Next-Generation Strategies for the Therapeutic Management of Schizophrenia

Diana O. Perkins, MD, MPHProfessor, Department of PsychiatryMedical Director OASIS Program(Outreach and Support Intervention Services)University of North Carolina at Chapel HillChapel Hill, North Carolina

Negative symptoms

Relationship of Symptom Domains in Schizophrenia

Mood symptoms

CognitionPositive

symptoms

Antipsychotics

What Do We Know?

• Antipsychotics improve positive symptoms

• Antipsychotics have a modest impact on:– Negative symptoms– Cognition

• Residual symptoms remain in most patients

• Residual symptoms underlie disability in chronic schizophrenia

Antipsychotic Efficacy: Symptoms

Meta-analysis: Efficacy of Second-Generation Antipsychotics on Symptoms in Schizophrenia

-0.6 -0.5 -0.4 -0.3 0.2 0.1 0 0.1 0.2 0.3 0.4 0.5 0.6

Adapted from Leucht S, et al. Mol Psychiatry. 2009;14(4):429-447.

Favors Antipsychotic Favors Placebo

Negative symptomsN = 36; n = 5403

Positive symptomsN = 30; n = 4941

SMD = change in symptoms on placebo (in “SD units”)—change in symptom on drug (in “SD units”)

Total symptomsN = 35; n = 5568

Meta-analysis: Use of EPS Medications

- 2.5 -2 -1.5 -1.0 -.5 1 0.5 1.0 1.5 2.0 2 2.5 3.0

Favors AntipsychoticFavors Placebo

AripiprazoleN = 6; n = 1310

OlanzapineN = 3; n = 481

ZiprasidoneN = 4; n = 598

HaloperidolN = 11; n = 1608

QuetiapineN = 3; n = 509

Adapted from Leucht S, et al. Mol Psychiatry. 2009;14(4):429-447.

RisperidoneN = 4; n = 323

Meta-analysis: EPS Rating Scale

Favors AntipsychoticFavors Placebo

AripiprazoleN = 6; n = 1591OlanzapineN = 3; n = 612

RisperidoneN = 5; n = 642

ZiprasidoneN = 1; n = 95

HaloperidolN = 7; n = 1004

QuetiapineN = 3; n = 529

Adapted from Leucht S, et al. Mol Psychiatry. 2009;14(4):429-447.

- 2.5 -2 -1.5 -1.0 -.5 1 0.5 1.0 1.5 2.0 2 2.5 3.0

Second-Generation vs First-Generation Antipsychotics

Leucht S, et al. Lancet. 2009;373(9657):31-41. Copyright © 2009 Elsevier Ltd.

N=n=

N=n=

N=n=

N=n=

N=n=N=

n=

Symptomatic Remission:Remission in Schizophrenia Working Group

• PANSS symptoms and signs mild or less (severity ≤ 3) for 6 months

• Positive symptoms– Delusions– Unusual thought content– Hallucinatory behavior

• Disorganization– Conceptual disorganization– Mannerisms/posturing

• Negative symptoms– Blunted affect– Social withdrawal– Lack of spontaneity

Andreasen NC, et al. Am J Psychiatry. 2005;162(3):441-449.

EPPIC StudyEarly Psychosis Prevention and Intervention Centre

Henry LP, et al. J Clin Psychiatry. 2010;71(6):716-728.

