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Introduction to Psychiatric
Disease
and the Drugs of Experience
J. Michael McIntosh, M.D.
University of Utah
1
Impact
• Mental Illness extracts a enormous toll on
the individual.
• Mental Illness places huge burdens on
society.
• The study of neuroscience and how
behavior influence CNS function will lead
to the best treatments and cures.
2
Impact
• The World Health Organization indicates that of the top
10 conditions that cause disability worldwide, 5 are
mental disorders:
• major depression; schizophrenia; bipolar disorder;
alcohol abuse and obsessive compulsive disorder.
• Depression is the leading cause of disability in the world
as measured by Years Lived with Disability and the
prevalence is increasing.
3
Epidemiology
•
Lifetime prevalence of schizophrenia is approximately
1% worldwide.
• Schizophrenia is equally prevalent in men and women.
• The onset is earlier in men, with peak onset at 15-25
years. For women peak onset is 25-35 years. Outcome
for female schizophrenics is generally better.
4
Suicide risk
• Suicide risk. About 50% of all patients with
schizophrenia attempt suicide at least once. 10-15% of
schizophrenic patients died by suicide in a 20 year
follow-up period.
• Major risk factors for suicide include the presence of
depressive symptoms, young age and high levels of
premorbid functioning (especially a college education).
5
Epidemiology
• A disproportionate number of schizophrenic patients are
in the low socio-economic groups.
•
Downward drift hypothesis suggests that schizophrenics
move into or fail to rise out of a low socio-economic
group. Social causation hypothesis proposes that
stresses in low socio-economic groups contribute to the
development of the disease.
• It is estimated that 50% of homeless people are
schizophrenic.
6
Economic Burden
• Financial cost to society. About 1% of the national
income goes toward the treatment of mental illness
(excluding substance-related disorders).
•
Schizophrenia accounts for 2.5% of all health care
expenditures. 75% of people with severe schizophrenia
are unable to work.
7
Diagnostic criteria for
schizophrenia
• Different systems are used. DSM-IV (Diagnostic and
Statistical Manual) most commonly used in the United
States.
•
It is a clinical diagnosis. There are no diagnostic
laboratory tests.
8
American Description (DSMIV)
Diagnostic Criteria
• Characteristic symptoms: Two (or more) of the
following, each present for a significant portion
of time during a 1-month period (or less if
successfully treated):
– delusions
– hallucinations
– disorganized speech (e.g., frequent derailment or
incoherence)
– grossly disorganized or catatonic behavior
– negative symptoms, i.e., affective flattening, alogia, or
avolition
9
Three Classes of clinical features.
• Positive symptoms include delusions (false beliefs)
hallucinations (false perceptions), and thought
disorganization.
•
Negative symptoms refer to social withdrawal,
diminished affect, poverty of speech, lack of energy, and
the inability to experience pleasure.
•
Disturbances in basic cognitive functions, such as
attention, verbal fluency, executive functions and
memory (particularly working memory). In addition,
many patients have co-existing mood symptoms
including depression and anxiety.
10
Mood Disorders
• Long recognized disorders.
• Depression. Hippocrates (460-357 BC) “black bile” a state of “aversion to food,
despondency, sleeplessness, irritability
and restlessness.”
11
Mania
• Aretaeus of Cappadocia (ca. 150 AD)
described “mania” “There are infinite
forms of mania but the disease is one. If
mania is associated with joy, the patient
may laugh, play, dance night and day, and
go to the market crowned as if victor in
some contest of skill. The ideas the
patients have are infinite. They believe
they are experts in astronomy, philosophy,
or poetry.”
12
Manic psychosis
• “The patient may become excitable,
suspicious, and irritable; hearing may
become sharp…get noises and buzzing
the ears; or may have visual
hallucinations; bad dreams and his sexual
desires may get uncontrollable; aroused to
anger, he may become wholly mad and
run unrestrainedly, roar aloud; kill his
keepers and lay violent hands upon
himself.”
