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Drugs and the Brain:
The Challenge of Schizophrenia
David A. Lewis, MD
Translational Neuroscience Program
Department of Psychiatry
Center for the Neuroscience of Mental Disorders
University of Pittsburgh
Leading Causes of Disability: Market Economies,
1990
All Causes
Total
(millions)*
46.8
% Total
1
2
Major Depression
Alcohol use
6.7
4.5
14.3
9.6
3
4
Osteoarthritis
Dementia
2.7
2.4
5.8
5.1
5
6
7
8
Schizophrenia
Bipolar disorder
Cerebrovascular
Diabetes
2.2
1.7
1.6
1.5
4.7
3.6
3.3
3.2
9
10
OCD
Drug use
1.5
1.4
3.1
3.0
The Burden of Schizophrenia
• Common: ~1% of population
• Chronic: Affected individuals typically ill
from adolescence or early adulthood
• Co-morbidity: Depression, substance
abuse, suicide (10%)
Suicide
• ~40,000 deaths by suicide in US annually.
• 95% of people who commit suicide are suffering
from a diagnosable psychiatric illness.
• Common diagnoses in suicide: major depression,
alcoholism, schizophrenia.
• 2/3 communicate their intent and 50% have
consulted a physician within the month prior to
death.
Schizophrenia:
Historical Perspectives 1
• 1893 Kraepelin distinguished “dementia
praecox” from manic-depressive psychosis
• Emphasized course and prognosis
– Early onset
– Deteriorating course
– Dementia as the end state
• An “organic” brain disorder
Schizophrenia:
Historical Perspectives 2
• 1911 Bleuler coins “schizophrenia” in reference to
the splitting of mental functions
• Emphasized psychological mechanisms
• Four fundamental features (“the 4 A’s”)
– Loosening of Associations
– Autistic behavior and thought
– Disturbance in Affect
– Ambivalence
• Psychosis = Accessory Symptoms
Schizophrenia:
Historical Perspectives 3
• 1939 Schneider emphasized diagnostic
reliability
• Described “first rank symptoms”
–
–
–
–
Audible thoughts
Voices arguing or commenting
Thought insertion, withdrawal or broadcasting
Made impulses, feelings or will
• Very common in schizophrenia but not
specific to this diagnosis
Video Interview
• Auditory hallucinations
• Paranoid delusions
• Thought disorder
–
–
–
–
–
Tangential associations
Blocking
Perseveration
Echolalia
Clanging
• Alogia
• Affective flattening
– Poor eye contact
– Paucity of expressive
gestures
– Inappropriate affect
• Motor disturbances
– Posturing
– Akathisia (drug-induced
restlessness)
• Depressed
– Poverty of speech
mood/suicidal ideation
– Poverty of speech content
• Lack of insight
• Avolition-apathy
Schizophrenia as a Genetic
Disorder
• The morbid risk of schizophrenia
increases in relation to the percentage of
genes shared with an affected individual.
Schizophrenia and Genetic Risk
relationship
% shared genes relative risk
Gen population NA
1%
3rd degree
12.5%
2%
2nd degree
25%
2-6%
1st degree
50%
6-17%
Both parents
100%
46%
Identical twin
100%
48%
The familial nature of schizophrenia is NOT
due simply to a shared environment
• The risk of schizophrenia is ~17% for
fraternal twins and ~48% for identical twins.
• The risk for adopted-away biological children
of individuals with schizophrenia…
– is elevated as expected for first-degree relatives.
– higher than rates of schizophrenia present in their
adoptive families.
– higher than rates of schizophrenia in the adoptedaway offspring of unaffected parents.
Inheritance is not sufficient for the
development of schizophrenia
• Conordance for schizophrenia in monozygotic
twins is only ~ 50%.
• ~ 60% of individuals with schizophrenia have
neither a 1st nor 2nd degree relative with the
disorder.
• Patterns of inheritance do not fit single gene,
Mendelian models, but suggest the influence of
multiple susceptibility genes, each of small
effect.
