warren.cognition.december.2008

Psychotic Illness, Cognition, and Functional Outcomes

Richard G Petty MD, MSc, MRCP(UK), MRCPsych,

Promedica Research Center, Georgia State University College of Health

Sciences, Loganville, Georgia,

[email protected]

Sunday, July 26, 2009

Disclosure

Richard G. Petty, MD, MSc, MRCP(UK), MRCPsych Consultant

AstraZeneca; Bristol Myers Squibb; Eli Lilly and Company; Janssen Pharmaceuticals

Speaker’s Bureau Abbott Laboratories; AstraZeneca; Avanir Pharmaceuticals;

Janssen Pharmaceuticals Grant Support

British Diabetic Association; Bristol Myers Squibb; British Heart Foundation; Du Pont Merck, Inc.; Eli Lilly and Company; Janssen; Medical Research Council (UK); National Institute of Mental Health; Pfizer

Dr. Petty’s presentation will include the discussion of off-label, experimental, and/or investigational use of drugs or devices


Learning Objectives

Define the domains of cognitive impairment observed in patients with psychotic illness

Identify differences among response, relapse prevention, remission, and functional recovery criteria in measuring and treating cognitive impairment

Evaluate treatment options that may positively or negatively impact cognition in schizophrenia and other psychotic illness

Review the roles of psychosocial interventions and cognitive remediation for improving functional outcomes


Schizophrenia and Bipolar Disorder: Causes and Courses


The Causes of Schizophrenia and Bipolar Disorder



It is often said that schizophrenia and bipolar disorder are diseases of unknown aetiology

This is inaccurate



It is often said that schizophrenia and bipolar disorder are diseases of unknown aetiology

This is inaccurate

We know a lot about the causes of these illnesses, but we do not know why they cause schizophrenia and bipolar disorder: i.e. we don’t understand all of

the pathogenic mechanisms


Heteromodal Association Cortex: •Dorsolateral Prefrontal Cortex (Brodmann areas 9 and 46)•Inferior Parietal Lobule (Brodmann area 39 and 40) •Superior Temporal Gyrus (Brodmann area 22)

Pearlson, G.D., Petty, R.G., et al. Neuropsychopharmacology 14:1-17, 1995


The Time Course of Schizophrenia


The Time Course of Schizophrenia

Earliest signs often identifiable in infancy and childhood: Motor incoordination1

Failure to acquire speech by age two increases risk of subsequent schizophrenia five fold2

At ages 7-11 pre-schizophrenic children show impaired language and mathematical skills2,3

Increased shyness and inconsequential behaviours3

Strong evidence for other abnormalities of neurodevelopment: Birth difficulties4

Minor physical anomalies of developmental origin5

Evidence of aberrant migration of frontal and temporal neurons6

1. Walker , E., and Lewine, Am J Psychiatry 1990; 89: 704-7162. Jones, P., et al., Lancet 1994; 344: 1398-14023. Done, DJ., et al., Brit Med Journal 1994; 309: 699-703.4. McNeil, TF. Epidemiological Reviews 1995; 17: 107-1125. Mellor ,CS. Brit J Psychiatry 1992; 160: 467-4726. Akbarian et al. Arch Gen Psychiatry 1993; 50: 178-187


The Time Course of Schizophrenia (Cont.)


The Time Course of Schizophrenia (Cont.)

Prodromal symptoms of depression and social withdrawal Gender differences in age of onset Variable course:

10-15% recover completely1

~50% function quite well 30 years after severe illness2

Duration of untreated psychosis (DUP) is a strong predictor of outcome3, despite having little impact on cognitive performance4, suggesting that psychosis itself may either damage only some regions of the brain, or that DUP undermines other aspects of development

Spreading waves of gray matter loss occur in early-onset schizophrenia5

1. Watt, DC., et al., Psychol Med 1983; 13: 663-6702. Harding, CM., et al., Br J Psychiatry 1992; 161 (Suppl 18): 27-373. Crow, TJ., et al., Br J Psychiatry 1986; 148: 120-1274. Norman, RMG., et al., Br J Psychiatry 2001; 179: 340-3455. Thompson, PM., et al., Proc Natl Acad Sci USA 2001: 98: 11650-11670


Thompson, P. et al., Proc Natl Acad Sci USA 2001; 98: 11650-11655Sunday, July 26, 2009

Thompson, P. et al., Proc Natl Acad Sci USA 2001; 98: 11650-11655


Brain Volume Changes in First-Episode Schizophrenia: A 1-Year Follow-Up Study

First-episode schizophrenia (n=34) and matched healthy subjects (n=36)

MRI obtained at inclusion and after 1

year

Outcome measured at 2 years

Total brain volume and cerebral gray volume significantly decreased and lateral ventricle volume significantly increased in patients compared with controls

The decrease in global gray matter volume significantly correlated with outcome and with cumulative dosage of antipsychotic medication

-4

-2

0

2

4

6

8

10

TotalBrain

Volume

CerebralGray

Volume

LateralVentricle

% C

hang

e in

Volu

me

Cahn, W., et al. Arch Gen Psychiatry. 2002;59(11):1002-1010.