13
• DSM-IV (Diagnostic and Statistical
Manual) most commonly used in the
United States.
• Clinical diagnosis. There are no
diagnostic laboratory tests.
• Psychotic features may accompany
major depression or bipolar disorder.
14
DSM IV Major Depression
• A) Five (or more) of the following symptoms have
been present during the same 2-week period and
represent a change from previous functioning; at least
one of the symptoms is either (1) depressed mood or (2)
loss of interest or pleasure
15
Depression
•
1) depressed mood most of the day, nearly every day, as indicated by either
subjective report (e.g., feels sad or empty) or observation made by others
(e.g., appears tearful). Note: In children and adolescents, can be irritable
mood.
2) markedly diminished interest or pleasure in all, or almost all, activities
most of the day, nearly every day (as indicated by either subjective account
or observation made by others)
3) significant weight loss when not dieting or weight gain (e.g., a change of
more than 5% of body weight in a month), or decrease or increase in
appetite nearly every day. Note: In children, consider failure to make
expected weight gains.
4) insomnia or hypersomnia nearly every day
5) psychomotor agitation or retardation nearly every day (observable by
others, not merely subjective feelings of restlessness or being slowed down)
6) fatigue or loss of energy nearly every day
7) feelings of worthlessness or excessive or inappropriate guilt (which may
be delusional) nearly every day (not merely self-reproach or guilt about
being sick)
8) diminished ability to think or concentrate, or indecisiveness, nearly every
day (either by subjective account or as observed by others)
9) recurrent thoughts of death (not just fear of dying), recurrent suicidal
ideation without a specific plan, or a suicide attempt or a specific plan for 16
committing suicide
Mania
•
A distinct period of abnormally and persistently elevated, expansive, or
irritable mood, lasting at least 1 week (or any duration if hospitalization
is necessary).
During the period of mood disturbance, three (or more) of the following
symptoms have persisted (four if the mood is only irritable) and have
been present to a significant degree:
•
–
–
–
–
–
–
–
inflated self-esteem or grandiosity
decreased need for sleep (e.g., feels rested after only 3 hours of sleep)
more talkative than usual or pressure to keep talking
flight of ideas or subjective experience that thoughts are racing
distractibility (i.e., attention too easily drawn to unimportant or irrelevant
external stimuli)
increase in goal-directed activity (either socially, at work or school, or sexually)
or psychomotor agitation
excessive involvement in pleasurable activities that have a high potential for
painful consequences (e.g., engaging in unrestrained buying sprees, sexual
indiscretions, or foolish business investments)
17
• Sex. Lifetime prevalence of major depression is higher
for women than men (10-22% vs. 6-12%).
•
Race. Prevalence of mood disorders does not vary
significantly by race or ethnicity.
• Trends. Depression has a higher prevalence in younger
age groups than in older ones. Hypothesized that birth
cohorts born after WWII are at appreciably greater risk
for major depressive disorder than older birth cohorts in
advanced Western society. The trend has been
observed not only in the United States but also in
Sweden, Germany, Canada, and New Zealand.
18
Suicide
• Each year 30,000 people in U.S. die by suicide. Number of
attempted suicides are 8-10 times that high.
• Depressive disorders account for 80 percent of this figure,
schizophrenia accounts for 10 percent.
• Men commit suicide more than three times as often as do women.
Women, however, are 4 times more likely to attempt suicide than are
men.
• The trends in suicide data among patients with mood disorders
parallel the trends in mood disorders (i.e. suicide rates are much
higher in younger persons today than they were in younger persons
30 years ago).
19
Etiology
• The etiologies of schizophrenia and mood
disorders are unknown.
• They likely represent heterogeneous
group of disorders with overlapping clinical
symptoms.
20
•Sigmund Freud
•1856-1939
• Austrian neurologist; founder of psychoanalysis.
• Freud was one of the first to infer that mental
disorders could be a result of individual history, and
not just physical impairment.
21
Much of mental life is
unconscious.
People like to think they are in
control of their lives, but factors
outside of conscious awareness
often influence behavior.
