optimizing care for patients with schizophrenia
TRANSCRIPT
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Optimizing Care for
Patients With Schizophrenia
(page 217 in syllabus)
Andrew J. Cutler, MD
Courtesy Assistant Professor, Department of Psychiatry
University of Florida
CEO and Medical Director, Florida Clinical Research Center, LLC
Sponsored by the Neuroscience Education Institute
Additionally sponsored by the American Society for the Advancement of Pharmacotherapy
This activity is supported by an educational grant from Lilly USA, LLC.
For further information concerning Lilly grant funding visit, www.lillygrantoffice.com.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Faculty Editor / Presenter
Andrew J. Cutler, MD, is a courtesy assistant professor in the department of psychiatry
at the University of Florida in Gainesville, and the CEO and chief medical officer of
Florida Clinical Research Center, LLC in Maitland.
Grant/Research: Alkermes, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb,
Dainippon Sumitomo, Forest, GlaxoSmithKline, Janssen, Johnson & Johnson, Lilly,
Lundbeck, Merck, Ortho-McNeil, Otsuka America, Quintiles Transnational, Roche,
Shionogi, Shire, Sunovion, Supernus, Takeda, Targacept
Consultant/Advisor: AstraZeneca, Bristol-Myers Squibb, Cypress, Dainippon Sumitomo,
Forest, Janssen, Labopharm, Lilly, Merck, Ortho-McNeil, Otsuka America, Pamlab,
PharmaNeuroBoost N.V., Quintiles Transnational, Shionogi, Shire, Sunovion, Supernus,
Takeda, Targacept
Speakers Bureau: AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo, Forest,
GlaxoSmithKline, Janssen, Labopharm, Lilly, Merck, Ortho-McNeil, Otsuka America,
Pamlab, Shionogi, Shire, Sunovion
Individual Disclosure Statement
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Learning Objectives
• Implement evidence-based treatment strategies
that are aligned with recovery goals set by the
patient
• Integrate novel treatment approaches into
clinical practice according to best practices
guidelines
• Include strategies for monitoring and addressing
adherence as part of the treatment plan for all
patients
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Pretest Question 1
Theresa is a 49-year-old patient with schizophrenia
and a history of nonadherence. She does not want to
try a depot formulation due to a fear of needles. Given
that complexity of dosage regimen may adversely
affect treatment adherence, which atypical
antipsychotic would you consider for Theresa?
1. Asenapine
2. Iloperidone
3. Quetiapine XR
4. Ziprasidone
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Pretest Question 2
Joel is a 23-year-old patient with schizoaffective
disorder. He is currently taking a relatively low dose of
clozapine but is considering stopping his medication
due to side effects, especially daytime sedation. Based
on receptor binding profiles, which antipsychotic has
the least risk of causing sedation?
1. Aripiprazole
2. Olanzapine
3. Quetiapine
4. Asenapine
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Pretest Question 3
Henry is a 34-year-old patient with schizophrenia.
Results from the Positive and Negative Syndrome
Scale (PANSS) reveal numerous symptoms, especially
in the General Psychopathology subscale. Imaging of
Henry’s brain would likely reveal loss of gray matter in
which brain region?
1. Temporal lobe
2. Frontal lobe
3. Anterior cingulate gyrus
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
What Should Ideal Care Provide for
Patients With Schizophrenia?
