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

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 Conditions
Anxiety frequently occurs with substance abuse, ADHD, bipolar, pain & sleep disorders
Stahl, S. (2008). Essential Psychopharmacology, p. 722.

5. Neurobiology of Anxiety
----------
CRH: Corticotropin Releasing Hormone; ACTH: Adrenocorticotropin
Hormone; CORT: cortisol
Stahl, 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 / 64
Kessler 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 Equal
Drug 2D6 3A4
escitalopramF weak 0
citalopram weak 0
fluoxetineF strong moderate
paroxetineF strong weak
sertraline 0
moderate
FFDA 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
 weak
Stahl, S. (2008). Essential Psychopharmacology, p. 511 – 541.

11. SNRI
Venlafaxine XR Duloxetine
Mechanism of Action SRI > NRI SRI > NRI
Half-Life 12
5 (10)
Adverse Effects sexual dysfunction sexual dysfunction
nausea nausea
somnolence dry mouth
Contraindications 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 support
Ashton, 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 testing
Low 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 testing
Low 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 settings
Reinhold 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
attacks
Kring, 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 treatment
http://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 months
Description (2 min): http://www.youtube.com/watch?v=Gk2hm3bqO1g
Kring, 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 approved
Kring, A. (2012). Abnormal Psychology, p. 134.