Download Lecture-23-2006

David Helfgott plays
Rachmaninov Piano Concerto #3
Copenhagen Philharmonic, 1995
RCA Victor-BMG Classics
as in the movie “Shine”
Born in Melbourne 1947
1962-1970 several schizophrenic
episodes
1966-70 Royal College of Music
1970-1980 Hospitalized in Australia
1984- present concert pianist
According to the biography by his wife, his present medication consists of:
(1) chlorpromazine (Thorazine), a D2 receptor blocker for schizophrenia; and
(2) an anticholinergic for tardive dyskenesia.
1
Bi 1
“Drugs and the Brain”
Lecture 23
Tuesday, May 16, 2006
Schizophrenia, a cognitive disorder;
Depression, a mood disorder
2
Schizophrenia. (Additional resource, Dr. Michael McIntosh’s lecture, #19) :
1. Clinical description (lecture 19, slides 9-10)
2. Genetics (lecture 19, slide 28)
4. Pathophysiology: schizophrenia as a developmental disorder
4. Pathophysiology: Objective measurements and animal models (lecture
19, slides 31, 32, 33, 34, )
5. No known heterozygote advantage
6. Therapeutic approaches: (also Lecture 19, slides 36, 37)
Disclaimer
Lectures 23 and 24 deal with psychiatric disease.
Henry Lester is not a psychiatrist--not even a physician.
Don’t change any medical treatment that you might now be receiving on the basis of
these lectures.
Don’t give any medical advice based on these lectures or problem set 7.
3
1. Clinical description
The range of clinical features shows that schizophrenia
affects multiple complex brain systems
Positive symptoms: Delusions, hallucinations, thought disorder
Negative symptoms: Decreased motivation, diminished emotional expression
Cognitive deficits: Impairments in attention, executive function,
some types of memory
Sensory abnormalities: Gating disturbances
Sensorimotor abnormalities: Eye tracking disturbances
Motor abnormalities: Posturing, impaired coordination
also Nestler p 389
4
2. Genetics
Schizophrenia is polygenic and probably genetically multifactorial
Twin data for concordance in schizophrenia vary enormously. In studies
published since 1968 (DSM criteria):
monozygotic
(n = 239)
22%
dizygotic
(n = 512)
8%
(general population
1%)
5
shared DNA
100%
Concordance for Lifetime Risk of Schizophrenia
identical twins
fraternal twins
50%
(1st-degree
relatives)
children
siblings
parents
half siblings
grandchildren
25%
nephews/nieces
uncles/aunts
12.5%
1st cousins
general population
0%
10%
20%
30%
40%
50%
6
Molecular Neuroscience
Clinical Neuroscience
Human Genome
and
Associated Data
7
We describe a map of 1.42 million single nucleotide polymorphisms (SNPs)
distributed throughout the human genome, providing an average density on
available sequence of one SNP every 1.9 kilobases. This high-density SNP
map provides a public resource for defining haplotype variation across the
genome, and should help to identify biomedically important genes for
diagnosis and therapy.
The International SNP Working Group (Lander et al)
8
Hunting for Genes with SNPs
specific place in sequence
Controls
sequence A1
20%
Schizophrenics
20%
sequence A1
Locus A
Chomosome 12
sequence A2
no linkage to
schizophrenia
sequence A2
80%
80%
40%
70%
Locus B
Chomosome 8
sequence B1
sequence B1
may be near a gene
that helps to cause
schizophrenia
sequence B2
sequence B2
60%
30%
9
Hunting for Genes with SNPs
Controls
sequence A1
20%
Schizophrenics
20%
sequence A1
Locus A
Chomosome 12
sequence A2
no linkage to
schizophrenia
sequence A2
80%
80%
40%
70%
recombination
Locus B
Chomosome 8
sequence B1
sequence B1
may be near a gene
that helps to cause
schizophrenia
sequence B2
sequence B2
60%
