Activity OverviewIn this activity, faculty will describe a patient with newlydiagnosed schizophrenia who has not been adherent to theprescribed antips chotic medications Participants illprescribed antipsychotic medications. Participants willevaluate data about proven methods for improvingmedication adherence. In addition, faculty will discuss thebenefits and limitations of integrating long-acting injectableantipsychotics, particularly for patients with a history ofnonadherence to medication.
Target AudienceThis activity is intended for psychiatrists.
Accreditation / Designation Statements
Med-IQ is accredited by the Accreditation Council forMed IQ is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Med-IQ designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Disclosure PolicyMed-IQ requires any person in a position to control the content of an educational activity to disclose all relevant financial relationships with any commercial interest Thefinancial relationships with any commercial interest. The ACCME defines “relevant financial relationships” as those in any amount occurring within the past 12 months, including those of a spouse/life partner, that could create a conflict of interest (COI). Individuals who refuse to disclose will not be permitted to contribute to this CME activity in any way. Med-IQ has policies in place that will identify and resolve COIs prior to this educational activity Med-IQ alsoresolve COIs prior to this educational activity. Med-IQ also requires faculty to disclose discussions of investigational products or unlabeled/unapproved uses of drugs or devices regulated by the US Food and Drug Administration.
Disclosure Statement
The content of this activity has been peer reviewed and has been approved for compliance. The faculty and contributors pp p yhave indicated the following financial relationship, which have been resolved through an established COI resolution process, and have stated that this reported relationship will not have any impact on their ability to give an unbiased presentation.
John Lauriello, MD, has indicated no real or apparent conflicts.
Disclosure Statements
The activity planners and peer reviewers have no financial relationships to disclose.
Acknowledgment of Commercial Support
This activity is supported by an educational grant from Otsuka America Pharmaceutical, Inc.
Copyrightpy g© 2014 Med-IQ®. All rights reserved.
Medium & Method of ParticipationTo receive credit, read the introductory CME material, watch the Webcast, and complete the evaluation, attestation, and post-test, answering at least 70% of the post-test questions correctly. g p q y
The evaluation, attestation, and post-test will be accessible by clicking the “Get Credit” tab at the bottom of the Webcast at the conclusion of the activity.
Contact InformationCall toll-free 866 858 7434E-mail [email protected]
Please visit us online at www.Med-IQ.com for additional activities sponsored by Med-IQ.
Sara C. Miller, MS
Assistant Director Educational Strategy and Content
Activity Planners
Assistant Director, Educational Strategy and Content
Med-IQ
Baltimore, MD
Amy Sison
Director of Continuing Medical EducationDirector of Continuing Medical Education
Med-IQ
Baltimore, MD
John Lauriello, MD
Professor and Chairman
Faculty
Professor and Chairman
Chancellor’s Chair of Excellence in Psychiatry
University of Missouri Department of Psychiatry
Columbia, MO
Upon completion, participants should be able to:
• Describe methods for improving medication
Learning Objectives
• Describe methods for improving medication nonadherence in the management of schizophrenia
• Outline the benefits and limitations of LAI medications for the treatment of schizophrenia
Meet Joe Again• Joe is a college student who has been diagnosed with
schizophrenia
• Has had several exacerbations/relapses attributed to substance use and not taking his oral medication consistently
• Factors commonly linked to adherence issues were discussed
• Joe’s psychiatrist discussed the diagnosis of schizophrenia and the importance of medication continuity
• His psychiatrist recommendsHis psychiatrist recommends that Joe take an LAI antipsychotic, but Joe would like to try an oral again
Solutions to Nonadherence
• PsychotherapeuticPatient and family education about the illness– Patient and family education about the illness
– Identifying any attitude and cognitive barriers
– Employing specific adherence strategies
• Psychopharmacologic– Long-acting medication
• Allows guaranteed delivery of medication• Allows guaranteed delivery of medication
• Immediately identifies nonadherence
• Not a “cure all”
• Can have in common and unique risks vs. orals
APA20041
TMAP20062
PORT20093
Guideline / Algorithm Recommendations
First episode SGA SGA SGA, FGA
Second choice SGA, FGA, C SGA, FGA SGA, FGA
Third choice C C C
Fourth choice (C+) C+ –
Fifth choice – FGA or SGA –
Combinations – C + SGA + FGA + ECT +
MS
–
MS
FGA: first-generation antipsychotic SGA: second-generation (atypical) antipsychotic C: clozapine C+: clozapine augmentation with FGA,SGA or ECTMS: mood stabilizer 1. APA. Practice Guideline for the Treatment of
Patients With Schizophrenia, 2e. 2004;2. Moore T, et al. J Clin Psychiatry. 2007;68:1751-62;
