Advances in the Treatment of Schizophrenia: New Approaches A Satellite Symposium at the XXVII CINP Congress The International College of Neuro-Psychopharmacology (CINP)

Welcome/Introductions W. Wolfgang Fleischhacker, MD Medical University Innsbruck

Disclosures

!!Supported by an educational grant from Dainippon Sumitomo Pharma America, Inc. !!On April 1, 2010, DSPA merged

with Sepracor Inc. creating one, united North American operation for our parent company, Dainippon Sumitomo Pharma Co., Ltd.

Disclosures

!!The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational uses (any use not approved by the US Food and Drug Administration) of products or devices

Agenda

12.25 Welcome/Introductions W. Wolfgang Fleischhacker, MD (Moderator)

12.25 – 12.45 Antipsychotic Efficacy: Comparing First-Generation to New-Generation Antipsychotics W. Wolfgang Fleischhacker, MD (Moderator)

12.45 – 12.55 Q&A 12.55 – 13.10 New-Generation Antipsychotics: Evidence for

Safety and Tolerability Donald C. Goff, MD

13.10 – 13.20 Q&A 13.20 – 13.35 Setting the Bar Higher: Functional Remission in

Schizophrenia Philip D. Harvey, PhD

13.35 – 13.45 Q&A

Antipsychotic Efficacy: Comparing First-Generation to New-Generation Antipsychotics W. Wolfgang Fleischhacker, MD Medical University Innsbruck

Disclosures

!! Grants/Research Support: Alkermes, Inc.; Bristol-Myers Squibb Company/Otsuka Pharmaceutical Group; Eli Lilly and Company; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.; Pfizer, Inc.

!! Consultant/Speaker’s Honoraria: AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company/Otsuka Pharmaceutical Group; H. Lundbeck A/S; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.; Merck & Co., Inc.; Pfizer, Inc.; United BioSource Corporation

Comparing Effectiveness of New-Generation Drugs to Traditional Antipsychotics

!! Collectively, the meta-analytic comparisons indicate that SGAs are modestly (though not consistently) more effective than FGAs in the treatment of schizophrenia1

!! Four of these drugs (amisulpride, clozapine, olanzapine, risperidone) were better than FGAs for overall efficacy, with small to medium effect sizes2

!! The spurious invention of the atypicals can now be regarded as invention only, clearly manipulated by drug industry and only now being exposed3

!! …even the low risk of tardive dyskinesia with atypical antipsychotics, the most serious neurological side effect, is not, by itself, likely to justify the greater expense of these drugs4

1. Tandon R, et al. Schizophr Res 2008;100:20-38. 2. Leucht S, et al. Lancet 2009;373:31-41. 3. Tyrer P, Kendall T. Lancet 2009;373:4-5. 4. Rosenheck RA. Lancet 2008;371:1048-1049.

First- vs. Second-Generation Antipsychotics

Comparative Effectiveness/Efficacy Studies

CATIE Schizophrenia Trial Design

Stroup TS, et al. Schizophr Bull 2003;29:15-31.

R

R

Phase 1 Phase 2 Phase 3

1,460 patients with chronic

schizophrenia

Clozapine (open-label)

Olanzapine, quetiapine, or risperidone Ziprasidone

Participants who discontinue Phase 1 choose either the

clozapine or the ziprasidone randomized pathway

R

Olanzapine n = 330

Quetiapine n = 329

Risperidone n = 333

Ziprasidone n = 183

Perphenazine n = 257

Participants who discontinue Phase 2

choose one of the following open-label treatments

•! Aripiprazole •! Clozapine •! Fluphenazine

decanoate •! Olanzapine •! Perphenazine •! Quetiapine •! Risperidone •! Ziprasidone •! 2 of the above

antipsychotics

Double-blind, random treatment assignment

No one assigned to same drug as in Phase 1

Olanzapine, quetiapine, or risperidone

0

0.2

0.4

0.6

0.8

1

0 3 6 9 12 15 18

Pro

porti

on o

f Pat

ient

s W

ithou

t Eve

nt

OLZ (n = 330) QUE (n = 329) RIS (n = 333) PER (n = 257) ZIP (n = 183)

Time to Discontinuation for Any Cause (Months)

CATIE: Time to Discontinuation for Any Cause

* Completed Phase I; p < .0001 for OLZ vs. QUE; p = .002 for OLZ vs. RIS Lieberman JA, et al. N Engl J Med 2005;353:1209-1223.

26% of all patients completed study on Phase I medication

36%*

26%*

25%*

21%*

18%*

Clinician is considering changing a patient’s antipsychotic medication—contacts CUtLASS

Eligible patient

DSM-IV Schizophrenia Age 18-65 years

CUtLASS 11

Change in medication due to inadequate

response or side effects

CUtLASS 22

Change in medication due to poor response

to 2 or more drugs

Patient randomized

FGA including sulpiride

SGA

quetiapine risperidone amisulpride olanzapine

Patient randomized

clozapine

CUtLASS Trial Design: Summary

1. Jones PB, et al. Arch Gen Psychiatry 2006;63:1079-1087. 2. Lewis SW, et al. Schizophr Bull 2006;32:715-723.

CUtLASS 1: Results

!! CUtLASS 1: “SGA (non-clozapine) will outperform FGA drugs in patients with schizophrenia responding poorly to, or intolerant of, current treatment” !! N = 227 !! FGA chosen: sulpiride 49%; SGA olanzapine 48% !! 81% follow up at one year !! Still on FGA: 54%; still on SGA 65% (ns) !! 48% of the participants randomized to sulpiride and 74%

of those randomized to olanzapine still on these drugs !! Trend to advantage for FGA on QLS and PANSS

(p = .15) !! No EPS difference overall !! No patient preference for either class

QLS = quality of life scale; ns = not significant Jones PB, et al. Arch Gen Psychiatry 2006;63:1079-1087.

The European First Episode Schizophrenia Trial1,2

1. Fleischhacker WW, et al. Schizophr Res 2005;78:147-156. 2. Kahn RS, Fleischhacker WW, et al. Lancet 2008;371:1085-1097.

Effectiveness of Antipsychotic Drugs in First-Episode Schizophrenia and Schizophreniform Disorder

!!Primary objective: To compare one-year retention on low doses of haloperidol as compared to amisulpride, olanzapine, quetiapine, and ziprasidone in patients with recent onset schizophrenia, schizoaffective, and schizophreniform disorder

Kahn RS, Fleischhacker WW, et al. Lancet 2008;371:1085-1097.

Haloperidol vs. Second-Generation Antipsychotic Drugs: Time to Treatment Discontinuation for Any Cause

HAL = haloperidol; AMI = amisulpride; OLZ = olanzapine; QUE = quetiapine; ZIP = ziprasidone Kahn RS, Fleischhacker WW, et al. Lancet 2008;371:1085-1097.