30%
10
SNP assays are now done in “high-throughput” modes:
hundreds of PCR reactions; results spotted onto chips;
mass spectrometry or other method to resolve single-nucleotide differences
slides from Lecture 15:
Two ways to amplify a DNA sequence
2. The polymerase chain reaction (PCR)
In fact, PCR uses dozens of sealed tubes simultaneously
in a heated and cooled metal block
PCR amplifies DNA exponentially
Starting PCR:
heat to
separate DNA
strands
cool to
bind primers
heat to
separate DNA
strands
cool to
bind primers
DNA
synthesis
heat to
separate DNA
strands
DNA
synthesis
cool to
bind primers
DNA
synthesis
> 12 nt
DNA polymerase requires a region of
double-stranded DNA
fragment
of DNA
to be detected
100 - 10,000 nucleotide pairs
1
17
Hunting for Genes with SNPs
Controls
sequence A1 20%
Schizophrenics
20%
sequence A1
Locus A
Chomosome 12
sequence A2
no linkage to
schizophrenia
sequence A2
80%
80%
40%
70%
Locus B
Chomosome 1
sequence B1
sequence B1
may be near a gene
that helps to cause
schizophrenia
sequence B2
sequence B2
60%
30%
11
Three concepts used in describing complex diseases
Polygenic
the disease occurs only if several genotypes are present together
Genetically Multifactorial
several distinct genes (or sets of genotypes) can independently cause the disease
Partially penetrant
nongenetic factors may also be required,
or the disease could be inherently stochastic
Genetically
Multifactorial
Polygenic
Partially
Penetrant
12
8p21, site of the latest schizophrenia linkage:
the neuregulin-1 gene
Little Alberts 5-13
© Garland
1 mm
13
Neuregulin-1 is a transmembrane protein
Neuregulin-1 is proteolyzed to release a growth factor
Cleavage #1
#2
14
See Angelo Stathopoulos cameo in lecture 20, and future Lecture 26
Like other growth factors,
The released fragment of neuregulin-1 activates specific genes
“Erb”
15
3. Pathophysiology.
Each new advance in neuroscience has been tried out on schizophrenia.
There is no satisfactory explanation yet.
In general, modern theories of schizophrenia emphasize abnormal neuronal
circuits or pathways, rather than individual neurons that either
(a) degenerate or
(b) fire too fast or too slow
Specific cell types may migrate incorrectly in embryonic development
16
“The known activities of neuregulins (NRGs) fit well with current hypotheses regarding the
neurobiological basis of schizophrenia.
Theory 1. Schizophrenia results from a deficiency of glutamatergic innervation relative to
dopaminergic innervation.
NRG knockout mice display hyperactivity in behavioral tests similar to hyperactivity observed in
mice treated with the psychogenic drug phencyclidine (PCP) or with mutations that impair
glutamatergic neurotransmission or enhance dopaminergic neurotransmission. Treatment with
clozapine reversed the hyperactivity of these mice, and they had reduced levels of the NMDA
type of glutamate receptors. Furthermore, application of soluble NRG1 to cultured neurons
stimulates transcription of NMDA receptors.
Theory 2. Abnormalities in glial biology contribute to the pathology of schizophrenia.
Neuregulins are required for initial differentiation of oligodendrocyte precursors and for their
survival. A variant of this idea is that a deficiency of glial growth factors––such as NRG––
predisposes to synaptic destabilization. It is clear that NRG signaling is required for the
stabilization of nerve-muscle synapses, and evidence for NRG involvement in astrocyte biology
might implicate neuregulins in formation or stabilization of central synapses.
Theory 3. Schizophrenia results from abnormalities in brain wiring.
