Neuropharmacology: Schizophrenia

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Lecture 22 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University. Focus is on typical and atypical antipsychotics.

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  • Preview Question 1: What patterns of thinking, perceiving, feeling, and behaving characterize schizophrenia?
  • Preview Question 1: What are the drug therapies? What criticisms have been leveled against drug therapies?
  • Neuropharmacology: Schizophrenia

    1. 1. Schizophrenia Brian J. Piper, Ph.D.
    2. 2. Goals Symptoms of Schizophrenia Causes Antipsychotics  Typical  Atypical
    3. 3. SchizophreniaThe Greek translation is schizein “split” and phren “mind” which refers to a split from reality. A group of severe disorders characterized by atypical: 1. Cognition 2. Behavior NOT Multiple Personality Disorder 3. Emotions
    4. 4. Symptoms of SchizophreniaPositive symptoms: the presence of inappropriatebehaviors delusions hallucinations: auditory >>> visual > other disorganized talking: “word salad” movementsNegative symptoms: the absence of appropriatebehaviors flat affect: joy, anger, disgust anhedonia catatonia: waxy flexibility
    5. 5. Disorganized & Delusional ThinkingThis morning when I was at Hillside [Hospital], I wasmaking a movie. I was surrounded by movie stars …I’m Mary Poppins. Is this room painted blue to get meupset? My grandmother died four weeks after myeighteenth birthday.” (Sheehan, 1982)Other forms of delusions include, delusions ofThis monologue illustrates fragmented, bizarrethinking with (“someone is following delusions persecution distorted beliefs called me”) or grandeur (“I am a king”). (“I’m Mary Poppins”).
    6. 6. Example PatientHaldol: classic antipsychotic drugDelusions of grandeur: inappropriate beliefs about one’s self-worth or special powersGerald (upto 2:30): http://www.youtube.com/watch?v=gGnl8dqEoPQ
    7. 7. Auditory HallucinationsFor almost 7 years, except during sleep, I continue to hear voices. They accompany me to every place and at all times, when I’m in conservations with other people, they persist,undeterred, even when I concentrate on other things, for instance, read a book, play thepiano, etc. Only when I’m talking aloud to other people or to myself are they drowned by the stronger sound of the spoken word and therefore inaudible to me. Recounted by Ann M. Kring, Ph.D. Pros & Cons Behavioral strategies (& family discord) Command Hallucinations
    8. 8. DSM5 Diagnosis of Schizophrenia• Two or more of the following, including 1, 2, or 3 1. Delusions 2. Hallucinations 3. Disorganized speech 4. Grossly abnormal psychomotor behavior 5. Negative symptoms• Duration: 1 month during last 6• Social/occupational dysfunction• Exclusion: medical condition or drug
    9. 9. Animal Models of Schizophrenia• Amphetamine: hyperactivity & stereotypy• Apomorphine: D1-5 agonist, causes hyperactivity & stereotypy (sniffing, grooming, head-bobbing, nail biting, and circling)• Phecyclidine (PCP): dopamine release & NMDA antagonist• Prepulse Inhibition: classical conditioning
    10. 10. Epidemiology of Schizophrenia Frequency: 0.7% Sex: Males > Females in # and severity Low SES (downward drift)/African-Americans Rule of thirdsSources: Anna K. Kring
    11. 11. Vincent van Gogh1853-1890 Mary Todd Lincoln 1818-1882 Brian Wilson 1942- Schizophrenia Jack Kerouac John Nash 1922-1969 1928-
    12. 12. Subtypes (DSM-IV-TR only) • Catatonic: immobility • Disorganized: disorganized speech or behavior, affective flattening • Paranoid: – Present: delusions & auditory hallucinations, possible religiosity – Absent: disorganized behavior & affective flatteningIllusory Correlation
    13. 13. Typical?The relationship between schizophrenia and aggression iscontroversial.Renfrew (1996). Aggression & Its Causes.
    14. 14. John W. Hinckley, Jr. Jared Lee LoughnerThe relationship between schizophrenia and aggression iscontroversial.Disorganized: Increased risk of victimizationParanoid: small increaseRenfrew (1996). Aggression & Its Causes.
    15. 15. Accuracy of Diagnosis Decision • 8 healthy pseduo-patients SCZ- SCZ+ presented to 12 psychiatric SCZ- Correct Type I hospitals with complaint of hearing Reality Diagnosis error voices • Acted normal but 11 diagnosed as SCZ+ Type II Correct schizophrenic error Diagnosis • Fellow patients, but not staff, were suspicious • Released after 7-52 days (mean = 19) 1929-20120:37-3:30: http://www.youtube.com/watch?v=Kq-7uvVOoykRosenhan (1973). Science, 179, 250-258.
    16. 16. Causes• Demonic possession• “Refrigerator mothers”• Neurodevelopmental Disorder• Biochemical Imbalance
