Download here - Olin Neuropsychiatry Research Center

Schizophrenia & Psychoses
A Clinical Introduction
Godfrey D. Pearlson, M.D.
Neuropsychiatry Research Center
Institute of Living
Yale University School of Medicine
Schizophrenia - Outline
1. Phenomenology
2. Epidemiology
3. Etiology - neurodevelopmental &
genetic factors
4. Spectrum disorders, biomarkers,
5. Treatments
6. Psychotic mood disorders
Core Concepts- 1
Affective Disorder:
Delirium:
Dementia:
Schizophrenia:
disturbance of mood
disturbance of consciousness
disturbance of (a prior level of)
cognition
??????????????????????
No obvious pathognomonic symptoms or
core“theme”.
Core Concepts II
1. Because it has no pathognomonic symptoms,
schizophrenia is a diagnosis of exclusion.
2. Widespread agreement that schizophrenia is
a heterogeneous disorder; but no agreement
on sub-typing.
3. Traditional subtypes (e.g. hebephrenic,
paranoid) mutate over time.
DELIRIUM
PLUS DISTURBED
CONSCIOUSNESS
DEMENTIA
PLUS COGNITIVE
DECLINE
AFFECTIVE
DISORDER
PLUS CHANGE IN
MOOD, SELF-ATTITUDE
AND VITAL SENSE
SCHIZOPHRENIA
HALLUCINATIONS,
DELUSIONS,
FORMAL THOUGHT DISORDER
SCHIZOPHRENIA– CASE STUDY 1
Frank S. 31 y.o. single WM
Upper middle class family, no FH of mental illness
Mother’s pregnancy – ‘flu’ at 15 weeks, forceps
delivery, Apgar in normal range
Shy, slightly withdrawn child – ‘grew out of it’ by age
14. IQ = 128 FS.
College – electrical engineering major. All ‘A’ grades in
freshman year.
Sophomore year – age 20, increasingly withdrawn,
preoccupied, ‘distant’, odd philosophical worries x 6
months.
SCHIZOPHRENIA– CASE STUDY 2
Became convinced messages on TV about him,
“aliens reading my mind.” “White House controlling my
body.”
Auditory hallucinations of “robot voices” saying good
and bad things about him, arguing.
Showed up at police HQ to warn of “plots”, taken to
ER for evaluation
Alert, O x 3. Not elated or depressed. MMS – 30/30.
Urine Toxicology screen negative. Physical exam and
labs all WNL. Brain MRI WNL.
SCHIZOPHRENIA– CASE STUDY 3
Hospitalized three weeks
Partial response to Haloperidol
Family “lost his spark”……but not due to medications
Unable to complete college
Halfway house – small apartment
Volunteer for state agency
3 subsequent hospitalizations in 10 years
Seclusive, poor self-care
Some improvement on olanzapine – initial gain
Now on ziprasodone – variable compliance
Positive and Negative Symptoms
Positive
Delusions
Hallucinations
Incoherence
Negative/Deficit
Poverty of speech
Flat affect
Social Withdrawal
Bizarre behavior
Apathy
(Remember-no pathognomonic symptoms.)
Source: DSM-IV Draft Criteria, 1993
Cognitive Deficits
An essential part of the syndrome.
Working Memory
Set Shifting
Verbal Memory
Attention / Continuous Performance
Epidemiology of Schizophrenia
About 1% prevalence in the population
Occurs in all cultures, all socioeconomic groups
Peak onset in men, ages 15 to 25
Peak onset in women, ages 22 to 30
Prevalence ultimately equal in men and women
50% of patients attempt suicide, 10% succeed
Most expensive of all mental disorders:
Chronic but non-fatal, many incarcerated, homeless
– Direct costs = 0.4% of the GNP
– Indirect costs = 1.6% of the GNP
20-year Follow-up of Patients with
SZ (Iceland)
All first-episode SZ diagnosed in 1966 to 1967
22% mortality and 9% suicide
60% never married; of the rest, most divorced
71% had persistent symptoms despite
neuroleptic treatment
95% had impaired social relationships
65% worked fewer than 5 months per year
29% had “an acceptable level of health”
Medical Illnesses in Psychosis
Proposed Etiology
Genetic predisposition /
vulnerability
Brain mal-development in utero
(genetic, toxic, infective)
Pregnancy & birth complications
Early psychosocial experience
Source: Mednick et al., 1991
GENE  CELL  SYSTEM  BEHAVIOR
Sensory motor
Integration
Gene
Cell
System
Behavior
Multiple susceptibility alleles, each of small
effect, low penetrance, that act in concert
Subtle metabolic abnormalities
Molecular bottlenecks?
Abnormal information processing
Cognitive inefficiency – memory and control
processes, Biomarkers
Not ≡ illness, e.g. as found in unaffected siblings
Complex functional interactions
Emergent phenomena
(After Weinberger, 2003)
Functioning
PHASES OF SCHIZOPHRENIA
PREMORBID
PRODROME
Course of Illness
ACTIVE
Disease Genes
Viral Infection
Environmental Toxins
Peri-natal/Birth
Complications
TRIGGERS: Environmental Stress
Biological Factors
Drug Use
Biological Vulnerability
Structure
Biochem
Function
Age
0
Neurol +
Cognitive
Deficits
5
Premorbid
Early
Negative
Sx
Weak
Positive
Sx
12
15
Early
Prodrome
Emerging
Psychotic
Sx
18
Late
Prodrome
21
Diagnostic Criteria for Schizophrenia
• DSM-IV -Based on phenomenology
• Highly reliable, but of dubious validity
• Could have been written 100 years ago
(in fact they were, essentially)
• No laboratory test, even to confirm
diagnosis, let alone a diagnostic test
related to pathophysiology
DIABETES
SCHIZOPHRENIA
Etiology

