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,
USA
rpettyus@aol.com

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


Disorder

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

This is inaccurate


Disorder

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: 704-716
2. Jones, P., et al., Lancet 1994; 344: 1398-1402
3. Done, DJ., et al., Brit Med Journal 1994; 309: 699-703.
4. McNeil, TF. Epidemiological Reviews 1995; 17: 107-112
5. Mellor ,CS. Brit J Psychiatry 1992; 160: 467-472
6. 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: 663-670
2. Harding, CM., et al., Br J Psychiatry 1992; 161 (Suppl 18): 27-37
3. Crow, TJ., et al., Br J Psychiatry 1986; 148: 120-127
4. Norman, RMG., et al., Br J Psychiatry 2001; 179: 340-345
5. Thompson, PM., et al., Proc Natl Acad Sci USA 2001: 98: 11650-11670


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

Brain Volume Changes in First-Episode
Schizophrenia: A 1-Year Follow-Up Study
 First-episode schizophrenia (n=34) 10
and matched healthy subjects (n=36)
8

% Change in Volume
 MRI obtained at inclusion and after 1 6
year
4
 Outcome measured at 2 years
2
 Total brain volume and cerebral gray
volume significantly decreased and 0
lateral ventricle volume significantly
increased in patients compared with -2
controls
-4
 The decrease in global gray matter Total Cerebral Lateral
volume significantly correlated with Brain Gray Ventricle
outcome and with cumulative dosage Volume Volume
of antipsychotic medication

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


Longitudinal MRI Assessment of
First-Episode Schizophrenia

29-year-old
4 episodes

26-year-old
3 episodes

23-year-old male
First episode

Courtesy of Dr Jeffrey Lieberman


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

Healthy twin

Twin with SZP
Gray matter may be 2-10% smaller in SZ. Olfactory bulbs
(General loss revealed best by ventricle size) may be ~ 20% smaller in SZ

Ruling out Medication Effects

Patients with
Schizophrenia

Medication-
matched patients
without
schizophrenia

Difference

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

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
A, abnormal ratio
Schizophrenia
patient
N, normal ratio

α


Early Insults Triggers?
Disease Genes Environment
Viral Infections e.g. Stress
Environmental
Toxins Biological
Factors

Cognitive Early Negative/ Attenuated Emerging
Brain Deficits Disorganized Positive Sx Psychotic Sx
Abnormalities Sx

Structural
Biochemical Targets for Intervention
Functional

AGE 0 9 12 15 18 21

Early Insults Triggers?
Disease Genes
Viral Infections
Environment SCHIZ
e.g. Stress
Environmental OPHR
Toxins Biological
Factors
ENIA

Biological Vulnerability

Cognitive Early Negative/ Attenuated Emerging
Brain Deficits Disorganized Positive Sx Psychotic Sx
Abnormalities Sx

Structural
Biochemical Targets for Intervention
Functional

AGE 0 9 12 15 18 21

Natural History of Schizophrenia
Good

Function

Psycho-
pathology

Poor

15 20 30 40 50 60 70

Age (Years)

Pathological
Process

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


Good

Mild motor,
Function
Social, cognitive
Non-specific
Impairments
Psycho- Behavioural
pathology
disturbances
Minor physical
anomalies

Stable
Premorbid Prodromal Progression Improving?
Relapsing

Poor

15 20 30 40 50 60 70

Age (Years)

Pathological
Process



Good

Mild motor,
Function
Social, cognitive
Non-specific
Impairments
Psycho- Behavioural
pathology
disturbances
Minor physical
anomalies

Stable
Premorbid Prodromal Progression Improving?
Relapsing

Poor

15 20 30 40 50 60 70

Age (Years)

Defects of cell Increased dopamine sensitivity Neurodegeneration
Pathological
Process migration Dysconnections
Decreased NMDA (?Increased Glutamate)
Apoptosis (?Oxidative stress; EAA?)



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

15
With
deficits
Without
deficits

85


Prevalence

15  As few as 15% of “stable”
outpatients would be
With considered
deficits “neuropsychologically
Without normal”
deficits  This implies an 85% rate of
impairment
85  In contrast, specific delusions
and hallucinations are
present in only 25% - 40% of
patients

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

Course of Cognitive Impairment in
Individuals with Schizophrenia Using “Typical Neuroleptics”
Standard deviations

0 Normal

–1

–2

–3

Initial 2 Years 20 Years
Premorbid Onset Therapy After Start After Onset
of Therapy


Course of Cognitive Impairment in
Individuals with Schizophrenia Using “Typical Neuroleptics”
Standard deviations

0 Normal
?
–1 Psychosis-Free
Patients

–2

–3

Initial 2 Years 20 Years
Premorbid Onset Therapy After Start After Onset
of Therapy


and Negative Symptoms

Cognitive Negative
Dysfunction 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


and Negative Symptoms

Cognitive Negative
Dysfunction 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


and 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


(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


(Continued)

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


(Continued)

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)


(Continued)

• 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


(Continued)

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?


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


What Impact Do Cognitive Symptoms Have On
Functioning?


What Impact Do Cognitive Symptoms Have On
Functioning?

 Decreased ability to prioritize
 Decreased ability to problem solve
 Impaired interpersonal skills
 Deceased ability to learn new
information


Neurocognitive Deficits and
Functional Ability
Community Functioning

Neurocognitive Instrumental and Social
Deficits Problem-Solving Skills

Psychosocial Skill
Acquisition
0.8
0.7
P<.0001
0.6
Large 0.5
0.4
Medium 0.3
0.2
Small 0.1
0.0
Secondary Immediate Executive Vigilance Summary
Verbal Verbal Function Scores
Memory Memory (Card
Sorting)
Green MF et al. Schizophrenia Bull. 2000;26:119-136.


