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Warren.Cognition.December.2008
1. 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
2. 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
Sunday, July 26, 2009
3. 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
Sunday, July 26, 2009
6. The Causes of Schizophrenia and Bipolar
Disorder
Sunday, July 26, 2009
7. The Causes of Schizophrenia and Bipolar
Disorder
It is often said that schizophrenia and bipolar
disorder are diseases of unknown aetiology
This is inaccurate
Sunday, July 26, 2009
8. The Causes of Schizophrenia and Bipolar
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
Sunday, July 26, 2009
9. 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
Sunday, July 26, 2009
10. 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
Sunday, July 26, 2009
12. 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
Sunday, July 26, 2009
13. The Time Course of Schizophrenia (Cont.)
Sunday, July 26, 2009
14. 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
Sunday, July 26, 2009
15. Thompson, P. et al., Proc Natl Acad Sci USA 2001; 98: 11650-11655
Sunday, July 26, 2009
16. Thompson, P. et al., Proc Natl Acad Sci USA 2001; 98: 11650-11655
Sunday, July 26, 2009
17. Thompson, P. et al., Proc Natl Acad Sci USA 2001; 98: 11650-11655
Sunday, July 26, 2009
18. 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.
Sunday, July 26, 2009
19. 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.
Sunday, July 26, 2009
20. 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
Sunday, July 26, 2009
21. 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
Sunday, July 26, 2009
22. 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
Sunday, July 26, 2009
23. 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
Sunday, July 26, 2009
24. 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
Sunday, July 26, 2009
25. 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
Sunday, July 26, 2009
26. 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
Sunday, July 26, 2009
27. Natural History of Schizophrenia
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
Robinson, D., et al., Am J Psychiatry. 1999;156(4)544-549
Lewis, DA., and Lieberman, JA. Neuron 2000; 28: 325-334
Sunday, July 26, 2009
28. Natural History of Schizophrenia
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?)
Robinson, D., et al., Am J Psychiatry. 1999;156(4)544-549
Lewis, DA., and Lieberman, JA. Neuron 2000; 28: 325-334
Sunday, July 26, 2009
33. 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”
Sunday, July 26, 2009
34. 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”
Sunday, July 26, 2009
35. 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”
Experimental approaches to the study of cognition
in schizophrenia are more than 100 years old
Sunday, July 26, 2009
37. Historical Perspective
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
Sunday, July 26, 2009
38. 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
Sunday, July 26, 2009
39. Prevalence
15
With
deficits
Without
deficits
85
Sunday, July 26, 2009
40. 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
Sunday, July 26, 2009
41. 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
Sunday, July 26, 2009
42. 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
Sunday, July 26, 2009
43. Cognitive Dysfunction
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
Sunday, July 26, 2009
44. Cognitive Dysfunction
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
Sunday, July 26, 2009
46. Cognitive Dysfunction
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
Sunday, July 26, 2009
47. 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
Sunday, July 26, 2009
48. 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
Sunday, July 26, 2009
49. 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
Sunday, July 26, 2009
50. 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
Sunday, July 26, 2009
51. 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
Sunday, July 26, 2009
52. Cognitive Impairments in Schizophrenia
(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
Sunday, July 26, 2009
53. Cognitive Impairments in Schizophrenia
(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)
Sunday, July 26, 2009
54. Cognitive Impairments in Schizophrenia
(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
Sunday, July 26, 2009
55. Cognitive Impairments in Schizophrenia
(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
Sunday, July 26, 2009
56. 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
Sunday, July 26, 2009
58. Cognitive Dysfunction
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
Sunday, July 26, 2009
59. Assessing Cognitive Dysfunction
A number of tests exist
to evaluate the type
and extent of cognitive
dysfunction
Some can be easily
performed by
clinicians!
Sunday, July 26, 2009
60. What Impact Do Cognitive Symptoms
Have On Functioning?
Sunday, July 26, 2009
61. 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
Sunday, July 26, 2009
62. What Impact Do Cognitive Symptoms Have On
Functioning?
Sunday, July 26, 2009
63. 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
Sunday, July 26, 2009
64. 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.
Sunday, July 26, 2009
65. 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.
Sunday, July 26, 2009
66. 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.
Sunday, July 26, 2009
67. 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?
Sunday, July 26, 2009
69. 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
Sunday, July 26, 2009
70. 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.
Sunday, July 26, 2009
71. 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.
Sunday, July 26, 2009
72. 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.
Sunday, July 26, 2009
73. 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.
Sunday, July 26, 2009
74. 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
Keefe RSE et al. Presented at: 61st SOBP Annual Meeting; May 18-20, 2006; Toronto, Canada.