Longitudinal MRI Assessment of First-Episode Schizophrenia

23-year-old male First episode

26-year-old 3 episodes

29-year-old 4 episodes

Courtesy of Dr Jeffrey Lieberman


So in Response to the Question: Do Schizophrenic Individuals Have a Difference in Brain Structure?

Gray matter may be 2-10% smaller in SZ.(General loss revealed best by ventricle size)

Olfactory bulbs may be ~ 20% smaller in SZ

Healthy twin

Twin with SZP


Ruling out Medication Effects

Difference

Patients withSchizophrenia

Medication-matched patientswithout schizophrenia

Vidal, CN., et al., 8th Annual Meeting of the Organization for Human Brain Mapping, Sendai, Japan, June 2002Sunday, July 26, 2009

Sensory gating anomaly measured electrophysiologically:(a) Observed in schizophrenic patients (~90%) but in only 8% of the general population(b) Autosomal dominant transmission, even in healthy relatives of schizophrenia patients(c) This trait has been mapped to the vicinity of a gene on chromosome 15: the gene is a nicotine receptor

α

A, abnormal ratio

N, normal ratio

Schizophrenia patient


Disease GenesViral InfectionsEnvironmental Toxins

CognitiveDeficits

Early Negative/ Disorganized

Sx

Attenuated Positive Sx

Environmente.g. Stress

Biological Factors

AGE 0 9 12 15 21

Emerging Psychotic Sx

Early Insults

Brain Abnormalities

Targets for Intervention

Triggers?

18

StructuralBiochemicalFunctional


Disease GenesViral InfectionsEnvironmental Toxins

CognitiveDeficits

Early Negative/ Disorganized

Sx

Attenuated Positive Sx

Environmente.g. Stress

Biological Factors

AGE 0 9 12 15 21

Emerging Psychotic Sx

Early Insults

Brain Abnormalities

Targets for Intervention

Triggers?

SCHIZOPHRENIA

18

StructuralBiochemicalFunctional

Biological Vulnerability


Natural History of Schizophrenia

Robinson, D., et al., Am J Psychiatry. 1999;156(4)544-549Lewis, DA., and Lieberman, JA. Neuron 2000; 28: 325-334

Age (Years)

Good

Function

Psycho-pathology

Poor

15 20 30 40 50 60 70

PathologicalProcess




Age (Years)

Good

Function

Psycho-pathology

Poor

15 20 30 40 50 60 70

Premorbid Prodromal ProgressionStable

RelapsingImproving?

Mild motor,Social, cognitiveImpairments

Minor physical anomalies

Non-specificBehaviouraldisturbances

PathologicalProcess




Age (Years)

Good

Function

Psycho-pathology

Poor

15 20 30 40 50 60 70

Defects of cell Increased dopamine sensitivity Neurodegenerationmigration Dysconnections Decreased NMDA (?Increased Glutamate) Apoptosis (?Oxidative stress; EAA?)

Premorbid Prodromal ProgressionStable

RelapsingImproving?

Mild motor,Social, cognitiveImpairments

Minor physical anomalies

Non-specificBehaviouraldisturbances

PathologicalProcess


Cognition: The Central Problem in Schizophrenia


Cognition: The Central Problem in Schizophrenia

Is There Any Way In Which We Can Improve It?