22
Freud postulated two basic Impulses:
Sexual Impulses (or more generally, life affirming
impulses) Libido (or libidinal energy) is the energy source
for this impulse. Basic Life impulses are referred to as
needs.
Aggressive Impulse (or more generally, death
encouraging impulses) Aggressive energy is the energy
source of this impulse.
As an Impulse grows, it becomes more likely that the
person will choose an action which will reduce this need.
23
Neurosis: a range of disorders resulting from
efforts by a patient to defend himself against
becoming aware of threatening (and therefore
repressed) feelings, fantasies, and memories.
Psychosis: a range of conditions in which
neurotic defenses break down, and the
person is “overwhelmed” by the fantasies and
needs of his or her unconscious.
24
Many of Freud’s Ideas Now Lampooned
25
However,
Freud’s concept that mental disorders
could be a result of individual history,
and not just physical impairment
remains an important cornerstone of
modern psychiatry with increasing
molecular evidence.
26
Physical Findings
1. Genetics
2. Neurobiology
3. Role of Experience?
27
28
29
• Monozygotic twins of a patient with a
mood disorder have a concordance rate of
approximately 60-90%
• Dizygotic twins. 16-35% concordance.
30
Neuropathology of schizophrenia
•
Increased size of cerebral ventricles (lateral and 3rd)
and decreased brain volume is the most widely
replicated finding. Ventricular enlargement is found in
affected twins of monozygotic pairs discordant for
schizophrenia. This enlargement appears to be stable
when patients are followed up prospectively.
•
Decreased cortical gray matter especially evident in
superior temporal gyrus, dorsal prefrontal cortex and
limbic areas such as the hippocampal formation and
anterior cingulate cortex. These abnormalities may be
present in first-episode, never-medicated patients.
31
32
• Decreased numbers of neurons have been
found in the hippocampus and the
dorsolateral prefrontal cortex. In studies of
monozygotic twins discordant for
schizophrenia diminished activation of the
dorsolateral prefrontal cortex as measured
by SPECT and PET studies is seen.
33
Abnormal dendridic spines in
prefrontal cortex- layer 3
34
Hallucinations
are real
Specific neuronal circuits
involving the thalamus, caudateputamen, anterior cingulate,
limbic and primary auditory
cortex, hippocampus and
parahippocampal gyrus are
activated in schizophrenics
during auditory hallucinations.
35
Dopamine antagonists used for treatment
of psychosis.
36
37
Mood & PET Studies
• The most widely reported finding in depression
is decreased anterior brain metabolism,
(agranular region of cingulate cortex L>R)
• This abnormality appears to be state dependent
and has been observed in both depressive and
bipolar disorders.
• There is a reversal in shifts from depression into
hypomania.
38
39
•
For severe cases of obsessive compulsive disorder (OCD) that are resistant to
pharmacotherapy, psychosurgery may be considered as an alternative
treatment. In OCD there is an increase in activity in a neuronal circuit running
from the frontal cortex to the cingulate gyrus, striatum, globus pallidus, thalamus
and back to the frontal cortex. Surgical interruption of this loop by cingulotomy
(destruction of 2–3 cm of white matter) at the anterior cingulate cortex disrupts
transmission from the frontal cortex and reduces the symptoms of OCD
40
Endogenous Drugs of
Experience
• What we experience effects who we are
both short term and long term.
41
Placebo Example
Placebo from the Latin “I shall please.”
“It’s all in your head.”
42
Placebo effect varies
according to information given the patient.
Can have opposite effects
on heart rate, or blood pressure,
depending on whether they are given
as tranquillizers or as stimulants.
43
• Pain, depression, and Parkinson’s
Disease are illnesses where placebo effect
can be prominent.
44
Parkinson’s Disease
• Symptoms caused by insufficient
dopamine release.
45
• PET studies using 11C raclopride – a
dopamine receptor binding molecule.
• Monitor striatum using PET scan.
• Increased release of dopamine levels
leads to decreased raclopride binding.
