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SPECIFIC NOSOLOGICAL ISSUES SCHIZOPHRENIA Wolfg
ang Gaebel Section on Schizophrenia Department
of Psychiatry and Psychotherapy
Heinrich-Heine-University Düsseldorf, Germany
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DIAGNOSTIC VALIDITY IN PSYCHIATRIC ILLNESS

• Clinical description
• Laboratory studies
• Delimitation from other disorders
• Follow-up studies
• Family studies

Robins and Guze (1970)
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TOWARDS A COMPREHENSIVE DIAGNOSTIC SCHEME IN
PSYCHIATRY

• Clinical Criteria

1. Clinical phenomenology2. Longitudinal
course3. Pedigree study4. Pharmacological
response
Research Criteria
5. Biochemical correlates6. Neuropsychological/ps
ychophysiological findings
Akiskal (1978)
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USE OF MULTIAXIAL ASSESSMENT

• Facilitating comprehensive and systematic
  evaluation
• Organizing and communicating clinical information
• Capturing the complexity of clinical situations
• Describing the heterogeneity of individuals
• Promoting the application of the biopsychosocial
  model

DSM-IV, APA (1994)
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CATEGORICAL VS DIMENSIONAL CLASSIFICATION
Dimensional systems . . .

• classify based on quantification of attributes
  rather than the assignment to categories
• work best in describing phenomena that are
  distributed continuously
• increase reliability and communicate more
  clinical information
• are less familiar
• lack agreement on the choice of optimal
  dimensions
• may be a research tool for the future

DSM-IV, APA (1994)
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The development of taxonomic concepts in the
study of mental disorder will probably show two
trends First, a continuation of the shift from
systems defined by reference to observable
characteristics to systems based on theoretical
concepts and second, a gradual shift from
classificatory concepts and methods to ordering
concepts and procedures, both of the
non-quantitative and of the quantitative
varieties.
Hempel (1965)
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• OUTLINE FOR A POSSIBLE FUTURE MULTIAXIAL
  SYSTEM (DSM-V)
• Axis I Genotype
• Identification of disease-/symptom-related genes
• Identification of resiliency/protective genes
• Identification of genes related to therapeutic
  responses to and side effects of specific
  psychotropic drugs
• Axis II Neurobiological phenotype
• Identification of intermediate phenotypes
  (neuroimaging, cognitive function, emotional
  regulation) related to genotype
• Relates to targeted pharmacotherapy
• Axis III Behavioral phenotype
• Range and frequency of expressed behaviors
  associated with genotype, neurobiological
  phenotype, and environment
• Relates to targeted therapies
• Axis IV Environmental modifiers or precipitants
• Environmental factors that alter the behavioral
  and neurobiological phenotype
• Axis V Therapeutic targets and response

Charney et al. (2002)
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Endophenotypes
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CLINICAL AND PATHOPHYSIOLOGICAL COURSE OF
SCHIZOPHRENIA
Lieberman et al. (2001)
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SCHIZOPHRENIA A CONCEPT OF ENDOPHENOTYPE

• Endophenotype An internal phenotype
  discoverable by a biochemical test or microscopic
  examination
• First used in schizophrenia genetics by
  Gottesmann and Shields (Br J Psychiatry 1973122
  15-30)
• Endophenotypes are a tool to study disorders with
  complex genetics
• Endophenotypes represent more elementary
  phenomena as opposed to behavioral phenomena, the
  number of genes required to produce such
  endophenotypes may be fewer than those involved
  in producing a psychiatric diagnostic entity

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ENDOPHENOTYPES IN SCHIZOPHRENIA Defining
categories for Endophenotypes I

• (I) The Endophenotype
• must be associated with schizophrenia in the
  population
• must be heritable
• must be state-independent
• must cosegregate with schizophrenia in families
• must be found in non-affected family members at a
  higher rate than in the general population
• Gottesman and Gould, Am J Psychiatry 2003
  160636-645

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ENDOPHENOTYPES IN SCHIZOPHRENIA Defining
categories for Endophenotypes II

• (II) The Endophenotype
• must be an easily measurable neurobiological
  variable associated with schizophrenia
• should be abnormal before disease manifestation
• should be stable over time and not influenced by
  medication or the disease
• should show a strong genetic influence
• should be associated with a genetically
  determined disease risk
• Zobel and Maier, Nervenarzt 200475205-214

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ENDOPHENOTYPES IN SCHIZOPHRENIA

• Sensory-motor gating
• Prepulse inhibition of the startle response
• P50 suppression
• Eye tracking dysfunction
• Smooth pursuit eye movements
• Working memory
• Neuropsychological tests
• fMRI
• (Gottesman and Gould, Am J Psychiatry 2003
  160636-645)
• Structural brain alterations
• Ventricular enlargement, regional atrophies
  (frontal cortex)
• Increased gyrification
• Late evoked potentials
• P300 oddball paradigm
• (Zobel and Maier, Nervenarzt 2004 75205-214)

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Behavioral Phenotype
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... Überhaupt wird es immer deutlicher, daß der
Bezugsrahmen für biologisch-psychiatrische
Befunde (...) über die bisher üblichen globalen
nosologischen Diagnosen hinausgehen muß, wenn
sich die biologische Psychiatrie nicht
wesentliche Erkenntnismöglichkeiten selbst
verstellen will. ... So müssen in Zukunft die
Befunde der biologi-schen Psychiatrie außer auf
nosologisch-diagnosti-scher Ebene auch im
Hinblick auf einen nosolo-gisch neutralen
syndromalen Bezugsrahmen, ja womöglich sogar auf
Symptom-Ebene ausgewertet werden.
Hippius und Matussek (1978)
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Wenn es überhaupt möglich ist, einen Fortschritt
der psychopathologischen Diagnostik
herbeizuführen, so sind es die
Untersuchungsmethoden der experimen-tellen
Psychologie, welche berufen erscheinen, die hier
vorhandene Lücke wenigstens teilweise ausfüllen
zu helfen.
Kraepelin (1887)
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SOURCES OF INFORMATION IN PSYCHOPATHOLOGY