Historical Perspective



The cognitive and functional impairments in schizophrenia have been the hallmark since the illness first emerged, and led Kraepelin to coin the term “Dementia Praecox” in 1896

Eugen Bleuler, while disagreeing with Kraepelin on some issues, viewed cognitive impairment as a core component of the “schizophrenias”



The cognitive and functional impairments in schizophrenia have been the hallmark since the illness first emerged, and led Kraepelin to coin the term “Dementia Praecox” in 1896

Eugen Bleuler, while disagreeing with Kraepelin on some issues, viewed cognitive impairment as a core component of the “schizophrenias”

Experimental approaches to the study of cognition in schizophrenia are more than 100 years old



Some of the earliest studies addressed topics that are still major issues of research today: Verbal skills Procedural learning

However, in the interim, the focus of treatment and research was heavily slanted toward other aspects of the illness Positive symptoms Negative symptoms


Cognitive Dysfunction

The Surgeon General’s Report (1999) notes that “dysfunction of fundamental cognitive processes is at the center of schizophrenia…” and goes on to say “Problems in such fundamental areas as paying selective attention, problem-solving, and remembering can cause serious difficulties in learning new skills and performing daily tasks.”

Page 272


Prevalence

85

15WithdeficitsWithoutdeficits


Prevalence

85

15WithdeficitsWithoutdeficits

As few as 15% of “stable” outpatients would be considered “neuropsychologically normal”

This implies an 85% rate of impairment

In contrast, specific delusions and hallucinations are present in only 25% - 40% of patients

Palmer, BW et al. Neuropsychology, 1997; 11: 437-477Paulsen, JS et al. J Int Neuropsych Soc, 1995; 1: 88-99


Course of Cognitive Impairment inIndividuals with Schizophrenia Using “Typical Neuroleptics”

Premorbid Onset InitialTherapy

2 YearsAfter Startof Therapy

20 YearsAfter Onset

Normal

Stan

dard

devia

tions 0

–1

–2

–3


Course of Cognitive Impairment inIndividuals with Schizophrenia Using “Typical Neuroleptics”

Premorbid Onset InitialTherapy

2 YearsAfter Startof Therapy

20 YearsAfter Onset

Normal

Stan

dard

devia

tions 0

–1

–2

–3

Psychosis-Free Patients

?


CognitiveDysfunction

NegativeSymptoms

Cognitive Dysfunctionand Negative Symptoms

Keefe RSE. The assessment of neurocognitive treatment response and its relation to negative symptoms in schizophrenia. In: Keefe RSE, McEvoy JP, eds. The Assessment of Negative Symptoms and Cognitive Deficit Treatment Response. Washington: American Psychiatric Press 2001


CognitiveDysfunction

NegativeSymptoms

Cognitive Dysfunctionand Negative Symptoms

Mutual Exacerbation

Keefe RSE. The assessment of neurocognitive treatment response and its relation to negative symptoms in schizophrenia. In: Keefe RSE, McEvoy JP, eds. The Assessment of Negative Symptoms and Cognitive Deficit Treatment Response. Washington: American Psychiatric Press 2001


Cognitive Dysfunctionand Adaptive Dysfunction



Cognitive deficits are more strongly correlated with adaptive dysfunction and outcome than any other symptom domain

Cognitive impairment predicts overall outcome better than negative symptoms

Positive symptoms, despite being distressing and distracting, do not predict adaptive dysfunction or outcome

Green, MF. Am J Psychiatry. 1996;153:321-330


Cognitive Dysfunction in Schizophrenia

The major determinant of outcome Can be subdivided into three principle domains:

Global cognitive function: Wechsler Digit Symbol Substitution Test

Specific deficits: Learning Executive function Working memory

Social cognition

Dickinson, D. British Journ al of Psychiatry 2008; 193: 354-356


Cognitive Impairments in Schizophrenia

Severe Impairments (2-3 SD below the mean)

Serial learning: Process of learning through exposure and practice

Vigilance: Ability to sustain attention and effort

Motor speed: Rate at which simple and skilled motor acts are performed

Verbal fluency: Producing words on demand based on conceptual categories or

phonological information

Note: The “mean” refers to the average level of performance of normal individuals who are similar in age and education attainment


Cognitive Impairments in Schizophrenia (Continued)

Severe Impairments (2-3 SD below the mean)

Executive function: Ability to concentrate Ability to distinguish important information from unimportant Ability to prioritize Ability to perform mental or physical acts in proper sequence Ability to modulate behavior based on social cues



Moderate Impairments (1-2 SD below the mean)

Delayed recall: Ability to recall information without cues or prompts

Distractibility: Inability to ignore irrelevant information and focus on relevant

information Immediate memory span

Ability to remember, briefly, a short list of information



Moderate Impairments (1-2 SD below the mean)

Visuomotor skills: Ability to integrate visual information and motor skills

Working memory: Ability to remember information for a very brief period

while using it for other operations (e.g. remembering a list of numbers while adding them together)



• Mild Impairments (0.5-1 SD below the mean)