3. Kreyenbuhl J, et al. Schizophr Bull. 2010;36:94-103.
Family Psychoeducation Interventions
• Offer family psychosocial intervention to patients who have ongoing contact (< 9 months) with their family or nonfamily
icaregivers
• Program should combine education about illness, family support, crisis intervention, and problem-solving skills training
• Do not restrict programs from families identified as having highlevels of “expressed emotion”(eg, criticism, hostility, ( g yoverinvolvement)
• Do not employ therapies based on thepremise that family dysfunction is theetiology of the problem
Dixon L, et al. Schizophr Bull. 2000;26:5-20.
Cognitive Adaptation Training
“A h i l t t t th t“A psychosocial treatment that uses environmental supports such as signs, checklists, alarms, and the organization
of belongings to cue and sequence adaptive behaviors in the home.”
CAT bypasses deficits in cognitive function
Velligan DJ, et al. Schizophr Bull. 2008;34:483-93.
Using CAT to Address Nonadherence
• Reasons for nonadherence– Failure to establish routines that promote adherenceFailure to establish routines that promote adherence
– Chaotic surroundings
– Unstable living arrangements
– Lack of necessary household items to track time/days
• Utilizes supports for medication adherence– Alarms
– SignsSigns
– Checklists
– New technologies (eg, Med-eMonitor™ System)
• Shown to improve adherence and community function and reduce rates of relapse
Velligan DJ, et al. Psychiatr Serv. 2006;57:219-24; Velligan DJ, et al. Psychiatr Serv. 2003;54:665-7.
Prior to CAT Intervention:Dresser and Drawers
Courtesy of Dawn Velligan, PhD
CAT Interventions
Did I takemy medication
today?
Courtesy of Dawn Velligan, PhD
1.00
Tailored Environmental Supports to Improve Medication Adherence
0.75
0.50
0.25Pro
po
rtio
n W
ith
ou
t S
ign
ific
ant
Rel
apse
or
Sig
nif
ican
t E
xace
rbat
ion
PharmCAT (n = 32)
CAT (n = 34)
CAT: cognitive adaptation therapy, environmental supports to cue behaviorPharmCAT: focus on medication and appointment adherence
3 6 9 12 15 180.00
Months to Relapse
S
( )
Treatment as usual (n = 29)
Velligan DJ, et al. Schizophr Bull. 2008;34:483-93.
Compliance Therapy
Multiple sessions (4-6) focused on:
A k l d t f ill (i i ht)• Acknowledgment of illness (insight)
• Misgivings about medication
• Analogies for maintenance treatmentof physical illness
• Medication to facilitate life goals
• Weighing of benefits and disadvantages
Kemp R, et al. Br J Psychiatry. 1998;172:413-9.
