Links Slide

http://www.webmd.com/video/generalizedanxiety-disorder http://www.webmd.com/balance/video/mana ging-phobias http://www.webmd.com/video/too-scaredsocial-anxiety-disorder http://www.youtube.com/watch?v=TkjWK3M gTgA http://www.youtube.com/watch?v=pfG6yHAQ5U&feature=related http://www.youtube.com/watch?v=4-

Anxiety Disorders
Dr. Christina Ragan Postdoctoral Fellow Department of Psychology, Neuroscience Program

Lecture Objectives

Students will be able to:

Discuss why anxiety exists Identify the 6 types of anxiety disorders and the criteria for each Analyze key brain regions, receptors, and neurotransmitters involved in anxiety Evaluate patient information for anxiety diagnosis Evaluate various treatments based on mechanism of action, efficacy, and side effects

In groups, answer

What necessary information do we need to understand how a disease or disorder works?

What do we need to know for treatment?

?

Why does anxiety exist?

Working from the outside, in

Behavior and Categories Brain regions involved in anxiety Receptors and neurotransmitters involved Treatments

Why does anxiety exist?

1. Psychoanalytic- Freud
Source of anxiety related to developmental issue
Automatic: traumatic, reality-oriented system was overwhelmed

-failure to repress unpleasant memories

2. Behavioral Lead to effective therapies Anxiety is conditioned response to environmental stimuli generalization

3. Existential
Awareness of profound feeling of nothingness in life Anxiety = response to void in existence and meaning

4. Biological
Autonomic nervous system Overstimulation of sympathetic nervous system Anxiety response to peripheral stimuli

Evolutionary
Adaptive Need to react quickly to dangerous stimuli Want to survive Some anxiety, increased alertness improves performance

Yerkes-Dodson (1906) Law - arousal, performance, task difficulty

Lets meet our patient!

Beck Anxiety Inventory

25

http://www.counselling-for-the-health-of-it.com/beck-anxiety-inventory.html

Interpretation of Scores

A score that is in the range of 0 to 21 reflects a low anxiety level, which can be a positive thing. However, it may also suggest that one is living in denial or has an unrealistic view of his life. A low score may also reflect the possibility that one is detached from the world, himself and his loved ones. A middle score of 22 to 35 means that the respondent is suffering moderate anxiety level. It can be interpreted that your body is trying to signal you to a situation. A score that is over 36 points indicates that the respondent has a very high anxiety level, and immediate action must be taken.

Anxiety as a Disease One of most common mental disorders - 1 in 4 people meet diagnostic criteria for anxiety D/O
- Unpleasant emotional state consisting of psychophysiological responses to anticipation of unreal or imagined danger

- Women (30.5%) > men (19.2%)

- Prevalence: with SES

- Can be substance-induced: hi co-morbidity
w/addiction, and some drug elicit anxiety-like

Pathological Anxiety
1. Fear & anxiety warning signal 2. Fear versus anxiety

Fear: definite stimulusan emotional response to a known or definite threat alley example Anxiety: no definite stimulus-> 3. Physiological effects - palpitations - sweating

4. Psychological effects - worry or shame - decreased concentration - distorted perceptions

Types of Anxiety Disorders

Non-pathological State anxiety: acute (short-term) Trait anxiety: long-term increase in anxiety Pathological 6 categories with similar behavioral and physiological characteristics by the DSM-IV (Diagnostic and Statistical Manual of the American Psychiatric Association Vol. 4) Severely disrupts everyday life Affects 20% of US population Can display more than one

Gross, et al. 2004

Generalized Anxiety Disorder (GAD)

Chronic Anxious of future Long-lasting worry Insomnia Unsure reasoning 5% lifetime prevalence (5% of US population will have GAD at some point in their lives)
http://www.webmd.com/video/generalized-anxiety-disorder
Beni Luschers presentation. Penn State University. Feb. 06. and Gross, et al. 2004

Panic Disorder
Unpredictable Brief but intense Fear of dying/losing control Recurrent Common behavior: panic attack while driving 3% lifetime prevalence

