Neuropharmacology: Anxiety Disorders

Anxiety Disorders

Brian J. Piper, Ph.D.

Primary Objectives

• Disorders– Generalized Anxiety Disorders– Panic Disorder– Phobias– Obsessive Compulsive Disorder– Post-Traumatic Stress Disorder

• Therapies– Barbiturates– Benzodiazepines– SSRIs– Others

• CBT• Psychosurgery

Secondary Objectives

• Neurochemistry– GABA– 5-HT

• Neuroanatomy– Amygdala– Anterior Cingulate Cortex– Basal Ganglia

• Methods– Open-field– Elevated Plus & Zero Mazes– Light-Dark Test– Conflict Test

Terminology• Fear (current) versus Anxiety (future)

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Anxiety Disorders

Panic Disorder Phobias Generalized Anxiety Disorder Social Anxiety Disorder Obsessive-Compulsive Disorder Post-Traumatic Stress Disorder

Epidemiology

Kessler et al. (2005). Archives of General Psychiatry, 62, 617-627.

Panic Disorder

Panic Attack: discrete period of intense fear, 4+ symptoms develop abruptly and peak within 10 minutes

Individual Differences: multi/day versus 1/week

Agoraphobia: fear of open-spaces

1st 2:30http://www.youtube.com/watch?v=2gNGUartUEI

Phobia

• Marked & persistent fear that is excessive or unreasonable, cued by presence or anticipation of object/situation

• The avoidance interferes significantly with normal routine, occupational or social activities.

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Kinds of Phobias

Phobia of blood.Hemophobia

Phobia of closed spaces.

Claustrophobia

Phobia of heights.Acrophobia

Phobia of spiders.Arachonophobia

Systematic Desensitization

• 1) Create hierarchy of fears• 2) Relaxation techniques• 3) Combine

Spider

↓

Joseph Wolpe, M.D.

1915-1997

Obsessive-Compulsive Disorder

• Obsessions– 1. Recurrent and persistent thoughts, urges, or

images that are experienced, at some time during the disturbance, as intrusive and unwanted and that in most individuals cause marked anxiety or distress

– 2. The person attempts to ignore or suppress such thoughts, urges, or images, or to neutralize them with some other thought or action (i.e., by performing a compulsion)

Compulsions

• 1. Repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) that the person feels driven to perform in response to an obsession, or according to rules that must be applied rigidly

• 2. The behaviors or mental acts are aimed at preventing or reducing anxiety or distress, or preventing some dreaded event or situation; however, these behaviors or mental acts either are not connected in a realistic way with what they are designed to neutralize or prevent, or are clearly excessive

OCD

• 1st Two Minutes:• http://www.youtube.com/watch?v=44DCWslb

sNM

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Cingulate Cortex

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Anterior Cingulate & OCD

• OCD and controls completed a difficult continuous performance test during fMRI.

• OCD > controls in Anterior Cingulate Cortex

• Target of psychosurgery

15Ursu et al. (2003). Psychological Science, 14, 347-353.

Psychosurgery

• 1949: Antonio Egas Moniz received Nobel prize for frontal leucotomy

• 1940s-1967: Walter Freeman develops frontal lobotomy (transorbital)

• Current: lesioning & deep brain stimulation is a last resort

1874-1955

Generalized Anxiety Disorder

A. Excessive anxiety and worry (apprehensive expectation), occurring more-days-than-not for at least 6 months.

B. The person finds it difficult to control the worry.

C. three (or more) of the following six symptoms:1. Restlessness2. Being easily fatigued3. Difficulty concentrating4. Irritability5. Muscle tension6. Sleep disturbance

DSM-IV-TR Criteria

Post-Traumatic Stress Disorder

Four or more weeks of the following symptoms constitute Post-Traumatic Stress Disorder (PTSD):

Re-experiencing: nightmares, flashbacks, intrusive thoughts

Avoidance: situation & associated

Physical Arousal: sleep, concentration, irritability

Significant social or occupational impairment3 min: http://www.youtube.com/watch?v=7aFs6695VyQ

Lifetime Prevalence: 5% men, 10% women

PTSD Talk Therapy• Participant groups matched based on prior trauma

(moderate), sex, and age• Eye Movement Desensitization & Reprocessing: imagine trauma + follow therapists

rapidly moving finger• Control: imagine trauma while staring at stationary object (same duration as

experimental

**

Dunn et al. (1996). J Behav Therapy Exp Psychiatry, 27, 231-239.