723 first-episode psychosis patients* treated for up to the first 2 years of illnessMedian follow-up: 7.2 years; mean age at follow-up: 28.7 years

*Includes schizophrenia, schizophreniform disorder, schizoaffective disorder, affective psychosis, and other psychosis

Remission/Recovery CriteriaSchizophrenia +

Schizophreniform Disorder (%)Total Cohort

(%)

Symptom remission

BPRS 50 59

BPRS + SANS 29 37

Social/vocational recovery 22 31

Social/vocational recovery + symptom remission

BPRS 18 26

BPRS + SANS 15 24

BPRS = Brief psychotic rating scaleSANS = Schedule for assessment of negative symptoms

Antipsychotic Efficacy: Cognition

Normative Data Compared With a Schizophrenia Sample on the RBANS Neuropsychological Test

RBANS = Repeatable Battery for Assessment of Neuropsychological Status

0

5

10

15

20

25

30

35

< 50-50 51-60 61-70 71-80 81-90 91-100 101-110 111-120 121-130 131-140 140+

Total Scale Score

% o

f C

ases

Schizophrenia (n = 575)Normal controls (n = 540)

Data from Wilk CM, et al. Schizophr Res. 2004;70(2-3):175-186.

0.4% 0% 0% 0%

16.5%

7.2%

22.8%20.6%

22.6%

7.9%

2.2%0.4%1.6%

7.0%

16.0%

25.0%

0%

16.0%

0.4% 1.6%

7.0%

25.0%

Effect Sizes* for Average Improvement in Cognition With Atypical Antipsychotics

Healthy Control Mean (Theoretical)

∆ in

Bas

elin

e (S

tan

dar

d D

evia

tio

n)

0.0

-0.5

-1.0

-1.5

*Values represent average improvement as measured by changes from baseline in standard deviations; figures are weighted for the study group size in each study and collapsed across all newer medications.

Adapted from Harvey PD, Keefe RS. Am J Psychiatry. 2001;158:176-184.

Immediate Memory

Secondary Memory

Vigilance ExecutiveFunctions

Visual Motor Skills

Verbal Fluency

Spatial Functions

.13

.39 .39

.18.27

.43

.20

Next-Generation Strategies

Next-Generation Strategies

• Prevention

• Psychotherapeutic interventions

• New pharmacological targets

Next-Generation Strategies: Public Education Program to Promote Early Intervention Impact on Symptoms

Data from Melle I, et al. Arch Gen Psychiatry. 2008;65(6):634-640.

Control group: n = 118, mean DUP = 16 weeks; Intervention group: n = 113, mean DUP = 4 weeks

25

Baseline 3 month 12 month 24 month

20

15

10

5

0

PA

NS

S S

core

Negative Sx (Control Group)

Negative Sx (Early Detection Group)

Positive Sx (Control Group)

Positive Sx (Early Detection Group)

Next-Generation Strategies: Psychotherapy

Data from Eack SM, et al. Psychiatr Serv. 2009;60(11):1468-1476.

Per

cen

t C

han

ge

at 2

Yea

rs 60

Total S

ympto

ms

(P =

0.0

08)

50

40

30

20

10

0

Cognitive Enhancement Therapy (n = 31)Enriched Supportive Therapy (n = 27)

Negat

ive

Sympto

ms

(P =

0.0

1)Neu

roco

gnition (P

= 0

.02)

Social

Cogniti

on (P <

0.0

01)

Next-Generation Strategies: Pharmacological

• Next-generation drug development driven by theoretical relationship of negative and cognitive symptoms to frontal cortical dysfunction and glutamate circuits

Hui C, Tsai GE. In: Brain Protection in Schizophrenia, Mood and Cognitive Disorders. New York, NY: Springer Science+Business Media; 2010.

Glutamate “Partners” at the NMDA Receptor

Meta-analysis: Efficacy of Glycine/Serine/Cycloserine Augmentation on Negative Symptoms

-0.4 -0.3 -0.2 -0.1 00 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2

Adapted from Tsai GE, et al. Curr Pharm Des. 2010;16(5):522-537.

Favors DrugFavors Placebo

GlycineN = 7; n = 261

D-serineN = 5; n = 208

D-cycloserineN = 8; n = 317

Meta-analysis: Efficacy of Glycine/Serine/Cycloserine Augmentation on Positive Symptoms

Favors DrugFavors Placebo

GlycineN = 6; n = 145

D-serineN = 5; n = 208

D-cycloserineN = 7; n = 212

Note: Consistent negative results for clozapine augmentation studies

Adapted from Tsai GE, et al. Curr Pharm Des. 2010;16(5):522-537.