•
Pathology

•
Biologic
Definition/Test

•
Genes
 (partial)
• (partial)
Biomarkers

 (partial)
Clues from Type-2 Diabetes “Spectrum Cases”
• Impaired GTT + impaired fasting glucose ~
40% of obese adults
• Gestational DM (~ 10% of pregnant women)
• Steroid-induced DM (~ 30% on hi-dose
systemic steroids)
All of the above are substantially increased in
first-degree relatives of Type-2 diabetics
(about 50% have insulin resistance), 15%
diabetes, 25% abnormal GTT.
Schizotypy and Spectrum Conditions 1
Early researchers into schizophrenia noticed
that unaffected family members exhibited
oddities and eccentricities.
Interpretation:
1.
Consequence of close association with
someone whose behavior was disturbed or
disturbing
2.
Lesser, “dilute” form of the disorder
Schizotypy and Spectrum Conditions 2
Kety’s genetic studies with the Danish twin and
disease registries, & Kendler’s Irish
kindreds confirm these ideas.
Mild or dilute forms of schizophrenia, or oddities
of thought and behavior occur more
commonly among close relatives of patients
with schizophrenia than in the population at
large. Genetic explanations best fit the
facts. These individuals have vulnerability
genes, insufficient for full-fledged
schizophrenia.
< Introduces concept of biomarkers >
SCHIZOPHRENIA VULNERABILITY
MARKERS “Biomarkers”
BIOMARKERS
Definition:
Physiological and clinical phenomena found
in association with a disorder, which are
quantifiable, and presumed to be more
closely connected to the vulnerability
gene than the illness diagnosis.
Schizophrenia Biomarkers
•
•
•
•
•
•
•
•
•
•
Gene markers – a few in last 3 yrs.
Electrophysiology – P-300, N-400, P450
Psychophysiology – oculomotor, PPI
Brain structure – Volumes of LV, STG,
Hippo
Brain Function – PET, fMRI with WCST, WM
Brain Chemistry – DA receptors, release
Development – neurologic, cognitive, social
Clinical exam – MPA’s, ‘soft’ neurologic
signs
Cognition – WM, attention
Niacin flush, fingerprints
Biomarkers and Schizophrenia
Summary:
• Promising avenue of research.
• Approach very useful in diabetes,
hypertension- may work for
schizophrenia.
Schizophrenia and Cognition
Major defects in:
•
Working memory
•
Executive functioning (abstraction, problem solving,
conceptualization, sequencing, inhibition, planning)
•
•
•
Attention
Verbal memory
Semantic tasks
Symptoms suggest frontal lobe dysfunction
Magnitude of Cognitive Deficits in Schizophrenia
Test
Domain
Md (mean effect
size difference)
# of studies
% Patients
Below Median
Verbal
Memory
Memory
1.41
31
78
Wisconsin
Card Sort
Executive 0.88
Function
43
69
1.15
29
75
Continuous
Performance
Sustained 1.16
Attention
14
75
Bilateral
Motor Skill
Motor
5
77
Verbal
Fluency
1.3
Heinrichs RW, Zakanis KK, Neuropsychology 2: 426-445
Cognitive Deficits in Schizophrenia
Core Features of Illness
Precede Onset of Illness
– ½ SD lower IQ
– Reading difficulties in grade through high school
– Delayed onset of hand dominance
Present at Disease Onset
Continued…
Sources: Green 1996; Heinrichs and Zakzanis 1998; Saykin 1991, 1994
Cognitive Deficits in Schizophrenia
Resist Medication Effects
Persist into Senescence
May Predict Psychosocial Function
Better Than Positive or Negative
Symptoms
Core Cognitive Domains
Compromised in Schizophrenia
Sustained attention
Working memory
Set shifting
Verbal Memory
Problem solving
Abstraction
These suggest compromised neural circuits
Symptoms suggestive of frontal