Perceptual skills: Ability to recognize and identify stimuli such as sounds, smell, and

sights Delayed recognition memory:

Ability to remember after a time delay Confrontation naming:

Presented with an object, ask to identify it IQ:

Most patients with schizophrenia have an IQ in the 90s



No Impairment Word recognition reading Long-term factual memory

Both of which have important implications for psychoeducation: Written materials are helpful Large font Short sentences Concepts explained in concrete terms


Cognitive Functioning: Implications for Psychoeducation

Use conversational tone; personalized, empathetic, motivational tone to materials

Interactive style with self-discovery quizzes, fill-in charts, open-ended questions, as well as interactive exercises with mental health professionals will facilitate learning

Graphic style should include: - Larger type, bold type



Cognitive deficits are more strongly correlated with adaptive dysfunction and outcome than any other symptom domain

Cognitive impairment predicts overall outcome better than negative symptoms

Positive symptoms, despite being distressing and distracting, do not predict adaptive dysfunction or outcome

Green, MF. Am J Psychiatry. 1996;153:321-330


Assessing Cognitive Dysfunction

A number of tests exist to evaluate the type and extent of cognitive dysfunction

Some can be easily performed by clinicians!


What Impact Do Cognitive Symptoms Have On Functioning?



Functional limitations vary from individual to individual Generally, we see:

Decreased concentration and attention Memory impairment Difficulty with following multi-step problems Difficulty remembering and following verbal commands Difficulty filtering irrelevant information



Decreased ability to prioritizeDecreased ability to problem solve Impaired interpersonal skillsDeceased ability to learn new

information


Psychosocial Skill Acquisition

Green MF et al. Schizophrenia Bull. 2000;26:119-136.

SecondaryVerbal

Memory

ImmediateVerbal

Memory

ExecutiveFunction

(Card Sorting)

Vigilance SummaryScores

Large

Medium

Small

NeurocognitiveDeficits

Community Functioning

Instrumental and SocialProblem-Solving Skills

P<.0001

Neurocognitive Deficits and Functional Ability

0.00.10.20.30.40.50.60.70.8


Typical Profile of Cognitive Deficits in Schizophrenia, Major Depressive Disorder, and Euthymic Bipolar

Disorder

WCST = Wisconsin Card Scoring Test.Buchanan RW et al. Schizophrenia Bull. 2005;31:5-19.

-2

-1.5

-1

-0.5

0

0.5

1

Verb Mem(delayed)

Verb Mem(immed)

Vis Mem Fluency Trails B WCST BlockDesign

Vocab

SchizophreniaMajor Depressive DisorderEuthymic Bipolar Disorder

Z Sc

ore

(SD

Uni

ts)


The Role of Antipsychotics in Cognitive Functioning

What role do medications play in enhancement of cognitive functioning?

Do “atypicals” show differences over the older medications?

Do the “atypicals” show differences among one another?


Conventional Antipsychotics and Cognitive Impairment


1Cassens, G, et al. Schizophr Bull. 1990;16:477-499; 2Medalia, A., et al. Clin Neuropsychol. 1988;3:249-271; 3Blyler, R., et al. Cognitive effects of typical antipsychotic treatment: another look. In: Sharma, T., Harvey, PD., eds. Cognitive Deficits in Schizophrenia. Oxford, UK: Oxford University Press 2001

Conventional Antipsychotics and Cognitive Impairment

Conventional antipsychotics are not effective for cognitive impairment1-3

Attention worsens initially but may improve slightly after several weeks of treatment1-3

Motor functions worsen1-3

Other functions remain about the same or worsen1-3

Absence of “practice effects”3


Rationale for Developing Interventions to Improve Cognition in Schizophrenia

• Evidence that cognitive deficits are core features of schizophrenia

• Evidence for relationships between cognition and functional outcome in schizophrenia

• Increasing research focus on the basic studies of neuropharmacology of cognition

• NIMH Initiative—Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS)

NIMH = National Institute of Mental Health.Buchanan RW et al. Schizophrenia Bull. 2005;31:5-19.