46
Placebo effect
• Amount of change seen with placebo (1719%) equal to therapeutic doses drugs to
treat Parkinson’s.
47
• ½ of patients perceived a benefit.
• All showed binding changes.
• Those who reported effect had greater
change (22% vs. 12%).
48
Pain and Placebo
"We are studying the effect of a medication that may
or may not relieve pain. This medication is thought to
have analgesic effects through the activation of brain
systems that suppress pain."
49
Effects of pain and placebo on the activation of mu-opioid receptor-mediated
neurotransmission
Zubieta, J.-K. et al. J. Neurosci. 2005;25:7754-7762
50
Copyright ©2005 Society for Neuroscience
Figure 3. Relationship between placebo-induced regional {micro}-opioid system activation
and expectation of analgesia
Zubieta, J.-K. et al. J. Neurosci. 2005;25:7754-7762
51
Copyright ©2005 Society for Neuroscience
Implications for psychotherapy
Treatment with Prozac or Behavior Therapy results
in similar brain changes.
L.R. Baxter Arch Gen Psychiatry 1992;49:681-689
52
Oxytocin, A Trust Hormone?
Trust and trustworthiness were operationalized using a
paradigm from experimental economics using monetary
transfers (a money game).
Subjects were informed that their own decisions and those
of the others will determine how much money they leave
with.
They are unacquainted with, the other decision makers.
53
Decision makers who
received an intentional trust
signal have nearly twice the
OT levels as decision
makers in the Random Draw
condition (F-test, one-tailed,
n = 38, P <.004.
Ovulating women are also statistically less trustworthy
(one-tailed t-test, P >.036), presumably because of the
inhibition of OT binding to its receptor by progesterone.
PAUL J. ZAK, Ann. N.Y. Acad. Sci. 1032: 224:227 (2004)
54
Intranasal administration
of oxytoxin increases
human trust.
Researchers got students to play a serious game.
The game involved real monetary exchanges
between two people playing the anonymous roles
of 'investor' and 'trustee.'
As a group, the investors who received oxytocin
exhibited more trust in the anonymous trustee
than did the investors who received the placebo.
55
Subjects given oxytocin seem better able to overcome
trust obstacles such as betrayal aversion.
The effect of oxytocin on trust is not due to a general
increase in the readiness to bear risks.
Oxytocin specifically affects an individual's willingness to
accept social risks arising through interpersonal
interactions.
Kosfeld M, et al., Nature, 2005 Jun 2;435(7042):673-6
56
(A and B) Affiliative behavior among subordinates can reduce the effects of stress.
(A) Chimpanzees engage in social grooming. (B) A female tamarin monkey cares
for another's young while the mother feeds. (C and D) Stressful dominance
behavior may take physical or psychosocial forms. (C) Male savanna baboons may
fight over a kill. (D) A dominant male baboon intimidates a subordinate. R.M.
Sapolsky Science 29 April 2005
57
A physical stressor is an external challenge to
homeostasis.
A psychosocial stressor is the anticipation, justified or
not, that a challenge to homeostasis looms.
Psychosocial stressors typically engender feelings of
lack of control and predictability and a sense of lacking
outlets for the frustration caused by the stressor.
Both types of stressor activate an array of endocrine and
neural adaptations.
58
Physiological correlates of the more stressful
social rank.
59
When mobilized in response to an acute physical
challenge to homeostasis (such as fleeing a predator),
the stress response is adaptive, mobilizing energy to
exercising muscle, increasing cardiovascular tone to
facilitate the delivery of such energy, and inhibiting
unessential anabolism, such as growth, repair, digestion,
and reproduction.
Chronic activation of the stress response by chronic
psychosocial stressors (such as constant close proximity
to an anxiety-provoking member of one's own species)
can increase the risk of numerous diseases including
psychiatric.
60
1. In some species, rank is lifelong and inherited (for
example, in female rhesus monkeys.