Barbiturates

• Barbital synthesized in 1903• Popular sleep aid until 1950s• Act on GABAA in limbic system

http://images.google.com/imgres?imgurl=http://pubs.acs.org/cen/img/83/i25/8325pheno_barbara.tifcxd.JPG&imgrefurl=http://pubs.acs.org/cen/coverstory/83/8325/8325phenobarbital.html&h=287&w=156&sz=46&hl=en&sig2=zuAuHA0TzlNEk45oUL1xHw&start=19&tbnid=heE_tNcgW041OM:&tbnh=115&tbnw=63&ei=bRW0RI6zEMaoaK-a5bAG&prev=/images%3Fq%3Dphenobarbital%26svnum%3D10%26hl%3Den%26lr%3D%26rls%3DCNDB,CNDB:2004-15,CNDB:en

Comparison

(Long)

(Ultrashort)

(Short)(Long)

Valium

• Invented by Leo Sternbach and began use in 1963

• Uses: anxiety, insomnia, cocaine OD• PK: long half life, bioactive metabolites• PD: Bezodiazepine site on GABAA

1908-2005

Animal Models of Anxiety: Elevated Zero Maze

• Dependent Variable: % Open

Braun et al. (2011). Pharmacol Biochem Behav, 97, 406-415.

Benzodiazepine Tolerance

• Mice received implants to deliver 2 mg/kg/day of lorazepam.

• Three behaviors were measured in an open field.

Fahey et al. (2001). Pharmacology Biochemistry Behavior 69, 1-8.

Cross Tolerance• The benzodiazepine chlordiazepoxide (CDP) or

diazepam (DZ) impaired tilt-plane performance.

• Ethanol caused a greater disruption in benzo naïve rats.

Khana et al. (1998) Pharm Biochem Behav 59, 511-519.

Flunitrazepam

• Rohypnol “roofies”• Half-life: 20 hours• 5-10 times more potent then valium

Self-administration

Opiates > Benzodiazepines > Hallucinogens

GABA Receptors

• Receptor is composed of 5 subunits.

• Binding of GABA results in influx of Chloride.

• Other drugs also bind to receptor.

• GABAA & GABAB

GABAA

Barbiturates: open channel

Benzodiazepines open channel only if GABA

present

Light Dark Test

• Dependent Measure: % time in lit area• Anxiolytic: increased % time in lit area• Anxiogenic: decreased % time in lit area

Light Dark Test

• Role of GABA or 5-HT in anxiety

--------------------------------- --------------------------------------------------

Vogel Conflict Test

• Water deprived animals will get mild footshock for drinking H2O

Basso et al. (2011). Behavioral Brain Research, 218, 174-183.

Gamma-hydroxybutyrate

• Georgia Home Boy, Grevious Bodily Harm, Liquid X

• Clear and salty liquid, rave & date rape drug• Medical uses: Narcolepsy (cataplexy) and anesthetic• PK: half-life of 40 min • PD: GABAB & GHB agonist

GABA GHB

Forensic Applications

Kintz (2005) J Forensic Sci 28(1), 1-6.

Forensic Applications

Kintz (2005) J Forensic Sci 28(1), 1-6.

GHB and Behavior

• Flies received GHB by injection (!).

• GHB increased immobility in normal (wild-type) and EtOH sensitive (Cheapdate) flies.

• A GABAB antagonist prevented these effects.

Dimitrijevic et al. (2005). European J Pharmacol, 519, 246-252.

Utility of Multimodal

• Children (ages 7-12, N=488) with one (GAD, separation anxiety disorder, social phobia: 21.9%), or more anxiety disorders (78.1%) were randomized to placebo, Cognitive Behavioral Therapy, sertraline, or sertraline/CBT for 12 weeks.

Walkup et al. (2005) NEJM, 359, 2753-2766.

Utility of Multimodal

ImprovementPlacebo: 7.0CBT: 8.1Sertraline: 9.0Combo: 12.0

But Differential Side-Effects Rates

Zoloft - Zoloft +0

5

10

15

20

25 *

Videocast

• Charney, Dennis S. (2002). Underlieing mechanisms of Anxiety & Post-Traumatic Stress. Starts at 04:00 to 36:00 http://videocast.nih.gov/launch.asp?10696

Summary

http://www.nimh.nih.gov/statistics/index.shtml

Disorder Adult Lifetime %

AdolescentLifetime %

1st Line Tx 2nd Line Tx

GAD 5.7 1.0 CBT, SSRI, SSNRI Benzos

Panic Disorder 4.7 2.3 CBT, SSRI

Phobias 12.5 15.1 Systematic Desensitization

OCD 1.6 - CBT, SSRI Benzospsychosurgery

PTSD 6.8 4.0 CBT, SSRI EMDR

Origins of Anxiety

• Learn: videotapes of fear response to fake snake or plastic flower

• Test: show a stimuli

Mineka, S. (1985). J Abnormal Psychol

Origins of Anxiety(Susan Mineka)

• Learn: videotapes of fear response to fake snake or plastic flower

• Test: show a stimuli• Response: Snake-Fear; Flower- No Fear• Supports Social-Learning & Evolutionary

Psychology