Effect Sizes* for Average Improvement in Cognition With “Atypical” Antipsychotics

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

Healthy Control Mean (Theoretical)

∆ in

Bas

elin

e (S

tand

ard

Dev

iatio

n)

Secondary Memory

Vigilance Executive Functions

VisualMotorSkills

Verbal Fluency

Spatial Functions

Immediate Memory

-1.5

-1.0

-0.5

0.0


Effect Sizes* for Average Improvement in Cognition With “Atypical” Antipsychotics

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

Healthy Control Mean (Theoretical)

∆ in

Bas

elin

e (S

tand

ard

Dev

iatio

n)

Secondary Memory

Vigilance Executive Functions

VisualMotorSkills

Verbal Fluency

Spatial Functions

Immediate Memory

.20

.43

.27.18

.39.39

.13

-1.5

-1.0

-0.5

0.0


No significant differences between treatments (P=.20) CATIE = Clinical Antipsychotic Trials of Intervention Effectiveness Study; TD = tardive dyskinesia.Keefe RSE et al. Presented at: 61st SOBP Annual Meeting; May 18-20, 2006; Toronto, Canada.

CATIE: Δ in Neurocognitive Composite Score After 2 Months Treatment

n=149

Z-Sc

ore Δ

Fro

mB

asel

ine

to 2

Mon

ths

0.0

0.1

0.2

0.3

TD PatientsExcluded

TD PatientsIncluded

TD PatientsExcluded

TD PatientsIncluded

Perphenazine Risperidone QuetiapineOlanzapine Ziprasidone

Ziprasidone Cohort

n=146

n=151

n=181

n=183

n=163

n=75

n=81

n=211

n=84

n=82

n=74

n=90

n=99

n=100

n=93


CATIE: Δ in Neurocognitive Domains After 2 Months of Treatment

Keefe RSE et al. Presented at: 61st SOBP Annual Meeting; May 18-20, 2006; Toronto, Canada.

Z-Sc

ore Δ

Fro

m B

asel

ine

to2

Mon

ths,

Exc

ludi

ng T

D P

atie

nts

Processing Speed

Reasoning Working Memory

VigilanceVerbal Memory

No significant differences between groups (all P>.08).

-0.1

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7 Perphenazine Risperidone Quetiapine Olanzapine Ziprasidone


Keefe RSE et al. Presented at: 61st SOBP Annual Meeting; May 18-20, 2006; Toronto, Canada.

CATIE: Δ in Neurocognitive Composite Score After 18 Months of Treatment

Ziprasidone Cohort

TD PatientsExcluded

TD Patients Included

TD PatientsExcluded

TD PatientsIncluded

Z-Sc

ore Δ

Fro

m

Bas

elin

e to

18

Mon

ths

Overall differences between treatments (P<.05)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7 Perphenazine RisperidoneQuetiapineOlanzapineZiprasidone

n=52

n=46

n=55

n=54

n=67

n=74

n=27

n=27

n=90

n=21

n=34

n=23

n=31

n=25

n=41

n=31


Neurocognitive Effect of Aripiprazole vs. Olanzapine

LOCF analyses.*P=.023; †P=.015; ‡P=.055; §P=.087; ║P<.0001 vs baseline.Adapted from Kern RS et al. Psychopharmacology. 2006;187:312-320.

0

0.5

0.4

0.3

0.2

0.1

Wk 8 Wk 26 Wk 8 Wk 26 Wk 8 Wk 26

General Cognitive Functioning

Executive Functioning

Verbal Learning

Δ F

rom

Bas

elin

e Aripiprazole(n=76)Olanzapine(n=93)

P=NS P=NSP=NSP=NS

P=.04

P=.02

*†

§

║

║

‡


Obstacles for Drug Development in Cognition

Lack of consensus on cognitive measures Uncertainty about relevant neuropharmacologic

targets Lack of consensus on appropriate animal and

human models Concerns regarding likelihood of FDA

acceptance of an indication in this area

Marder SR, Fenton W. Schizophrenia Res. 2004;72:5-9; Buchanan RW et al. Schizophrenia Res. 2005;31:5-19; Breier A. Schizophrenia Bull. 2005;31:816-822.


NIMH/MATRICS Approach to a Clinical Target

Use a consensus-building process to Define the basic elements (separable domains) of

the target Develop methods for measuring each element as a

potential endpoint in clinical trials Develop a clinical trials methodology Develop animal models Prioritize molecular targets

Marder SR, Fenton W. Schizophrenia Res. 2004;72:5-9; Buchanan RW et al. Schizophrenia Res. 2005;31:5-19.


Separable Cognitive Domains in Schizophrenia

Speed of processing Attention/vigilance Working memory Verbal learning

and memory

Visual learning and memory

Reasoning and problem solving

Social cognition

Nuechterlein KH et al. Schizophrenia Res. 2004;72:29-39.


