Psychopharmacology of Anxiety Disorders I: GAD & SAD

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This PPT is part 1 of 2 lectures given to second year pharmacy students in a pharmacology & toxicology class.

This PPT is part 1 of 2 lectures given to second year pharmacy students in a pharmacology & toxicology class.

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  • Anxiety (aka worry, concern, apprehension, nervousness, angst).
  • Anxiety’s final common pathway involves over-activity of the HPA axis or a failure of negative feedback to turn off this system.
  • Interview conducted with a large (N=9000) nationally representative sample. Notice tremendous individual differences in onset age.
  • Good general description (2 min): http://www.youtube.com/watch?v=NPWFXZJ59JsAnxiety is out of proportion from the concern.
  • Paroxetine is a moderate antagonist of muscarinic (M1) receptors. R-citalopram is also a weak anti-histamine inhibitor.
  • Low dose venlafaxine has more pronounced effects on SRI than NRI. The NRI effects become more pronounced with higher doses. The half-life of venlafaxine is 5 hours but its metabolite desvenlafaxine is twice as long.Duloxetine moderately inhibits 2D6.
  • Seizures are rare but have been reported. For a video from Heather Ashton, see: http://www.youtube.com/watch?v=UsjhqdE7-6AApproximately 1/3rd of long-term benzo users will have difficulties with withdrawal. The dose reduction process can last months or even years. She recommends a plan that is developed in collaboration between patient and their health care provider. This could involve 1 mg diazepam/2 weeks.
  • This is a very subtle modification which involves going to the drug binding site and replacing a the amino acid Histidine (H) with an Arginine (A).
  • This is a very subtle modification which involves going to the drug binding site and replacing a the amino acid Histidine (H) with an Arginine (A).
  • Metabolized by 3A4.
  • Cued panic attack (e.g. snakes) = phobia.
  • DSM-IVTR refers to Social Phobia but this will be changed to Social Anxiety Disorder for DSM 5. SAD has high rates of alcohol dependence (20%).
  • Symptoms typically improve with a few days of menses. PMDD may occur in 3-5% of women.