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12

HAL (n = 103) AMI (n = 104) OLZ (n = 105) QUE (n = 104) ZIP (n = 82)

Pro

porti

on W

ithou

t Tr

eatm

ent D

isco

ntin

uatio

n

Time (Months)

-0.8

-0.6

-0.4

-0.2

0

0.2

SG

A

Wor

se

SG

A

Bet

ter

Second-Generation vs. First-Generation Antipsychotic Drugs for Schizophrenia Efficacy: Overall Symptoms

AMI = amisulpride; ARI = aripiprazole; CLO = clozapine; OLZ = olanzapine; QUE = quetiapine; RIS = risperidone; SER = sertindole; ZIP = ziprasidone; ZOT = zotepine * Not approved by the US Food and Drug Administration Four second-generation drugs (AMI, CLO, OLZ, and RIS) were more efficacious for the treatment of overall schizophrenia symptoms than first-generation drugs

Leucht S, et al. Lancet 2009;373:31-41.

Hed

ges

g (9

5% C

I)

AMI* n = 1,017

ARI n = 2,049

CLO n = 1,997

OLZ n = 4,966

QUE n = 2,412

RIS n = 4,173

SER* n = 1,344

ZIP n = 980

ZOT n = 1,125

p = .326 p = .0001 p = .0001 p = .308 p = .002 p = .836 p = .438 p = .212 p = .0001

Recently Approved Antipsychotics and Drugs in a Late Stage of Development

!! Asenapine* !! Bishara D, Taylor D. Neuropsychiatr Dis Treat 2009;5:483-490.

!! Blonanserin†

!! Deeks ED, Keating GM. CNS Drugs 2010;24:65-84.

!! Iloperidone* !! Citrome L. Int J Clin Pract 2010;64:707-718.

!! Lurasidone†† !! Meyer JM, et al. Expert Opin Investing Drugs 2009;18:1715-1726.

* Approved by the US Food and Drug Administration † Indicated for use in patients with schizophrenia in Japan and Korea; not approved

by the US Food and Drug Administration †† Not approved by the US Food and Drug Administration or any other regulatory

agencies

Asenapine

!! Discovered by Organon !! Clinical profile !!Efficacy shown in schizophrenia !!Small EPS risk !!Minimal effect on weight and lipid profile !!? Potential role in treatment of negative symptoms !!Sublingual formulation requires BID dosing

!! Approved in the United States for the acute treatment of schizophrenia in adults, and the acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults1

!! In review for approval in Europe

1. Drugs@FDA. Available at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/.

-20

-16

-12

-8

-4

0

0 7 14 21 28 35 42 49

Asenapine vs. Placebo and Haloperidol: PANSS Total (LOCF)

PBO = placebo; ASE = asenapine; HAL = haloperidol; LOCF = last observation carried forward; * p < .05 vs. PBO Baseline means: PBO = 89.0; ASE 5 mg = 88.9; ASE 10 mg = 89.4; HAL = 88.5 Kane JM, et al. J Clin Psychopharmacol 2010;30:106-115.

PBO (n = 122)

HAL 4 mg BID (n = 112)

ASE 5 mg BID (n = 109)

ASE 10 mg BID (n = 105)

Mea

n C

hang

e fro

m B

asel

ine

Day

* * * *

* * * *

4

* *

EP

Iloperidone

!!Discovered by Hoechst Marion Roussel !!Clinical profile !!Efficacy shown in schizophrenia !!Less potent than risperidone? !!Minimal EPS risk !!Dose dependent weight and lipid impact !!Genetic markers may be associated with efficacy !!BID dosing; dose titration required !!Prolongation of QT interval

!!Approved in the United States for the acute treatment of schizophrenia in adults1

1. Drugs@FDA. Available at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/.

Iloperidone in Acute Schizophrenia: PANSS Total Score

-12

-10

-8

-6

-4

-2

0 0 7 14 21 28

LS M

ean

Cha

nge

from

Bas

elin

e

PAN

SS

Tot

al

ILO 24 mg/day (n = 295) ZIP 160 mg/day (n = 149) PBO (n = 149)

ILO = iloperidone; ZIP = ziprasidone; PBO = placebo; * p < .05 (2-tailed) vs. PBO; † p < .01 (2-tailed) vs. PBO Cutler AJ, et al. J Clin Psychopharmacology 2008;28:S20-S28.

* *

* *

† *

Day

Lurasidone*

!!Discovered by Dainippon Sumitomo Pharma !!Clinical profile !!Efficacy shown in schizophrenia !!High affinity for 5-HT7, 5-HT1A, "2c receptors

(implicated in enhancement of cognitive function) !!Minimal EPS risk !!Minimal effect on weight and lipid profile !!QD dosing; no dose titration required

!!Current status—late phase III trials ongoing in schizophrenia. NDA has been submitted in United States only

* Not approved by the US Food and Drug Administration or any other regulatory agencies

PEARL 2: Study Design

PEARL = Program to Evaluate the Antipsychotic Response to Lurasidone Meltzer H, et al. Poster presented at APA 2010.

Open-Label Extension Phase Double-Blind Phase

6 Weeks 6 Months

Scr

eeni

ng

Bas

elin

e

Lurasidone 40 mg/day

Placebo

Lurasidone 120 mg/day

Olanzapine 15 mg/day Lurasidone 40-120 mg/day

PEARL 2: PANSS Total (MMRM)

* p < .05; † p < .01; PBO = placebo; LUR = lurasidone; OLZ = olanzapine; MMRM = mixed method repeated measures Meltzer H, et al. Poster presented at APA 2010.

PBO (n = 114)

LUR 40 mg/day (n = 118) LUR 120 mg/day (n = 118)

OLZ 15 mg/day (n = 121)

LS M

ean

Cha

nge

from

Bas

elin

e

-30

-25

-20

-15

-10

-5

0 Baseline

† *

Day 4 Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6

Endpoint

† †

†

† †

†

†

† †

† †

†

† †

*

Blonanserin*

!!Discovered by Dainippon Sumitomo Pharma !!Clinical profile1,2

!!Effective in the treatment of patients with schizophrenia

!!Demonstrated efficacy in management of negative symptoms2

!!Minimal effect on weight and lipid profile !! Indicated for use in patients with

schizophrenia in Japan and Korea1

* Not approved by the US Food and Drug Administration 1. Deeks ED, Keating GM. CNS Drugs 2010;24:65-84. 2. Garcia E, et al. CNS Drugs 2009;23:615-625.

Blonanserin* in Acute Schizophrenia: PANSS Total Score

-35 -30 -25 -20 -15 -10 -5 0 5

Baseline 1 2 3 4 5 6

BLO 2.5 mg BLO 5 mg BLO 10 mg HAL 10 mg PBO

Cha

nge

in P

AN

SS

Tot

al S

core

Week N = 307; BLO = blonanserin; HAL = haloperidol; PBO = placebo * Indicated for use in patients with schizophrenia in Japan and Korea; not approved by the US Food and Drug Administration Garcia E, et al. CNS Drugs 2009;23:615-625.

