Anxiety and Depression November 3rd 2006

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Anxiety and DepressionNovember 3rd 2006

• Anxiety
• Prevalence
• Types of anxiety disorders
• Neural basis of anxiety
• Treatment
• Depression
• Prevalence
• Types of anxiety disorders
• Neural basis of anxiety
• Treatment

Munch, 1893
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AnxietyPrevalence

• Anxiety affects approximately 25 million
  Americans.
• 19.5 of women and 8 of men have an anxiety
  disorder.
• Up to 65 of people with anxiety become depressed
  and 95 of people with depression have at least
  one symptom of anxiety.

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AnxietyTypes and Symptoms

• panic disorder,
• obsessive-compulsive disorder,
• post-traumatic stress disorder,
• social phobia (or social anxiety disorder),
• specific phobias, and
• generalized anxiety disorder.

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AnxietyTypes and Symptoms

• panic disorder

"It started 10 years ago, when I had just
graduated from college and started a new job. I
was sitting in a business seminar in a hotel and
this thing came out of the blue. I felt like I
was dying. "For me, a panic attack is almost a
violent experience. I feel disconnected from
reality. I feel like I'm losing control in a very
extreme way. My heart pounds really hard, I feel
like I can't get my breath, and there's an
overwhelming feeling that things are crashing in
on me. "In between attacks there is this dread
and anxiety that it's going to happen again. I'm
afraid to go back to places where I've had an
attack. Unless I get help, there soon won't be
anyplace where I can go and feel safe from
panic."
If you are having a panic attack. your heart
will pound you may feel sweaty, weak, faint, or
dizzy. your hands may tingle or feel numb, and
you might feel flushed or chilled you may have
nausea, chest pain or smothering sensations, a
sense of unreality, or fear of impending doom you
may genuinely believe you're having a heart
attack or losing your mind, or on the verge of
death.
http//www.nimh.nih.gov/publicat/anxiety.cfmanx1
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AnxietyTypes and Symptoms

• Obsessive compulsive disorder

I couldn't do anything without rituals. They
invaded every aspect of my life. Counting really
bogged me down. I would wash my hair three times
as opposed to once because three was a good luck
number and one wasn't. It took me longer to read
because I'd count the lines in a paragraph. When
I set my alarm at night, I had to set it to a
number that wouldn't add up to a "bad"
number. "Getting dressed in the morning was
tough because I had a routine, and if I didn't
follow the routine, I'd get anxious and would
have to get dressed again. I always worried that
if I didn't do something, my parents were going
to die. I'd have these terrible thoughts of
harming my parents. That was completely
irrational, but the thoughts triggered more
anxiety and more senseless behavior. Because of
the time I spent on rituals, I was unable to do a
lot of things that were important to me.
If you have obsessive compulsive disorder you
may. have anxious thoughts or rituals you feel
you can't control. be plagued by persistent,
unwelcome thoughts or images, or by the urgent
need to engage in certain rituals. be obsessed
with germs or dirt, so you wash your hands over
and over be filled with doubt and feel the need
to check things repeatedly. have frequent
thoughts of violence, and fear that you will harm
people close to you. spend long periods touching
things or counting be pre-occupied by order or
symmetry have persistent thoughts of performing
sexual acts that are repugnant to you be troubled
by thoughts that are against your religious
beliefs.
http//www.nimh.nih.gov/publicat/anxiety.cfmanx1
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AnxietyTypes and Symptoms

• Post traumatic stress disorder

"I was raped when I was 25 years old. For a long
time, I spoke about the rape as though it was
something that happened to someone else. I was
very aware that it had happened to me, but there
was just no feeling. Then I started having
flashbacks. They kind of came over me like a
splash of water. I would be terrified. Suddenly I
was reliving the rape. Every instant was
startling. I wasn't aware of anything around me,
I was in a bubble, just kind of floating. And it
was scary. Having a flashback can wring you
out. The rape happened the week before
Thanksgiving, and I can't believe the anxiety and
fear I feel every year around the anniversary
date. It's as though I've seen a werewolf. I
can't relax, can't sleep, don't want to be with
anyone. I wonder whether I'll ever be free of
this terrible problem."
If you have PTSD you may. have persistent
frightening thoughts and memories of a traumatic
event feel emotionally numb, especially with
people they were once close to. relive the
trauma in the form of nightmares and disturbing
recollections during the day. experience other
sleep problems feel detached or numb be easily
startled lose interest in things they used to
enjoy and have trouble feeling affectionate.
feel irritable, more aggressive than before, or
even violent.
http//www.nimh.nih.gov/publicat/anxiety.cfmanx1
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AnxietyTypes and Symptoms