Gross, et al. 2004

Specific Phobia

Fear of specific situations or objects Common fears: spiders, blood, heights Drug therapy not helpful 11% lifetime prevalence

http://www.webmd.com/balance/video/manag ing-phobias

Gross, et al. 2004

Social Phobia
Occurs in or before experiencing unfamiliar social settings Fearful of interacting with others Self-conscious May intentionally avoid situations to prevent anxiety 13% lifetime prevalence

Gross, et al. 2004

http://www.webmd.com/video/too-scared-social-anxiety-disorder

Obsessive Compulsive Disorder (OCD)

Repetitive, ritualized actions to cope with anxiety Recurrent Time consuming Common behavior: excessive handwashing, worries of forgetting to do something 2% lifetime prevalence Monk

(Tony Shalhoub) suffers from OCD

Gross, et al. 2004

Fig: http://ltc.uww.edu/showcase/Content/poormanp/monk.htm

Post-traumatic Stress Disorder (PTSD)

Caused by intensely stressful situation Triggering of emotions by memories of trauma (flashback) Recurrent Common in patients expose to combat (formally known as shell-shock) 3% lifetime prevalence

Gross, et al. 2004

What brain regions are involved?

?

Basic Functional Neuroanatomy of Anxiety

Posterior Cingulate, Parietal & Motor Cortex
Visuospatial processing & assessment of threat

Sensory inputs

Sensory gateway

Cerebellum
Anterior Cingulate, orbitofrontal, subcallosal gyrus;

Planning, execution, inhibition of responses, extinction of fear response

memory Emotional valence

Hypothalamus
J Douglas Bremner, MD

Motor responses, peripheral sympathetic and cortisol response

PTSD study on veterans

40 pairs of monozygotic twins One twin in Vietnam combat, the other at home Comparing fMRI

Results
Hippocampus Susceptibility to environmental stress

Cornelius Gross and Rene Hen, vol 5, 2004

Hippocampal Volume Reduction in PTSD

NORMAL PTSD

Bremner et al., Am. J. Psychiatry 1995; 152:973-981. Bremner et al., Biol. Psychiatry 1997; 41:23-32. Gurvits et al., Biol Psychiatry 1996;40:192-199.

J Douglas Bremner, MD, Emory University

Important Receptors in the Brain

GABAA

-aminobutyric acid GABA receptor GABA is amino acid derived from glutamate by glutamic acid decarboxylase
5-hydroxytryptamine (serotonin) receptor Serotonin is derived from tryptophan

5-HT1A

Gross, et al. 2004

Neurotransmitters

Norepinephrine (NE)

Catecholamine; fight-or flight hormone; causes vasoconstriction Over activation of noradrenergic neurons opposite of depression Neurons located in locus coeruleus Presynaptic nerves contain terminal and somatodendritic 2 adrenergic receptors

Serotonin (5-HT)-regulates/stabilizes mood

5-HT neurons project to: cerebral cortex, limbic system, hypothalamusstress response cascade 5-HT excess in anxiety 5-HT receptor downregulation 5HT1A autoreceptors too much 5-HT

5-HT autoreceptors: http://www.youtube.com/watch?v=TkjWK3MgTgA

5HT1A receptor resensitization

Slows down neuronal impulse

5-HT release

Anxiety

-aminobutyric acid (GABA)

Normally: GABAA receptors bind neurotransmitter GABA inhibition Anxiety: Dysregulated GABAA receptors in amygdala (FEAR circuit desensitized)

Paul Ekman Group (www.paulekman.com)

Activations associated with specific anxiety

Social anxiety

Trait anxiety

A: Response in left amygdala and right anterior insula to emotional faces was significantly associated with social anxiety.
B: Response in left amygdala and left anterior insula to negative faces was significantly associated with trait anxiety. Ball et al., 2012

How should we treat our patient?

VALIUM (diazepam)

PROZAC (fluoxetine)

WELLBUTRIN (bupropion)

INDERAL (propranolol)

Cognitive Behavioral Therapy (CBT)

Benzodiazepines (BZ)

Katzung, et. al.