Conclusions

!! Neither first- nor new-generation antipsychotics represent a homogeneous class

!! Most new-generation antipsychotics are at least as effective as haloperidol

!! Specific drugs may have advantages over first-generation antipsychotics, e.g., certain subsyndromes of schizophrenia (positive symptoms, negative symptoms, suicidality, aggression, cognitive impairment, depression)

!! Choice of treatment cannot be based on efficacy alone !! Safety/tolerability and subjective acceptance need to be accounted

for as well

!! There is not, as of yet, a reliable way to predict efficacy in individual patients

Q & A

W. Wolfgang Fleischhacker, MD

New-Generation Antipsychotics: Evidence for Safety and Tolerability Donald C. Goff, MD Massachusetts General Hospital, Harvard Medical School

Disclosures

!!Grants: GlaxoSmithKline; Novartis Pharmaceuticals Corporation; Pfizer, Inc.

!!Consultant: Biovail Pharmaceuticals, Inc.; Dainippon Sumitomo Pharma Co., Ltd.; Eli Lilly and Company; H. Lundbeck A/S; Hoffmann-La Roche Ltd.; Indevus Pharmaceuticals, Inc.; Otsuka America Pharmaceutical, Inc.; Schering-Plough Corporation; Solvay Pharmaceuticals, Inc.; Takeda Pharmaceuticals North America, Inc.

Schizophrenia Treatment Algorithm: Reasons for Switching

Intolerant Ineffective

Unsafe

First-Line Antipsychotic

0

3

6

9

12

15

18

PER RIS OLZ QUE ZIP

The CATIE Study: Discontinuations Due to Intolerability

!! N = 1,460 !! Risperidone: lowest

rate of discontinuation at 10% (mean dose 3.9 mg/day)

!! Olanzapine: 9% dropouts due to weight gain

!! Perphenazine: 8% dropouts due to EPS

PER = perphenazine; RIS = risperidone; OLZ = olanzapine; QUE = quetiapine; ZIP = ziprasidone Lieberman JA, et al. N Engl J Med 2005;353:1209-1223.

Treatment Discontinuation

Per

cent

Adherence: A Difficult Balance

Alliance

Perceived benefits

Side effects

Lack of insight

Disorganization

Subjective Well-Being Scale: Total Analysis

11.7 9.4

7.5 8.6 9.1 7.8 6.4

15.9 13.6

11.1 11.8

15.6

8.5 9.1

0 3 6 9

12 15 18

OLZ RIS QUE AMI CLO PO Typical

Depot Typical

3 Months 6 Months

SWN = subjective well-being with neuroleptics; OLZ = olanzapine; RIS = risperidone; QUE = quetiapine; AMI = amisulpride; CLO = clozapine; Scale = short form (20 items); range from 20 (worst) to 120 (best); n = patients with evaluable differences from baseline to 6 months Naber D, et al. Schizophr Res 2001;50:79-88.

Mea

n C

hang

e fro

m B

asel

ine

in

SW

N T

otal

Sco

re

(n = 1,223) (n = 292) (n = 170) (n = 159) (n = 66)

(n = 173) (n = 156)

Medication Effects: Well-Being vs. Distressing Side Effects

Well-Being Distressing

Sleeping pill

Anxiolytic

Antidepressant

Antipsychotic

Sedation, fatigue

Sexual side effects

EPS

Weight gain

Sedation

Clozapine ++++

Low-potency conventionals ++++

Quetiapine +++

Olanzapine +++

Risperidone ++

High-potency conventionals +

Aripiprazole +

Ziprasidone +

!! Sedation at bedtime is often welcome

!! Difficulty arising and daytime sedation are perceived negatively

Goff DC, et al. Mosby Elsevier, Philadelphia 2008:577-594.

EPS

Goff DC, et al. Mosby Elsevier, Philadelphia 2008:577-594.

High-potency conventionals ++++

Low-potency conventionals +++

Risperidone ++

Ziprasidone +

Olanzapine +

Aripiprazole +

Quetiapine –

Clozapine –

!! EPS is dose-related

!! Early parkinsonism from conventional neuroleptics predicts TD

!! Akathisia associated with nonadherence, poor outcomes

Sexual Side Effects

!! Related to prolactin, muscarinic, anticholinergic, and alpha-adrenergic effects

!! Common reason for young males to stop medication

!! Often not spontaneously reported

Goff DC, et al. Mosby Elsevier, Philadelphia 2008:577-594.

Risperidone/paliperidone +++

Low-potency conventionals +++

High-potency conventionals +++

Olanzapine ++

Ziprasidone +

Aripiprazole +

Quetiapine +

Clozapine +

Weight Gain

!!Weight gain is associated with: !!Treatment

discontinuation !!Low self-esteem !!Stigma !!Medical morbidity !!Criticism by

family members and lack of support for treatment

Goff DC, et al. Mosby Elsevier, Philadelphia 2008:577-594.

Clozapine ++++

Olanzapine ++++ Low-potency conventionals +++

Quetiapine ++

Risperidone ++ High-potency conventionals +

Aripiprazole +

Ziprasidone –

Tolerability of New and Emerging Second-Generation Antipsychotics

Dose (mg/day)

Mean Wt Gain in 6-Wk Trials

(kg)

QTc (mean change msec)

Prolactin (mean change from BL ng/mL)

EPS (%)

DRUG PBO DRUG DRUG PBO DRUG PBO

ASE 10-20 1.1 0.1 2-5 0.4 0.0 10.0 7.0

ILO 20-24 2.0 -0.1 9 2.6 -6.3 13.5 15.1

LUR 40-120 .67 0.36 1.5 1.1 -0.5 2.0 1.5

BLO 5-10 0.08-0.57 ND ND ND ND 10.3-26.6 9.4

ASE = asenapine; ILO = iloperidone; LUR = lurasidone; BLO = blonanserin; ND = No data See supplemental bibliography for full references.

Treatment-Emergent Adverse Events in Lurasidone Pooled Trials

Adverse Event All LUR (n = 1,004)

HAL (n = 72)

OLZ (n = 122)

PBO (n = 455)

Akathisia 15.0% 19.4% 7.4% 3.3% Nausea 12.0% 5.6% 4.9% 5.9% Sedation 11.9% 20.8% 14.8% 5.5%

Somnolence 10.7% 12.5% 9.0% 4.6% Insomnia 8.4% 16.7% 10.7% 6.6% Anxiety 6.3% 13.9% 5.7% 3.3%

Dystonia 3.5% 12.5% 0.8% 0.7% Weight Increased 2.4% 0% 20.5% 2.0%

Extrapyramidal Disorder 2.0% 18.1% 0% 1.5% # 1 Adverse Event 78.9% 87.5% 82.8% 71.4%

AEs # 10% and # 2-times placebo; LUR = lurasidone; HAL = haloperidol; OLZ = olanzapine; PBO = placebo Cucchiario J, et al. Poster NR6-20 presented at APA 2010. Accessed at http://www.posterview.com/apa/PosterSearch.aspx.

Mea

n W

eigh

t Gai

n/M

onth

(lb)

CATIE: Weight Gain Per Month of Treatment

p < .001; OLZ = olanzapine; QUE = quetiapine; RIS = risperidone; PER = perphenazine; ZIP = ziprasidone Lieberman JA, et al. N Engl J Med 2005;353:1209-1223.