• Specific Phobia

I'm scared to death of flying, and I never do it
anymore. I used to start dreading a plane trip a
month before I was due to leave. It was an awful
feeling when that airplane door closed and I felt
trapped. My heart would pound and I would sweat
bullets. When the airplane would start to ascend,
it just reinforced the feeling that I couldn't
get out. When I think about flying, I picture
myself losing control, freaking out, climbing the
walls, but of course I never did that. I'm not
afraid of crashing or hitting turbulence. It's
just that feeling of being trapped. Whenever I've
thought about changing jobs, I've had to
think,'Would I be under pressure to fly?' These
days I only go places where I can drive or take a
train. My friends always point out that I
couldn't get off a train traveling at high speeds
either, so why don't trains bother me? I just
tell them it isn't a rational fear."
If you have a phobia you may. have an intense
fear of something that poses little or no actual
danger. Have severe anxiety or panic even when
thinkig about the feared object or situation.
http//www.nimh.nih.gov/publicat/anxiety.cfmanx1
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Fear and AnxietyNeural Basis
change in HR
dMNV
Amygdala
change in activity
PAG
CE
BLA
LA
exaggerated reflexes
PnC
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Fear and AnxietyNeural Basis
Kathleen M. Thomas, PhD Wayne C. Drevets, MD
Ronald E. Dahl, MD Neal D. Ryan, MD Boris
Birmaher, MD Clayton H. Eccard David Axelson,
MD Paul J. Whalen, PhD B. J. Casey, PhD Arch
Gen Psychiatry. 2001581057-1063.
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Fear and AnxietyNeural Basis
Rauch SL, Whalen PJ, Shin LM, et al Exaggerated
amygdala response to masked facial stimuli in
posttraumatic stress disorder a functional MRI
study. Biol Psychiatry 2000 47769-776
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Fear and AnxietyNeural Basis
Are fear and anxiety on in the same?
Inactivation of the amygdala interferes with fear
but not anxiety
Walker Davis (1997). J. Neurosci., 17 9375 -
9383
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Fear and AnxietyNeural Basis
Are fear and anxiety on in the same?
Inactivation of the bed nucleus of the stria
terminalis (BNST) interferes with anxiety but not
fear.
Walker Davis (1997). J. Neurosci., 17 9375 -
9383
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Fear and AnxietyNeural Basis
Are fear and anxiety on in the same?
Inactivation of the bed nucleus of the stria
terminalis (BNST) interferes with anxiety
produced by the stress hormone CRF
Walker Davis (1997). J. Neurosci., 17 9375 -
9383
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Fear and AnxietyNeural Basis
Are fear and anxiety on in the same?

• Lesions of the BNST, but not the amygdala reduce
  fear-like responding to
• bright lights
• intracerebroventricular corticotropin-releasing
  factor
• uncontrollable shock
• exposure to predator odor

Walker and Davis argue that the amygdala mediates
responding to short-duration, predictable
stimuli, whereas the BNST mediates responding to
long-duration stimuli that may have an element of
unpredictability.
Walker Davis (1997). J. Neurosci., 17 9375 -
9383
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AnxietyNeural BasisAmygdala (and BNST) as Part
of a disregulated circuit?
BNST?
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AnxietyTreatment
http//www.blackwellpublishers.co.uk/matthews/neur
otrans.html
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AnxietyTreatment
Serotonin Drugs that increase serotonin reduce
anxiety
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AnxietyTreatment - Causes
Mice lacking the serotonin 1A receptor, show
increased anxiety
Cornelius Gross, Xiaoxi Zhuang, Kimberly Stark,
Sylvie Ramboz, Ronald Oosting, Lynn Kirby, Luca
Santarelli, Sheryl Beck, René Hen, Nature   416,
396 - 400
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AnxietyExtinction and the Amygdala
a lot
fear
little
exposures
Turning off the amygdala during exposure prevents
extinction of fear. Facilitating activity in the
amygdala enhances extinction of fear.
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AnxietyExtinction and the Amygdala
Turning off the amygdala during exposure prevents
extinction of fear.
Falls, W. A., Miserendino, M. J. D., Davis, M.
(1992). Extinction of fear-potentiated startle
Blockade by infusion of an excitatory amino acid
antagonist into the amygdala. Journal of
Neuroscience, 12(3), 854-863.
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AnxietyExtinction and the Amygdala
Walker DL. Ressler KJ. Lu KT. Davis M.
Facilitation of conditioned fear extinction by
systemic administration or intra-amygdala
infusions of D-cycloserine as assessed with
fear-potentiated startle in rats. Journal
Article Journal of Neuroscience. 22(6)2343-51,
2002
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AnxietyExtinction and the Amygdala
Oral D-cycloserine enhances exposure therapy for
elevator phobia.
Ressler KJ. Rothbaum BO. Tannenbaum L. Anderson
P. Graap K. Zimand E. Hodges L. Davis M. (2004).
Cognitive enhancers as adjuncts to psychotherapy
use of D-cycloserine in phobic individuals to
facilitate extinction of fear. Clinical Trial.
Journal Article. Randomized Controlled Trial
Archives of General Psychiatry. 61(11)1136-44.
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AnxietyExtinction and the Amygdala
Maintenance and generalization in reduction of
acrophobia. Reduction in fear compared with
pretreatment baseline on general measures of
acrophobia in the real world 1 week after the
first therapy session (midtreatment), 1 to 2
weeks after the second therapy session, or at
3-month follow-up. (black bars are d-cycloserine)
Oral D-cycloserine enhances exposure therapy for
elevator phobia.
Ressler KJ. Rothbaum BO. Tannenbaum L. Anderson
P. Graap K. Zimand E. Hodges L. Davis M. (2004).
Cognitive enhancers as adjuncts to psychotherapy
use of D-cycloserine in phobic individuals to
facilitate extinction of fear. Clinical Trial.
Journal Article. Randomized Controlled Trial
Archives of General Psychiatry. 61(11)1136-44.
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DepressionPrevalence