Sunday, July 26, 2009
75. 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
Keefe RSE et al. Presented at: 61st SOBP Annual Meeting; May 18-20, 2006; Toronto, Canada.
Sunday, July 26, 2009
76. 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.
Sunday, July 26, 2009
77. 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.
Sunday, July 26, 2009
78. 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.
Sunday, July 26, 2009
79. 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.
Sunday, July 26, 2009
80. 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.
Sunday, July 26, 2009
81. 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.
Sunday, July 26, 2009
82. 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.
Sunday, July 26, 2009
84. 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.
Sunday, July 26, 2009
85. Dopamine D1 Receptor in Schizophrenia
Goldman-Rakic PS et al. Psychopharmacology (Berl). 2004;174:3-16.
Sunday, July 26, 2009
86. Dopamine D1 Receptor in Schizophrenia
Patients with schizophrenia have substantial
impairments in working memory
Goldman-Rakic PS et al. Psychopharmacology (Berl). 2004;174:3-16.
Sunday, July 26, 2009
87. Dopamine D1 Receptor in Schizophrenia
Patients with schizophrenia have substantial
impairments in working memory
D1 receptors in the prefrontal cortex regulate
working memory with D1 agonists improving
working memory
Goldman-Rakic PS et al. Psychopharmacology (Berl). 2004;174:3-16.
Sunday, July 26, 2009
88. Dopamine D1 Receptor in Schizophrenia
Patients with schizophrenia have substantial
impairments in 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
Goldman-Rakic PS et al. Psychopharmacology (Berl). 2004;174:3-16.
Sunday, July 26, 2009
90. Serotonin Receptors
5-HT1A receptors are concentrated in the
hippocampus; partial agonists and antagonists
both improve cognition in animal models
Roth BL et al. Psychopharmacology. 2004;174:17-24.
Sunday, July 26, 2009
91. Serotonin Receptors
5-HT1A receptors are concentrated in the
hippocampus; partial agonists and antagonists
both improve cognition in animal models
5-HT2A receptors affect both glutamate and
dopamine release; studies in animals suggest
that 5-HT2A antagonists improve cognition
Roth BL et al. Psychopharmacology. 2004;174:17-24.
Sunday, July 26, 2009
92. Serotonin Receptors
5-HT1A receptors are concentrated in the
hippocampus; partial agonists and antagonists
both improve cognition in animal models
5-HT2A receptors affect both glutamate and
dopamine release; studies in animals suggest
that 5-HT2A antagonists improve cognition
5-HT6 antagonists are in late-stage testing for
cognition
Roth BL et al. Psychopharmacology. 2004;174:17-24.
Sunday, July 26, 2009
93. Serotonin Receptors
5-HT1A receptors are concentrated in the
hippocampus; partial agonists and antagonists
both improve cognition in animal models
5-HT2A receptors affect both glutamate and
dopamine release; studies in animals suggest
that 5-HT2A antagonists improve cognition
5-HT6 antagonists are in late-stage testing for
cognition
Drugs affecting these 3 receptors are currently
being tested in patient populations
Roth BL et al. Psychopharmacology. 2004;174:17-24.
Sunday, July 26, 2009
94. Glutamate as a Target
Coyle JT, Tsai G. Psychopharmacology (Berl). 2004;174:32-38; Lewis DA, Moghaddam B. Arch Neurol.
2006;63:1372-1376.
Sunday, July 26, 2009
95. Glutamate as a Target
Glutamate can affect neurotransmission by acting at
multiple receptors, including NMDA and AMPA receptors,
as well as metabotropic glutamate (mGlu) receptors
Coyle JT, Tsai G. Psychopharmacology (Berl). 2004;174:32-38; Lewis DA, Moghaddam B. Arch Neurol.
2006;63:1372-1376.
Sunday, July 26, 2009
96. Glutamate as a Target
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
Coyle JT, Tsai G. Psychopharmacology (Berl). 2004;174:32-38; Lewis DA, Moghaddam B. Arch Neurol.
2006;63:1372-1376.
Sunday, July 26, 2009
97. Glutamate as a Target
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
Coyle JT, Tsai G. Psychopharmacology (Berl). 2004;174:32-38; Lewis DA, Moghaddam B. Arch Neurol.
2006;63:1372-1376.
Sunday, July 26, 2009
98. Glutamate as a Target
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
Drugs affecting AMPA receptors in schizophrenia are
currently in clinical trials; agents targeting mGlu 2,3,5
receptors are at different stages of development
Coyle JT, Tsai G. Psychopharmacology (Berl). 2004;174:32-38; Lewis DA, Moghaddam B. Arch Neurol.
