Optimizing Care for Patients With Schizophreniacdn.neiglobal.com/content/encore/congress/2012/slides_at... · 2018. 8. 13. · Functional Groups Responsible for Side Effects Cardiometabolic

Copyright © 2012 Neuroscience Education Institute. All rights reserved.

Optimizing Care for

Patients With Schizophrenia

(page 109 in syllabus)

Andrew J. Cutler, MD

Courtesy Assistant Professor, Department of Psychiatry,

University of Florida

CEO and Chief Medical Officer, Florida Clinical Research Center, LLC

Sponsored by the Neuroscience Education Institute

Additionally sponsored by Fairleigh Dickinson University School of Psychology

This activity is supported by an educational grant from Sunovion Pharmaceuticals Inc.

.

Handout for the Neuroscience Education Institute (NEI) online activity:


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 Bradenton.

Grant/Research: Abbott, Alkermes, AstraZeneca, Boehringer Ingelheim,

Bristol-Myers Squibb, Forest, GlaxoSmithKline, Janssen, Johnson & Johnson,

Lilly, Lundbeck, Merck, Neos, Novartis, Otsuka America, Pfizer, Quintiles,

Roche, Rhodes, sanofi-aventis, Shionogi, Shire, Sunovion, Supernus, Takeda,

Targacept, Theravance, Vanda

Consultant/Advisor: AstraZeneca, Bristol-Myers Squibb, Forest, Genomind,

Janssen, Lilly, Lundbeck, Merck, Neos, Novartis, Otsuka America, Rhodes,

Shionogi, Shire, Sunovion, Supernus, Takeda, Targacept, Theravance, Vanda

Speakers Bureau: AstraZeneca, Bristol-Myers Squibb, Forest, Janssen, Lilly,

Merck, Novartis, Otsuka America, Pamlab, Shionogi, Shire, Sunovion

Individual Disclosure Statement


Learning Objectives

• Implement evidence-based treatment strategies

that are aligned with recovery goals set by the

patient

• Make evidence-based treatment adjustments to

address side effects and inadequate response

• Include strategies for monitoring and addressing

adherence as an integral part of the treatment

plan for all patients


Jenny is a 25-year-old patient with schizophrenia who

has refused to take any antipsychotic for the past 3

years. Her twin sister Jill also has schizophrenia but

has been continuously adherent for several years.

Longitudinal imaging of Jenny's (nonadherent) brain

compared to Jill's (adherent) brain would likely reveal:

1. Decreased gray matter volume in Jenny's brain

2. An equal decrease in gray matter volume

3. Increased gray matter volume in Jenny's brain

4. An equal increase in gray matter volume

Pretest Question 1


Which of the following is NOT one of the 2009

Patient Outcomes Research Team (PORT)

treatment recommendations?

1. Clozapine for treatment-resistant psychosis

2. Higher antipsychotic doses for patients with multiple

psychotic episodes

3. Supported employment for patients with schizophrenia

4. Aripiprazole for patients with treatment-resistant

auditory hallucinations

Pretest Question 2


Douglas is a 34-year-old patient with schizoaffective

disorder. His symptoms have been fairly well controlled

with quetiapine for the past 2 years, but he has gained a

substantial amount of weight and is now pre-diabetic.

You would like to switch him to an antipsychotic with less

metabolic risk. Which of the following antipsychotics

would be the best choice?

1. Clozapine

2. Ziprasidone

3. Iloperidone

4. Paliperidone

Pretest Question 3


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


DO TREATMENTS FOR

SCHIZOPHRENIA WORK?


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 is associated with

lower mortality compared to no antipsychotic use

in patients with schizophrenia

Favors antipsychotic Favors no antipsychotic


Effectiveness of Antipsychotics

CGI-S PANSS ITAQ

Guo X et al. Psychopharmacology 2011;216(4):475-84.


Time as a Drug

Potkin SG et al. Int J Neuropsychopharmacol 2009;12:1233-48.


Time as a Drug

Stahl SM 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


The Bottom Line

For many patients

• Antipsychotic treatments may continue to

ameliorate symptoms of schizophrenia if

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.


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.

http://www.sciencedirect.com/science?_ob=MiamiCaptionURL&_method=retrieve&_udi=B6TC2-51DG6S4-1&_image=B6TC2-51DG6S4-1-4&_ba=&_rdoc=1&_fmt=full&_orig=na&_issn=09209964&_pii=S0920996410015501&view=full&_isHiQual=Y&_acct=C000059602&_version=1&_urlVersion=0&_userid=4429&md5=a0f38c69f5d16ba00067d04525f4e3b3


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


Even Partial Nonadherence Is

Detrimental

• Missing even <25% of medication for >2 weeks increases the risk of psychotic relapse

Subotnik KL et al. Am J Psychiatry 2011;168:286-92.

http://ajp.psychiatryonline.org/content/vol168/issue3/images/large/appi.ajp.2011.168.3.286.jpeg


Strategies to Improve Adherence

• Basic communication

– Take the patient's preferences into account

– Explain the benefits and hazards of treatment options

• Strategy-specific interventions

– Adjust medication timing and dosage for least intrusion

– Minimize adverse effects and maximize effectiveness

– Utilize long-acting depot formulations

• Psychosocial interventions

• Maximize cognitive functioning

• Evaluate adherence regularly

Mitchell, Selmes. Adv Psychiatr Treatment 2007;13:336-46.


