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Prevalence of Anxiety Disorders. Kessler et al. Arch Gen Psychiatry . 1995;52:1048. Kessler et al. Arch Gen Psychiatry . 1994;51:8. Outcome of Panic Disorder at Long-Term Follow-up. Roy-Byrne & Cowley, 1995. Pharmacopoeia for Anxiety Disorders. Antidepressants

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prevalence of anxiety disorders
Prevalence of Anxiety Disorders

Kessler et al. Arch Gen Psychiatry. 1995;52:1048.

Kessler et al. Arch Gen Psychiatry. 1994;51:8.

pharmacopoeia for anxiety disorders
Pharmacopoeia for Anxiety Disorders

Antidepressants

Serotonin Selective Reuptake Inhibitors (SSRIs)

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Atypical Antidepressants

Tricyclic Antidepressants (TCAs)

Monoamine Oxidase Inhibitors (MAOIs)

Benzodiazepines

Other Agents

Azaspirones

Beta blockers

Anticonvulsants

Other strategies

serotonin selective reuptake inhibitors
Serotonin Selective Reuptake Inhibitors
  • Fluoxetine (Prozac), 20-80 mg/d
    • Initiate with 5-10 mg/d
  • Sertraline (Zoloft), 50-200 mg/d
    • Initiate with 25-50 mg/d
  • Paroxetine (Paxil), 20-50 mg/d
    • Initiate with 10mg/d
  • Fluvoxamine (Luvox), 50-300 mg/d
    • Initiate with 25 mg/d
  • Citalopram (Celexa)

- Initiate with 10-20 mg/d

  • Start low to minimize anxiety

Adjunctive BZD, beta blocker

serotonin selective reuptake inhibitors cont
Serotonin Selective Reuptake Inhibitors (cont)
  • Typical SSRI side effects:
    • GI distress, jitteriness, headaches, sleep disturbance, sexual disturbance
  • Clomipramine (Anafranil), 25-250 mg/d
    • Initiate with 25 mg/d
  • Efficacy: PDAG, PTSD, SP, OCD, GAD
sertraline in comorbid ptsd and alcoholism
Sertraline In Comorbid PTSD And Alcoholism

Pre-treatment

Post-treatment

140

60

40

70

IES

score

Standard

drinks/week

20

0

0

IES

Alcohol use

Brady et al. J Clin Psychiatry. 1995;56:502.