• Anxiety affects approximately 18 million
  Americans.
• In any one year approximately 9.5 of the
  population suffers from depression
• Up to 95 of people with depression have at least
  one symptom of anxiety.

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DepressionTypes and Symptoms

• Types
• major depression
• dysthymia
• bipolar disorder

• Symptoms
• Persistent sad, anxious, or "empty" mood
• Feelings of hopelessness, pessimism
• Feelings of guilt, worthlessness, helplessness
• Loss of interest or pleasure in hobbies and
  activities that were once enjoyed
• Decreased energy, fatigue, being "slowed down"
• Difficulty concentrating, remembering, making
  decisions
• Insomnia, early-morning awakening, or
  oversleeping
• Appetite and/or weight loss or overeating and
  weight gain
• Thoughts of death or suicide suicide attempts
• Restlessness, irritability
• Persistent physical symptoms that do not respond
  to treatment

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DepressionTreatments and Causes

• Antidepressant drugs
• Monoamine oxidase inhibitors iproniazid
• Trycyclic antidepressants imipramine
• Serotonin-specific reuptake inhibitors

• SSRIs
• Prozac
• Zoloft
• Luvox
• Remeron

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DepressionTreatments and Causes
Serotonin pathways in the brain..
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DepressionTreatments and CausesLearned
Helplessness?
Escape deficits are associated with activation of
the dorsal raphe
Rats given uncontrollable tail shocks show escape
deficits
Cage control
0 shocks
Takase LF. Nogueira MI. Bland ST. Baratta M.
Watkins LR. Maier SF. Fornal CA. Jacobs BL. 2005.
Behavioural Brain Research. 162(2)299-306
100 shocks
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DepressionTreatments and Causes

• Genetics of depression The concordance rate
  among identical twins is approximately 40
• Environmental Factors Stress plays a critical
  role in the development of depression (more on
  this later).
• Brain areas involved in depression Depression
  is associated with decreased activity in the
  frontal and temporal lobes and decreased
  serotonin function

decreased activity
Decreased serotonin function (right)
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DepressionTreatments and CausesWhat about
Serotonin?
Tryptophan is the precursor for the synthesis of
serotonin. Tryptophan depletion produces
depressive symptoms in remitted depressed
individuals
tryptophan depleted
sham depleted
Neumeister et al 2004, Archives of General
Psychiatry, 61 765 - 773
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DepressionTreatments and CausesWhat about
Serotonin?
PET studies show decreased serotonin receptor
binding in depressed individuals.
Participants were injected with radioactive
WAY-100635
Drevets et al 1999, Biological Psychiatry, 46
1375-1387
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DepressionTreatments and CausesWhat about
Serotonin?
Binding to the reuptake site is reduced in
postmortem tissue from depressed patients.
Mann et al 2000, Archives of General
Psychiatry, 57 729-738.
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DepressionTreatments and CausesStress-diathesis
Hypothesis

• HPA hyperactivity
• Stress activates the HPA.

Nemeroff, (1998). Scientific American, 278, 42-47.
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DepressionTreatments and CausesStress-diathesis
Hypothesis

• HPA hyperactivity
• Stress activates the HPA.
• Prolonged and early traumatic stress can cause
  this system to be over-reactive.

Nemeroff, (1998). Scientific American, 278, 42-47.
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DepressionTreatments and CausesStress-diathesis
Hypothesis

• HPA hyperactivity
• Stress activates the HPA.
• Prolonged and early traumatic stress can cause
  this system to be over-reactive.
• Depressed individuals have elevated levels of
  CRF.
• Animals subject to stress also have elevated
  levels of CRF.

Nemeroff, (1998). Scientific American, 278, 42-47.
36
DepressionTreatments and CausesStress-diathesis
Hypothesis

• HPA hyperactivity
• Stress activates the HPA (below).
• Prolonged and early traumatic stress can cause
  this system to be over-reactive.
• Depressed individuals have elevated levels of
  CRF.
• Animals subject to stress also have elevated
  levels of CRF.
• Depressed individuals have heightened activity in
  areas of the brain known to be sensitive to CRF.
• SSRIs may normalize these elevated levels of
  CRF.

Nemeroff, (1998). Scientific American, 278, 42-47.