-1

0

1

2

OLZ RIS PER QUE ZIP

CATIE: Metabolic Changes from Baseline

OLZ = olanzapine; QUE = quetiapine; RIS = risperidone; PER = perphenazine; ZIP = ziprasidone Lieberman JA, et al. N Engl J Med 2005;353:1209-1223.

9.4 6.6

-1.3

1.3

-8.2

40.5

21.2

-2.4

9.2

-16.5 -20

-10

0

10

20

30

40

50 Cholesterol (mg/dL) Triglycerides (mg/dL)

OLZ RIS PER QUE ZIP

Metabolic Profiles of Lurasidone and Olanzapine in PEARL 2 6-Week, Double-Blind, Placebo-Controlled Trial

* p < .001; LUR = lurasidone; OLZ = olanzapine; PBO = placebo Meyer J, et al. Poster NR6-19 presented at APA 2010. Accessed at http://www.posterview.com/apa/PosterSearch.aspx.

% o

f Pat

ient

s

Proportion of Patients with Clinically Significant Weight Gain (# 7%)

7.2%

40.2%

8.7%

0%

10%

20%

30%

40%

50%

LUR (n = 237) OLZ (n = 122) PBO (n = 116)

*

Differential Metabolic Profiles of Lurasidone and Olanzapine 6-Week, Double-Blind, Placebo-Controlled Trial

* p < .001; † p < .01; LUR = lurasidone; OLZ = olanzapine; PBO = placebo Meyer J, et al. Poster NR6-19 presented at APA 2010. Accessed at http://www.posterview.com/apa/PosterSearch.aspx.

-7 -5

0

9 7

-2

-5 -4

-1

-8

-4

0

4

8

12

Total, mg/dL LDL, mg/dL HDL, mg/dL

LUR (n = 217) OLZ (n = 115) PBO (n = 107) †

*

Med

ian

Cha

nge

LO

CF-

End

poin

t Endpoint Change in Cholesterol: Total, HDL, and LDL

Recommendations for Monitoring Patients Starting Second-Generation Antipsychotics

More frequent assessments may be warranted based on clinical status American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Diabetes Care 2004;27:596-601.

Baseline 4 Weeks

8 Weeks

12 Weeks Quarterly Annually Q5

Years

Personal/family history X X

Weight (BMI) X X X X X

Waist circumference X X

Blood pressure X X X

Fasting plasma glucose X X X

Fasting lipid profile X X X

Lifestyle Intervention and Metformin for Treatment of Antipsychotic-Induced Weight Gain: A Randomized Controlled Trial

-15

-10

-5

0

5

Lifestyle + Metformin

Metformin Lifestyle + Placebo

Placebo

Weight FBS Insulin

N = 128 Wu RR, et al. JAMA 2008;299:185-193.

12-week placebo-controlled trial, metformin 750 mg/day

Cha

nge

from

Bas

elin

e

Risk of Serious Events Within 30-Day Period in the Elderly by Medication Status

n = 241 Rochon PA, et al. Arch Intern Med 2008;168:1090-1096.

0.0 2.0 4.0 6.0 8.0

10.0 12.0 14.0 16.0 18.0

Extrapyramidal Symptoms

Cerebrovascular Events

Falls/Hip Fracture Other Acute Care Hospital Admissions

Death Any Serious Event

No Antipsychotic Therapy Atypical Therapy Conventional Therapy

Inci

denc

e %

Known Serious Events

Acute Care Hospital Admissions

0.1 0.1 0.1 0.2 0.2 0.5 1.0 1.2 2.5

4.5 5.2 3.3

5.2 6.5

5.6

9.4

11.6

Rates of Sudden Cardiac Death Among Antipsychotic Drugs

N = 26,749 person-years for current moderate-dose antipsychotic use N = 1,186,501 person-years for no use

Ray WA, et al. Arch Gen Psychiatry 2001;58:1161-1167.

Dea

ths

per 1

0,00

0 P

erso

n-Ye

ars

0

200

400

600

None Mild Moderate Severe

Non-Users Moderate-Dose Users

Prior Cardiovascular Disease

p = .12 p < .001 p = .03

p = .001

Deaths 328 12 338 18 374 9 297 7 Person-Years 781,342 18,382 255,210 6,451 124,263 1,764 25,686 152

Baseline Correction: QTc Changes at Maximal Dose and with Metabolic Inhibitor (CI Testing)

-10

0

10

20

30

40

ZIP RIS OLZ QUE THIO HAL

QTc

Cha

nge

from

Bas

elin

e (m

sec)

and

95%

CI

SS = at steady state; +MI = with metabolic inhibitor; ZIP = ziprasidone; RIS = risperidone; OLZ = olanzapine; QUE = quetiapine; THIO = thioridazine; HAL = haloperidol

Study 054 Pfizer presentation to FDA Advisory Committee Meeting, July 2000.

SS +MI SS SS +MI SS +MI SS +MI SS +MI SS +MI

*

Number of Deaths

Person- Years Mortality Adjusted

HR Adjusted HR

(95% Confidence Interval)

CLO 182 32,000 5.69 .74 PER 193 17,930 10.77 1.00 POLY 1,481 132,320 11.19 1.08 OLZ 264 25,130 10.50 1.13 THIO 227 18,420 12.32 1.14 RIS 295 19,410 15.20 1.34 HAL 135 7,040 19.19 1.37 QUE 89 5,360 16.60 1.41 Other 1,234 70,520 17.50 1.45

11-Year Follow-Up Mortality in Schizophrenia Patients vs. Total Population of Finland

N = 66,881; HR = Hazard Ratio; CLO = clozapine; PER = perphenazine; POLY = polypharmacy; OLZ = olanzapine; THIO = thioridazine; RIS = risperidone; HAL = haloperidol; QUE = quetiapine Tiihonen J, et al. Lancet 2009;374:620-627.

Any Cause

20 1

Odds Ratios for Hip Fractures in Women

Odds Ratio p-value Schizophrenia 1.0 .98 Antipsychotic 1.9 < .0001 Overweight .55 < .0001 SSRI 1.24 < .0001 Estrogen .62 < .0001 Smoker 1.3 < .0001 Ex-smoker 1.0 .98

N = 16,341 and matched controls Howard L, et al. Br J Psychiatry 2007;190:129-134.

Medication Selection

!!Several trials may be needed to select the optimal drug

!!Patients (and families) should be fully informed and participate in the decision

!!Many factors contribute: efficacy, safety, tolerability, stigma (weight gain and TD)

!!The decision should be revisited as indicated by safety monitoring

Antipsychotic Selection

Morbidity

Adherence Efficacy

Goal: The most effective and medically benign agent that the patient will take reliably

Q & A

Donald C. Goff, MD

Setting the Bar Higher: Functional Remission in Schizophrenia Philip D. Harvey, PhD Emory University School of Medicine

Disclosures

!!Consultant: Abbott Laboratories; Dainippon Sumitomo Pharma Co., Ltd.; Eli Lilly and Company; Shire Pharmaceuticals; Solvay Pharmaceuticals, Inc.; Wyeth Pharmaceuticals

!!Research Grants: AstraZeneca Pharmaceuticals LP

Outcome of Schizophrenia in the 20th Century

Hegarty JD, et al. Am J Psychiatry 1994;151:1409-1416.

