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. 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. Categorical Diagnosis

4. 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. Dimensional Diagnosis

5. 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. Shared Mechanisms

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.

7. 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.

8. 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.

9. 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 Genetic Predisposition

10. 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.

11. 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.

12. 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. Test Battery Protocol

13. 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 Dimensions Assessed

14. 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.