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Recovery
• Recovery from illness
– Cure of illness, absence of illness
vs
• Recovery in illness: being in recovery
– Process of managing illness more effectively
– Having a meaningful life in the community
– Moving ahead with one’s life despite illness
Davidson L et al. Schizophr Bull 2008;34:5-8.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Symptom management
Physical health
Reduced hospitalization
Reduced criminal activity
Reduced substance abuse
Stable housing
Employment
Treatment alliance
Cognitive ability
Empowerment
Community involvement
Family involvement
RECOVERY
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Schizophrenia PORT
• Patient Outcomes Research Team
• Makes conservative recommendations based
solely on substantial scientific evidence
– From systematic literature reviews
• Includes psychopharmacological and
psychosocial treatment recommendations
Kreyenbuhl et al. Schizophr Bull 2010;36(1):94-103.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
2009 Updated PORT Psychopharmacological
Treatment Recommendations • First and Foremost
– Conventional or atypical antipsychotics as first-line treatments • Clozapine and olanzapine should not be used first line
• More Is More – Higher doses of antipsychotics for patients with multiple episodes
• Don’t Stop – Continuous antipsychotic maintenance treatment
• Not Just a Pain in the… – Long-acting injectable formulations
• Shake It Up • Antiparkinson medications to prevent EPS
• Be Cloz-Minded – Clozapine for treatment-resistant cases
• Chillax! – Benzodiazepines for acute agitation
• Quitters Win – Smoking cessation assistance
• A Little Shocking – Repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant
auditory hallucinations
Buchanan et al. Schizophr Bull 2010;36(1):71-93.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
2009 Updated PORT Psychosocial Treatment
Recommendations
• Get Your ACT Together – Assertive Community Treatment
• Hi-Ho, Hi-Ho, It’s Off To Work We Go – Supported employment
• Out of the Frying Pan and Into the Skill-et – Skills training
• Think About It – Cognitive psychotherapy
• You Can Do It! – Positive reinforcement
• It’s a Family Affair – Family intervention
• Drugs Are Bad, Mmkay? – Substance abuse treatment
• Be a Loser – Weight management
Dixon et al. Schizophr Bull 2010;36(1):48-70.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Symptom Management
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Early Risperidone Responders Show Early and
Consistent Improvement: Clinical Outcomes
Kinon B et al. Schizophr Res 2010;118:176-82.
0 2 4 6 8 10 12 14
0
-5
-10
-15
-20
-25
-30
-35
-40
Weeks
Least
Sq
uare
s M
ean
Ch
an
ge in
PA
NS
S T
ota
l S
co
re
* * * * * *
Early Responders (ER) (n = 144)
Early Non-Responders (ENR) (n = 192)
*P < 0.001
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Early Risperidone Responders Show Early and
Consistent Improvement: Functional Outcomes
Kinon B et al. Schizophr Res 2010;118:176-82.
SOFI: Schizophrenia Objective Functioning Instrument
Overall Living
Situation
Instrumental
Activity
Productive
Activity
Social
Functioning
Le
ast
Sq
uare
s M
ean
Ch
an
ge in
SO
FI
Baseli
ne t
o E
nd
po
int
*P < 0.001
0
-2
-4
6
4
2
12
10
8
16
14
ER Group
ENR Group *
*
* * *
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Duration and Severity of Untreated Psychosis
and Outcome in First-Episode Schizophrenia
• Meta-analysis of 43 publications
• Prolonged duration of untreated psychosis prior to the initiation
of treatment was associated with poorer symptomatic and
functional recovery in initial episodes
Perkins DO et al. Am J Psychiatry 2005;162(10):1785-1804.
Effect Size (95% CI)
-0.2 0.0 0.2 0.4
Global Psychopathology
Positive Symptom Severity
Negative Symptom Severity
Global Functional Outcome
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
FIN-11 Study
Tiihonen et al. Lancet 2009;374(9690):620-7.
Risk of death from any cause vs cumulative use of any antipsychotic drug
*Mortality = unadjusted absolute risk per 1000 person-years
†No antipsychotic drug = patients (18,914) who had not used any antipsychotic drugs during follow-up
• Long-term antipsychotic use associated with
lower mortality compared to no antipsychotic use
in patients with schizophrenia
Favors antipsychotic Favors no antipsychotic
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Efficacy of Antipsychotics on Positive and
Negative Symptoms of Schizophrenia
Potkin SG et al. Int J Neuropsychopharmacol 2009;12:1233-48.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Efficacy of Antipsychotics on Symptoms of
Schizophrenia
Guo X et al. Psychopharmacology 2011; Epub ahead of print.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Efficacy of Antipsychotics on Negative
Symptoms of Schizophrenia
Stahl S et al. J Clin Psychopharmacol 2010;30:425-30.