0%

10%

20%

30%

40%

50%

Outcome

Fresh Air Metrazol ECT Lobotomy Chlorpromazine Depot

Per

cent

age

of P

atie

nts

Livi

ng In

depe

nden

tly

Impact of Cognitive Dysfunction in Schizophrenia

!! Cognitive dysfunctions are present in 80% of patients with schizophrenia !! Deficits common in attention, memory, speed processing, and

executive functioning !! Well-known functional consequences on daily life, social

functioning, and rehabilitation outcome

!! Cognitive deficits, rather than the positive or negative symptoms of schizophrenia, predict poor performance in basic activities of daily living

!! Family members caring for these patients have additional daily work burden, and suffer psychological anguish and anxiety

!! Reducing cognitive deficits may decrease the economic burden to health care systems through lower numbers of hospital admissions and shorter hospitalization periods

Dimensions of Functional Impairment

!!Objective !!Occupational !!Social !!Self-care !!Independent living

!!Subjective !!Subjective QoL !!Perceived illness burden

QoL = quality of life

Rates of Real-World Functioning in Schizophrenia1,2

0%

5%

10%

15%

20%

25%

30%

1. Leung WW, et al. J Int Neuropsychol Soc 2008;14:479-488. 2. Harvey PD, et al. Am J Psychiatry 2009;166:821-827.

Per

cent

age

of C

ases

Ach

ievi

ng

Func

tiona

l Com

pete

nce

Employment Residence Marriage

Early Onset of Disability: Treatment of Primary Symptoms as a Poor Predictor of Disability Reduction

!!90% of first-episode schizophrenia patients experience remission at the end of one year of treatment1

!!At 5-year follow-up 18% had recovered1

!!85% had relapsed at least once1

!!50% are receiving disability compensation within 6 months of first admission2

1. Robinson DG, et al. Am J Psychiatry 2004;161:473-479. 2. Ho BC, et al. Psychiatr Serv 1997;48:948-950.

How Do You Assess Functional Disability?

!!Self-report

!!Informant report

!!Direct observation

!!Objective information

!!Performance-based tests

Limitations of Assessment Domains

!!Objective information !!Availability, relevance, low rate of occurrence

!! Informant report !!Opportunities, situation specificity

!!Self-report !!Bias, cognitive limitations

!!Observation !!Situation specificity, low target frequency

!!Performance-based !!Practicality, content validity, difficulty

The UCSD Performance-Based Skills Assessment (UPSA)

!!Performance-based assessment of skills in 5 functional domains !!Finance, communication, planning,

transportation, home activities

!!Administered in a test-based format with real props and stimuli !!30-minute assessment aimed at

independent living Patterson TL, et al. Schizophr Bull 2001;27:235-245.

What Is Consistent Across Studies?

!!UPSA is correlated to cognition !!Twamley et al: r = .64 !!McKibbin et al: r = .63 !!Bowie et al: r = .60 !!Keefe et al: r = .65 !!Green et al: r = .61 !!Harvey et al: r = .54* !!MATRICS-CT r = .67

* UPSA-B administered in Swedish; 4-test neuropsychological assessment See supplemental bibliography for full references.

Disability as a Cross-Cultural Central Illness Feature: Measuring Disability Across Different Countries

NP = neuropsychological; UPSA-B = UCSD Performance-Based Skills Assessment-Brief Version; RW = real world; SLOF = Specific Levels of Functioning Scale

Harvey PD, et al. Am J Psychiatry 2009;166:821-827.

0 10 20 30 40 50 60

UPSA-B SLOF NP Tscore

Sweden NYC

UPSA Scores, NP Performance, and SLOF Everyday Functioning !!Rural Sweden

!!Urban New York !!Same outcomes

measured: !!NP performance;

UPSA-B scores; rated RW outcomes (SLOF); RW milestones

UPSA-B in China

!!Large sample of Beijing residents

!!Healthy comparison (n = 282), schizophrenia (n = 274), unipolar (n = 51), and bipolar (n = 60) subjects*

!!Wide-ranging age and educational status

!!UPSA-B translated and transliterated for use in China

* Some patients with bipolar disorder had history of psychosis MacIntosh B, et al. Poster presented at Biological Psychiatry 2010.

UPSA-B as a Function of Educational Attainment

* Some patients with bipolar disorder had history of psychosis MacIntosh B, et al. Poster presented at Biological Psychiatry 2010.

0 10 20 30 40 50 60 70 80 90

Elementary Middle School High School College or Higher

Healthy Control Schizophrenia Bipolar Disorder* Unipolar Depression

A Recovery Perspective

!!This model has several features !!Symptom control: achieving clinical remission !!Improvement in functional status !!A cooperative perspective on treatment !!A focus on development of independence and

autonomy

!!One of the major determinants of recovery will be the use of functional abilities in the real world

Harvey PD. Schizophr Bull 2009;35:299.

Criteria for Clinical Remission

!!Focus on clinical symptoms !!None of the main Criterion A symptoms are

present: !!Delusions (P1) !!Hallucinations (P3) !!Unusual Thought Content (G9) !!Conceptual Disorganization (P2) !!Mannerisms and Posturing (G5) !!Blunted Affect (N1) !!Social Withdrawal (N4) !!Lack of Spontaneity (N6)

!!Period is defined as 6 months or more Andreasen NC, et al. Am J Psychiatry 2005;162:441-449.

Functional Remission: A Developing Perspective

!!Recovery includes both sustained symptomatic remission and functional improvements

!! It is possible to define functional remission !!Such a definition should cover both the

breadth of functional improvement and significance of improvement

!!Domains of functioning include !!Social !!Vocational !!Independent living

Harvey PD, Bellack AS. Schizophr Bull 2009;35:300-306.

Treatments Aimed at Functional Remission

!!Psychosocial treatments, including rehabilitation interventions and cognitive remediation !!Pharmacological treatments

Success of Cognitive Remediation

!!Three separate studies have shown that cognitive remediation leads to important functional improvements in patients who are attempting to achieve psychosocial gains1-3

!!Some of these improvements are substantial

1. McGurk SR, et al. Am J Psychiatry 2007;164:437-441. 2. Bell MD, et al. Schizophr Res 2008;105:18-29. 3. Hogarty GE, et al. Arch Gen Psychiatry 2004;61:866-876.