2. In contrast, in other species, high-ranking individuals
maintain dominance through psychological intimidation
rather than aggression (where, for example, mere eye
contact with the alpha individual might elicit subordination
gestures).
Subordination as in #2 is associated with the greatest
physiological indices, plausibly reflecting the frequent
psychological stressors for subordinates and the paucity of
physical stressors for dominant individuals.
61
This reflects the high rates of physical and psychological
harassment of subordinates, their relative lack of social
control and predictability, their need to work harder to
obtain food, and their lack of social outlets such as
grooming or displacing aggression onto someone more
subordinate.
During major hierarchical reorganization, however,
dominant individuals at the center of the social tensions
typically experience the greatest amounts of physical and
psychological stress. As a result, during such
reorganization among wild baboons or soon after group
formation among species of captive primates, dominant
individuals have the greatest physiological indices of
stress.
62
We know that a particular rank gives rise to a particular
physiological profile, rather than visa versa, because
studies of individual captive animals before they are
placed in social groups indicate that physiological profiles
of singly-housed subjects do not predict their subsequent
ranks in a social group.
63
Several stress-related physiological endpoints have been
found to be sensitive to rank.
The most frequently studied endpoint is the blood level of
glucocorticoids (GCs), adrenal steroid hormones that are
secreted during stress, such as cortisol or hydrocortisone
in primates and corticosterone in many rodent species.
GCs typify the double-edged nature of the stress
response, as they help mediate adaptation to short-term
physical stressors yet are pathogenic when secreted
chronically.
64
Animals who are socially stressed by the dominance
hierarchy for prolonged periods undergo neurobiological
changes.
This can involve inhibition of neurogenesis, dendritic
atrophy, and impairment of synaptic plasticity in the
hippocampus and altered patterns of apoptotic cell death
(increases in the cortex and decreases in the
hippocampus) and enhanced benzodiazepine tone.
65
Poverty associated with long -term stress
in humans
Subjective socioeconomic status (SES) can be at least as
predictive of health as is objective SES.
Feeling poor may be at the core of why being poor
predicts poor health.
Schizophrenia is increased with lower SES.
66
There is evidence from MRI volumetric studies that
hippocampal volume is reduced in posttraumatic
stress disorder (PTSD or combat-related stress)
The hippocampus may also be affected in chronic
depression.
67
Coming up Short
• Some people are more vulnerable to
stress.
• 5-HTT- two common forms, long (l) and
short (s).
• Mice and Monkeys that are l/l cope better
with stress than those that are s/l or s/s.
• Monkeys with s allele that are raised in
stressful conditions have impaired
serotonin transmission.
68
Humans?
• 847 individuals were assessed with
various tests for the past 23 years.
• Assessments were from ages 3 to 26 and
included counting major stresses from 2126.
• At age 26 assessed for whether they had
been depressed in the past year.
• 17% reported major depression.
69
• Those with no major stressor had the
same risk regardless of allele status
(~10%)
• With 4+ life events this rose to 26% for l/l
and 43% for s/s.
• Abuse as a child predicted depression
after age 18 only in people carrying at
least one s allele.
70
50% of Caucasian population
carries one copy of s
Caspi et al., 2003, Science, 301:386
71
Child Maltreatment Effects
Caspi et al., 2003, Science, 301:386
72
The hazard ratio of onset of major depression within a 2-month period as a result of (1) sex (men
vs women), (2) genotype at the 5-HTT polymorphism (SS vs LS and LL), (3) the occurrence, in the
first month, of a stressful life event (SLE) based on 549 twins.
Kendler, K. S. et al. Arch Gen Psychiatry 2005;62:529-535.
73
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The hazard ratio of onset of major
depression within a 2-month
period as a result of (1) sex (men
vs women), (2) genotype at the M
polymorphism (SS vs LS and LL),
(3) the level of long-term
contextual threat experienced in
the first month.
Kendler, K. S. et al. Arch Gen Psychiatry 2005;62:529-535.
74
Copyright restrictions may apply.
Help our genes
Believe in
yourself.
Be a good
monkey.
75