* P < 0.05 vs HAL; ** P < 0.01 vs HAL
n = 227 n = 221 n = 151
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Efficacy of Antipsychotics on Cognitive
Symptoms of Schizophrenia
Harvey PD et al. J Neuropsychiatry Clin Neurosci 2006;18:54-63.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Antipsychotics Can Improve Illness Insight
Guo X et al. Psychopharmacology 2011; Epub ahead of print.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
The Bottom Line
For many patients
• Antipsychotic treatments may ameliorate
symptoms of schizophrenia if they are
maintained for an extended period of time
• Continuous maintenance antipsychotic
medication results in ~70% reduction in risk of
relapse
Lindenmayer et al. J Clin Psychiatry 2009;70(7):990-6;
Marder. J Clin Psychiatry 2003;64(Suppl):3-9.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Treatment Adherence
Antipsychotics Don’t Work At All
If They Aren’t Taken
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
How Common Is Nonadherence?
• Nonadherence is estimated to be as high as 60%
• 40% of annual costs for rehospitalization are due to
nonadherence
• 75% of patients who discontinue their medication
experience significant symptom exacerbation over 1
year compared to 25% of those who adhere to their
medication
• Treatment nonadherence is associated with up to a
7-fold increased risk of suicide attempt
Lindenmayer et al. J Clin Psychiatry 2009;70(7):990-6;
Marder. J Clin Psychiatry 2003;64(Suppl):3-9.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Assessing Nonadherence
•Unreliable
Patient self-report
•Overly optimistic
Physician report
•Easily manipulated
Pill counts
•Medication must be obtained from a single source
Rx renewals
•Expensive
Microelectric monitoring of pill caps
• Invasive
Physiological monitoring
Rx
llorca et al. Psychiatry Res 2008;161:235-47;
Marder. J Clin Psychiatry 2003;64(Suppl):3-9;
Velligan et al. Psychiatr Serv 2007;58(9):1187-92. .
.
Feasib
ility
Accu
rac
y
Nope, Doc,
I haven’t
missed a
single dose
She seems
like an
adherent
patient
Ouch!
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Why Don’t Patients Take Their
Medicine?
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Factors That May Affect
Medication Adherence
• Poor illness insight
• Cognitive deficits
• Positive symptoms
• Doctor/patient relationship
• Treatment efficacy
• Side effects
• Treatment regimen
• Drug abuse
Lieberman et al. N Engl J Med 2005;353(12):1209-23;
Piette et al. Arch Intern Med 2005;165(15):1749-55; Novick et al. Psychiatry Res 2010;176:109-13.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Relationship Between Symptoms and
Adherence
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Consequences of Nonadherence
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Progressive Gray Matter Loss in Adolescent Patients With Schizophrenia Over 5 Years
Thompson PM et al. PNAS 2001;98(20):11650-5.
Normal Subjects
Subjects With Schizophrenia
Difference
0.00002
0.0001
0.0005 0.001
0.005 0.01 0.05
P-Value
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
-5.05
-6.52
-6.00
Talairach coordinate (axial): z=3
Baseline
Gray Matter Loss in Adult Patients With
Schizophrenia at Baseline and 5-Year Follow-Up
van Haren NE et al. Neuropsychopharmacology 2007;32(10):2057-66.
-5.05
-7.60
-6.00
-7.00
5-year Follow-Up
Talairach coordinate (axial): z=3
Excessive gray matter loss was related to an increased number of hospitalizations (increased psychotic episodes)
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Psychosis and Brain Volume Changes During
the First 5 Years of Schizophrenia
Gray Matter Lateral Ventricle Volume 3rd Ventricle Volume
Duration of Psychosis (months) Duration of Psychosis (months) Duration of Psychosis (months)
Cahn W et al. Eur Neuropsychopharm 2009;19:147-51.
N = 48
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Reduced Gray Matter Volume in Antipsychotic-Naïve
Patients With First-Episode Schizophrenia Correlates With
Functional Deficits
Lui S et al. Am J Psychiatry 2009;166:196-205.
