Transcript PhenoChipping of Psychotic Disorders: Phenotype to

PhenoChipping of
Psychotic Disorders:
Phenotype to Genotype
Integration
Nabeel T. Yehyawi, M.A.
Laboratory of Neurophenomics
Department of Psychiatry
Indiana University School of Medicine
History & Development of
Diagnostic Classification
 In 1883:
psychiatrist/psychopharm
pioneer, Emil Kraepelin,
published an early taxonomy
of psychiatric disorders that
anticipated current
classification systems.
 Coined terms: paranoia,
manic-depressive psychosis,
and dementia praecox
(premature deterioration; later
renamed schizophrenia or
“splitting of the mind” by
Bleuler).
 Staunch opponent of
psychoanalysis, saw it as art,
not science. Believed root of
psychopathology to be largely
organic.
Categorical Diagnosis
 DSM-IV is a categorical
classification that divides
mental disorders into types
based on criteria sets with
defining features, similar to all
other medical diagnostic
models.
 This approach works best
when members of a diagnostic
class are homogeneous, with
clear boundaries between
classes, and different classes
are mutually exclusive.
 This system has provided a
common language for
psychiatrists and
psychologists, with good interrater reliability.
 However, DSM-IV makes no
assumptions that each disorder
category is a discrete entity with
absolute boundaries.
 DSM-IV makes no assumption
that individuals with the same
disorder are alike in all important
ways.
 DSM-IV is categorical, not
dimensional, and has not been
empirically derived on a consistent
basis.
Dimensional Diagnosis
 Dimensional system classifies
 However, such models have
clinical presentations based on
quantification of attributes, not
assignment to categories.
 Works best in describing
phenomenon that are
continuous and lack clear
boundaries.
 When DSM-IV was developed,
it was proposed that a change
be made from categorical to
dimensional models.
 Such models increase
reliability and communicate
more clinical information.
been less useful than
categorical systems in clinical
practice and research.
 Numerical dimensional models
are much less familiar than
categorical names; yet no
agreement on optimal
dimensions to use in
classification.
Shared Mechanisms
 Schizophrenia, Schizoaffective
disorder, and Bipolar disorder
have a clinical overlap of
phenotypic expression,
suggesting a shared
mechanism between these
disorders, yet still displaying
some heterogeneity.
 This is bolstered by the
recognition that certain
pharmacological treatments
can be efficacious across
these disorders, while other
medications are only useful in
treating one of these disorders.
 Thus, it becomes apparent that
there is overlap between, but
heterogeneity within each of
these disorders. Reason:
neurobiology/genetic origins.
Classifying Psychiatric Phenotypes
 Classifying psychiatric phenotypes
on the basis of empirical data may
assist in quantifying various traits
that will lead to a dimensional
classification and clarify the
relationship between overlap and
heterogeneity.
 In identifying subtypes using
various genetic and performance
measures, the underlying
neurobiological etiologies become
easier to attain.
 However, to develop subtypes it is
necessary to examine which
attributes of individuals with
Schizophrenia are critical for
inclusion in a dimensional model.
Phenochipping of Psychotic
Disorders
 Phenochipping: a combination of results
attained from a series of psychological
examinations, motor coordination
computer assessments, and gene
analysis.
 Subjects: Individuals with Schizophrenia,
Schizoaffective d/o, Bipolar d/o, and
Normal Controls.
Schizophrenia
 Characteristic Symptoms include:
delusions, hallucinations,
disorganized speech, grossly
disorganized or catatonic
behavior, & negative symptoms
(flat affect, avolition).
 Other criteria include
Social/Occupational dysfunction,
Duration, SZA/MD exclusion,
Substance/Med condition
exclusion.
 Subtypes include: Paranoid,
Disorganized, Catatonic,
Undifferentiated, and Residual.
 TESTS: DIGS structured clinical
interview, PANSS, Hamilton
Depression Scale, Young Mania
Scale.
Genetic Predisposition
 1st degree relatives of SZs are
10x as likely to develop the
disorder.
 Concordance rates higher in
monozygotic than in dizygotic
twins.
 Individuals with both parents
d/o with SZ are 49% more
likely to develop disorder.
 TESTS: RNA and DNA via
blood and saliva samples.
Questionnaires on genetic and
family medical/mental health
history
Environmental Stressors
 SZs have high incidence of
premorbid neurological disorders
such as: head injury, perinatal
complications, childhood illnesses.
 Personality and temperament
measures have been developed
by Akiskal and Cloninger to
suggest that psychopathology is
on one end of a continuum, with
normality on the other end.
 Despite the genetic implications,
the diathesis stress model of SZ is
still considered relavent.
 TESTS: Numerous
questionnaires on affect,
temperament, personality,
childhood events, history of
aggression, and visual analogue
scales.
Neuropsychology of Schizophrenia
 As a group, SZs perform below
expectations on a wide range of
cognitive tests, specifically those
associated with frontal lobe
regulation: attention, strategy use,
and problem solving.
 Memory is often impaired as well.
SZs resemble patients with
subcortical pathology in this area.
 SZs may present with rigidity and
catatonic behavior as a course of
the disorder or secondary to
pharmacotherapy.
 TESTS: Hopkins Verbal Learning
Test, Velocity Scaling Test, Force
Stability Test, Neuroscript.
Test Battery Protocol
 Objective measures: RNA via
blood draws, DNA via blood
swabs/saliva samples, Force
Stability Test, Velocity Scaling
Test, Neuroscript measures,
Hopkins Memory Scale.
 Subjective measures:
Structured Clinical Interview
(DIGS), PANSS, HDS, Visual
Analogue Scales, Various
questionnaires and
assessments pertaining to
affective states & traits.
Dimensions Assessed
 History/Categorical Diagnosis:
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DIGS
Memory: HVLT
Motor Funk: FST, VST,
Neuroscript, Annett
Handedness Questionnaire
Substance Use: Alcohol/Drug
Checklist, VA records, EtOH
VAS
Psychotic Sx: PANSS
Depressive Sx: HRS-D
Manic Sx: YMRS
 Personality/Temperament:
Akiskal Temperament Scale,
ZKPQ, Temperament and
Character Inventory, BLMS,
Wender
 Life Event History: Lifetime
History of Aggression
Questionnaire, Childhood Life
Events Scale
 Medical Background: SF-36,
Questionnaire about Genetic
Risk
 State/Trait: STAI, VAS-Mood,
VAS-Anxiety, VAS
Research Goals and Future
Implications
 Via research such as this, we hope to identify the genes associated
with various levels of psychopathology in the psychotic disorders.
 In kind, it is hoped that these genes will be associated with differing
levels of performance (neuropsych measures) and we will better
understand the effects, if any, of environmental stressors on the
development of these disorders.
 Research such as this may allow for a quantifiable dimensional
model of diagnosis that will better serve individuals with psychotic
disorders.
 In the future, with the assistance of further research such as this, it
may be possible for individual to be diagnosed and receive
treatment sooner via a simple blood test and a series of
performance measures.