discontinuation of treatment for anxiety disorders
Discontinuation of Treatment for Anxiety Disorders
  • Withdrawal/rebound more common with Bzd than other anxiolytic treatment
  • Relapse: a significant problem across treatments. Many patients require maintenance therapy
  • Bzd abuse is rare in non-predisposed individuals
  • Clinical decision: balance comfort/compliance/ comorbidity during maintenance treatment with discontinuation-associated difficulties
strategies for anxiolytic discontinuation
Strategies for Anxiolytic Discontinuation
  • Slow taper
  • Switch to longer-acting agent for taper
  • Cognitive-Behavioral therapy
  • Adjunctive
    • Antidepressant
    • Anticonvulsant
    • ?clonidine, ?beta blockers, ? buspirone
serotonin norepinephrine reuptake inhibitor
Serotonin-Norepinephrine Reuptake Inhibitor
  • Venlafaxine-XR (Effexor-XR) 75-300 mg/d
    • Initiate with 37.5 mg/d
  • Indicated for GAD; effective for panic disorder, social phobia, PTSD, OCD
  • Typical side effects
    • GI distress, jitteriness, headaches, sexual disturbance
atypical antidepressants
Atypical Antidepressants
  • Nefazadone (300-500 mg/d)
    • 5-HT reuptake inhibitor
    • 5-HT2 antagonist
    • Initiate with 50 mg bid
  • Mirtazapine
    • Limited experience to date in anxiety disorders
atypical antidepressants cont
Atypical Antidepressants (cont.)
  • Bupropion
    • Based on limited data, considered less effective for panic and other anxiety disorders, but reports suggestive of efficacy for
      • panic disorder
      • social anxiety disorder
      • PTSD
  • Trazodone
    • Based on limited data, considered less effective for panic and other anxiety disorders
tricyclic antidepressants
Tricyclic Antidepressants
  • Imipramine (Tofranil)
  • Nortriptyline (Pamelor)
  • Desipramine (Norpramin)
  • Amitriptyline (Elavil)
  • Doxepin (Sinequan)
  • Effective in anxiety with or without comorbid depression
  • Recommended dosage 2.25 mg/kg/d Imipramine or its equivalent for panic
  • Initial anxiety worsening (Initiate with “test” dose, e.g. 10 mg/d IMI)
tricyclic antidepressants cont
Tricyclic Antidepressants (cont)
  • Typical TCA side effects
    • anticholinergic effects (dry mouth, blurred vision, constipation)
    • orthostatic hypotension
    • cardiac conduction disturbance
    • weight gain
    • sexual dysfunction
  • Lethal in overdose
  • Weight gain and sedation often become increasingly problematic over time
  • Efficacy: PDAG, GAD, PTSD
monoamine oxidase inhibitors
Monoamine Oxidase Inhibitors
  • Phenelzine (Nardil) 45-90 mg/d
  • Tranylcypromine (Parnate) 30-60 mg/d
  • Isocarboxacid (Marplan) 10-30 mg/d
  • Initial worsening of anxiety is unusual
  • Side effects: light-headedness, neurological symptoms, weight gain, sexual dysfunction, edema
  • Dietary restrictions/Hypertensive crisis; “cheese reaction”
  • Risk of lethal overdose and toxicity
  • Generally reserved for refractory cases
  • Efficacy: PDAG, SP, OCD, PTSD
benzodiazepines
Benzodiazepines
  • Potency was considered critical determinant of anti-panic efficacy
    • Alprazolam (Xanax)
    • Clonazepam (Klonopin)
    • +/- Lorazepam (Ativan)
  • But comparable doses of diazepam as effective as alprazolam
  • All benzodiazepines effective for generalized anxiety
potential benefits of benzodiazepine therapy
Potential Benefits of Benzodiazepine Therapy
  • Effective
  • Short latency of therapeutic onset
  • Well tolerated
  • Rapid dose adjustment feasible
  • Can be used “prn” for situational anxiety
potential drawbacks of benzodiazepine therapy
Potential Drawbacks of Benzodiazepine Therapy
  • Initial sedation
  • Discontinuation difficulties
  • Potential for abuse in substance abusers
  • Not effective for comorbid depression
alprazolam

Alprazolam

Effective as AD in panic

Advantages: rapid onset of effect, lacks typical AD side effects

Disadvantages: short duration of effect (i.e., multiple dosing, interdose rebound), discontinuation syndromes, early relapse, abuse potential, disinhibition

Dosing: anticipate initial sedation (tachyphylaxis usually develops).

Range: 2-10 mg/d (4-6 mg/d usual) (QID dosing)

clonazepam
Clonazepam
  • Labeled as anticonvulsant
  • As effective as alprazolam for panic; issue of potency for anti-panic efficacy
  • Advantages: Pharmacokinetic: longer duration of effect results in less frequent dosing, interdose symptoms, early relapse, or acute withdrawal symptoms. Slower onset of effect diminishes abuse potential
  • Disadvantages: Depression not more frequent than with other Bzd”s; disinhibition, headaches
  • Dosing: anticipate initial sedation (initiate at 0.25-0.5 mg qhs)
  • Range: 1-5 mg/d (BID dosing)
combining antidepressants with benzodiazepines
Combining Antidepressantswith Benzodiazepines
  • Provides rapid anxiolysis during antidepressant lag
  • Decreases early anxiety associated with initiation of antidepressant
  • Treats residual anxiety wtih antidepressant treatment
  • Prevents and treats depression on benzodiazepines
slide24

*

*

*

*

Clonazepam Taper Phase

* Together the Clonazepam groups differ from the Placebo group at p< .05

† Clonazepam groups differ from each other at p<.05

Pollack, et al 2001

buspirone
Buspirone
  • Non-benzodiazepine anxiolytic
  • Non-sedating, muscle relaxant, anticonvulsant
  • Effects on serotonin and dopamine receptors
  • Indicated for GAD; weak antidepressant effects
  • Useful as SSRI augmentation for panic, social phobia, depression, sexual dysfunction
  • Dosing: 30-60 mg/d
beta blockers
Beta Blockers
  • Decrease autonomic arousal
  • May be useful as adjunct for somatic symptoms of panic and GAD but not as primary treatment
  • Useful for non-generalized social phobia, performance anxiety subtype
  • Propranolol 10-60 mg/d; Atenolol 50-150 mg/d
anticonvulsants
Anticonvulsants
  • Valproate and gabapentin effective for non-ictal panic
  • Gabapentin effective for social phobia
  • Gabapentin (600-5400 mg/d) used as alternative to benzodiazepine
  • Valproate, Carbamazepine, Gabapentin, Topiramate and Lamotrigine for PTSD
strategies for refractory anxiety disorder
Strategies for Refractory Anxiety Disorder
  • Maximize dose
  • Combine antidepressant and benzodiazepine
  • Administer cognitive-behavioral therapy
  • Attend to psychosocial issues

