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Psychiatrie & Neurowetenschappen
Psychotische stoornissenaz
sint jan en pz
onze-lieve-vrouw
21 januari 2010Bernard Sabbe
Schizofrenie: een complex syndroom
1.
Positieve symptomen: wanen, hallucinaties, onsamenhangende spraak, chaotisch of katatoon
gedrag
2.
Negatieve symptomen: vervlakking van het affect, gedachten-
of spraakarmoede,
apathie3.
Cognitieve symptomen
4.
Depressieve symptomen (verhoogd suïciderisico)
Clinical neuropsychology
•
Kraepelin; Bleuler: core deficits•
“dementia praecox”
•
present across
the lifespan
–
quite
stable•
functional
neuronal
networks
(↔
dichotomy
functional-organic)Link cortical
and subcortical
regions
through
patterns
of linked
activation
during
task performance.
Cognitive
impairments
Cognitive
impairments
• Frontal deficits
• Medial temporal hippocampal
deficits
•
generalized (1 factor) vs
specific (6 factor solutions)
•
>> cognitive capacity; processing speed•
<< the use of information acquired prior to the onset of the disease.
Onset
•
At the moment of receiving
the diagnosis = more chronic
patients
•
Not
continuously
progressive•
Population-based
studies: clear
group
differences
between
individuals
that
will/won’t develop
the disease
•
Some
level of sensitivity
and specificity•
≠
diagnostic
indicator
Cognitive
decline?
•
Substantial minority: cognitive impairment that worsen over time
•
Older patients; chronic course of treatment-refractory positive symptoms, institutionalized care
•
Effects of institutionalization?•
Neurodegenerative / vascular pathology
Presence
in relatives
and individuals with
“spectrum”
conditions
•
Relatives•
Attentional
deficits predict the development of
schizophrenia in high risk children with at least 1 schizophrenic parent
•
Schizotypal
personality disorders•
Stable correlate of some aspects of the predisposition to schizophrenia
•
Endophenotypes?
Functional
relevance
•
NP impairment
= single strongest
correlate
of impairments
In everyday living skillsSocial outcomeSeeking + maintaining employment/otherproductive activities
•
Compositie scores –
everyday
disability: r=0.7 (50% of shared
variance) [positive
symptoms: r=0.1 (1% of
shared
variance)]•
Correlations
with
“functional
capacity”
> real
world
performance•
Opportunities, disability
compensation, environmental
support, familial
resources discrepancies between“competence” and everyday “performance”
•
Performance based
tests
Treatment
of cognitive
impairment
•
Pharmacological
interventions: modest effects
(E.S.:0.24 -
0.16)
•
Cognitive
remediation
interventions
Schizophrenia:
•
One in five sufficiently recovered to work. •
+/-
90% with first episode go on to relapse.
•
Medicines of limited effect in 25-30%.•
Deficits and cognitive symptoms remain largely resistant to available drugs.
•
Reached ceiling with available drugs?
Limitations in Current Therapeutics
•
DSM Disorders Dissected into Dimensions: New Clinical Targets More Proximate to Pathophysiology.
•
New Molecular Targets: With clinical effect on currently untreated
dimensions of psychopathology.
Psychopharmacology of Future?
•
Glutamatergic
modulators (d-serine, cycloserine, glycine)
•
Dopamine D1 receptor agonists
•
Serotonin 5-HT2A
Receptor Antagonists
•
α-2 Noradrenergic agonists
•
Cholinesterase inhibitors
•
Muscarinic
agonists
•
Nicotinic agonists
Cognition in Schizophrenia: Scientific Opportunity
•
Create a standardized cognitive battery for use in clinical trials that represents a consensus among experts.
•
Define optimal experimental designs.•
Facilitate path to FDA approval.
•
Attract large pharmaceutical companies to focus efforts on this important clinical target.
Goals of NIMH-MATRICS Initiative:
Evolution in Psychiatric Drug Claims over Past 15 Years
•
Previous approach: Broad claims (mostly anxiety, depression, psychosis)
•
Current approach: – Specific diseases/syndromes– Specific symptoms or symptom clusters– Nonspecific symptoms
Current Regulatory Approach to Schizophrenia
•
Schizophrenia viewed as single clinical target–
New antipsychotics approved for the “treatment of schizophrenia”
•
Cognitive deficits acknowledged as one aspect of the schizophrenic syndrome, but not teased apart as a distinct target (Note: not part of DSM-IV criteria)
•
Assessment focus is on positive symptoms (but with some attention to “negative symptoms”)
•
Trial Designs –
4-6 week acute studies
–
Randomized withdrawal studies for longer-term efficacy
1.
Speed of Processing2.
Attention/Vigilance
3.
Working Memory4.
Verbal Learning and Memory
5.
Visual Learning and Memory6.
Reasoning
and Problem
Solving
7.