Joe’s Treatment Plan• Dr. L works with Joe to reduce side effects
from the medication
• Dr. L also refers the family to psychoeducation, a support group, and a “staying sober” group for Joe
• To help with remembering to take the medication, Dr. L’s nurse develops some environmental cues to remind Joe to take his pillstake his pills
• It seems like this is helpful, but Joe stillmisses doses and is experiencing paranoia
Treatment Options for Joe
• Dr. L decides to introduce a peer bridger, Manuel, at the clinic who is taking an LAI, g
• Manuel and Joe talk over several weeks, and Joe decides to give the LAI antipsychotic a try
• Joe’s psychiatrist opts for an atypical antipsychotic with a 4-week interval
• He also recommends that Joe continueworking with his peer bridger andworking with his peer bridger and attending sobriety groups
Peer Support / Bridger
• Can be patient-to-patient or family member-to-family membermember
– NAMI: Family-to-Family http://www.nami.org/
– WRAP®: www.mentalhealthrecovery.com/wrap/
• Can be a complementary relationship to the traditional medical model
• Recent study showed improved medication adherence with a problem-solving, peer-support program
– Weekly telephone contact between peer and patient
Duckworth, et al. Curr Opin Psychiatry. 2014;27:216-21.
Does Delivery Matter?
Continuous vs. Targeted Maintenance
33
Rates of Relapse After 1 Year
35
30
29
55
15
7
10
Pietzcker, et al
Jolley, et al
Herz, et al
Carpenter et al
Continuous therapy
32
20
0 10 20 30 40 50 60
Schooler, et al
Rates of Relapse, %
Kane JM. N Engl J Med. 1996;334:34-41.
Continuous therapyTargeted therapy
Options to Deliver Antipsychotic Medication
• Pills including one sublingualPills, including one sublingual
• Liquid: common option for typicals and some atypicals
• Quick dissolve
• Patches: no options
• Pumps: no options
• Long-acting injectable agentsg g j g
LAI Antipsychotics to Improve Medication Adherence
Balancing
• Ensured medication delivery• Continuous antipsychotic coverage• Reduced risk of relapse• More frequent contact with
treatment team • Increasing number of options
available
Advantages and Disadvantages• Cost/insurance coverage• More appointments• Oral-to-LAI conversion• Perceived stigma• Negative perceptions by clinicians
Relapse-Free Survival Rates With Oral and Depot Fluphenazine
100 –
Fluphenazine decanoate (n = 55)O l fl h i ( 50)
9 –
8 –
7 –
6 –
5 –
4 –rop
ort
ion
Su
rviv
ing
–0 3 6 9 12 15 18 21 24
Months in Community
Oral fluphenazine (n = 50)
3 –
Pr
Hogarty GE, et al. Arch Gen Psychiatry. 1979;36:1283-94.
Antipsychotic Continuity in Schizophrenia
0.9
1
ent
0 2
0.3
0.4
0.5
0.6
0.7
0.8
ort
ion
of
Pat
ien
ts A
dh
ere
OralLAI
0
0.1
0.2
0 25 50 75 100 125 150 175 200 225 250 275 300 325 350
Days to Discontinuation
Pro
po
Analysis limited to patients who were adherent for at least the first 60 days on first-generation oral (n = 202) or LAI (n = 97) agents. Adherence determined by switch or gap > 30 days; log-rank P < 0.001.
Zhu B, et al. Psychiatr Serv. 2008;59:315-7.
LAI
50
pit
al
%
Rehospitalization Rates in Schizophrenia: Naturalistic Study
34
12*14* 13*
10
20
30
40
ents
Rea
dm
itte
d t
o H
osp
hin
1 Y
ear
of
Dis
char
ge,
0Decanoate
(Haloperidol, Fluphenazine;
n = 58)
Risperidone(n = 109)
Clozapine(n = 49)
Olanzapine(n = 156)
Pat
ieW
ith
Conley RR, et al. Ann Clin Psychiatry. 2003;15:23‐31.*P = 0.0008 vs. decanoate.
Nationwide Cohort Study of Oral and Depot Antipsychotics After First
Hospitalization for Schizophrenia
• 2,588 patients with schizophrenia in Finland
• First hospitalization, 2000-2007
• 54.3% did not pick up medication within 30 days of hospitalization
• Patients receiving depots had a one-third risk of hospitalization compared with those receiving orals
• Use of any antipsychotic is associated with lower mortality
Tihonen J, et al. Am J Psychiatry. 2011;168:603-9.
