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Neuropharmacology: Anxiety Disorders

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Lecture 21 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University. Focus is on DSM IV TR criteria for anxiety disorders and their pharmacological treatments.

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Neuropharmacology: Anxiety Disorders

  1. 1. Anxiety Disorders Brian J. Piper, Ph.D.
  2. 2. Primary Objectives• Disorders • Therapies – Generalized Anxiety Disorders – Barbiturates – Panic Disorder – Benzodiazepines – Phobias – SSRIs – Obsessive Compulsive Disorder – Others – Post-Traumatic Stress Disorder • CBT • Psychosurgery
  3. 3. Secondary Objectives• Neurochemistry • Methods – GABA – Open-field – 5-HT – Elevated Plus & Zero Mazes• Neuroanatomy – Light-Dark Test – Amygdala – Conflict Test – Anterior Cingulate Cortex – Basal Ganglia
  4. 4. Terminology• Fear (current) versus Anxiety (future) 4
  5. 5. Anxiety Disorders Panic Disorder Phobias Generalized Anxiety Disorder Social Anxiety Disorder Obsessive-Compulsive Disorder Post-Traumatic Stress Disorder
  6. 6. EpidemiologyKessler et al. (2005). Archives of General Psychiatry, 62, 617-627.
  7. 7. 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-spaces1st 2:30http://www.youtube.com/watch?v=2gNGUartUEI
  8. 8. 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. 8
  9. 9. Kinds of PhobiasArachonophobia Phobia of spiders. Acrophobia Phobia of heights.Claustrophobia Phobia of closed spaces. Hemophobia Phobia of blood.
  10. 10. Systematic Desensitization Spider• 1) Create hierarchy of fears ↓• 2) Relaxation techniques• 3) Combine Joseph Wolpe, M.D. 1915-1997
  11. 11. 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)
  12. 12. 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
  13. 13. OCD• 1st Two Minutes:• http://www.youtube.com/watch?v=44DCWslb sNM 13
  14. 14. Cingulate Cortex 14
  15. 15. Anterior Cingulate & OCD• OCD and controls completed a difficult continuous performance test during fMRI.• OCD > controls in Anterior Cingulate Cortex• Target of psychosurgery 15 Ursu et al. (2003). Psychological Science, 14, 347-353.
  16. 16. Psychosurgery1874-1955 • 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
  17. 17. Generalized Anxiety Disorder DSM-IV-TR CriteriaA. 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
  18. 18. Post-Traumatic Stress Disorder Four or more weeks of the following symptoms constitute Post-Traumatic Stress Disorder (PTSD):Re-experiencing: nightmares, flashbacks, intrusive thoughtsAvoidance: situation & associatedPhysical Arousal: sleep, concentration, irritabilityLifetime Prevalence: 5% men, 10% women Significant social or occupational impairment :3 min http://www.youtube.com/watch?v=7aFs6695VyQ
  19. 19. 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.
  20. 20. 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=zuAuHA0TzlNEk45oUL1xH w&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
  21. 21. Comparison (Long) (Short)(Long) (Ultrashort)
  22. 22. Valium• Invented by Leo Sternbach and began use in 1963• Uses: anxiety, insomnia, cocaine OD 1908-2005• PK: long half life, bioactive metabolites• PD: Bezodiazepine site on GABAA
  23. 23. Animal Models of Anxiety: Elevated Zero Maze• Dependent Variable: % Open Braun et al. (2011). Pharmacol Biochem Behav, 97, 406-415.
  24. 24. 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 .
  25. 25. 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.
  26. 26. Flunitrazepam• Rohypnol “roofies”• Half-life: 20 hours• 5-10 times more potent then valium
  27. 27. Self-administrationOpiates > Benzodiazepines > Hallucinogens
  28. 28. GABA Receptors• Receptor is composed of 5 subunits.• Binding of GABA results in influx of Chloride.• Other drugs also bind to receptor.• GABAA & GABAB
  29. 29. GABAABarbiturates:open channelBenzodiazepinesopen channel only if GABA present
  30. 30. Light Dark Test• Dependent Measure: % time in lit area• Anxiolytic: increased % time in lit area• Anxiogenic: decreased % time in lit area
  31. 31. Light Dark Test• Role of GABA or 5-HT in anxiety --------------------------------- --------------------------------------------------
  32. 32. Vogel Conflict Test • Water deprived animals will get mild footshock for drinking H2OBasso et al. (2011). Behavioral Brain Research, 218, 174-183.
  33. 33. 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
  34. 34. Forensic ApplicationsKintz (2005) J Forensic Sci 28(1), 1-6.
  35. 35. Forensic ApplicationsKintz (2005) J Forensic Sci 28(1), 1-6.
  36. 36. 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.
  37. 37. 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.
  38. 38. Utility of Multimodal Improvement Placebo: 7.0 CBT: 8.1 Sertraline: 9.0 Combo: 12.0
  39. 39. But Differential Side-Effects Rates 25 * 20 15 10 5 0 Zoloft - Zoloft +
  40. 40. 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
  41. 41. SummaryDisorder Adult Adolescent 1st Line Tx 2nd Line Tx Lifetime % Lifetime %GAD 5.7 1.0 CBT, SSRI, SSNRI BenzosPanic Disorder 4.7 2.3 CBT, SSRIPhobias 12.5 15.1 Systematic DesensitizationOCD 1.6 - CBT, SSRI Benzos psychosurgeryPTSD 6.8 4.0 CBT, SSRI EMDRhttp://www.nimh.nih.gov/statistics/index.shtml
  42. 42. Origins of Anxiety• Learn: videotapes of fear response to fake snake or plastic flower• Test: show a stimuli Mineka, S. (1985). J Abnormal Psychol
  43. 43. 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

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