Path Analysis: Neurocognition, Social Cognition, and Functional Outcome (Global Outcome)

*P<.05; †P<.01, one-tailed.Brekke J et al. Schizophrenia Res. 2005;80:213-225.

Social support

Social competence

Socialcognition:Perception of emotion

Neurocognition

.01

.56†

.16* .27†

.30†

.20† .10

• Social • Work• Independent

living

Functional outcome domains:


MATRICS Consensus Cognitive Battery(Estimated Administration Time: 63.5 min)

Cognitive Domain Tests Included

Speed of Processing• Category Fluency• BACS Symbol Coding• Trial Making A

Attention/Vigilance • CPT—Identical Pairs version

Working Memory • Maryland Letter Number Span• WMS-III Spatial Span

Verbal Learning • Hopkins Verbal Learning Test

Visual Learning • Brief Visuospatial Memory Test

Reasoning and Problem Solving • NAB Mazes

Social Cognition • MSCEIT™ Managing Emotions

BACS = Brief Assessment of Cognition in Schizophrenia; CPT = Current Procedural Terminology; WMS = Working Memory in Schizophrenia; NAB = Neuropsychological Assessment Battery; MSCEIT™ = Mayer-Salovey-Caruso Emotional Intelligence Test.MATRICS NCC. Provisional Consensus Cognitive Battery. Available at: http://www.matrics.ucla.edu/provisional-MATRICS-battery-core-11-30-04.pdf. Accessed February 9, 2007.


Selected Recommendations From NIMH/FDA Conference, April 23, 2004

Include subjects who are clinically stable Exclude subjects only if impairment compromises test

validity or if they perform at ceiling For co-medication: compare addition of drug or placebo

to current antipsychotic For broad spectrum antipsychotic: compare

experimental drug to an antipsychotic that does not impair cognition

Monitor outcome with MATRICS Cognitive Battery and a co-primary measure of functional capacity or interview-based cognitive assessment

Buchanan RW et al. Schizophrenia Res. 2005;31:5-19.


MATRICS Ranking of Targets

Target # NominationsAlpha-7 nicotinic–receptor agonists 31D1-receptor agonists 30AMPA glutamatergic–receptor agonists 14Alpha-2 adrenergic–receptor agonists 14NMDA glutamatergic–receptor agonists 12Metabotropic glutamate receptor agonists 12Glycine-reuptake inhibitors 8M1 muscarinic–receptor agonists 7GABA alpha-2 subtype–selective agonists 5

AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; NMDA = N-methyl-D-aspartate;GABA = γ-aminobutyric acid.Tamminga CA. J Clin Psychiatry. 2006;67(suppl 9):9-13; Marder SR. J Clin Psychiatry. 2006;67(suppl 9):31-35.


Trial of DMXB-A, an α-7 Nicotinic Agonist

12 patients administered double-blind DMXB-A at 2 doses and placebo

Treatment was for a single day with 2 doses administered

DMXB-A was associated with greater improvement on a cognitive battery

Olincy A et al. Arch Gen Psychiatry. 2006;63:630-638.


Dopamine D1 Receptor in Schizophrenia

Goldman-Rakic PS et al. Psychopharmacology (Berl). 2004;174:3-16.




Patients with schizophrenia have substantial impairments in working memory





D1 receptors in the prefrontal cortex regulate working memory with D1 agonists improving working memory





D1 receptors in the prefrontal cortex regulate working memory with D1 agonists improving working memory

The effectiveness of D1 agonists for improving working memory has been demonstrated in rodents and nonhuman primates. Studies in schizophrenia patients are being initiated


Serotonin Receptors

Roth BL et al. Psychopharmacology. 2004;174:17-24.


Serotonin Receptors


5-HT1A receptors are concentrated in the hippocampus; partial agonists and antagonists both improve cognition in animal models


Serotonin Receptors



5-HT2A receptors affect both glutamate and dopamine release; studies in animals suggest that 5-HT2A antagonists improve cognition


Serotonin Receptors




5-HT6 antagonists are in late-stage testing for cognition


Serotonin Receptors




5-HT6 antagonists are in late-stage testing for cognition

Drugs affecting these 3 receptors are currently being tested in patient populations


Glutamate as a Target

Coyle JT, Tsai G. Psychopharmacology (Berl). 2004;174:32-38; Lewis DA, Moghaddam B. Arch Neurol. 2006;63:1372-1376.