Act on GABAA receptors Allosterically bind to receptor Enhance GABA binding affinity GABAA receptors have binding sites for BZs BZs work to increase transmission of GABA increased inhibition ValiumR, XanaxR

Fig: http://homepage.psy.utexas.edu/homepage/class/Psy332/ Salinas/Neurotransmitters/Slide14.GIF

Facilitate Cl- channel opening in GABAA membrane Cl-influx depresses neuronal excitability by hyperpolarizing cell slows neuronal firing Advantages and Disadvantages of Benzodiazepines Pros Cons
Acts rapidly-lipid solubility Hard to overdose (lethal = 1000x normal) Addictive psychologically and dependence-producing tolerance Can severely impair motor skills- sedative Worsens with alcohol alcohol in pill form
http://www.youtube.com/watch?v=-pfG6yHAQ5U&feature=related

Does the brain have its own endogenous Valium?

Yes b/c theres a binding site on the receptor suggesting that Valium mimics an endogenous ligand

How should we treat our patient?

VALIUM (diazepam)

PROZAC (fluoxetine)

WELLBUTRIN (bupropion)

INDERAL (propranolol)

Cognitive Behavioral Therapy (CBT)

Selective Serotonin Reuptake Inhibitors (SSR

Act on 5-HT transporter Prevent serotonin reuptake by SERT Induce neurogenesis Mechanism unknown PaxilR, ProzacR, ZoloftR

Fig: http://www.chm.davidson.edu/student/che105/fesantamarina/website/SSRIs.html Katzung, et al. and Gross, et. al, 2002

Advantages and Disadvantages of SSRIs

Pros
Non-addictive Non-sedative

Cons
Acts slowly (2-4 weeks after treatment) Anxiogenic in small amounts, must use long-term

Katzung, et al., Gorden et. al., 2004, and Gross, et. al, 2002

 Partial 5-HT agonists (act like 5-HT) help some anxious individuals Bind to rec. to prevent overstimulationdec. 5HT
Buspirone
Works as a net antagonistkeeps 5-HT from binding to autorec.resets receptor function Correct receptor dysregulation and overproduction of 5HT 5HT-1A partial agonists: resensitize somatodendritic autoreceptors back to normalfunctions on own again No sedative or synergistic effects Takes awhile to kick in

How should we treat our patient?

VALIUM (diazepam)

PROZAC (fluoxetine)

WELLBUTRIN (bupropion)

INDERAL (propranolol)

Cognitive Behavioral Therapy (CBT)

Beta Blockers

Block adrenaline Primarily used to treat high blood pressure Treat only physical effects, not psychological Ideal for stage fright LevatolR, LopressorR

http://www.mc.uky.edu/pharmacology/instruction/decor/ar/bhkbbl.jpg

http://www.mayoclinic.com/health/phobias/DS00272/DSECTION=7

Normally: 2 Rs terminal autoreceptors negative feedback receptors stop flow of NE

Anxiety: Post-synaptic flow of NE NE (opposite of depression) Treatment: effects by blocking post-synaptic NE receptors Beta ()blockers NE can bind to autoreceptors to shut off flow

How should we treat our patient?

VALIUM (diazepam)

PROZAC (fluoxetine)

WELLBUTRIN (bupropion)

INDERAL (propranolol)

Cognitive Behavioral Therapy (CBT)

Cognitive Behavioral Therapy

Work with a therapist Change thought patterns to cope with anxiety Understand advantages of conquering fear

http://www.youtube.com/watch?v=4kj66VKR0k
http://www.mayoclinic.com/health/phobias/DS00272/DSECTION=7

Behavioral Therapy
Exposure to adverse stimulus (ex. spider phobia therapy at right)

http://www.mayoclinic.com/health/phobias/DS00272/DSECTION=7

http://www.hitl.washington.edu/projects/exposure/

Behavioral therapy helps with controlling anxiety psychologically and physically Drug therapy helps with controlling anxiety physiologically and chemically Combination of behavioral therapy and drug therapy give the most effective results for combating anxiety

How should we treat our patient?

VALIUM (diazepam)

PROZAC (fluoxetine)

WELLBUTRIN (bupropion)

INDERAL (propranolol)

Cognitive Behavioral Therapy (CBT)

Summary

Anxiety is necessary, but damaging if chronic PFC, amygdala, hypothalamus, hippocampus are major brain regions involved

GABA, serotonin, and norepinephrine are major neurotransmitters involved Drugs target above chemicals, but efficacy