Typical Profile of Cognitive Deficits in Schizophrenia,
Major Depressive Disorder, and Euthymic Bipolar
Disorder
Schizophrenia
1 Major Depressive Disorder
Euthymic Bipolar Disorder
0.5
Z Score (SD Units)

0

-0.5

-1

-1.5

-2
Verb Mem Verb Mem Vis Mem Fluency Trails B WCST Block Vocab
(delayed) (immed) Design

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

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


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

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

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
Healthy Control Mean (Theoretical)
0.0
∆ in Baseline (Standard Deviation)

-0.5

-1.0

-1.5
Immediate Secondary Vigilance Executive Visual Verbal Spatial
Memory Memory Functions Motor Fluency Functions
Skills

*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.


Effect Sizes* for Average Improvement in
Cognition With “Atypical” Antipsychotics
Healthy Control Mean (Theoretical)
0.0
∆ in Baseline (Standard Deviation)

-0.5

-1.0 .39 .39 .43

.27
.18 .20
.13

-1.5
Immediate Secondary Vigilance Executive Visual Verbal Spatial
Memory Memory Functions Motor Fluency Functions
Skills

*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.


CATIE: Δ in Neurocognitive Composite Score
After 2 Months Treatment
Perphenazine Risperidone Quetiapine
Olanzapine Ziprasidone
0.3
Baseline to 2 Months
Z-Score Δ From

0.2

0.1

n= n= n= n= n= n= n= n= n= n= n= n= n= n= n= n=
149 151 146 163 183 181 211 81 75 84 82 74 90 99 100 93
0.0
TD Patients TD Patients TD Patients TD Patients
Excluded Included Excluded Included
Ziprasidone Cohort

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 Domains After 2
Months of Treatment
Perphenazine
0.7 No significant differences Risperidone
2 Months, Excluding TD Patients

between groups (all P>.08). Quetiapine
0.6
Z-Score Δ From Baseline to

Olanzapine
0.5 Ziprasidone

0.4

0.3

0.2

0.1

0.0

-0.1
Processing Reasoning Working Verbal Vigilance
Speed Memory Memory


CATIE: Δ in Neurocognitive Composite
Score After 18 Months of Treatment
0.7 Overall differences Perphenazine
between treatments (P<.05)
Risperidone
0.6 Quetiapine
Baseline to 18 Months

Olanzapine
0.5
Z-Score Δ From

Ziprasidone

0.4

0.3

0.2

0.1
n= n= n= n= n= n= n= n= n= n= n= n= n= n= n= n=
52 55 46 74 67 54 90 27 27 21 34 23 31 25 41 31
0.0
TD Patients TD Patients TD Patients TD Patients
Excluded Included Excluded Included

Ziprasidone Cohort


Neurocognitive Effect of
Aripiprazole vs. Olanzapine
P=.02

0.5 ║ P=.04

║ Aripiprazole
(n=76)
Δ From Baseline

0.4
Olanzapine
0.3 (n=93)
P=NS P=NS
0.2 P=NS P=NS
†
* ‡ §
0.1

0
Wk 8 Wk 26 Wk 8 Wk 26 Wk 8 Wk 26
General Cognitive Executive Verbal Learning
Functioning Functioning

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.

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  Visual learning
 Attention/vigilance and memory
 Working memory  Reasoning and
 Verbal learning problem solving
and memory  Social cognition

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


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

.01

Functional
Social outcome
competence .27
.16* †

Social
domains:
.56† cognition: .30† • Social
Neurocognition Perception
of emotion • Work
.20† .10
Social • Independent
support living

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


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

Cognitive Domain Tests Included

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

Attention/Vigilance • CPT—Identical Pairs version

• Maryland Letter Number Span
Working Memory • 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 # Nominations
Alpha-7 nicotinic–receptor agonists 31
D1-receptor agonists 30
AMPA glutamatergic–receptor agonists 14
Alpha-2 adrenergic–receptor agonists 14
NMDA glutamatergic–receptor agonists 12
Metabotropic glutamate receptor agonists 12
Glycine-reuptake inhibitors 8
M1 muscarinic–receptor agonists 7
GABA 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

2006;63:1372-1376.


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

2006;63:1372-1376.


 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

2006;63:1372-1376.


 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

2006;63:1372-1376.


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, 117-21
3. 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



“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

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


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.

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


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.


Targets
 Facial affect recognition can be enhanced with
special training1



Targets
special training1
 Cognitive training can improve working memory2



Targets
special training1
 Attention can be improved with specialized
training3



Targets
special training1
 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)

100
90
80
70
60
CAP
50
OLZ
40
30
20
10
0
Baseline Endpoint


Comparison of Conventional Antipsychotics
and Olanzapine (Total IPT Scores)

100
90 p <.0001
80
70 p =0.13
60
CAP
50
OLZ
40
30
20
10
0
Baseline Endpoint
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
Supported employment with
45 cognitive training
40 Supported employment alone
35

30
Percent Working

25

20

15

10

5

0
1 3 5 7 9 11 13 15 17 19 21 23 25 27
Month

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


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 2007

Useful Addresses


Healia.com


www.RichardGPettyMD.com


rpettyus@aol.com


Warren.Cognition.December.2008

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