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%