Neuregulins regulate migration of neuronal precursors in culture.
Theory 4. Schizophrenia results from abnormalities in synaptic plasticity.
Neuregulin-1 inhibits induction of long-term potentiation, a form of synaptic plasticity
studied as a model for the neurophysiological substrates of learning and memory.”
17
Nongenetic contributions: the other 50%
(1) Nourishment and health of the fetus
Viral infections during pregnancy,
Possibly leading to low-level inflammation
(Prof. Paul Patterson, Caltech)?
(2) Head injury
18
4. Objective physiological measurements that correlate with schizophrenia
Biomarkers are objective, measurable biochemical, genetic, or other biological
indicators of a physiological or disease process. . . complex conditions, such as
mental illness, might benefit from constellations of several different biomarkers
being used in concert. . . biomarkers could facilitate definitive diagnosis of
mental disorders in individuals, assess the susceptibility of individuals to a
particular disorder, indicate changes in the severity of a disorder, and show the
response of a disorder to a given treatment. . .
Some disorders appear as a broad spectrum where signs and symptoms vary
enormously but yet collectively represent one general disorder (e.g. autism
spectrum disorders). In other instances, a particular symptom may appear
across a variety of mental disorders (e.g., cognitive impairment) or represent an
exaggeration of a dimension seen in healthy individuals (e.g., depressed
mood). . . Biomarkers could aid clinicians in categorizing particular signs and
symptoms so that a spectrum disorder could be broken down into well-defined
subcategories, allowing differential analysis or treatment.
Biomarkers . . . could be used in basic research to map the variability of a
marker across healthy populations.
19
4. Objective physiological measurements that correlate with schizophrenia
1. Electroencephalograms
2. Eye pursuit
20
Sensory gating anomaly measured electrophysiologically:
(a) Observed in schizophrenics (~90%) but in only 8% of the general population
(b) Autosomal dominant transmission, even in healthy relatives of schizophrenics
(c) This trait has been mapped to the vicinity of a gene on chromosome 15.
The gene is a nicotinic acetylcholine receptor.
A, abnormal ratio
schizophrenic
N, normal ratio
a
21
5.
Therapeutic approaches
Dopamine D2 blockers are the classical “antipsychotic” drugs.
See Nestler Figure 17-11, p 402
And Problem Set 7
All dopamine receptors are GPCRs.
22
from several previous lectures
Again, we highlight neurons that make dopamine;
here, note their postsynaptic targets in the frontal cortex
Nestler Figure 8-6
23
from lectures 22 and 24
Dyskinesia results from prolonged use of typical
antischizophrenic drugs.
Dyskinesia has some symptoms like
Huntington’s Disease
GABA-producing
“medium spiny” neurons
die in HD
Nestler Figure 8-6
24
Current Treatment of Schizophrenia
Drug class
Receptor actions
Symptomatic
effects
Side effects
Cost
“Classical” antipsychotics
“Atypical” antipsychotics
High affinity dopamine D2
Low affinity D2, high affinity
antagonists
serotonin-2A antagonists
Reduce positive symptoms;
little effect on negative /
cognitive symptoms
Reduce broad range of
symptoms
Frequent extrapyramidal side
Blood abnormalities, weight
effects and tardive dyskinesia
gain, glucose intolerance,
Off patent
$$$
25
from Lecture 13
System-level Action
Dopamine
“Pleasure”
system
morphine-heroin
Noradrenaline
“Readiness”
system
“PerceptionAssociation”
system