lobe dysfunction
Emotional dullness
Impaired judgment
Poor initiative, motivation, drive
Lack of insight
Difficulty in planning
Impaired problem-solving/abstract
reasoning
Decreased concern for personal hygiene
Social withdrawal
Cognitive Rehabilitation
RemediationRepeated practice and acquisition of
compensatory strategies on cognitive exercises
designed to engage under-functioning brain
circuits
Adaptation
History of Antipsychotic Medications
Dopamine and other Neurotransmitters
Atypical neuroleptics
•
Off D2 graph
•
Other receptors
•
Antipsychotic with EPS!
•
Effective against negative symptoms
(late!)
•
Atypically expensive
Annual Cost Estimates of Typical Doses
Clozaril (Sandoz)
$3,694
,
5 mg. BID, Haldol
(McNeil)
$944
Haldol (Generic)
$254
3 mg. BID, Risperdal
(Janssen)
$2,843
(Not including monitoring
which adds significant
extra cost)
10mg of Zyprexa $1/mg = $3,650
(Pfizer)
Psychosis in Mood Disorders
Phenomenology and Schneider’s
First-Rank Symptoms
Kurt Schneider, 1939, places high value on certain
symptoms in the diagnosis of schizophrenia, naming
them “ first rank symptoms”.
These include: audible thoughts, voices heard
arguing, voices heard commenting on one's actions,
somatic passivity experiences, thought withdrawal &
diffusion, delusional perception, and “made”
impulses, drives and volitional acts experienced by
the patient as the work or influence of others.
“When any of these modes of experience is
undeniably present and no basis of somatic illness can
be found, we may make the decisive clinical
diagnosis of schizophrenia.”
Why we Downgraded FRS
Three sets of observations tend to undermine
this distinction. These come from the work of
Gabrielle Carlson, Carpenter and Strauss and
the St. Louis group.
First-rank symptoms occur commonly in cases
of mania (up to 40%).
Not useful in terms of diagnostic distinction, do
not predict outcome of illness or response to
treatment.
Carlson describes a “third
stage" of mania
Manifested by bizarre behavior, moodincongruent hallucinations & delusions
paranoia and extreme dysphoria.
“Despite symptoms that might have
otherwise prompted the diagnosis of
schizophrenia, …. patients appeared
clearly manic both earlier in the course
and later as the episode was resolving.”
Example from Carlson:
Patient frightened, talking and crying
constantly, pacing. “I will never get out”.
“I have cats eyes”. “He crawls around
inside me, and he cannot stand the light.”
Profane, hypersexual, uncooperative. “Oh
please let me die, I can’t take it anymore”.
“National Institute of Hell.”
Following treatment, patient reverted to a
typical manic state: hypersexual, bizarre
attire (wearing three dresses at a time),
grandiose, incessant talking.
Chromosomal locations of potential
BP/SZ overlap genes.
Berretini and others
Separate Genes May Code for
Sub-Syndromes ?
E.G. Psychosis, Mood Instability
Assortative Mating Muddies the
Waters
?
Summary: Levels of identification of diseases
Etiology: e.g. genes, viral infections
Pathophysiology: e.g. developmental or degenerative
process
Brain structure: e.g. structures, circuits
Brain function: e.g. neurotransmitters, rCBF,
metabolism
Cognitive function: e.g. memory, attention, executive
function
Epidemiology: e.g. sex ratios, age cohort effects
Clinical presentation: e.g. symptoms, age of onset,
course
Response to treatment
GENE  CELL  SYSTEM  BEHAVIOR
THANK YOU!