Cognitive Training and Supported Employment: 1- and 3-Year Results from a Randomized Control Trial

0

200

400

600

800

1000

1200

1400 Income Time Worked

1. McGurk SR, et al. Schizophr Bull 2005;31:898-909. 2. McGurk SR, et al. Am J Psychiatry 2007;164:437-441.

% Im

prov

emen

t Com

pare

d to

Con

trol C

ondi

tion

1-Year Difference1 (%) 3-Year Difference2 (%)

Improvement in Cognitive Function: MCCB Effect Size for Lurasidone and Ziprasidone

0

0.1

0.2

0.3

TMT BACS AN LNS WMS HVLT BVMT NAB COMP

Effe

ct S

ize

LUR (n = 123) ZIP (n = 111)

MCCB = MATRICS Consensus Cognitive Battery, www.matricsinc.org Harvey PD, et al. Poster presented at ICOSR 2009.

3-week study in stable patients with schizophrenia

Schizophrenia Cognition Rating Scale (SCoRS) Mean Change

-0.6

-0.4

-0.2

0.0 LUR 120 mg (n = 116) ZIP 160 mg (n = 121)

LS M

ean

Cha

nge

from

Bas

elin

e

** p < .01 from baseline; NS (p = .161) between groups (ITT, LOCF); SCoRS = Schizophrenia Cognition Rating Scale Harvey PD, et al. Poster presented at ICOSR 2009.

** Effect size: .35 .17

IMP

RO

VE

ME

NT

MK-801 Induced Passive Avoidance Deficit Model

MK-801 = dizocilpine Ishiyama T, et al. Eur J Pharmacol 2007;572:160-170.

Inescapable shock

+ Lurasidone

1 day later

1 day later

Test Training

1 day later

Olanzapine (mg/kg)

Evaluating Atypical Antipsychotic Ability to Reverse MK-801 Induced Impairment

Ishiyama T, et al. Eur J Pharmacol 2007;572:160-170.

0

20%

40%

60%

80%

100%

% o

f Ani

mal

s Av

oidi

ng

Vehicle +

Saline

Vehicle 1 3 Lurasidone (mg/kg)

+MK-801

0

20%

40%

60%

80%

100%

Vehicle +

Saline

Vehicle 3 10 Quetiapine (mg/kg)

+MK-801

0

20%

40%

60%

80%

Vehicle +

Saline

Vehicle 0.3 1 Clozapine (mg/kg)

+MK-801

100%

0

20%

40%

60%

80%

100%

% o

f Ani

mal

s Av

oidi

ng

Vehicle +

Saline

Vehicle 0.3 1 Risperidone (mg/kg)

+MK-801

0

20%

40%

60%

80%

100%

Vehicle +

Saline

Vehicle 0.3 1 Haloperidol (mg/kg)

+MK-801

0

20%

40%

60%

80%

100%

Vehicle +

Saline

Vehicle 0.3 1

+MK-801

0

20%

40%

60%

80%

100%

Vehicle +

Saline

Vehicle 1 3

+MK-801

Aripiprazole (mg/kg)

Lurasidone Quetiapine Clozapine

Risperidone Haloperidol Olanzapine Aripiprazole

Conclusions

!! Disability is present across the course of schizophrenia, with similar impairments found in people with schizophrenia across different Western and Eastern cultures

!! Current thinking about treatment focuses on remission and recovery

!! Functional remission can be defined and measured !! Psychosocial and pharmacological treatments have

shown potential for inducing some components of remission

!! Integrated psychosocial and pharmacological treatments may be most important for advancing remission and promoting recovery

Q & A

Philip D. Harvey, PhD

Panel Questions and Answers

W. Wolfgang Fleischhacker, MD Donald C. Goff, MD Philip D. Harvey, PhD

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Advances in the Treatment of Schizophrenia:New Approaches

Glossary of Terms and Bibliography

A Satellite Symposium at the XXVII CINP CongressThe International College of Neuro-Psychopharmacology (CINP)

Advances in the Treatment of Schizophrenia: New Approaches

1

Glossary of Terms AMI Amisulpride AN Animal Naming test ASE Asenapine BACS Brief Assessment of Cognition in Schizophrenia BID Twice daily BLO Blonanserin BMI Body mass index BVMT Brief Visuospatial Memory Test CATIE Clinical Antipsychotic Trials of Intervention Effectiveness CI Confidence interval CLO Clozapine COMP Composite score CUtLASS Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study CVD Cardiovascular disease DAI Drug Attitude Inventory DM Diabetes mellitus DSM-IV Diagnostic and Statistical Manual of Mental Disorders, 4th edition ECT Electroconvulsive therapy EPS Extrapyramidal symptoms EUFEST European First Episode Schizophrenia Trial FBS Fasting blood sugar FGA First generation antipsychotic HAL Haloperidol HAM-D Hamilton Depression Rating Scale HDL High-density lipoprotein HR Hazard ratio HTN Hypertension HVLT Hopkins Verbal Learning Test IGT Iowa Gambling Task ILO Iloperidone IQ Intelligence quotient ITT Intention to treat LDL Low-density lipoprotein LNS Letter-Number Sequencing LOCF Last observation carried forward LS Least squared MATRICS-CT Measurement and Treatment Research to Improve Cognition in Schizophrenia-Cognitive

Test Battery MCCB MATRICS Consensus Cognitive Battery

Advances in the Treatment of Schizophrenia: New Approaches

2

Glossary of Terms, continued

MI Metabolic inhibitor MK-801 Dizocilpine MMRM Mixed-Effect Model Repeated Measure NAB Neuropsychological Assessment Battery NP Neuropsychological NS Not significant NYC New York City OLZ Olanzapine PANSS Positive and Negative Syndrome Scale PEARL Program to Evaluate the Antipsychotic Response to Lurasidone PER Perphenazine PBO Placebo PO Psychiatric-organic QD Once daily QLS Quality of Life Scale QoL Quality of life QTc Corrected QT interval QUE Quetiapine REAP Research on East Asia Psychotropic Prescription RIS Risperidone RW Real world SCoRS Schizophrenia Cognition Rating Scale SER Sertindole SGA Second-generation antipsychotic SLOF Specific Levels of Functioning Scale SS Steady state SSRI Selective serotonin reuptake inhibitor SWN Subjective well-being with neuroleptics TC Total cholesterol TD Tardive dyskinesia THIO Thioridazine TMT Trail Making Test UCSD University of California, San Diego UPSA UCSD Performance-Based Skills Assessment UPSA-B UCSD Performance-Based Skills Assessment–Brief Version WCST Wisconsin Card Sorting Test WMS Wechsler Memory Scale ZIP Ziprasidone ZOT Zotepine

Advances in the Treatment of Schizophrenia: New Approaches

3

BibliographyAmerican Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004;27:596-601.

Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry 2005;162:441-449.

Bell MD, Zito W, Greig T, Wexler BE. Neurocognitive enhancement therapy with vocational services: work outcomes at two-year follow-up. Schizophr Res 2008;105:18-29.

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Bowie CR, Harvey PD. Cognitive deficits and functional outcome in schizophrenia. Neuropsychiatr Dis Treat 2006;2:531-536.

Chong MY, Tan CH, Shinfuku N, et al. Prescribing antipsychotic drugs for inpatients with schizophrenia in Asia: comparison of REAP-2001 and REAP-2004 studies. Asia-Pacific Psychiatry 2010;2:77-84.