• Subjective-verbal
• Motor
• Physiological

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METHODOLOGICAL APPROACHES TO PSYCHOPATHOLOGY

• Self-rating
• Observer rating
• Behavioral observation
• Measurement of reaction

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CLASSIFICATION OF PSYCHOPATHOLOGICAL SYMPTOMS
ACCORDING TO THE METHODOLOGICAL APPROACH
Symptom categories Items S So SO sO O Disorders
of consciousness 4 - 1 - 1 2 Disturbances of
orientation 4 - - - 4 - Disturbances of
attention and memory 6 - - - 4 2 Formal
disorders of thought 12 3 - 1 - 8 Phobias and
compulsions 6 2 1 2 1 - Delusions 14 - 1 2 10 1 Di
sorders of perception 6 6 - - - - Disorders of
ego 6 6 - - - - Disturbances of
affect 21 6 3 - 8 4 Disorders of drive
and psychomotility 9 1 - 2 2 4 Circadian
Disturbances 3 - 3 - - - Other disturbances 9 - 1
2 5 1 100 24 10 9 35 22
AMDP-Sytem
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FUNCTIONAL PSYCHOPATHOLOGY

• Dissection of a psychopathological syndrome in
  its com- ponent parts, i.e. psychological
  dysfunctions, as a com- plement to the
  nosological/categorical approach, to
• . Shed new light on the non-specificity of
  biological variables related to psychiatric
  disorders
• . Increase the chance of finding meaningful
  relations between biological and behavioral
  variables
• . Explain the uncomprehended non-specificity of
  certain psychotropic drugs.

Van Praag et al. (1987)
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EXPERIMENTAL PSYCHOPATHOLOGY I- Methods and
aims -

• To systematize the assessment of psycho-
  pathology
• Application of objective assessment methods
• Experimental variation of assessment
• conditions
• To develop a functional psychopathology
• To sharpen the phenotype for basic research
• To improve diagnosis and treatment

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EXPERIMENTAL PSYCHOPATHOLOGY II- Fields of
application -

• Assessment of psychopathology in patients by
  means of experimental methods
• Experimental induction of psychopathology in
  patients (e.g. pharmacological challenge)
• Experimental induction of psychopathology in
  healthy probands
• Experimental modelling of psychopathological
  equivalents in animals

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TOWARDS A FUNCTIONAL CLASSIFICATION OF MENTAL
DISORDERS
Disrupted life performance Special case
history Clinical psychopathology Operational
diagnostic classification Experimental
psychopathology Psychobiological tests of
function Functional classification
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SYSTEM OF FUNCTIONAL PSYCHOPATHOLOGY

• Taxonomy of normal (basic) functions (BF)
• Formal characteristics of disturbances of BF
• Quantitative (hypo-/hyperfunction)
• Qualitative (dysfunction)
• Temporal (gradient, rhythm, reversibility)
• Identity of the underlying functional disturbance
  (FD)
• Disturbance of functional/regional brain modules
• Formal characteristics of underlying FD
• Loss/increase
• Inhibition/disinhibition
• Determinants of underlying FD
• Primary (bio-psycho-social disturbance)
• Secondary (bio-psycho-social adaptation/compensati
  on/ plasticity)

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EXPERIMENTAL SETUP FOR THE ASSESSMENT OF
PSYCHOPATHOLOGY
?
Subject
?
FD
?
Debic 80
(eye movement recording)
Infrared-light camera (eye movements)
PC (stimulus material)
/
\
Camera1 (facial expression)
Camera 2 (gestures)
Videorecorder (stimulus material)
Monitor (scene)
Camera 3
Interviewer
\
/
Video-Mixer
face
body
scene
/
\
Videorecorder (recording)
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RESEARCH STRATEGIES IN DEVELOPING A TAXONOMY OF
PSYCHOBIOLOGICAL BASIC FUNCTIONS

• Research strategy Example
• __________________________________________________
  ___________________
• Category Affect
• Definition e. g. facial expression
• Modelling
• psychological/cultural En-/Decoding of emotions
• neurobiological Affect specific modules
• Operationalization Facial action units (FACS)
• Assessment situation Interview / experiment
• Variation of conditions
• Expressive Spontaneous / voluntary
• Perceptive Perception of affect
• Standardization Normal probands
• Deviation from standard Quantitative /
  qualitative
• Nosological specificity Psychiatric controls
• Trait-/state specificity Pre- / intra- /
  postepisode / family
• Determinants/treatment response e. g.
  psychotropic drugs
• Biological correlates Specificity of brain modules

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MENTAL DISORDERS OVERLAPPING NETWORK
DYSFUNCTIONS
Perception
Psychosis
SocialFunction
Cognition
Emotion
Dementia
Depression
Parkinson
Motor Function
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SUMMARY AND CONCLUSIONS

• Application of behavior-oriented objective
  assessment methods and experimental variation of
  assessment conditions in psychopathology together
  with the assessment of brain function could
  provide a more valid starting point for
• the differentiation between related/similar
  syndromes
• the investigation of longitudinal stability,
  illness specificity and effects of various
  treatment modalities
• the identification of meaningful correlations
  between biological and behavioral variables
  (brain-behavior-relationship)
• and thus could add a functional reformulation
  of psycho-pathology as a new tool for diagnosis
  and classification.