-0.4 -0.3 -0.2 -0.1 00 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2

Next-Generation Strategies: Pharmacological

• Next-generation drug development driven by theoretical relationship of negative and cognitive symptoms to frontal cortical dysfunction and glutamate circuits

Hui C, Tsai GE. In: Brain Protection in Schizophrenia, Mood and Cognitive Disorders. New York, NY: Springer Science+Business Media; 2010.

Glycine Reuptake Inhibitors

Javitt DC, et al. Mol Psychiatry. 2005;10(3):275-287. Copyright © 2004 Nature Publishing Group.

Inhibition of Glycine Transport by Clozapine

% C

on

tro

l [3 H

] G

lyci

ne

Up

take

100

80

60

40

20

0

0.01 0.1 1 10 100

Clozapine Concentration (mcg/mL)

plasma

brain

**

*

**

***

***

*P < 0.05 vs control; **P < 0.01; ***P < 0.001.

-0.4 -0.3 -0.2 -0.1 00 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2

Meta-analysis: Efficacy of Sarcosine Augmentation on Schizophrenia Symptoms

Favors DrugFavors Placebo

PositiveN = 5; n = 162

Total SymptomsN = 5; n = 162

NegativeN = 5; n = 162

Adapted from Tsai GE, et al. Curr Pharm Des. 2010;16(5):522-537.

Glycine Reuptake InhibitorsRG1678 Study Design

• Subjects: 323 clinically stable schizophrenia patients with predominantly negative symptoms, low severity of positive symptoms

• Design: 8-week, randomized, double-blind, placebo-controlled trial

• Treatment: 10 mg, 30 mg, and 60 mg of RG1678 added to ongoing treatment

• Outcomes: negative symptom severity, overall symptom severity, function

Umbricht D, et al. Neuropsychopharmacology. 2010;35(suppl 1):49.

RESULTS: Negative Symptom (PANSS) Change

Data from Umbricht D, et al. Neuropsychopharmacology. 2010;35(suppl 1):49.

0

-1

-2

-3

-4

-5

-6

-7

-8

Baseline Week 1 Week 2 Week 4 Week 6 Week 8

PlaceboRG1678 10 mg/dayRG1678 30 mg/dayRG1678 60 mg/day

10 mg vs placebo P < 0.1

10 mg vs placebo 30 mg vs placebo

P < 0.110 mg vs placebo

P < 0.1

10 mg vs placebo 30 mg vs placebo

P < 0.05

∆ N

SF

S s

core

Mixed model repeated measures analysis

Results: CGI Negative Symptom Scale

Data from Umbricht D, et al. Neuropsychopharmacology. 2010;35(suppl 1):49.

50

40

30

20

10

0

Very much improved

Much improved

Minimally improved

No change

Placebo RG167830 mg/day

RG167810 mg/day

RG167860 mg/day

P < 0.05

P < 0.1

Pat

ien

ts (

%)

Data from Umbricht D, et al. Neuropsychopharmacology. 2010;35(suppl 1):49.

Results: Functional Improvement

60

58

56

54

52

0

Baseline

Week 4

Week 8

Placebo RG167830 mg/day

RG167810 mg/day

RG167860 mg/day

P < 0.1

Pat

ien

ts (

%)

50

P value is vs placebo; analysis of covariance

Safety Data

Data from Umbricht D, et al. Neuropsychopharmacology. 2010;35(suppl 1):49.

Summary and Clinical Implications

• Cognitive, negative, and residual positive symptoms occur in most patients with schizophrenia

• Residual symptoms lead to functional disability

• Early intervention and relapse prevention may lessen severity of residual symptoms

• Psychotherapeutic strategies may augment antipsychotic medications

• Glycine reuptake inhibitors are a promising approach to treat residual symptoms