Cucchiario J, Pikalov A, Ogasa M, Silva R, Hsu J, Xu J. Safety of lurasidone: pooled analysis of five placebo-controlled trials in patients with schizophrenia. Presented at the American Psychiatric Association 2010 Annual Meeting, May 23-27, 2010. Poster NR6-20.

Cutler AJ, Kalali AH, Weiden PJ, Hamilton J, Wolfgang CD. Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. J Clin Psychopharmacol 2008;28:S20-S28.

Deeks ED, Keating GM. Blonanserin: a review of its use in the management of schizophrenia. CNS Drugs 2010;24:65-84.

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Garcia E, Robert M, Peris F, Nakamura H, Sato N, Terazawa Y. The efficacy and safety of blonanserin compared with haloperidol in acute-phase schizophrenia: a randomized, double-blind, placebo-controlled, multicentre study. CNS Drugs 2009;23:615-625.

Goff, DC, Freudenreich O, Henderson DC. Antipsychotic Drugs. In: Stern TA, Rosenbaum JR, Fava M, Biederman J, Rauch SL, eds. Massachusetts General Hospital Comprehensive Clinical Psychiatry, 1st ed. Philadelphia, PA: Mosby Elsevier: 2008: 577-594.

Green MF, Nuechterlein KH, Kern RS, et al. Functional co-primary measures for clinical trials in schizophrenia: results from the MATRICS Psychometric and Standardization Study. Am J Psychiatry 2008;165:221-228.

Advances in the Treatment of Schizophrenia: New Approaches

4

Bibliography, continuedHanssens L, van Winkel R, Wampers M, et al. A cross-sectional evaluation of adiponectin plasma levels in patients with schizophrenia and schizoaffective disorder. Schizophr Res 2008;106:308-314.

Harvey PD, Bellack AS. Toward a terminology of functional recovery in schizophrenia: is functional remission a viable concept? Schizophr Bull 2009;35:300-306.

Harvey PD, Helldin L, Bowie CR, et al. Performance-based measurement of functional disability in schizophrenia: a cross-national study in the United States and Sweden. Am J Psychiatry 2009;166:821-827.

Harvey PD, Loebel A, Ogasa M, Cucciaro J, Keefe R. A double-blind comparison of the effects of lurasidone and ziprasidone on cognitive function: differential sensitivity of performance-based and interview measures. Presented at ICOSR 2009.

Harvey PD, Pappadopulos E, Lombardo I, Kremer CM. Reduction of functional disability with atypical antipsychotic treatment: a randomized long term comparison of ziprasidone and haloperidol. Schizophr Res 2009;115:24-29.

Harvey PD. Functional recovery in schizophrenia: raising the bar for outcomes in people with schizophrenia. Schizophr Bull 2009;35:299.

Heaton RK, Marcotte TD, Mindt MR, et al. The impact of HIV-associated neuropsychological impairment on everyday functioning. J Int Neuropsychol Soc 2004;10:317-331.

Hegarty JD, Baldessarini RJ, Tohen M, Waternaux C, Oepen G. One hundred years of schizophrenia: a meta-analysis of the outcome literature. Am J Psychiatry 1994;151:1409-1416.

Ho BC, Andreasen N, Flaum M. Dependence on public financial support early in the course of schizophrenia. Psychiatr Serv 1997;48:948-950.

Hogan TP, Awad AG, Eastwood R. A self-report scale predictive of drug compliance in schizophrenics: reliability and discriminative validity. Psychol Med 1983;13:177-183.

Hogarty GE, Flesher S, Ulrich R, et al. Cognitive enhancement therapy for schizophrenia: effects of a 2-year randomized trial on cognition and behavior. Arch Gen Psychiatry 2004;61:866-876.

Howard L, Kirkwood G, Leese M. Risk of hip fracture in patients with a history of schizophrenia. Br J Psychiatry 2007;190:129-134.

Ishiyama T, Tokuda K, Ishibashi T, Ito A, Toma S, Ohno Y. Lurasidone (SM-13496), a novel atypical antipsychotic drug, reverses MK-801-induced impairment of learning and memory in the rat passive-avoidance test. Eur J Pharmacol 2007;572:160-170.

Jones PB, Barnes TR, Davies L, et al. Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006;63:1079-1087.

Kahn RS, Fleischhacker WW, Boter H, et al.; EUFEST study group. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 2008;371:1085-1097.

Kane JM, Cohen M, Zhao J, Alphs L, Panagides J. Efficacy and safety of asenapine in a placebo- and haloperidol-controlled trial in patients with acute exacerbation of schizophrenia. J Clin Psychopharmacol 2010;30:106-115.

Keefe RS, Poe M, Walker TM, Kang JW, Harvey PD. The Schizophrenia Cognition Rating Scale: an interview-based assessment and its relationship to cognition, real-world functioning, and functional capacity. Am J Psychiatry 2006;163:426-432.

Advances in the Treatment of Schizophrenia: New Approaches

5

Bibliography, continuedKendall DM, Bergenstal RM. The International Diabetes Center, Minneapolis, MN. Copyright 2005. Available at: http://www.internationaldiabetescenter.com.

Kendall DM, Peters Harmel AL. Type 2 diabetes and the metabolic syndrome: understanding the role of insulin resistance. Am J Manag Care 2002;8:S635-S653.

Kerwin R. Connecting patient needs with treatment management. Acta Psychiatr Scand Suppl 2009;438:33-39.

Kraemer HC, Glick ID, Klein DF. Clinical trial design lessons from the CATIE study. Am J Psychiatry 2009;166:122-1228.

Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009;373:31-41.

Leucht S, Komossa K, Rummel-Kluge C, et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry 2009;166:152-163.

Leung WW, Bowie CR, Harvey PD. Functional implications of neuropsychological normality and symptom remission in older outpatients diagnosed with schizophrenia: a cross-sectional study. J Int Neuropsychol Soc 2008;14:479-488.

Lewis SW, Barnes TR, Davies L, et al. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull 2006;32:715-723.

Lieberman JA, Stroup TS, McEvoy JP, et al.; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-1223.

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Mausbach BT, Bowie CR, Harvey PD, et al. Usefulness of the UCSD performance-based skills assessment (UPSA) for predicting residential independence in patients with chronic schizophrenia. J Psychiatr Res 2008;42:320-327.

McGurk SR, Meltzer HY. The role of cognition in vocational functioning in schizophrenia. Schizophr Res 2000;45:175-184.

McGurk SR, Mueser KT, Feldman K, Wolfe R, Pascaris A. Cognitive training for supported employment: 2-3 year outcomes of a randomized controlled trial. Am J Psychiatry 2007;164:437-441.

McGurk SR, Mueser KT, Pascaris A. Cognitive training and supported employment for persons with severe mental illness: one-year results from a randomized controlled trial. Schizophr Bull 2005;31:898-909.

McKibbin CL, Brekke JS, Sires D, Jeste DV, Patterson TL. Direct assessment of functional abilities: relevance to persons with schizophrenia. Schizophr Res 2004;72:53-67.

