Anxiety I: Agents for GAD and SAD

Brian J. Piper, Ph.D., M.S.

January 30, 2013

Objectives

• Anxiety overview• Generalized Anxiety Disorder (GAD)• Panic Disorder• Social Anxiety Disorder (SAD)• Premenstrual Dysphoric Disorder (PMDD)

Terminology

• Fear = current; Anxiety = future• Disorder = – personal distress– social or occupation impairment

Comorbid Conditions

Stahl, S. (2008). Essential Psychopharmacology, p. 722.

Anxiety frequently occurs with substance abuse, ADHD, bipolar, pain & sleep disorders

Neurobiology of Anxiety

----------

Stahl, S. (2008). Essential Psychopharmacology, p. 727.

CRH: Corticotropin Releasing Hormone; ACTH: AdrenocorticotropinHormone; CORT: cortisol

Comparison of % Time With Symptoms

• High--|-----------|-----------------|----------------|--Low GAD PTSD/OCD Panic Disorder SAD

Most Common of Psychiatric DisordersLifetime Prevalence Onset Age

(50%)Onset Age (5%/95%)

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.

Dramatized Example (0:30-1:40): http://www.youtube.com/watch?v=3mOkkCkajsI

All SRI’s Are Not EqualDrug 2D6 3A4escitalopramF weak 0

citalopram weak 0

fluoxetineF strong moderate

paroxetineF strong weak

sertraline moderate 0

Spina et al. (2008). Clinical Therapeutics, 30(7), 1206-1227.0: negligibleFFDA approved for GAD

All SRIs Are Not Equalfluoxetine sertraline escitalopram

paroxetine citalopram

Stahl, S. (2008). Essential Psychopharmacology, p. 511 – 541.

weak

SNRI

Venlafaxine XR Duloxetine

Mechanism of Action SRI > NRI SRI > NRIHalf-Life 5 (10) 12

Adverse Effects sexual dysfunctionnauseasomnolence

sexual dysfunctionnauseadry mouth

Contraindications MAO-Is MAO-Is

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

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.

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.

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.

Buspirone

• MOA: 5-HT1A agonist, D2 (moderate)• Indications: FDA approved for GAD, 3rd-line• Adverse Effects: sedation ( < benzos)• Contraindications: MAO-Is

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.

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.

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

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

Kring, A. (2012). Abnormal Psychology, p. 178.Description (2 min): http://www.youtube.com/watch?v=Gk2hm3bqO1g

Melton, S. & Kirkwood, C. (2011). In DiPiro’s Pharmacotherapy, p. 1223.

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.

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.

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.