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 info@med-iq.com

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

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ith

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ign

ific

ant

Rel

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or

Sig

nif

ican

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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

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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

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Dis

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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

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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

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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

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ut

a R

elap

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esti

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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

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Pat

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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

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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

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PROACTIVE:NIMH Relapse Prevention Study

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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

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10.00

11.00

12.00

13.00

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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

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ent

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30

50

40

20

Time to Relapse, days from randomization

10

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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.