Relapse Prevention With Risperidone LAI vs. Oral Quetiapine
1.0
se
0.9
0.8
0.7
0.6
0.5
0.4
y o
f N
ot
Hav
ing
a R
elap
s
Quetiapine (n = 337)0 3
Gaebel W, et al. Neuropsychopharmacol. 2010;35:2367-77.
0.2
0.1
0.00 90 180 270 360 450 540 720
Days
Pro
bab
ility Quetiapine (n 337)
RLAI (n = 329)Censored patients quetiapineCensored patients RLAI
Log-rank test: P < 0.0001
0.3
630 810
Paliperidone Palmitate Injectable Time to Relapse in Adults With Schizophrenia
100ts
Wit
ho
ut
a R
elap
se,
esti
mat
ed %
40
60
80
Log rank test P < 0 0001
20 60 100 140 180 220 260 300
Days Following Randomization
Paliperidone (n = 205)Placebo (n = 203)
Pat
ien
0
20
Log-rank test P < 0.0001
Hough D, et al. Schizophr Res. 2010;116:107-17.
Olanzapine LAI24-Week Maintenance Study
1.0
0.9
0.8
0.7
0.6
0 4rop
ort
ion
of
Pat
ien
ts
0.5 High dose (n = 141)Stabilized oral dose (n = 322)
High dose: 300 mg every 2 weeksMedium dose: 405 mg every 4 weeksLow dose: 150 mg every 2 weekVery low dose: 45 mg every 4 weeks Kane J, et al. Am J Psychiatry. 2010;167:181-9.
0.4
0.3
0.20 28 56 70 98 140150
Days to Relapse
Pr
Medium dose (n = 318)Low dose (n = 140)Very low (reference) dose (n = 144)
14 42 84 112126 168
RLAI and Oral Antipsychotics in Unstable Schizophrenia
• RLAI was not superior to a
Time to Hospitalization After Randomization
1.0superior to a psychiatrist's choice of oral treatment
1.0
0.8
0.4
0.2
0 0
Fre
edo
m F
rom
H
osp
ital
izai
ton
0.6
Injectable risperidoneOral antipsychotic
P = 0.39 by the log-rank test
Rosenheck RA, et al. N Engl J Med. 2011;364:842-51.
0.00 9 15 21 24
Months After Randomization
3 6 12 18
No. at RiskOral antipsychotic 182 136 116 96 84 71 58 49 28RLAI 187 136 110 92 82 65 53 45 37
1.00
tio
n
PROACTIVE:NIMH Relapse Prevention Study
0.25
rviv
al
Dis
trib
uti
on
Fu
nct
0.50
Oral SGAsLAI
0.75
Study Duration, visit no.
Buckley P, et al. Schizophrenia Bulletin. [in press]
0.00 40 50
Su LAI
10 20
Test Chi-Square df Chi-Square
Log rank 2.2214 1 0.1361
Wilcoxon 1.7206 1 0.1896
-2Log (LR) 2.3117 1 0.1284
30 7060
13 00
14.00
Comparison of Blinded Ratings of BPRS Psychosis Over Time
co
re
9.00
10.00
11.00
12.00
13.00
atr
ic R
ati
ng
Sc
ale
To
tal
S
6.00
7.00
8.00
0 7 14 20 27 33 40 46 53 59 66Study Duration, visit no.
Buckley P, et al. Schizophrenia Bulletin. [in press]
LAI-actualOral SGA-actual
Bri
ef
Ps
ych
i
Aripiprazole LAI vs. Placebo
e, %
Aripiprazole monohydrate (N = 269)Placebo (N = 134)
80
70
60
ts W
ith
Tre
atm
ent
Fai
lur
30
50
40
20
Time to Relapse, days from randomization
10
00
Pat
ien
t
40035030025020015010050
Kane JM, et al. J Clin Psychiatry. 2012;73:617-24.
LAI Advantages
• Confidence in medication availabilityPredictable and stable plasma levels– Predictable and stable plasma levels
– No first-pass metabolism• Lower dose possible
– A missed injection does not lead to abrupt withdrawal
• Advantages for patients– Freedom from daily pill takingFreedom from daily pill taking
– Consistent contact with treatment team
Kane JM ,et al. Eur Neuropsychopharmacol. 1998;8:55-66.