2006;63:1372-1376.
Sunday, July 26, 2009
99. GABA and Schizophrenia
mRNA = messenger RNA.
Lewis DA, Moghaddam B. Arch Neurol. 2006;63:1372-1376.
Sunday, July 26, 2009
100. GABA and Schizophrenia
Coordinated firing of GABA neurons in prefrontal
cortex is necessary for pyramidal cell functioning
mRNA = messenger RNA.
Lewis DA, Moghaddam B. Arch Neurol. 2006;63:1372-1376.
Sunday, July 26, 2009
101. GABA and Schizophrenia
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
mRNA = messenger RNA.
Lewis DA, Moghaddam B. Arch Neurol. 2006;63:1372-1376.
Sunday, July 26, 2009
102. GABA and Schizophrenia
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
Clinical trials of a GABAA α2 partial agonist are
underway
mRNA = messenger RNA.
Lewis DA, Moghaddam B. Arch Neurol. 2006;63:1372-1376.
Sunday, July 26, 2009
103. Muscarinic Cholinergic Targets
CNS = central nervous system.
Friedman JI. Psychopharmacology (Berl). 2004;174:45-53.
Sunday, July 26, 2009
104. Muscarinic Cholinergic Targets
Reduction in CNS Ach function impairs cognition,
as in Alzheimer’s disease
CNS = central nervous system.
Friedman JI. Psychopharmacology (Berl). 2004;174:45-53.
Sunday, July 26, 2009
105. Muscarinic Cholinergic Targets
Reduction in CNS Ach function impairs cognition,
as in Alzheimer’s disease
In animals, cholinergic agonists enhance, and
antagonists impair, cognition
CNS = central nervous system.
Friedman JI. Psychopharmacology (Berl). 2004;174:45-53.
Sunday, July 26, 2009
106. Muscarinic Cholinergic Targets
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
CNS = central nervous system.
Friedman JI. Psychopharmacology (Berl). 2004;174:45-53.
Sunday, July 26, 2009
107. Muscarinic Cholinergic Targets
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
Studies of cholinesterase inhibitors in
schizophrenia have shown mixed results; best
results are with dual cholinesterase inhibitors
CNS = central nervous system.
Friedman JI. Psychopharmacology (Berl). 2004;174:45-53.
Sunday, July 26, 2009
108. 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.
Sunday, July 26, 2009
111. 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
Sunday, July 26, 2009
112. 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
1. Brothers, L. Concepts in Neuroscience 1990; 1: 27-61
Sunday, July 26, 2009
113. 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
Sunday, July 26, 2009
114. 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
Sunday, July 26, 2009
115. 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.
Sunday, July 26, 2009
116. 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
Sunday, July 26, 2009
117. 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.
Sunday, July 26, 2009
118. 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.
Sunday, July 26, 2009
119. Psychosocial Approaches to Specific
Targets
Facial affect recognition can be enhanced with
special training1
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.
Sunday, July 26, 2009
120. Psychosocial Approaches to Specific
Targets
Facial affect recognition can be enhanced with
special training1
Cognitive training can improve working memory2
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.
Sunday, July 26, 2009
121. Psychosocial Approaches to Specific
Targets
Facial affect recognition can be enhanced with
special training1
Cognitive training can improve working memory2
Attention can be improved with specialized
training3
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.
Sunday, July 26, 2009
122. Psychosocial Approaches to Specific
Targets
Facial affect recognition can be enhanced with
special training1
Cognitive training can improve working memory2
Attention can be improved with specialized
training3
Cognitive Enhancement Therapy (CET) improved
neurocognition and processing speed4
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.
Sunday, July 26, 2009
123. A First Study on Using Medication to
Enhance Social Cognition
Sunday, July 26, 2009
124. 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)
Sunday, July 26, 2009
125. 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)
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.
Sunday, July 26, 2009
126. Interpersonal Perception Task (IPT)
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
Sunday, July 26, 2009
127. Comparison of Conventional Antipsychotics
and Olanzapine (Total IPT Scores)
100
90
80
70
60
CAP
50
OLZ
40
30
20
10
0
Baseline Endpoint
Sunday, July 26, 2009
128. 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
Sunday, July 26, 2009
129. 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.
Sunday, July 26, 2009
130. 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.
Sunday, July 26, 2009
131. 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
Sunday, July 26, 2009
132. Lithium and Cortical Grey Matter
Bearden, CE., et al. Biological Psychiatry, June 2007
Sunday, July 26, 2009