MAXIMIZING TREATMENT

EFFICACY WHILE

MINIMIZING SIDE EFFECTS


Functional Groups Responsible for Therapeutic Effects

Vast Molecular Polypharmacy

Functional Groups Responsible for Side Effects

Cardiometabolic

side effects,

including

weight gain, insulin

resistance, and

increased fasting

triglycerides

Sedation

EPS

Tardive Dyskinesia

Increased Prolactin


Maximize Treatment Efficacy While Minimizing Side Effects

for the Individual Patient


Antipsychotics Target 60-80% Dopamine

D2 Receptor Occupancy


The “Pines”

• In general, more sedating and carry more

cardiometabolic risk than the “dones”

– Asenapine may be the exception

Clozapine

Olanzapine

Quetiapine

Asenapine


Clozapine

• The prototypical atypical

antipsychotic

• Typically dosed to occupy

<60% of D2 receptors

• Not recommended first-line

• Best choice for treatment-

resistant or highly aggressive

patients

• May reduce suicidality

• Associated with agranulocytosis

in 0.5-2% of patients

Sedation Weight Gain EPS


Olanzapine

• Low risk of EPS, even at

high doses

• High risk of

cardiometabolic side

effects

• May improve mood in

schizophrenia, bipolar

disorder, and depression

• Available as a long-acting

depot and ODT “Zydis”



Quetiapine

• Many binding properties

are due to the metabolite,

norquetiapine

• Available in both

immediate and extended

release formulations

• May have different

properties at different

doses

• Strong antidepressant

evidence (NRI?)



Quetiapine and The Three Bears

150-300 mg 25-50 mg 800 mg


Asenapine

• Not absorbed once swallowed; must be administered sublingually

– Common side effect: oral hypoesthesia

• Not approved for depression

but may have antidepressant

properties

• May be useful as a rapid

onset prn since rapidly

absorbed after sublingual

administration



N

N

N

CH 3

Asenapine and Mirtazapine

N

3 CH

3 CH

= mirtazapine

= asenapine


The “Dones”

Risperidone

Paliperidone

Ziprasidone

Iloperidone

Lurasidone


Risperidone

• May act more as a

conventional at higher

doses

• May increase prolactin

levels, even at low

doses (PGP substrate)

• Available as a long-

acting depot



Paliperidone

• Active metabolite of

risperidone, OROS delivery

system

• Not hepatically metabolized

• May be more tolerable than

risperidone

• Available as a long-acting

depot

• Has a lower incidence of

EPS than risperidone



Ziprasidone

• Must be given 2X/day with

food

• Does not cause dose-

dependent QTc

prolongation

• Not approved for

depression but binding

profile suggests possible

antidepressant properties



Iloperidone

• Recommended twice daily, but

dosing not well-studied

• Must be titrated to avoid

orthostasis and sedation due to

strong alpha-1 binding

• Not approved for mania or

depression, but potentially

effective

• Potent alpha 1 antagonism

suggests utility in PTSD

• Has lowest EPS/akathisia,

possibly linked to alpha 1

antagonism (blocking properties)



Lurasidone

• Lack of H1 epitope suggests

reduced risk of metabolic side

effects and sedation

• 5-HT7 antagonism may be

beneficial for mood, cognition,

circadian rhythm

• Dose once-daily with food

• Schizophrenia dosing now up to

160 mg/day

• Two new positive studies in

bipolar depression:

– Monotherapy

– Augmentation to Li or VPA



Tandospirone and Lurasidone

N

N N O

O

H

H

N S

N

N N

N

N

O

O

H

H


The “Pip”: Aripiprazole

• D2 partial agonist

• Acts as an agonist in the

presence of a D2 antagonist

• Acts as an antagonist in the

presence of a D2 agonist

such as dopamine

• Approved as an adjunctive

treatment for depression

• Has moderate 5HT1A and

5HT7 properties



Minimizing the Risk of Side Effects

SEDATION

Aripiprazole

Iloperidone

Lurasidone

Paliperidone

Risperidone

Ziprasidone

Asenapine

Olanzapine

Clozapine

Quetiapine

WEIGHT GAIN

Aripiprazole

Lurasidone

Ziprasidone

Asenapine

Iloperidone

Paliperidone

Risperidone

Quetiapine

Clozapine

Olanzapine

EPS

Clozapine

Iloperidone

Quetiapine

Aripiprazole

Asenapine

Lurasidone

Olanzapine

Ziprasidone

Paliperidone

Risperidone

Best choice

Worst choice


done #2 done #3 done #1 pine #2 pine #3 pine #1

1 week to switch

time

dose

1 week 1 week 1 week 1 week 1 week

Switching from One Pine or Done to Another:

