Prevalence of anxiety disorder

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Kessler et al. Arch Gen Psychiatry. 1995;52:1048. Kessler et al. Arch Gen Psychiatry. 1994;51:8. Prevalence of Anxiety Disorders

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Outcome of Panic Disorder at Long-Term Follow-up Roy-Byrne & Cowley, 1995

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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

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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

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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

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Post-treatment Brady et al. J Clin Psychiatry. 1995;56:502. Pre-treatment Standard drinks/week 140 IES Alcohol use 0 70 0 20 40 60 IES score Sertraline In Comorbid PTSD And Alcoholism

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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

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Strategies for Anxiolytic Discontinuation Slow taper Switch to longer-acting agent for taper Cognitive-Behavioral therapy Adjunctive Antidepressant Anticonvulsant ?clonidine, ?beta blockers, ? buspirone

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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

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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

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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

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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)

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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

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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

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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

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Potential Benefits of Benzodiazepine Therapy Effective Short latency of therapeutic onset Well tolerated Rapid dose adjustment feasible Can be used “prn” for situational anxiety

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Potential Drawbacks of Benzodiazepine Therapy Initial sedation Discontinuation difficulties Potential for abuse in substance abusers Not effective for comorbid depression

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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)

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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)

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Combining Antidepressants with 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

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† * * * * * Together the Clonazepam groups differ from the Placebo group at p< .05 † Clonazepam groups differ from each other at p<.05 Clonazepam Taper Phase Pollack, et al 2001

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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

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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

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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

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Strategies for Refractory Anxiety Disorder Maximize dose Combine antidepressant and benzodiazepine Administer cognitive-behavioral therapy Attend to psychosocial issues .

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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

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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 .

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Responder = > 30% decrease CAPS and CGI-S = 1 or 2 Londborg et al. J Clin Psychiatry, in press. Sustained Response Converted to responder Acute Phase Responder Status Continued non-response Lost response Continuation Phase Responder Status Continuation Phase Outcome with Sertraline Treatment of PTSD Based on Acute Phase Response Category Acute Phase Non-responders

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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.

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Effect Of Venlafaxine On Total HAM-A Scores 0 -2 -4 -6 -8 -10 -12 -14 -16 -18 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Week Of Treatment Change In Mean HAM-A Total Score Placebo (N=123) Venlafaxine XR (N=115) 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.

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0 10 20 30 40 50 60 70 80 Patients (%) Paroxetine Long-Term GAD Treatment % Remission * P<.01 vs placebo. Remission = HAM-A ?7; LOCF dataset. GlaxoSmithKline data on file, 2001. Randomization Week Phase I: Single-Blind Phase II: Double-Blind 1 2 3 4 6 8 12 16 20 24 28 32

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