Fluphenazine Decanoate
Haloperidol Decanoate
Risperidone Microspheres
Paliperidone Palmitate
Olanzapine Pamoate
Aripiprazole Monohydrate
Available dosage strengths
25 mg/mL(variable dose)
50 mg/mL100 mg/mL
12.5 mg25 mg
39 mg78 mg
210 mg300 mg
300 mg400 mg
Comparison of the Available LAIs in the United States
g ( ) g(variable dose)
g37.5 mg50 mg
g117 mg156 mg234 mg
g405 mg
g
Dose range, mg 12.5-100 20-450 12.5-50 39 -234 150-405 160-400
Maximum recommended dose
100 mg every 2 weeks
450 mg every 4 weeks
50 mg every 2 weeks
234 mg every 4 weeks
300 mg every 2 weeks or 405 mg every 4 weeks
400 mg every4 weeks
Injection site Deltoid or gluteal Deltoid or gluteal Deltoid or gluteal Deltoid or gluteal Gluteal only Gluteal only
Injection technique
Z-Track Z-Track Standard Standard Standard Standard
Solubilization and vehicle
Ester in sesame seed oil
Ester in sesame seed oil
Microsphere matrix in aqueous suspension
Nanoparticles in aqueous suspension
Nanoparticles in aqueous suspension
Lyophilized powder reconstituted with sterile water to formsuspension suspension suspension sterile water to form an injectable suspension
Initiation or loading
Loading possible Loading possible None Initiation required Initiation required None
Time to peak 8-24 hours 3-9 days 4-5 weeks 13 days < 1 week 5-7 days
Overlap with oral 1 week 4 weeks; none if loading
3 weeks None None 2 weeks
Time to steady state
2-3 months 2-3 months 6-8 weeks 36 days 3 months 3-4 months
Derived from prescribing information for individual agents and from Kennedy WK. Curr Psychiatr. 2012;11:40-3.
Comparison of the Available LAIs in the United States
Fluphenazine Decanoate
Haloperidol Decanoate
Risperidone Microspheres
Paliperidone Palmitate
Olanzapine Pamoate
Aripiprazole Monohydrate
Patient considerations
Inconvenience of 2-week interval,
Injection can be painful, may need
Inconvenience of 2-week interval,
Prolactin elevation may be an issue.
Can require 2-week interval for
Relatively long oral coverage at
to consider injection can be painful, may need side effect medication
p yside effect medication prolactin elevation a
potential issue, needs relatively long oral coverage
Cost
y
Costsome, have to wait in clinic for 3 hours postinjection
Cost
ginitiation
Cost
Common side effects
Extrapyramidal symptoms, depression, blurred vision, excess salivation, hyperprolactinemia, metabolic changes
Extrapyramidal symptoms, metabolic changes, increased risk of cardiovascular effects (hyperprolactinemia)
Headache, Parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increase, pain in extremities, and dry mouth, hyperprolac-tinemia
Injection-site reactions, somnolence/ sedation, dizziness, akathisia, extrapyramidal disorder, metabolic changes, hyperpro-lactinemia
Post injection delirium syndrome; most common side effects are sedation, extrapyramidal symptoms, metabolic changes, increased appetite
Headache, agitation, insomnia, anxiety, nausea tardive dyskinesia, metabolic changes
Derived from prescribing information for individual agents and from Kennedy WK. Curr Psychiatr. 2012;11:40-3.
How Is Joe Doing Now?
• It has been 6 months since Joe has started the LAI antipsychotic
• His psychotic symptoms arewell controlled, and Joe is attending community college
• Joe needs some coaxing to go to his appointments, but is cooperative overall
• The family has worked with local support groups and has a better understanding of bothJoe and his uncle
To receive credit, click the “Get Credit” tab at the bottom of the Webcast for access to the evaluation,
attestation, and post-test.
© 2014
Content is being used for illustrative purposes only and any person depicted is a model.
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