Schizophrenia as an Environmental
Disorder
• A variety of “environmental” events appear to
increase the risk for schizophrenia:
–
–
–
–
Pregnancy and labor/delivery complications
Late winter/early spring births
Urban place of birth and rearing
Advanced paternal age
• However, the predictive value of all of these
risk factors is low.
Schizophrenia as a
Neurodevelopmental Disorder
• During childhood and adolescence,
individuals who subsequently manifest
schizophrenia may exhibit…
– Motor abnormalities
– Social abnormalities
– Impairments in IQ and school
performance
Schizophrenia as a Neurodevelopmental
Disorder
• Early model: Brain lesion from early in life
remains clinically silent until normal
developmental processes during adolescence
bring the structures affected by the lesion
“on line.”
• Late model: Brain dysfunction arises as a
result of altered brain development (e.g.,
synaptic pruning) during adolescence.
The Disease Process of Schizophrenia
Pathogenesis
Etiology
Pathophysiology
Pathological
Entity
Clinical
Syndrome
Adapted from Paul R. McHugh, M.D.
The Neurobiological Challenges of
Schizophrenia
• The apparent absence of neuropathological
abnormalities.
• The complexity of the brain systems that are
dysfunctional.
Neuropathological Markers: A Tale of
Two Disorders
• Alzheimer’s Disease
• 1906 clinical description
• 1906 neuritic plaques (NP)
and neurofibrillary tangles
• 1984 amyloid protein in NP
• 1987 gene for beta-amyloid
protein (BAP)
• 1990’s molecular
mechanisms underlying
BAP deposition
• 1990’s genes for rare
familial forms and
susceptibility genes for
common forms
•
•
•
•
Schizophrenia
1895 clinical description
1979 enlarged ventricles
2000 alterations in
thalamo-cortical-striatal
circuitry
• 2002 first compelling
risk genes identified
Biological Complexity of the
Clinical Features of Schizophrenia
• Disturbances in Vision
–Visual field defects vs. visual
hallucinations
Sensory-Motor vs. Cognitive Circuits
• The activities of encoding sensory
information and commanding
movements occupy only about 20% of the
volume of the cerebral cortex.
• The remaining association cortices are
concerned with attending to and
recognizing complex stimuli, and to
storing (both short and long term) such
information in order to plan appropriate
responses. Such abilities are termed
cognitive processes.
Neuroscience
, Purves et al
Fig 12.8 Neuroscience, Purves. P260.
Fig 2 Cerebral Cortex, VanEssen. 1991.
Fig 4 Cerebral Cortex, Van Essen. 1991.
The Disease Process of Schizophrenia
Pathogenesis
Etiology
Pathophysiology
Pathological
Entity
Clinical
Syndrome
Adapted from Paul R. McHugh, M.D.
Schizophrenia affects multiple complex
brain systems as evidenced by the range of
clinical features
• Positive symptoms: Delusions, hallucinations,
thought disorder
• Negative symptoms: Decreased motivation,
diminished emotional expression
• Cognitive deficits: Impairments in attention,
executive function, certain types of memory
• Sensory abnormalities: “Gating” disturbances
• Sensorimotor abnormalities: Eye tracking
disturbances
• Motor abnormalities: Posturing, impaired
coordination
Cognitive Deficits in Schizophrenia:
Core Features of the Illness
•
•
•
•
Present in individuals at high risk
Premorbid and prodromal phase marker
Persistent (progressive?) during illness
Predictor of long-term outcome
Cognitive Deficits in Schizophrenia
• Include impaired working memory, the
ability to keep in mind briefly a bit of
information in order to guide subsequent
behavior.
• Working memory deficits are associated
with dysfunction of the dorsolateral
prefrontal cortex (DLPFC).