Temporal Lobe Abnormalities Anterior Cingulate Gyrus Abnormalities
Correlate with:
Global Assessment of Functioning (GAF) Scale
PANSS Positive Symptoms
PANSS General Psychopathology
PANSS Thought Disturbance
PANSS Activation
PANSS Paranoia
PANSS Impulsive Aggression
Correlate with:
Global Assessment of Functioning (GAF) Scale
PANSS Positive Symptoms
PANSS Thought Disturbance
PANSS Activation
PANSS Paranoia
PANSS Impulsive Aggression
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Gray Matter Loss Is Worse in Patients With a
Longer Duration of Untreated Psychosis
Colored voxels depict brain areas of significantly greater gray matter loss in
patients with a long duration of untreated psychosis (>18 wks) compared to those
with a short duration (<18 wks)
Malla AK et al. Schizophr Res 2011;125(1):13-20.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Antipsychotic Treatment Improves Cerebral Functioning
Lui S et al. Arch Gen Psychiatry 2010;67(8):783-92.
Baseline untreated patients with first-episode
schizophrenia have decreased amplitude of
low-frequency fluctuations
Patients treated for 6 wks with antipsychotics
have increased amplitude of low-frequency
fluctuations compared to baseline
Patients treated for 6 wks with
antipsychotics have increased
amplitude of low-frequency
fluctuations compared to controls
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Consequences of Nonadherence on
Functional Outcomes
• Nonadherence is associated with:
– Alcohol-related problems
– Reduced mental functioning
– Reduced satisfaction with life
– Psychiatric hospitalizations
– Use of emergency psychiatric services
– Arrests
– Violence
– Victimizations
– Substance use
Ascher-Svanum et al. J Clin Psychiatry 2006;67(3):453-60.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Nonadherence Is Associated With Increased
Hospitalization
Weiden et al. Psychiatr Serv 2004;55:886-91.
0
5
10
15
20
25
0 1-10 11-30 >30 Total
% o
f P
ati
en
ts H
osp
itali
zed
Maximum Gap in Therapy (days within one year)
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Partial Nonadherence
• Patient reduces dose of drug or fails to take
drug from time to time
• Can lead to unexplained and unanticipated
adverse events
• Suboptimal treatment increases risk of relapse
– A 20% reduction in treatment compliance predicts a
3.1 point increase in PANSS total score
Perkins et al. J Clin Psychiatry 2008;69(1):106-13;
Docherty et al. American College of Neuropsychology 41st Annual Meeting. Abstract 2002:154.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Even Partial Nonadherence Is Detrimental
• Nonadherent patients defined here are those who miss <50% of
their medication for 2 weeks or more
• Missing even <25% of medication for >2 weeks increases the risk
for psychotic relapse
Subotnik KL et al. Am J Psychiatry 2011;168:286-92.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Improving Treatment Adherence
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
How to Improve Adherence
• Minimize side effects and increase drug efficacy
– By switching to another antipsychotic
• Utilize long-term depot formulations
• Psychosocial interventions
• Maximize cognitive functioning
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Strategies to Improve Adherence
• Basic communication
– Take the patient's preferences into account
– Explain the benefits and hazards of treatment options
• Strategy-specific interventions
– Adjusting medication timing and dosage for least intrusion
– Minimize adverse effects and maximize effectiveness
• Reminders (psychosocial interventions)
• Evaluate adherence regularly
Mitchell, Selmes. Adv Psychiatr Treatment 2007;13:336-46.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Maximize Treatment Efficacy While Minimizing
Side Effects for the Individual Patient
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Long-Acting Depot Formulations
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Long-Acting Injectable (LAI) Antipsychotics to
Improve Medication Adherence
• Cost/insurance coverage
• More appointments
• Oral to LAI conversion
• Perceived stigma
• Negative perceptions by clinicians
• Assured medication delivery
• Continuous antipsychotic coverage
• No need to remember to take medication every
day
• Drug remains in system for 1-2 weeks after a
missed dose
• Reduced risk of relapse and rehospitalization
• Avoidance of first-pass metabolism
• Peak plasma level is lower and occurs less
often (less side effects?)