“Decreased
neuronal
activity”


tetrahydrocannabinol
nicotine


cocaine


amphetamine


ethanol
?



LSD
caffeine

phencyclidine




26
from Lecture 13
Endogenous ligand
morphineheroin
agonist
endorphins (peptides)
THC
agonist
anandamide
nicotine
agonist
acetylcholine
cocaine
antagonist
dopamine
amphetamine
antagonist
noradrenaline, serotonin,
dopamine
ethanol
agonist
?G protein?
LSD
agonist
serotonin
caffeine
inhibitor
cyclic AMP (intracellular)
phencyclidine
antagonist
glutamate
27
from Lecture 13
Primary Target
Details
(dates:
)
morphine-heroin
GPCR (G protein-coupled
receptor) (Gi)
m-opioid receptor
1985-1993
THC
GPCR (Gi)
cannabinoid receptor 1988
nicotine
agonist-activated channel
a4 nicotinic acetylcholine
receptor 1905-1995
cocaine
cell membrane
neurotransmitter transporter
dopamine transporter
1980-1991
amphetamine
vesicular / cell membrane
neurotransmitter transporter
vesicular monoamine
transporter 1990 - 1995
ethanol
? K channel ?
G protein-gated inward
rectifier GIRK1/2 1993 - 1999
LSD
GPCR (Gq)
5-HT2a receptor 1985-1990
caffeine
enzyme
cyclic AMP
phosphodiesterase 1965
phencyclidine
ligand-activated channel
NMDA glutamate receptor
28
Most antipsychotic drugs take at least 2 weeks to exert their
effects on the symptoms of schizophrenia.
Therefore these drugs teach us too little about the
cause(s) of schizophrenia.
What happens during those 2 weeks? We don’t know.
Presumably the nervous system responds to the initial effect of the
drug by readjusting synapses, gene activation, and other
processes.
29
Major Depressive Disorder: a Mood Disorder
1. Clinical description (McIntosh lecture #19, slides 11, 15, 16, 18)
2. Genetics (lecture 19, slide 29, 30
3. Possible causes (lecture 19, slide 67, 68 – 74)
4. Heterozygote advantage?
5. Therapeutic approaches
31
From DSM-IV
Summary description of a Major Depressive Episode :
The essential feature of a Major Depressive Episode is a period of at least 2 weeks during which
there is either depressed mood or the loss of interest or pleasure in nearly all activities.
In children, adolescents, and some adults, the mood may be irritable rather than sad.
The individual must also experience at least four additional symptoms drawn from a list that
includes:
• changes in appetite or weight, sleep, and psychomotor activity;
• decreased energy;
• feelings of worthlessness or guilt;
• difficulty thinking, concentrating, or making decisions; or
• recurrent thoughts of death or suicidal ideation, plans, or attempts.
To count toward a Major Depressive Episode, a symptom must either be newly present or must
have clearly worsened. The symptoms must persist for most of the day, nearly every day, for at
least 2 consecutive weeks.
The episode must be accompanied by clinically significant distress or impairment in social,
occupational, or other important areas of functioning.
32
DSM-IV details a Major Depressive Episode
(click on the text
to read
the entire excerpt
in Word)
The mood in a Major Depressive Episode is often described by the person as depressed, sad,
hopeless, discouraged, or "down in the dumps". In some cases, sadness may be denied at first,
but may subsequently be elicited by interview (e.g., by pointing out that the individual looks
as if he or she is about to cry). In some individuals who complain of feeling "blah," having no
feelings, or feeling anxious, the presence of a depressed mood can be inferred from the
person's facial expression and demeanor. Some individuals emphasize somatic complaints
(e.g., bodily aches and pains) rather than reporting feelings of sadness. Many individuals
report or exhibit increased irritability (e.g., persistent anger, a tendency to respond to events
with angry outbursts or blaming others, or an exaggerated sense of frustration over minor
matters). In children and adolescents, an irritable or cranky mood may develop rather than a
sad or dejected mood. This presentation should be differentiated from a "spoiled child"
pattern of irritability when frustrated.
Loss of interest or pleasure is nearly always present, at least to some degree. Individuals may
report feeling less interested in hobbies, "not caring anymore," or not feeling any enjoyment
in activities that were previously considered pleasurable. Family members often notice social
withdrawal or neglect of pleasurable avocations. In some individuals, there is a significant
reduction from previous levels of sexual interest or desire.
Appetite is usually reduced, and many individuals feel that they have to force themselves to
eat. Other individuals, particularly those encountered in ambulatory settings, may have
increased appetite and may crave specific foods (e.g., sweets or other carbohydrates). When
appetite changes are severe (in either direction), there may be a significant loss or gain in