Social Cognition(Emotional
processing, ToM, social perception, social knowledge,…)
Cognitive Symptoms: MATRICS
MATRICS: Measurement and Treatment Research to Improve Cognition
in Schizophrenia
(NIMH)Nuechterlein
et al., 2004 ; Green et al., 2005
Test Quality
Median rank: 1 = most important 9 = least important
Ranking of Test Qualities
1. High immediate test-retest reliability 2. Good coverage of key individual cognitive constructs3. Comparable alternative forms 4. Clear relationship to functional outcome5. Strong internal consistency of individual scales6. Well-established norms for general population7. Highly interpretable overall summary score8. Clear relationship to known neural systems9. Clear relationship to clinical symptoms
FDA-NIMH-MATRICS guidelines
on
clinical
trial designs for
neurocognitive
drugs for
schizophrenia
I.
Inclusion
criteriaII.
Outcome
measures
III.
Other
design and statistical
issues
Do existing animal model paradigms map effectively onto the seven cognitive domains relevant to schizophrenia, as identified by
MATRICS?
Cognitive Domains Affected in Schizophrenia (MATRICS Proposed Battery)
Cognitive Domain Animal Models/Tests Clinical Battery (Beta version) Working memory T-maze DNMT or DMTP
Barnes MazeRadial arm mazeSome operant tasks
BACSWMS-III Spatial SpanWAIS-III Letter-Number sequenceUoM Letter-Number SpanSpatial Delayed Response Task
Attention/vigilance andpre-attentive processing
5-Choice Serial Reaction Time TaskPPI, auditory gating
3-7 CPTIdentical pairs CPT
Verbal learning and memory
NAB- Daily Living MemoryHVLT-Revised
Visual learning & memory Novel Object Recognition NAB – Shape LearningBVMT-Revised
Speed of processing 5-Choice Serial Reaction TimeSimple Reaction time tasks
Category fluencyTrail making AWAIS-III Digit Symbol-CodingBACS – Symbol Coding
Reasoning & problem solving
Attentional set shiftingMaze tasks
WAIS-III Block designBACS- Tower of LondonNAB - Mazes
Social cognition Social interactionSocial recognition task
MSCEIT – Managing emotionsMSCEIT – Perceiving emotions
6 cognitive
and affective
systems
•
Working
memory•
Episodic
memory
•
Attention•
Executive
functions
•
Perception•
Social
cognition
and affective
processing
CNTRICS
•
Increased
specificity
→ increased sensitivity
to drug effects
•
↔ ↓ psychometric
properties↓
practicalities
of administration
•
Integrating
(basic) cognitive
neuroscience in drug development
Results of Survey Criteria
Total(N=141)
Academics(N=125)
Industry(N=16)
Readily measured in humans 3.40 (1) 3.41 (1) 3.31 (2)Strong evidence of impairment in schizophrenia 3.35 (2) 3.34 (2) 3.50 (1)Linked to functional outcome in schizophrenia 2.79 (3) 2.78 (4) 2.88 (6)Clarity of the understanding/specification of the cognitivesystem/mechanism
2.76 (4) 2.80 (3) 2.50 (9)
Clarity of the link to a specific neural circuit 2.48 (5) 2.50 (5) 2.25(13)Measures practically amenable for use in human imaging studies 2.41 (6) 2.44 (6) 2.19 (14)Link to neural systems in humans through functionalneuroimaging
2.41 (7) 2.35 (7) 2.56 (7)
Link to neural systems in humans throughneuropsychopharmacology
2.36 (8) 2.35 (8) 2.44 (10)
Linked to the signs and/or symptoms of schizophrenia 2.35 (9) 2.26 (9) 3.0 (4)Evidence for amenability to improvement in schizophrenia 2.26 (10) 2.25 (10) 2.44 (11)Degree of homology between the human and animal models 2.14 (11) 2.04 (12) 2.94 (5)Linked to neural system in animals through neuropsychopharmacology 2.11 (12) 2.05 (11) 2.56 (8)Clarity of the link to a specific neurotransmitter system 2.06 (13) 2.02 (13) 2.38 (12)Availability of an explicit animal model 2.06 (14) 1.92 (5) 3.13 (3)Link to neural systems in humans through neuropsychology 1.92 (15) 1.98 (14) 1.50 (18)Formal similarity between the measures in humans and animals 1.79 (16) 1.78 (16) 1.94 (15)Associated with schizophrenia relevant genetic polymorphisms 1.76 (17) 1.78 (17) 1.69 (16)Linked to neural system in animals through electrophysiological studies 1.72 (18) 1.76 (18) 1.44 (19)Linked to neural system in animals through lesion studies 1.71 (19) 1.73 (19) 1.56 (17)
Benchmark Values -
Entire SampleCharacteristic
Optimal
“Worst Acceptable”
Internal Consistency
.85
.60Test-Retest
.90
.70
Alternate Form
.90
.65Length (in minutes)
15 min
30 min
Minimum # of Trials
30 trials
15 trialsPractice Effect (in SD units)
.20 SD
.50 SD
Floor Effect (% diff from 0)
20%
10%Ceiling Effect (% diff from 100)
25%
15%
Benchmark Values -
Higher ConfidenceCharacteristic
Optimal
“Worst Acceptable”
Internal Consistency
.875
.60Test-Retest
.90
.70
Alternate Form
.90
.70Length (in minutes)
10 min
30 min
Minimum # of Trials
25 trials
10 trialsPractice Effect (in SD units)
.20 SD
.50 SD
Floor Effect (% diff from 0)
25%
10%Ceiling Effect (% diff from 100)
37.5%
12.5%