TWO APPROACHES TO GENES

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TWO APPROACHES TO GENES PSYCHOPATHOLOGY

• Genome-wide Association Studies scan for
  variations in the DNA sequence for single
  nucleotide polymorphisms (SNPs) that tend to
  occur in individuals with a particular condition.
  They use many subjects and many SNPs (millions)
  from each subject.
• Intermediate Phenotypes use candidate genes
  (where theres good reason to believe that they
  confer risk) and look for intermediate phenotype
  (enzyme change, structural change in an area of
  the brain, etc.) and not look at disease
  symptoms. This questions whether there are
  indeed strict and distinct disease entities.
  Studies show that relatives of the mentally ill
  may display similar brain dysfunctions but no
  clinical pathology (suggest that genes affect
  biology greater penetrance at the neural level
  more than at the level of clinical
  phenomenology.

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Schizophrenia vs.
DepressionWho among us has not felt deeply
depressed in response to some event in our
lives, such as loss in a competition, death of a
pet, end of a relationship, etc. Yet,
invariably we know that this will end and things
will more or less return to normal. In this way,
we see depression as a swing in our normal mood
continuum. When that swing becomes chronic and
we see no way out, then it is a pathological
state we call Depression.Contrary to that, how
many of us have felt schizophrenic. Other than
for a split second, how often have you felt that
the world is a totally chaotic place, where
nothing seems to make sense? This is not simply
a movement along a normal continuum.
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CONSERVATIVE STRAIGHT-LACED / ORTHODOX HIP /
ARTSY ECCENTRIC STRANGE WEIRD BIZARRE ILL NO
N-FUNCTIONAL
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MOOD DISORDERS

• Major Depressive Disorder (MDD) vs
  Dysthymia
• Typical vs
  Atypical
• Bipolar vs Unipolar
• Chronic
  vs Acute

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Are we overdiagnosing depression?  Are some
things that used to be diagnosed as something
else now being called depression?Is all the
publicity over depression, antidepressants, the
easy prescription of Prozac, etc. increasing the
"apparent" prevalence of depression?Are more
women diagnosed with depression because men
choose to tough it out or are too macho to
admit that they are depressed and need HELP?  In
general, do more women than men seek therapy?
Has insurance coverage of mental health made it
easier to seek help?
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STRESS-RELATED DISORDERS
Curious Overlap
MULTIPLE CHEMICAL SENSITIVITY - symptoms in
multiple organ systems in response to multiple
substances other exposure syndromes Gulf War
Illness
FIBROMYALGIA 2 - 4 of population defined by
widespread pain and tenderness
CHRONIC FATIGUE SYNDROME 1 of population
fatigue and 4/8 minor criteria
Irritable Bowel Syndrome up to 80 overlap with
other syndromes
SOMATOFORM DISORDERS 4 of population multiple
unexplained symptoms - no organic findings
DEPRESSION
CHRONIC LYME DISEASE
Clauw, 2002
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MOVIE
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CONSISTENT FINDINGS IN MAJOR CLINICAL DEPRESSION

• Life Events may Trigger
• Presence of Intimate Others Lowers Risk
• Highly Recurrrent
• It is Common ( therefore its trigger factors are
  probably common)
• Rates Surge during Mid-Late Adolescence
• Incidence in Women 2x that in Men
• Heterogeneous, with Multiple Causes

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Table 1. Diagnostic Criteria for Major Depression
Depressed mood Irritability Low self
esteem Feelings of hopelessness, worthlessness,
and guilt Decreased ability to concentrate and
think Decreased or increased appetite Weight loss
or weight gain Insomnia or hypersomnia Low
energy, fatigue, or increased agitation Decreased
interest in pleasurable stimuli (e.g. sex,
food, social interactions) Recurrent thoughts of
death and suicide
A diagnosis of major depression is made when a
certain number of the above symptoms are reported
for longer than a 2 week period of time, and when
the symptoms disrupt normal social and
occupa- tional functioning (see DSM IV, 2000).
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TWO ADDITIONAL CRITICAL VARIABLES

• As many as 80 of MDDs are Comorbid for Anxiety
  Disorder
• MDDs are often Comorbid for Heavy Smoking and/or
  Drug Abuse/Dependence

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Worldwide Incidence of
Depression
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Incidence of Depression Varies across the Life
Cycle

• High in Early Adulthood
• Lower in Middle Age
• High again after 60

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Depression Across Time

• Typical episode lasts 6 - 9 mo. 70 will have
  recovered 1 yr. later. The other 20 -30 may
  have an episode lasting for years.
• Only 25 of patients will have only 1 episode.