Glutamate can affect neurotransmission by acting at multiple receptors, including NMDA and AMPA receptors, as well as metabotropic glutamate (mGlu) receptors





NMDA antagonists such as phencyclidine can cause symptoms of schizophrenia and impair cognition






Some, but not all, studies of drugs affecting the glycine modulatory site of NMDA receptors—glycine, d-cycloserine, sarcosine, and D-serine—have shown improvement in negative symptoms and cognition in schizophrenia






Some, but not all, studies of drugs affecting the glycine modulatory site of NMDA receptors—glycine, d-cycloserine, sarcosine, and D-serine—have shown improvement in negative symptoms and cognition in schizophrenia

Drugs affecting AMPA receptors in schizophrenia are currently in clinical trials; agents targeting mGlu 2,3,5 receptors are at different stages of development



GABA and Schizophrenia

mRNA = messenger RNA.Lewis DA, Moghaddam B. Arch Neurol. 2006;63:1372-1376.



Coordinated firing of GABA neurons in prefrontal cortex is necessary for pyramidal cell functioning





Reduced expression of the mRNA for an enzyme that synthesizes GABA has been found in schizophrenia; a subtype, GABAA α2, appears increased in schizophrenia





Reduced expression of the mRNA for an enzyme that synthesizes GABA has been found in schizophrenia; a subtype, GABAA α2, appears increased in schizophrenia

Clinical trials of a GABAA α2 partial agonist are underway



Muscarinic Cholinergic Targets

CNS = central nervous system.Friedman JI. Psychopharmacology (Berl). 2004;174:45-53.



Reduction in CNS Ach function impairs cognition, as in Alzheimer’s disease





In animals, cholinergic agonists enhance, and antagonists impair, cognition






Patients with schizophrenia have reduced M1 receptor numbers in neocortex






Patients with schizophrenia have reduced M1 receptor numbers in neocortex

Studies of cholinesterase inhibitors in schizophrenia have shown mixed results; best results are with dual cholinesterase inhibitors



Dementia Treatments in Schizophrenia

Memantine does not help cognitive function in schizophrenia1,2

Donepezil has also failed to show cognitive improvement in schizophrenia3

1. Lieberman, J. A., et al. Neuropsychopharmacology advance online publication, 12 November 2008; doi:10.1038/npp.2008.200.2. Krivoy, A., et al Eur Neuropsychopharmacol 2008; 18, 117-213. Akhondzadeh, S., Gerami, M., Noroozian, M., Karamghadiri, N., Ghoreishi, A., Abbasi, S. H., et al. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32, 1810-5.


Social Cognition


What is Social Cognition?



“The mental operations underlying social interactions, which include the human ability to perceive the intentions and dispositions of others”1

i.e. How we perceive, recall, think about, and interpret information about our actions and the actions of others



Includes: Impression formation Attribution theory Social schemas Heuristics

“The mental operations underlying social interactions, which include the human ability to perceive the intentions and dispositions of others”1

i.e. How we perceive, recall, think about, and interpret information about our actions and the actions of others

1. Brothers, L. Concepts in Neuroscience 1990; 1: 27-61


Social Cognition

• Much of the work in social cognition has been directed at understanding how we overcome limitations in our ability to process information

• Despite our substantial intellect, we are not able to process all of the stimuli we encounter at any moment

• This information overload requires us to develop shortcuts and strategies that make information processing fast and efficient


Social Cognition and Schizophrenia: Background

Effective social functioning incorporates many skills, including interpreting verbal and nonverbal social cues

Previous studies investigating social cognition in schizophrenia have focused on the ability to interpret facial expressions and results generally indicate patient deficits in this skill1-3

Additionally, patients with schizophrenia may have more difficulty in recognizing negative facial expressions4,5


Social Cognition and Schizophrenia: Background

Effective social functioning incorporates many skills, including interpreting verbal and nonverbal social cues

Previous studies investigating social cognition in schizophrenia have focused on the ability to interpret facial expressions and results generally indicate patient deficits in this skill1-3

Additionally, patients with schizophrenia may have more difficulty in recognizing negative facial expressions4,5

1. Walker, E., McGuire, M., & Bettes, B. The British Journal of Clinical Psychology, 1984; 23: 37-44.2. Feinberg, T.E., Rifkin, A., Schaffer, C., et al. Archives of General Psychiatry, 1986; 43, 276-279.3. Zuroff, D.C. & Colussy, S.A. Journal of Clinical Psychology, 1986; 42: 411-417.4. Burch, J.W. (1995). Journal of Clinical Psychology,1995; 51: 140-151. 5. Bell, M., Bryson, G., Lysaker, P. Psychiatry Research, 1997; 73: 73-82.