DLPFC Activation as a Function of Working
Memory Load in Schizophrenia
% fMRI Signal Change
R DLPFC (BA46)
.30
Controls
Patients
.20
.10
n = 16 per group
0
0-back
+28 mm
1-back
2-back
WM Load
Courtesy of Dr. Cameron Carter
Cognitive Deficits in Schizophrenia
• Working memory requires an intact
dopamine innervation of the dorsolateral
prefrontal cortex.
• Dopamine-containing axons project from
the ventral mesencephalon (VTA) to the
cerebral cortex.
Catechol-O-methyltransferase (COMT)
• Enzyme involved in the metabolic degradation of
dopamine.
• COMT appears to be the major contributor to the
termination of dopamine action in the prefrontal
cortex due to low levels of the dopamine transporter.
• Single guanine to adenine transition (common)
changes val to met at codon 108.
• Val-COMT has 4-fold greater activity than metCOMT, leading to decreased prefrontal dopamine
levels.
• Schizophrenic individuals with val/val COMT show
greater impairments on working memory tasks.
Deficits in Prefrontal Cortical Dopamine
Neurotransmission in Schizophrenia
• Normal function of the DLPFC depends upon
appropriate stimulation of dopamine D1
receptors
• Individuals with schizophrenia may have
• Decreased dopamine axons in the DLPFC
• Increased levels of D1 receptors in the DLPFC
• Improvement in DLPFC function with
dopamine agonists
But, Schizophrenia Also Appears to be
Associated with an Excess of Dopamine
Neurotransmission
• Amphetamines can induce psychotic
symptoms.
• All antipsychotic drugs share antagonism
of the dopamine D2 receptor.
• Subjects with schizophrenia show excess
release of dopamine in the striatum.
Dopamine Neurotransmission in
Schizophrenia
• The cognitive symptoms of schizophrenia
may be associated with a functional deficit of
dopamine at D1 receptors in the prefrontal
cortex.
• The psychotic features of schizophrenia may
be associated with a functional excess of
dopamine at D2 receptors in the striatum
(caudate/putamen).
Structural Brain Abnormalities in
Schizophrenia
• ~40% increase in 3rd and lateral
ventricular volumes
– Associated with more neuropsychological
impairments and negative symptoms
– More prominent in males
• 3-4% decrease in whole brain volume
Structural Brain Abnormalities in
Schizophrenia
• Hippocampus and Association Cortices
– Decreased gray matter volume
– No cell loss
– Reductions in pre- and post-synaptic
markers
Basic Neurochemistry, 1994
Structural Brain Abnormalities in
Schizophrenia
• Mediodorsal thalamic nucleus
– Decreased volume
– ~30% Decrease in neuronal number
Structural Brain Abnormalities in
Schizophrenia
• Convergent lines of evidence indicate that
schizophrenia is associated with
– A reduction in synaptic connections in the
hippocampus and cerebral cortex.
– Fewer neurons in the mediodorsal thalamus.
• Which neurotransmitter systems are
involved in these abnormalities?
Altered Glutamate Neurotransmission - 1
• Phencyclidine (PCP) and ketamine, noncompetitive antagonists of the NMDA
subtype of glutamate receptors…
– Exacerbate clinical features of
schizophrenia.
– May induce transiently some positive,
negative and cognitive symptoms resembling
those of schizophrenia in normal adults.
– Rarely cause such symptoms in children.
Altered Glutamate Neurotransmission - 2
• The symptoms of schizophrenia,
especially cognitive deficits, have been
reported to be improved by…
– Glycine, which facilitates NMDA receptor
function by binding to a modulatory site on
the receptor.
– D-cycloserine, a selective partial agonist at
the glycine modulatory site of the NMDA
receptor.
Current Treatment of Schizophrenia
• Classical APD
• High affinity D2
antagonists
• Reduces positive sx
• Limited against
negative/cognitive
• High rates of EPS
and TD
• Atypical APD
• Low affinity D2, high
affinity 5HT2A
antagonists
• Broader efficacy
• Blood dyscrasias,
weight gain, glucose
intolerance, $$$