.

strategies for refractory anxiety disorders
Augmentation

Anticonvulsants

Gabapentin

Valproate

Topiramate

Beta blocker

Buspirone

Clonidine/Guanfacine

Pindolol

Dopaminergic agonists (e.g., Ropinirole) for social phobia

Cyproheptadine

Combined SSRI/TCA

Alternative antidepressant

Clomipramine

MAOI

Other

Inositol

Kava-kava

Atypical neuroleptics

Strategies for Refractory Anxiety Disorders
cognitive behavioral therapy for anxiety disorders
Cognitive-Behavioral Therapy for Anxiety Disorders
  • CBT useful alone or in combination with medication for
    • Refractory symptoms
    • Persistent cognitive factors, behavioral patterns and anxiety sensitivity
    • Comorbid conditions
    • Early intervention for PTSD prophylaxis
  • CBT may be provided by therapist or self-administered (TherapyWorks manuals 800-228-0752///http://www.psychcorp.com)
  • CBT may facilitate medication discontinuation

.

continuation phase outcome with sertraline treatment of ptsd based on acute phase response category
Continuation Phase Outcome with Sertraline Treatment of PTSD Based on Acute Phase Response Category

Acute PhaseResponder Status

Continuation PhaseResponder Status

Sustained Response

Lost response

Converted to responder

Acute PhaseNon-responders

Continued non-response

Responder = > 30% decrease CAPS and CGI-S = 1 or 2

Londborg et al. J Clin Psychiatry, in press.

long term treatment of gad
Long-Term Treatment Of GAD
  • Need to treat long-term
  • Full relapse in approximately 25% of patients 1 month after stopping treatment
  • 60%-80% relapse within 1st year after stopping treatment

Hales et al. J Clin Psychiatry. 1997;58(suppl 3):76.

Rickels et al. J Clin Psychopharmacol. 1990;10(3 suppl):101S.

effect of venlafaxine on total ham a scores
Effect Of Venlafaxine On TotalHAM-A Scores

0

Placebo (N=123)

-2

Venlafaxine XR (N=115)

-4

-6

Change In Mean HAM-A Total Score

-8

-10

-12

-14

-16

-18

0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

Week Of Treatment

P<.001 for venlafaxine XR vs placebo for all study weeks except week 1 (.003), week 4 (.002), and week 20 (.007)

Venlafaxine XR doses: 75 to 225 mg/d.

Gelenberg et al. JAMA. 2000;283:3082.

paroxetine long term gad treatment remission

Placebo (N=274)

Paroxetine 20-50 mg(N=599 responders)

*

*

Paroxetine (N=285)

*

*

*

*

Paroxetine Long-Term GAD Treatment % Remission

Phase I: Single-Blind

Phase II: Double-Blind

80

70

Randomization

60

Patients(%)

50

40

30

20

10

0

1

16

2

3

4

6

8

12

20

24

28

32

Week

* P<.01 vs placebo.

Remission = HAM-A 7; LOCF dataset.

GlaxoSmithKline data on file, 2001.

discontinuation of treatment for anxiety disorders1
Discontinuation of Treatment for Anxiety Disorders
  • Withdrawal/rebound more common with Bzd than other anxiolytic treatment
  • Relapse: a significant problem across treatments. Many patients require maintenance therapy
  • Bzd abuse is rare in non-predisposed individuals
  • Clinical decision: balance comfort/compliance/ comorbidity during maintenance treatment with discontinuation-associated difficulties
strategies for anxiolytic discontinuation1
Strategies for Anxiolytic Discontinuation
  • Slow taper
  • Switch to longer-acting agent for taper
  • Cognitive-Behavioral therapy
  • Adjunctive
    • Antidepressant
    • Anticonvulsant
    • ?clonidine, ?beta blockers, ? buspirone