
Note some agents more efficacious for
certain behaviors (evidence document pg 28 table 9)
Treatment Algorithm for
Behavioral Symptoms of Dementia
Nursing Home Intervention Study
↓ reduction in use of targeted drugs
↑ in memory of patients previously taking
APMs
Level of staff distress = Ø∆ !
Source: NEJM, 1992
Pediatric Maladaptive
Aggression
(Non-Autistic)
APMs in Pediatrics
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Effective 1st line tx for agitation/aggression in
autism
Increasingly used for aggressive behavior w/o
autism (off-label use)
Side effects serious, can continue after tx
ends
Should be used w/ proven psychosocial tx
Consider discontinuing after 6 months
Percentage of Mainers Prescribed
Antipsychotic Medications (2010)
7
6
5
4
MaineCare
3
Private Insurance
2
1
0
Age3 0-6
Age 7-17
Age 18+
APMs and Children in Foster Care
in Maine
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Children in foster care are 4x more likely to be
prescribed an APM
20% of children in foster care are prescribed
an APM at any given time
Clinically significant behavioral health
problems are more prevalent in foster youth
– 48% in foster care vs 5 to 10% in gen. population
Flow Chart for Pediatric
tx of Aggression
Page 2
Pediatric
Supplement
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Maximize proven
psychotherapy
interventions
Consider other dx/rx
MICIS Gem
Evidence-based tx options for
a broad spectrum of pediatric
psychiatric diagnoses
p.3
pediatric supplement
Variation ≠ Quality
Medicaid children in
the top 6 counties in
Maine receive APM
Rx at twice the rate
of children in the
bottom 7 counties.
Variation ≠ Quality
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Maine is in top quartile of Medicaid children
receiving APM Rx.
Twice the rate of APM Rx compared to 16state median.
Special Considerations for Children

Higher metabolic rate & higher density of dopamine
receptors
– leading to different dosing needs.
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More sensitive to metabolic SE’s than adults
Significant weight gain
– even with least weight-gain causing APMs

Weight gain may be difficult to reverse
– even when tx discontinued
Sources:Pediatric Psychopharmacology Principles and Practice, 2011.
Journal of the American Academy of Child and Adolescent Psychiatry,
2006
Kids and APMs
Side effects can have a long-lasting
impact on the child’s health, though
tx with the drug may be short-lived.
Screening Guidelines for APMs
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Metabolic Effects
Neurologic Effects
Cardiovascular Effects
Other Effects
UN-AD PAGE 10
COST
Take Home Points
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APMs are commonly prescribed in primary
care necessitating a firm understanding of
indications, efficacy, and risks.
Side effects in 1st generation APMs→EPS
Side effects in 2nd generation APMs →weight
gain/metabolic syndrome
(different drugs have different risk profiles)
Take Home Points
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PCPs should perform and document
recommended screening for all patients on
APMs (and carefully coordinate with
psychiatry)
For major depression resistant to multiple
first and second line treatments, APMs may
be of benefit – none is superior to another for
depression treatment. Consider psychiatry
referral.
Take Home Points
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Exhaust all non-pharmacologic modalities
before using APMs for behavior management
in dementia.
If used, target drug to symptom (no FDA
indication).
Risk: benefit analysis → for every 53
dementia patients Rx’d APM, 1 will die
prematurely.
Take Home Points - Pediatrics
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Aggression a symptom of another condition?
Psychosocial interventions maximized?
Less toxic meds tried and failed?
Dx/targeted behavior goal warrants APM?
Informed consent re: SEs and monitoring?
Long-term plan – d/c after 6 months?
Questions?
Antipsychotic medications
in primary care:
Limited benefit, sizable risk