neuropharmacology: anxiety disorders
DESCRIPTION
Lecture 21 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. ([email protected]) at Willamette University. Focus is on DSM IV TR criteria for anxiety disorders and their pharmacological treatments.TRANSCRIPT
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Anxiety Disorders
Brian J. Piper, Ph.D.
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Primary Objectives
• Disorders– Generalized Anxiety Disorders– Panic Disorder– Phobias– Obsessive Compulsive Disorder– Post-Traumatic Stress Disorder
• Therapies– Barbiturates– Benzodiazepines– SSRIs– Others
• CBT• Psychosurgery
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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
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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
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Epidemiology
Kessler et al. (2005). Archives of General Psychiatry, 62, 617-627.
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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
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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
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Systematic Desensitization
• 1) Create hierarchy of fears• 2) Relaxation techniques• 3) Combine
Spider
↓
Joseph Wolpe, M.D.
1915-1997
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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)
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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
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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.
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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
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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
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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
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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.
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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
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Comparison
(Long)
(Ultrashort)
(Short)(Long)
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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
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Animal Models of Anxiety: Elevated Zero Maze
• Dependent Variable: % Open
Braun et al. (2011). Pharmacol Biochem Behav, 97, 406-415.
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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.
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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.
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Flunitrazepam
• Rohypnol “roofies”• Half-life: 20 hours• 5-10 times more potent then valium
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Self-administration
Opiates > Benzodiazepines > Hallucinogens
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GABA Receptors
• Receptor is composed of 5 subunits.
• Binding of GABA results in influx of Chloride.
• Other drugs also bind to receptor.
• GABAA & GABAB
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GABAA
Barbiturates: open channel
Benzodiazepines open channel only if GABA
present
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Light Dark Test
• Dependent Measure: % time in lit area• Anxiolytic: increased % time in lit area• Anxiogenic: decreased % time in lit area
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Light Dark Test
• Role of GABA or 5-HT in anxiety
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Vogel Conflict Test
• Water deprived animals will get mild footshock for drinking H2O
Basso et al. (2011). Behavioral Brain Research, 218, 174-183.
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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
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Forensic Applications
Kintz (2005) J Forensic Sci 28(1), 1-6.
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Forensic Applications
Kintz (2005) J Forensic Sci 28(1), 1-6.
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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.
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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.
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Utility of Multimodal
ImprovementPlacebo: 7.0CBT: 8.1Sertraline: 9.0Combo: 12.0
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But Differential Side-Effects Rates
Zoloft - Zoloft +0
5
10
15
20
25 *
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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
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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
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Origins of Anxiety
• Learn: videotapes of fear response to fake snake or plastic flower
• Test: show a stimuli
Mineka, S. (1985). J Abnormal Psychol
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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