Social Cognition and Schizophrenia: Background (Continued)

Relatives of patients with schizophrenia also performed more poorly than controls in recognizing nonverbal cues1

A social-cognitive model of the etiology and development of schizophrenia is necessary to account for the associated deficits in social cognition and other symptomatology2

Emerging evidence analyzing brain activity in schizophrenia indicates that deficits in facial affect recognition could be a result of hypoactivity in specific brain regions3

“Atypical” antipsychotics seem to positively influence social cognition in schizophrenia patients4


Social Cognition and Schizophrenia: Background (Continued)

Relatives of patients with schizophrenia also performed more poorly than controls in recognizing nonverbal cues1

A social-cognitive model of the etiology and development of schizophrenia is necessary to account for the associated deficits in social cognition and other symptomatology2

Emerging evidence analyzing brain activity in schizophrenia indicates that deficits in facial affect recognition could be a result of hypoactivity in specific brain regions3

“Atypical” antipsychotics seem to positively influence social cognition in schizophrenia patients4

1. Toomey, R., Seidman, L.J., Lyons, M.J., et al. Schizophrenia Research, 1999; 40: 121-130.2. Penn, D. L., Spaulding, W., Reed, D., & Sullivan, M. Schizophrenia Research, 1996; 20: 327-335.3. Streit, M., Ioannides, A., Sinnemann, T., et al. American Journal of Psychiatry, 2001; 158: 1429-1436.4. Kee, K.S., Kern, R.S., Marshall, B.D. Jr., & Green, M.F. Schizophrenia Research, 1998; 31: 159-165.


Psychosocial Approaches to Specific Targets

1. Wolwer W et al. Schizophr Res. 2005;80:295-303; 2. Bell MD et al. J Rehabil Res Dev. 2005;42:829-838;3. Silverstein S et al. Psychiatr Q. 1998;69:95-105; 4. Hogarty GE et al. Psychiatr Serv. 2006;57:1751-1757.



Facial affect recognition can be enhanced with special training1





Cognitive training can improve working memory2





Cognitive training can improve working memory2 Attention can be improved with specialized

training3





Cognitive training can improve working memory2 Attention can be improved with specialized

training3

Cognitive Enhancement Therapy (CET) improved neurocognition and processing speed4



A First Study on Using Medication to Enhance Social Cognition


Interpersonal Perception Task (IPT)

The IPT was developed to assess nonverbal communication and social perception1

The IPT evaluates 5 domains of social cognition: - Status - Intimacy - Kinship - Competition - Deception (Lying)



The IPT was developed to assess nonverbal communication and social perception1

The IPT evaluates 5 domains of social cognition: - Status - Intimacy - Kinship - Competition - Deception (Lying)

1. Archer, D. & Costanzo, M. (1988). The interpersonal perception task: A new video about non-verbal communication and social perception. Berkeley, CA: University of California, Extension Media Center.



IPT contains 30 brief videotape scenes Each scene is 30-60 seconds in length Each scene is paired with a question that has 2 or 3 possible

answers The people in each scene are not actors and the situations are real Viewer must “decode” something important about the people she or

he has just seen Decoding is based on non-verbal information


Comparison of Conventional Antipsychotics and Olanzapine (Total IPT Scores)

0102030405060708090

100

Baseline Endpoint

CAPOLZ


Comparison of Conventional Antipsychotics and Olanzapine (Total IPT Scores)

0102030405060708090

100

Baseline Endpoint

CAPOLZ

p =0.13

p <.0001

p Values based on two-tailed t-tests for independent samples

Littrell, K. H., Petty, R. G., et al. Schizophrenia Research 66(2), 201-202, 2004


Cognitive Training: Effects on Employment Rate

McGurk SR, et al. Am J Psychiatry. 2007; 164:437-441.

Supported employment withcognitive training

Supported employment alone

45

40

35

30

25

20

15

10

5

0

1 3 5 7 9 11 13 15 17 19 21 23 25 27

Perc

ent W

orki

ng

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Conclusions

Improvement of functional outcomes in schizophrenia is likely to emerge from medicines that target neurocognitive impairments, as well as persistent positive or negative symptoms

Additional improvement in these domains may occur with targeted psychosocial interventions


Lithium and Cortical Grey Matter

Bearden, CE., et al. Biological Psychiatry, June 2007Sunday, July 26, 2009

Useful Addresses

Healia.com

www.RichardGPettyMD.com

[email protected]


warren.cognition.december.2008

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