• More frequent contact with treatment team
• Increasing number of options available
Advantages Disadvantages
Gerlach. Int Clin Psychopharmacol 1995;9(5):17-20.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Atypical Antipsychotics With Long-Acting
Depot Formulations
aripiprazole 4 wk in trials
iloperidone 4 wk in trials
olanzapine 2 wk
4 wk
risperidone 2 wk
4 wk in trials paliperidone
4 wk
12 wk in trials
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Depot Injections Are Associated With a 50-65% Lower Risk of Rehospitalization Compared to Their
Oral Counterparts
Tiihonen J et al. Am J Psychiatry 2011;168:603-9.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Not All Studies Show Superiority of Depot
Antipsychotics
Rosenheck RA et al. N Engl J Med 2011;364:842-51.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Characteristics That May Affect Adherence
Morrissette D, Stahl S. Neuroscience Education Institute. http://www.neiglobal.com. Accessed Sept 2010.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Psychosocial Intervention
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Psychosocial Interventions
• Supported employment
• Cognitive behavioral therapy (CBT)
• Cognitive adaptation therapy (CAT)
• Cognitive remediation therapy (CRT)
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Pharmacy-Based Intervention
Valenstein et al. Schizophr Bull 2009; Epub ahead of print.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Cognitive Remediation Therapy
McGurk et al. Am J Psychiatry 2007;164:1791-1802.
0
0.1
0.2
0.3
0.4
0.5
0.6
Eff
ect
Siz
e
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
ACT Now!
Recovery Is Going Fast!
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Elements of ACT
• Developed in the 1970s
• Goal
– Replace crisis-oriented clinical care with intensive
community-based intervention
• Design
– Integrative care is continuous and offered for as
long as it is needed
– Care is available 24/7
– Team approach to care
Dixon L. Psychiatr Serv 2000;51(6):759-65.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
The ACT Team
ACT leader
Psychiatrists
Psychiatric nurses
Employment specialist
Substance abuse specialist
Peer specialist
Additional mental health professionals
Program assistant
• The team meets regularly to discuss each case
• At least one team member visits the patient on a regular basis to assess medication efficacy, treatment adherence, medication side effects, physical health, and other issues that could potentially affect recovery
Dixon L. Psychiatr Serv 2000;51(6):759-65.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Symptom management
Physical health
Reduced hospitalization
Reduced criminal activity
Reduced substance abuse
Stable housing
Employment
Treatment alliance
Cognitive ability
Empowerment
Community involvement
Family involvement
RECOVERY
ACT Services Element of Recovery
•Medication prescription, administration, and monitoring •Illness management and recovery skills •Continuous assessment and intervention
•Medication prescription, administration, and monitoring •Continuous assessment and intervention •Medical care
•Crisis assessment and intervention •Illness management and recovery skills •Medication prescription, administration, and monitoring •Illness management and recovery skills •Medication prescription, administration, and monitoring •Individual supportive therapy
•Substance abuse treatment •Illness management and recovery skills •Individual supportive therapy
•Housing support services
•Employment-support services
•Transportation
•Intervention with support networks
•Transportation
•Intervention with support networks
•Individual supportive therapy
•Frequent interaction with ACT team members
•Integration of patient’s wishes in treatment planning
•Individual supportive therapy •Assistance with activities of daily living •Case management
•Integration of patient’s wishes in treatment planning
•Incorporation of recovering patients as peer specialists on ACT team
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Is ACT Worth It?
• Direct and indirect costs of treating schizophrenia are ~$60 billion
– 2/3 of these costs are from hospitalizations
• Increased cost of ACT-based care is offset by:
– Reduced hospitalizations
– Reduced use of emergency services
– Reduced criminal activities and justice system use
– Increased engagement in the workforce
– Decreased use of welfare services
– Reduced death from suicide
• May be most cost-effective for patients who are severely disabled by their illness, have numerous hospitalizations, or are at high risk for relapse
Rosen A et al. J Rehab Res Dev 2007;44(6):813-26; Gilmer TP et al. 2010;67(6):645-52;
McCrone P et al. Br J Psychiatr 2010;196:377-82.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Summary
• Symptom management is just a portion of what is necessary for optimizing outcomes for patients with schizophrenia
• Antipsychotic treatments ameliorate symptoms of schizophrenia for many patients and should be initiated early in the disease course
• Treatment nonadherence greatly increases the risk of poor functional outcomes in schizophrenia; even partial nonadherence increases the risk for relapse
• Minimization of treatment side effects may help to maximize treatment adherence; establishing a strong treatment alliance and optimizing treatment for the individual patient can increase adherence
• Long-acting depot formulations of antipsychotics offer the benefit of better ensuring treatment adherence
• Psychosocial interventions and the mediation of cognitive deficits should also be integral parts of treatment for schizophrenia