weight, or, in children, a failure to make expected weight gains may be noted (Criterion A3).
The most common sleep disturbance associated with a Major Depressive Episode is insomnia
(Criterion A4). Individuals typically have middle insomnia (i.e., waking up during the night
and having difficulty returning to sleep) or terminal insomnia (i.e., waking too early and
being unable to return to sleep. Less frequently, individuals present with oversleeping
33
Leading Causes of Disability in Advanced Economies, 1990
Total (millions)*
% Total
All Causes
46.8
1
Major Depression
6.7
14.3
2
Alcohol use
4.5
9.6
3
Osteoarthritis
2.7
5.8
4
Dementia
2.4
5.1
5
Schizophrenia
2.2
4.7
6
Bipolar disorder
1.7
3.6
7
Cerebrovascular
1.6
3.3
8
Diabetes
1.5
3.2
9
Obsessive-Compulsive Disorder
1.5
3.1
10
Drug use
1.4
3.0
*Years lived with a disability
Murray and Lopez, The Global Burden of Disease, 1996
34
Prevalence
Major depressive disorder is by far the most common major psychiatric disease.
The lifetime risk for Major depressive disorder in community samples has varied
from 10% to 25% for women and from 5% to 12% for men.
Major depressive disorder may begin at any age, with an average age at onset in
the mid-20s.
Approximately 50%-60% of individuals with major depressive disorder, single
episode, can be expected to have a second episode. Individuals who have had
two episodes have a 70% chance of having a third, and individuals who have had
three episodes have a 90% chance of having a fourth.
35
2. Genetics
Major depressive disorder is 1.5-3 times more common among first-degree
biological relatives of persons with this disorder than among the general
population.
Major depressive disorder is so heterogeneous that very few scientists have tried
gene scanning approaches like the approaches that succeeded for cystic fibrosis,
Huntington’s disease, and (perhaps) schizophrenia.
“Candidate gene” approaches are being pursued.
There is evidence for an increased risk of alcohol dependence in adult first-degree
biological relatives, and there may be an increased incidence of attentiondeficit/hyperactivity disorder in the children of adults with this disorder.
36
4. Possible causes
37
Multiple transmitter systems are affected in major depressive disorder,
suggesting a fundamental cellular defect.
Serotonergic system
Noradrenaline system
Dopamine system
Acetylcholine system
Glutamate system
Steroid-based hormonal systems
(the hypothalamic-pituitaryadrenal axis)
Nestler 13-3
38
useful arguments
questionable
arguments
based on
therapies
Manji et al
39
5. Therapeutic Approaches to Major Depression
“The tailored subtype-specific ligand”
1.
Cloning: isolate the genes for all human receptors for a given drug.
2.
Neurobiology: select the appropriate receptor
3.
Express each subtype
4.
Identify ligands that bind specifically to the target subtype.
We now know that there are > 18 genes for serotonin receptors.
Most of them are GPCR’s,
(but at least 2 are ligand-activated channels).
But there is only a single serotonin transporter,
and it’s present at all known serotonin synapses.
And yet, . . .
40
from Lecture 11:
Summary:
Prozac doesn’t change personality;
it enables the true personality to function
41
from Lecture 13:
Neurons that make serotonin
raphe
nuclei
42
How might SSRIs work?
Perhaps one serotonin receptor is much more able to change levels
Lecture 14
Activated GPCRs are sometimes phosphorylated and endocytosed.
This terminates signalling.
a
b g
During activation, the G protein leaves . . .
. . . revealing
phosphorylation
kinase sites . . .
. . . triggering
endocytosis.
P
P
. . .other proteins
bind to the
phosphates . . .
But continual signalling
can activate genes
(not a
synaptic
vesicle)
P
P
43
The present discussion about the wisdom of prescribing SSRI’s to teenagers
DSM-IV:
“The presence in a depressed patient of a positive family history of bipolar
disorder or acute psychosis probably increases the chances that the patient's
own depressive disorder is a manifestation of bipolar rather than unipolar
disorder and that antidepressant therapy may incite a switch into mania.”
44
Recent uses for SSRI’s
depression
irritability
obsessive-compulsive disorder (OCD)
social phobia
premenstrual syndrome
eating disorders
45
Nonpharmacological Treatments for Depression
(in conjunction with antidepressants,
or after antidepressants have failed)
Goal = reduce symptoms of depression and return patient to full, active life
•
Psychotherapy
-
•
Cognitive behavioral therapy
Interpersonal therapy
Psychodynamic therapy
Electroconvulsive therapy
46
Public Service Announcements:
“Real Men, Real Depression”
See also
http://menanddepression.nimh.nih.gov/
47
Bi 1
“Drugs and the Brain”
End of Lecture 23
48