Pines to Pines or Dones to Dones

Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.


pine

done

2 weeks to switch

time

dose


Switching from a Pine to a Done:

Stop the Pine Slowly



4 weeks monotherapy

time

dose


Always Stop Clozapine Slowly



pine done

2 weeks to switch

time

dose


Switching from a Done to a Pine:

Start the Pine Slowly



pine

time

dose


pip

3-7 days

to add pip

Start a middle (not a low) dose

when adding aripiprazole

2 weeks to taper pine

Switching from a Pine to Aripiprazole



done

time

dose


pip

3-7 days

to add pip


when adding aripiprazole

1 wk to

taper done

Switching from a Done to Aripiprazole



pine pip

2 weeks to add pine

time

dose


Immediate stop

of aripiprazole


when adding to aripiprazole

Switching from Aripiprazole to a Pine



done pip

time

dose


1 week to

add done

Immediate stop

of aripiprazole


when adding to aripiprazole

Switching from Aripiprazole to a Done



PSYCHOSOCIAL

INTERVENTIONS


Compliance Therapy

• Underscore importance of treatment alliance and patient

participation

• Review medical history with patient

– Indicate how medication cessation may have correlated with relapse

• Acknowledge negative treatment experiences

• Discuss how denial of illness and need for treatment has had social

and lifestyle consequences

• Explore feelings toward treatment, including misconceptions about

disease symptoms vs. treatment side effects

• Discuss tendency for patients to stop medication when feeling well

• Use analogies to physical illnesses that require maintenance

treatment

• Emphasize importance of staying well to fulfill goals Kemp et al. BMJ 1996;312:345-9.


Cognitive Behavioral Therapy (CBT)

• Psychotherapy with emphasis on current thoughts, emotions, and behaviors

• Focus on undoing old learning and teaching new behaviors

• Although patients receiving CBT usually report significant improvement after developing strategies for modifying unhelpful situational cognitions, the greatest amount of change is usually observed when unhelpful core beliefs are identified and modified

De Oliviera IR et al. CNS Spectr 2012;17(1):16-23.


Cognitive Adaptation Training (CAT)

• Includes environmental supports to help patient compensate for cognitive deficits

• May include:

– Alarm reminders to alert patient to take medicine, attend appointments, etc.

– Checklists with tasks broken down into steps

– Organization of belongings • e.g., placing matching outfits in separate containers

– Removal of distracting stimuli • e.g., removing clothing that does not fit from wardrobe

Draper et al. J Clin Psychol 2009;65(8):842-53.


Pharmacy-Based Intervention

Valenstein et al. Schizophr Bull 2011;37(4):727-36.


Cognitive Remediation Therapy

Penades et al. Schizophr Res 2006;87:323-31; Penades et al. Psychiatry Res 2010;177:41-45;

Medalia, Choi. Neuropsychol Rev 2009;19:353-64; Eack et al. Arch Gen Psychiatry 2010;67(7):674-82.

• Designed to improve neurocognitive abilities, including attention and memory

• May include:

– Pencil and paper tasks

– Computer exercises

• Can be tailored to address individual areas of weakness

• Improvement in executive functioning predicts improved daily functioning

• May protect against gray matter loss


Cognitive Therapy May Protect Against

Gray Matter Loss in Schizophrenia

Eack SM. Arch Gen Psychiatry 2010;67(7):674-82.

CET = Cognitive Enhancement Therapy: computer-based neurocognitive training focused on the remediation of social and nonsocial deficits in schizophrenia EST = Enriched Supportive Therapy: individual psychotherapy focused on illness management through psychoeducation and coping skills


Assertive Community Treatment (ACT)

• Goal: replace crisis-oriented clinical care with intensive community-based intervention

• Integrative care is available 24/7 and offered for as long as needed

• Team approach – Team meets regularly to discuss each case

– At least 1 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

• May be most cost-effective for patients who are severely disabled by their illness, have had numerous hospitalizations, or are at high risk for relapse

Dixon L. Psychiatr Serv 2000;51(6):759-65; Rosen A et al. J Rehabil Res Dev 2007;44(6):813-26;

Gilmer TP et al. 2010;67(6):645-52; McCrone P et al. Br J Psychiatry 2010;196:377-82.


Summary

• Optimal outcomes for patients with schizophrenia includes maximizing function, not just managing symptoms

• Antipsychotics ameliorate symptoms of schizophrenia for many patients and should be initiated early and maintained

• 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 therapeutic 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 schizophrenia treatment

Documents

Optimizing Care for Patients With Schizophreniacdn.neiglobal.com/content/encore/congress/2012/slides_at... · 2018. 8. 13. · Functional Groups Responsible for Side Effects Cardiometabolic