Meltzer H, et al. Poster presented at: American Psychiatric Association 2010 Annual Meeting; May 23-27, 2010.

Meyer J, Cucchiaro, J, Pikalov A, Hsu J, Loebel A. Differential metabolic profiles of lurasidone and olanzapine. Data from a 6 week, double-blind, placebo controlled schizophrenia trial. Presented at the American Psychiatric Association 2010 Annual Meeting, May 23-27, 2010; Poster NR6-19.

Naber D, Moritz S, Lambert M, et al. Improvement of schizophrenic patients’ subjective well-being under atypical antipsychotic drugs. Schizophr Res 2001;50:79-88.

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Bibliography, continuedNakamura M, Ogasa M, Guarino J, et al. Lurasidone in the treatment of acute schizophrenia: a double-blind, placebo-controlled trial. J Clin Psychiatry 2009;70:829-836.

Narvaez JM, Twamley EW, McKibbin CL, Heaton RK, Patterson TL. Subjective and objective quality of life in schizophrenia. Schizophr Res 2008;98:201-208.

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Robinson DG, Woerner MG, McMeniman M, Mendelowitz A, Bilder RM. Symptomatic and functional recovery from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry 2004;161:473-479.

Rochon PA, Normand SL, Gomes T, et al. Antipsychotic therapy and short-term serious events in older adults with dementia. Arch Intern Med 2008;168:1090-1096.

Rosenheck RA. Pharmacotherapy of first-episode schizophrenia. Lancet 2008;371:1048-1049.

Sablier J, Stip E, Franck N. Cognitive remediation and cognitive assistive technologies in schizophrenia. Encephale 2009;35:160-167.

Stroup TS, McEvoy JP, Swartz MS, et al. The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development. Schizophr Bull 2003;29:15-31.

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Tandon R, Belmaker RH, Gattaz WF, et al.; Section of Pharmacopsychiatry, World Psychiatric Association. World Psychiatric Association Pharmacopsychiatry Section statement on comparative effectiveness of antipsychotics in the treatment of schizophrenia. Schizophr Res 2008;100:20-38.

Tiihonen J, Lönnqvist J, Wahlbeck K, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 2009;374:620-627.

Twamley EW, Doshi RR, Nayak GV, et al. Generalized cognitive impairments, ability to perform everyday tasks, and level of independence in community living situations of older patients with psychosis. Am J Psychiatry 2002;159:2013-2020.

Tyrer P, Kendall T. The spurious advance of antipsychotic drug therapy. Lancet 2009;373:4-5.

Advances in the Treatment of Schizophrenia: New Approaches

7

Bibliography, continuedWang PS, Walker AM, Tsuang MT, et al. Dopamine antagonists and the development of breast cancer. Arch Gen Psychiatry 2002;59:1147-1154.

Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998;97:1837-1847.

Wu RR, Zhao JP, Jin H, et al. Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial. JAMA 2008;299:185-193.

Young JW, Powell SB, Risbrough V, Marston HM, Geyer MA. Using the MATRICS to guide development of a preclinical cognitive test battery for research in schizophrenia. Pharmacol Ther 2009;122:150-202.

Advances in the Treatment of Schizophrenia: New Approaches

8

Supplemental BibliographySetting the Bar Higher: Functional Remission in SchizophreniaPhilip D. Harvey, PhD

Slide Title: Cognition, Functional Capacity, and Real-World Outcome

1. Twamley EW, Doshi RR, Nayak GV, et al. Cognitive impairments, ability to perform everyday tasks, and level of independence in community living situations of older patients with psychosis. Am J Psychiatry 2002;159:2013-2020.

2. McKibbin CL, Brekke JS, Sires D, Jeste DV, Patterson TL. Direct assessment of functional abilities: relevance to persons with schizophrenia. Schizophr Res 2004;72:53-67.

3. Bowie CR, Harvey PD. Cognitive deficits and functional outcome in schizophrenia. Neuropsychiatr Dis Treat 2006;2:531-536.

4. Keefe RS, Poe M, Walker TM, Kang JW, Harvey PD. The Schizophrenia Cognition Rating Scale: an interview-based assessment and its relationship to cognition, real-world functioning, and functional capacity. Am J Psychiatry 2006;163:426-432.

5. Green MF, Nuechterlein KH, Kern RS, et al. Functional co-primary measures for clinical trials in schizophrenia: results from the MATRICS Psychometric and Standardization Study. Am J Psychiatry 2008;165:221-228.

6. Harvey PD, Helldin L, Bowie CR, et al. Performance-based measurement of functional disability in schizophrenia: a cross-national study in the United States and Sweden. Am J Psychiatry 2009;166:821-827.

7. Pietrzak RH, Olver J, Norman T, Piskulic D, Maruff P, Snyder PJ. A comparison of the CogState Schizophrenia Battery and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Battery in assessing cognitive impairment in chronic schizophrenia. J Clin Exp Neuropsychol 2009;31:848-859.

8. Young JW, Powell SB, Risbrough V, Marston HM, Geyer MA. Using the MATRICS to guide development of a preclinical cognitive test battery for research in schizophrenia. Pharmacol Ther 2009;122:150-202.

Slide Title: What Is Consistent Across Studies?

1. Twamley EW, Doshi RR, Nayak GV, et al. Cognitive impairments, ability to perform everyday tasks, and level of independence in community living situations of older patients with psychosis. Am J Psychiatry 2002;159:2013-2020.

2. McKibbin CL, Brekke JS, Sires D, Jeste DV, Patterson TL. Direct assessment of functional abilities: relevance to persons with schizophrenia. Schizophr Res 2004;72:53-67.

3. Bowie CR, Harvey PD. Cognitive deficits and functional outcome in schizophrenia. Neuropsychiatr Dis Treat 2006;2:531-536.

4. Keefe RS, Poe M, Walker TM, Kang JW, Harvey PD. The Schizophrenia Cognition Rating Scale: an interview-based assessment and its relationship to cognition, real-world functioning, and functional capacity. Am J Psychiatry 2006;163:426-432.

5. Green MF, Nuechterlein KH, Kern RS, et al. Functional co-primary measures for clinical trials in schizophrenia: results from the MATRICS Psychometric and Standardization Study. Am J Psychiatry 2008;165:221-228.

Advances in the Treatment of Schizophrenia: New Approaches

9

Supplemental Bibliography, continued6. Harvey PD, Helldin L, Bowie CR, et al. Performance-based measurement of functional disability

in schizophrenia: a cross-national study in the United States and Sweden. Am J Psychiatry 2009;166:821-827.

7. Pietrzak RH, Olver J, Norman T, Piskulic D, Maruff P, Snyder PJ. A comparison of the CogState Schizophrenia Battery and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Battery in assessing cognitive impairment in chronic schizophrenia. J Clin Exp Neuropsychol 2009;31:848-859.

8. Young JW, Powell SB, Risbrough V, Marston HM, Geyer MA. Using the MATRICS to guide development of a preclinical cognitive test battery for research in schizophrenia. Pharmacol Ther 2009;122:150-202.