    17. 17. Abnormal Brain Morphology Some schizophrenia patients exhibitmorphological changes in the brain like enlargement of fluid-filled ventricles. Both Photos: Courtesy of Daniel R. Weinberger, M.D., NIH-NIMH/ NSC
    18. 18. Meta-Analysis • 58 studies Region (Left or Right) % of Control • 1,588 SCZ patients L Lateral Ventricle 130 R Lateral Ventricle 120 Gray Matter 96 White Matter 98 L Frontal Lobe 95 L Hippocampus 95 L Amygdala 91 L Thalamus 96 R Thalamus 96Wright et al. (2000). Am J Psychiatry, 157, 16-25.
    19. 19. Genetic Factors
    20. 20. Genetic Factors The following shows the prevalence ofschizophrenia in identical twins as seen in different countries.
    21. 21. Genain Sisters“Genain”: Greek “dire birth”, born 1930, allhospitalized for schizophrenia by early 20s, probability = 1.5 billion Nora: intermediate (jobs, no family) Iris: intermediate (jobs, no family) Myra: secretary, married, 2 sons Hester: showed signs at age 11, institutionalized Genetics: identical Environment: identical (schizophrenic mom) Prenatal: ?
    22. 22. Wisconsin Card Sorting Test• Developed by Esta Berg in 1950s• Measures cognitive flexibility and perseverative behaviors (number, color, shape)
    23. 23. Neuropsych Testing of Genain Sisters at age 68• Digit Span: working memory• Trail Making Test: set shifting• Continuous Performance Test: attention Mirsky et al. (2000). Schizophrenia Bulletin, 26, 699-708.
    24. 24. Individual Differences in SCZ
    25. 25. Hypofrontality During WCST
    26. 26. Hypofrontality During Continuous Performance Test • fMRI was completed during a Continuous Performance testVolz et al. (1999). European Psychiatry, 14, 17-24.
    27. 27. Hypofrontality During Continuous Performance Test • fMRI was completed during a Continuous Performance testVolz et al. (1999). European Psychiatry, 14, 17-24.
    28. 28. Neurochemical Imbalance Typical Origin 1952 Example Chlorpromazine Haloperidol Mechanism D2 antagonist Treats + symptoms Side-Effects Tardive dyskinesiaTD (20 sec): http://www.youtube.com/watch?v=fLwZQBJs8fI
    29. 29. Drug TherapiesPsychopharmacology is the study of drug effects on mind and behavior. With the advent of drugs, hospitalization in mental institutions has rapidly declined.
    30. 30. Comparison Typical AtypicalOrigin 1950s 1970Example Chlorpromazine Clozapine HaloperidolMechanism D2 antagonist D2 & 5-HT2A antagonistTreats + symptoms + symptomsSide-Effects Tardive dyskinesia Weight gain
    31. 31. Concern • Adult monkeys received typical * (haloperidol) or * atypical (olanzapine) antipsychotics for 2 years at doses similar to schizophrenics. • Gray matter in parietal cortex was examined.Konopaske et al. (2007). Neuropsychopharmacology, 32, 1216-1223.
    32. 32. Beyond D2• the dopaminergic (or serotonergic) model of schizophrenia may be too simplistic Kerwin et al. (1999). Neuroscience, 39, 25-32.
    33. 33. Schizophrenia in Children • More frequently recognized8 min: http://www.youtube.com/watch?v=UTUMt05_nCI9 min: http://www.youtube.com/watch?v=B9v4FsKXmj8
    34. 34. Self-Medication?• Marijuana• Nicotine
    35. 35. Reduced Lifespan (N = 5,036,662)! Male Male Female Female Life Expectancy Years Life Years Lost Lost ExpectancyAll (Psychiatric 76.5 NA 80.9 NAHistory - )Schizophrenia 57.8 18.7 64.6 16.3Bipolar 62.9 13.6 68.8 12.1 Laursen (2011). Schizophrenia Research, 131, 101-104 .
    36. 36. Reduced Lifespan (N = 5,036,662)! Male Male Female Female Life Expectancy Years Life Years Lost Lost ExpectancyAll (Psychiatric 76.5 NA 80.9 NAHistory - )Schizophrenia 57.8 18.7 64.6 16.3Bipolar 62.9 13.6 68.8 12.1 Contributing Factors suicide, accident, homicides, self-care, metabolic (?) Laursen (2011). Schizophrenia Research, 131, 101-104 .
    37. 37. Art During Disease Progression• A English artist, who was fascinated by cats, painted these pictures over a period of time in which he became mentally ill.• Pro – Paranoia – Disorganization• Con Louis Wain (1860-1939) – Schizophrenia – Order
    38. 38. Summary• Symptoms ( + and - )• Current Biological Components (Not Diagnostic) – Genetics – Brain Structure – Dopamine Receptors
    39. 39. VideocastOverman, Gerald (2010). Antipsychotic treatment & tolerability. Starts about 4:40 (ends abruptly):http://videocast.nih.gov/Summary.asp?File=15991What are the pros and cons of the typical and atypicalantipsychotics?What is EPS? What areas of the brain are important for this?If you had a family member that was recently diagnosed withSCZ, what drug (or drug class) would you hope that thepsychiatrist would prescribe?

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