Transcript

  • 1. Anxiety I: Agents for GAD and SAD Brian J. Piper, Ph.D., M.S. January 30, 2013
  • 2. Objectives• Anxiety overview• Generalized Anxiety Disorder (GAD)• Panic Disorder• Social Anxiety Disorder (SAD)• Premenstrual Dysphoric Disorder (PMDD)
  • 3. Terminology• Fear = current; Anxiety = future• Disorder = – personal distress – social or occupation impairment
  • 4. Comorbid ConditionsAnxiety frequently occurs with substance abuse, ADHD, bipolar, pain & sleep disordersStahl, S. (2008). Essential Psychopharmacology, p. 722.
  • 5. Neurobiology of Anxiety ---------- CRH: Corticotropin Releasing Hormone; ACTH: Adrenocorticotropin Hormone; CORT: cortisolStahl, S. (2008). Essential Psychopharmacology, p. 727.
  • 6. Comparison of % Time With Symptoms• High--|-----------|-----------------|----------------|--Low GAD PTSD/OCD Panic Disorder SAD
  • 7. Most Common of Psychiatric Disorders Lifetime Prevalence Onset Age Onset Age (5%/95%) (50%) OCD 1.6% 19 10 / 54 Panic Disorder 4.7% 24 6 / 56 GAD 5.7% 31 8 / 66 PTSD 6.8% 23 6 / 61 Phobia 12.5% 7 4 / 91 MDD 16.6% 32 12 / 64Kessler et al. (2005). Archives of General Psychiatry, 62, 592 – 602.
  • 8. Dramatized Example (0:30-1:40): http://www.youtube.com/watch?v=3mOkkCkajsI
  • 9. All SRI’s Are Not EqualDrug 2D6 3A4escitalopramF weak 0citalopram weak 0fluoxetineF strong moderateparoxetineF strong weaksertraline 0 moderateFFDA approved for GAD 0: negligible Spina et al. (2008). Clinical Therapeutics, 30(7), 1206-1227.
  • 10. All SRIs Are Not Equal fluoxetine sertraline escitalopram paroxetine citalopram  weakStahl, S. (2008). Essential Psychopharmacology, p. 511 – 541.
  • 11. SNRI Venlafaxine XR DuloxetineMechanism of Action SRI > NRI SRI > NRIHalf-Life 12 5 (10)Adverse Effects sexual dysfunction sexual dysfunction nausea nausea somnolence dry mouthContraindications MAO-Is MAO-Is
  • 12. Benzodiazepines & GAD• MOA: ↑ frequency of GABAA α1, α2, α3, α5 Cl-• Onset: rapid (hours) versus 2+ weeks for SRI/SNRI• Recommendation: Addiction concerns indicate tertiary use• Reality: very commonly used
  • 13. Ashton’s Recommendations of Benzo Withdrawal • Frequency: 30%? • Symptoms: flu-like, sweating, flushing, convulsions, muscle ache, pain, fatigue, energy, stiffness, depression, seizures • Strategy – gradual/individualized dosage recommendation – anti-depressants may be needed (SRIs) – psychological supportAshton, H. (1994). Addiction, 89, 1535-1541.
  • 14. Future: A More Selective Benzo? • Determination of which GABAA α subunit is required for anxiolytic effect of benzodiazepines. • Mice with α2 subunit modified so diazepam doesn’t bind completed behavioral testingLow et al. (2004). Science, 290(5489), 131-134.
  • 15. Future: A More Selective Benzo? • Determination of which GABAA α subunit is required for anxiolytic effect of benzodiazepines. • Mice with α2 subunit modified so diazepam doesn’t bind completed behavioral testingLow et al. (2004). Science, 290(5489), 131-134.
  • 16. Buspirone• MOA: 5-HT1A agonist, D2 (moderate)• Indications: FDA approved for GAD, 3rd-line• Adverse Effects: sedation ( < benzos)• Contraindications: MAO-Is
  • 17. GAD Summary • GAD treatment was focused on acute symptom management (Benzo). Recent focus is on prevention (SSRI). • SSRIs show 60% response, 30% remission • Benzos continue to be commonly prescribed as a first-line in primary care settingsReinhold et al. (2011). Expert Opinion in Pharmacotherapy, 12(16), 2457-2467.
  • 18. Panic Disorder• Panic Attacks: – Psychological: sudden, intense anxiety/terror, depersonalization/derealization – Physical: labored breathing, heart palpitations, chest pain, sweating, chills, trembling• Criteria – May co-occur with agoraphobia – Recurrent uncued panic attacks – At least 1 month of concern about future attacksKring, A. (2012). Abnormal Psychology, p. 179.
  • 19. Contrast • APA recommends: – 1) SSRI: fluoxetine, sertraline, paroxetine – 2) SNRI: venlafaxine ER – 3) TCA: imipramine – 4) Benzos: alprazolam • Benzos continue to be very common for long- term Panic Disorder treatmenthttp://psychiatryonline.org/content.aspx?bookid=28&sectionid=1680635
  • 20. Social Anxiety Disorder (Social Phobia) • Marked & disproportionate fear consistently triggered by exposure to potential social scrutiny • Trigger situations are avoided or endured with intense anxiety • Symptoms persist for at least 6 monthsDescription (2 min): http://www.youtube.com/watch?v=Gk2hm3bqO1gKring, A. (2012). Abnormal Psychology, p. 178.
  • 21. Melton, S. & Kirkwood, C. (2011). In DiPiro’s Pharmacotherapy, p. 1223.
  • 22. Kava Kava • Piper methysticum • MOA: ?, GABAA • Pronounced acute anxiolytic effects • Liver toxicity cases (N > 100)Sarris, et al. (2011). Australian & New Zealand Journal of Psychiatry, 45, 27-35.
  • 23. Summary• Anxiety disorders are extremely common psychiatric conditions.• Although Benzodiazepines are commonly used for their acute anxiolytic effects, practice guidelines consistently recommend SSRI/SNRI as first line pharmacotherapies for long-term symptomatic management for GAD, SAD, and Panic Disorder.
  • 24. Prementrual Dysphorphic Disorder • In most menstrual cycles during the past year, at least 5 in the final week before menses: – Affective lability – Irritability – Anxiety – Diminished interest in usual activities – Sleeping too much or too little – Physical symptoms: breast tenderness, joint/muscle pain, bloating • SSRIs are FDA approvedKring, A. (2012). Abnormal Psychology, p. 134.