Biological Etiology Research


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Biological Etiology Research

  1. 1. Research in Clinical Psychology • Research in etiology of major mental disorders (costly/common problems): – Schizophrenia, other chronic psychoses – Major affective disorders – Alcoholism, drug abuse – Criminality, antisocial behavior – Other disorders
  2. 2. Research in Clinical Psychology, cont’d • Research in etiology – Biological factors – Psychosocial factors – Not not research on complementary influences of these two factors • Research on assessment • Research on treatment
  3. 3. Research on Biological Etiological Factors • Three questions about factor X: – (1) Does X make a difference? • Risk for disorder • Development of disorder (e.g., age of onset) • Phenomenology (symptoms) of disorder • Course of disorder over time – (2) How much difference does X make? – (3) What is mechanism for X to influence disorder?
  4. 4. Classes of Biological Factors • Genetics • Neurochemistry, including neuroendocrine • Structural brain abnormalities – Gross anatomy – Microstructural changes/deficits • Neuropsychological (functional brain) abnormalites
  5. 5. Designs for Studying Factors • Case-control – Depressives vs. normals, compared on serum cortisol – Schizophrenics vs. depressives, compared on dopamine receptor counts – The “taraxein”/coffee problem (confounding variables)
  6. 6. Designs, cont’d • Experimental psychopathology: provoke/ heighten/dissect abnormality in disordered group vs. controls – tryptophan depletion in depressives – frontal lobe-demanding tasks in schizophrenics) • Family-genetic studies – nuclear family (no control) – twin & twin-family (DZ twin = control), adoption – pedigree linkage (control provided by null hypothesis)
  7. 7. Designs, cont’d • Animal models, where possible – Feeding & satiety---eating disorders – Drug-seeking---psychoactive substance use disorders – Stereotyped behavior in monkey/rat---OCD?
  8. 8. Types of Genetic Studies I • Family studies---yield ambiguous results • Liability = hypothetical (unobserved) trait, with genetic AND environmental causes, that controls risk for developing disorder • Heritability = degree to which liability is controlled by additive genetic factors in population • Twin studies (see next slide) • Adoption studies (see slide after that)
  9. 9. Twin Studies • Twin studies: MZ vs. DZ twins – h2 = 2(rMZ – rDZ) – General population twin registries – Twins enrolled at psychiatric institutions • Twins reared apart (MZA) studies – h2 = rMZA – Too hard to do for less common conditions
  10. 10. Adoption Studies • Adopted-away offspring • Relatives of disordered adoptees, vs. those of normal adoptees • Cross-fostering • Twins-reared-apart design is really an adoption design • Need adoptees reared by non-relatives, from early age
  11. 11. Types of Genetic Studies II • Segregation studies (e.g., familial hyper- cholesterolemia): fit math models to family data • Linkage studies (e.g., Alzheimer disease in N = 2,000 Venezuelan pedigree): fit math models to family data with markers • Candidate gene studies (e.g., D5 receptor in schizophrenia), gene cloning & identification • Animal studies – e.g. “Knockout” studies in the mouse
  12. 12. Heston Adoption Study • Design: adopted-away offspring – Schizophrenic mothers – Psychiatrically normal controls • Dependent variable: rate of schizophrenia – Also look at “schizoid” personality • Result: big rate in at-risk adoptees, zero in controls • Criticism: diagnoses not blind
  13. 13. Subsequent Copenhagen Adoption Studies • Adopted-away design (Rosenthal) • Biological vs. adoptive relatives of schizophrenic & control adoptees design (Kety) • Cross-fostering design (Wender) – Didn’t really get off the ground---too hard to find schizophrenic adoptive parents
  14. 14. How Much Effect? Twin Studies • Twin studies from 1920’s to today • Every study shows rMZ > rDZ • Average heritability about .42 (bipolar is higher, about .7) • Older studies (inpatients) give higher heritability than newer studies (more outpatients), e.g., h2 = .7 • Severity predicts risk to co-twin
  15. 15. Segregation Studies • In schizophrenia, segregation analyses (i.e., analyses of fit of family distribution of illness data, to genetic models) hasn’t convinced most that there’s a common single major gene for schizophrenia • In some panic disorder families, and maybe some Tourette families, there may be a major gene
  16. 16. Linkage Studies • This would provide best evidence (short of actually identifying gene) for operation of a genetic factor in mental disorder ABC • Many reports of linkage for schizophrenia (C5, C6); essentially zero confirmations from independent labs • Mixed confirmation for gene (short arm of X) in a fraction of cases of bipolar illness
  17. 17. Types of Neurological Studies • Neuroimaging – Obsolete technologies---pneumoencephalogram – Modern technologies---CT, MRI (structural) SPECT, PET, fMRI (functional) • Neuroanatomy (gross, microscopic) • Neurotransmitter (receptor) studies • Neuropsychological (functional) studies
  18. 18. Principal Findings • Skull, brain (esp. frontal) of schizophrenics (& bipolars?) smaller on average (CT, MRI) – As skull forms around brain in utero, this is developmental process • Enlarged cerebral ventricles (& sulci?) in schizophrenia---many replications (CT, MRI) – Esp. 4th ventricle – Not artifact of institutionalization or meds---present in teen-aged schizophrenics – Effect size sensitive to selection of controls
  19. 19. Findings, cont’d • Brains of schizophrenics relatively more hypoactive frontally, when engaged in tasks calling on frontal lobe function • Midbrain---hippocampal cell derangement in schizophrenia • Excess D2 receptors (esp. in hippocampus?), excess D2 receptor sensitivity in schizophrenics – Hotly disputed (Johns Hopkins vs. Karolinska)