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ARTISTS AND AFFECTIVE DISORDERS
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UNLIKELY THAT ANY SINGLE GENE CODES FOR A
PSYCHIATRIC CONDITION

• Susceptibility genes interacting with
• Developmental factors, and
• Profound environmental events, and
• Epigenetic DNA modifications

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Heritability of Psychiatric Disorders

• The proportion of individual differences in
  liability to illness that results from genetic
  differences between individuals in a particular
  population
• Anxiety Disorders 20-30
• Major Depression 30-40
• Alcoholism 50-60
• Schizophrenia, autism
• Bipolar Illness 80

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More Recent Treatments

• Vagal stimulation
• Deep brain stimulation
• Transcranial magnetic stimulation

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Left Hemispheric Hypoactivity is Associated with
Depression
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DEEP BRAIN STIMULATION Direct electrical
stimulation of cortical area 25 (subgenual
cingulate region), just above the roof of the
mouth, produces a large decrease in neuronal
activity there and an associated remission of
treatment-resistant depression in 4 of 6
patients. The effect was also long lasting.
This brain stimulation also reversed a frontal
cortex hypoactivity.
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Mayberg et al.
(2005) Neuron, vol. 45, pp. 651-660.
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What is CBT? Cognitive behavior therapy
combines two effective kinds of psychotherapy
cognitive therapy and behavior therapy.
Behavior therapy helps you weaken the connections
between troublesome situations and your habitual
reactions to them. Reactions such as fear,
depression or rage, and self-defeating or
self-damaging behavior. It also teaches you how
to calm your mind and body, so you can feel
better, think more clearly, and make better
decisions. Cognitive therapy teaches you how
certain thinking patterns are causing your
symptoms by giving you a distorted picture of
what's going on in your life, and making you feel
anxious, depressed or angry for no good reason,
or provoking you into ill-chosen actions. When
combined into CBT, behavior therapy and cognitive
therapy provide very powerful tools for stopping
symptoms and getting life on a more satisfying
track.
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MOST EMPHASIS HAS BEEN
ON1. low serotonin (genetic or
stress-induced). Were trying to see if the
initial activation of serotonin by traumatic
stressors is followed by a significant and
long-lasting decrease.2. high CORT (mostly
driven by stress, by some genetic predisposition
remember Cushings and patients given
glucocorticoids).3. and their complex
interaction.
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SOME GENE TARGETS FORANTIDEPRESSANTS

• Serotonin transporter 5-HTT
• Serotonin autoreceptor 5-HT1a
• Glucocorticoid receptor

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Activity of Serotonergic Neurons as a Function of
Behavioral State
AW
QW
SWS
REM
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Spontaneous CPG-Mediated Behaviors Activate
Raphe Neurons
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Tonic Response
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Princeton Affiliate
Wow, does this feel great! Professor
Jacobs was right about exercise.
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The Rat Hippocampus
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BrdU-labeled Cells in the Rat Hippocampus
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Chronic Fluoxetine (PROZAC) Augments Hippocampal
Cell Proliferation
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SEASONAL AFFECTIVE DISORDER (SAD) Normally,
light, acting via the nucleus suprachiasmaticus
(SCN), suppresses the pineals secretion of
melatonin. As the days shorten, there is less
inhibition and therefore more melatonin. Some
individuals are more sensitive to this and
develop SAD. For the same reason, this is
probably related to the negative feelings
associated with jet-lag. The treatment for both
is exposure to intense morning light, which turns
off melatonin secretion.
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