PhenoChipping of Psychotic Disorders: Phenotype to Genotype Integration

1
PhenoChipping of Psychotic Disorders Phenotype
to Genotype Integration

• Nabeel T. Yehyawi, M.A.
• Laboratory of Neurophenomics
• Department of Psychiatry
• Indiana University School of Medicine

2
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.

3
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
  inter-rater 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.

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Dimensional Diagnosis

• Dimensional system classifies 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.

• However, such models have 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.

5
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.

6
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.

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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.

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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.

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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

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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.

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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.

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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.

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Dimensions Assessed

• History/Categorical Diagnosis 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

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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.