neuropharmacology: schizophrenia

Schizophrenia

Brian J. Piper, Ph.D.

Goals Symptoms of Schizophrenia

Causes

Antipsychotics Typical

Atypical

Schizophrenia

The Greek translation is schizein “split” and phren “mind” which refers to a split from

reality. A group of severe disorders characterized by atypical:

1. Cognition2. Behavior 3. Emotions

NOT Multiple PersonalityDisorder

Symptoms of Schizophrenia

Positive symptoms: the presence of inappropriate behaviors

delusions

hallucinations: auditory >>> visual > other

disorganized talking: “word salad”

movements

Negative symptoms: the absence of appropriate behaviors

flat affect: joy, anger, disgust

anhedonia

catatonia: waxy flexibility

Other forms of delusions include, delusions of persecution (“someone is following me”) or grandeur (“I am a

king”).

Disorganized & Delusional Thinking

This morning when I was at Hillside [Hospital], I was making a movie. I was surrounded by movie stars … I’m Mary Poppins. Is this room painted blue to get me upset? My grandmother died four weeks after my eighteenth birthday.”

(Sheehan, 1982)

This monologue illustrates fragmented, bizarre thinking with distorted beliefs called delusions (“I’m Mary Poppins”).

Example Patient

Gerald (upto 2:30): http://www.youtube.com/watch?v=gGnl8dqEoPQ

Haldol: classic antipsychotic drug

Delusions of grandeur: inappropriate beliefs about one’s self-worth or specialpowers

Auditory Hallucinations

For 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 the piano, 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

DSM5 Diagnosis of Schizophrenia

• Two or more of the following, including 1, 2, or 31. 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

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

Epidemiology of Schizophrenia

Frequency: 0.7%Sex: Males > Females in # and severityLow SES (downward drift)/African-AmericansRule of thirds

Sources: Anna K. Kring

Vincent van Gogh1853-1890

Brian Wilson1942-

John Nash1928-

Jack Kerouac1922-1969

Mary Todd Lincoln1818-1882

Schizophrenia

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

flattening

Illusory Correlation

Typical?

The relationship between schizophrenia and aggression is controversial.

Renfrew (1996). Aggression & Its Causes.

The relationship between schizophrenia and aggression is controversial.

Disorganized: Increased risk of victimizationParanoid: small increase

Renfrew (1996). Aggression & Its Causes.

John W. Hinckley, Jr.Jared Lee Loughner

Accuracy of Diagnosis

SCZ- SCZ+

SCZ- Correct Diagnosis

Type Ierror

SCZ+ Type IIerror

CorrectDiagnosis

• 8 healthy pseduo-patients presented to 12 psychiatric hospitals with complaint of hearing voices

• Acted normal but 11 diagnosed as schizophrenic

• Fellow patients, but not staff, were suspicious

• Released after 7-52 days (mean = 19)

Decision

Rea

lity

Rosenhan (1973). Science, 179, 250-258.

0:37-3:30: http://www.youtube.com/watch?v=Kq-7uvVOoyk

1929-2012

Causes

• Demonic possession• “Refrigerator mothers”• Neurodevelopmental Disorder• Biochemical Imbalance

Abnormal Brain MorphologySome schizophrenia patients exhibit

morphological changes in the brain like enlargement of fluid-filled ventricles.

Both Photos: C

ourtesy of Daniel R

. Weinberger, M

.D., N

IH-N

IMH

/ NSC

Meta-Analysis

• 58 studies

• 1,588 SCZ patients

Region (Left or Right) % of Control

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 96

Wright et al. (2000). Am J Psychiatry, 157, 16-25.

Genetic Factors

Genetic Factors

The following shows the prevalence of schizophrenia in identical twins as seen

in different countries.

Genain Sisters“Genain”: Greek “dire birth”, born 1930, all hospitalized for schizophrenia by early 20s,

probability = 1.5 billion

Nora: intermediate (jobs, no family)Iris: intermediate (jobs, no family)Myra: secretary, married, 2 sonsHester: showed signs at age 11, institutionalized

Genetics: identicalEnvironment: identical (schizophrenic mom)Prenatal: ?

Wisconsin Card Sorting Test

• Developed by Esta Berg in 1950s

• Measures cognitive flexibility and perseverative behaviors (number, color, shape)

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.

Individual Differences in SCZ

Hypofrontality During WCST

Hypofrontality During Continuous Performance Test

• fMRI was completed during a Continuous Performance test

Volz et al. (1999). European Psychiatry, 14, 17-24.

Hypofrontality During Continuous Performance Test

• fMRI was completed during a Continuous Performance test

Volz et al. (1999). European Psychiatry, 14, 17-24.

Neurochemical ImbalanceTypical

Origin 1952

Example ChlorpromazineHaloperidol

Mechanism D2 antagonist

Treats + symptoms

Side-Effects Tardive dyskinesia

TD (20 sec): http://www.youtube.com/watch?v=fLwZQBJs8fI

Drug Therapies

Psychopharmacology is the study of drug effects on mind and behavior.

With the advent of drugs, hospitalization in mental institutions has rapidly declined.

ComparisonTypical Atypical

Origin 1950s 1970

Example ChlorpromazineHaloperidol

Clozapine

Mechanism D2 antagonist D2 & 5-HT2A antagonist

Treats + symptoms + symptoms

Side-Effects Tardive dyskinesia Weight gain

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.

**

Beyond D2

• the dopaminergic (or serotonergic) model of schizophrenia may be too simplistic

Kerwin et al. (1999). Neuroscience, 39, 25-32.

Schizophrenia in Children

• More frequently recognized

9 min: http://www.youtube.com/watch?v=B9v4FsKXmj8

8 min: http://www.youtube.com/watch?v=UTUMt05_nCI

Self-Medication?

• Marijuana• Nicotine

Reduced Lifespan (N = 5,036,662)!

Male Life Expectancy

MaleYears Lost

FemaleLifeExpectancy

FemaleYears Lost

All (Psychiatric History - )

76.5 NA 80.9 NA

Schizophrenia 57.8 18.7 64.6 16.3

Bipolar 62.9 13.6 68.8 12.1

Laursen (2011). Schizophrenia Research, 131, 101-104.

Reduced Lifespan (N = 5,036,662)!

Male Life Expectancy

MaleYears Lost

FemaleLifeExpectancy

FemaleYears Lost

All (Psychiatric History - )

76.5 NA 80.9 NA

Schizophrenia 57.8 18.7 64.6 16.3

Bipolar 62.9 13.6 68.8 12.1

Laursen (2011). Schizophrenia Research, 131, 101-104.

Contributing Factorssuicide, accident, homicides, self-care, metabolic (?)

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– Schizophrenia– Order

Louis Wain (1860-1939)

Summary

• Symptoms ( + and - )• Current Biological Components (Not Diagnostic)

– Genetics– Brain Structure– Dopamine Receptors

VideocastOverman, Gerald (2010). Antipsychotic treatment & tolerability. Starts about 4:40 (ends abruptly):

http://videocast.nih.gov/Summary.asp?File=15991

What are the pros and cons of the typical and atypical antipsychotics?

What is EPS? What areas of the brain are important for this?

If you had a family member that was recently diagnosed with SCZ, what drug (or drug class) would you hope that the psychiatrist would prescribe?