Serotonin Selective Reuptake Inhibitors - CME

Lifetime Prevalence (%)
Prevalence of Anxiety Disorders
27
24
21
18
15
12
9
6
3
0
Any Anxiety
Disorder
Social
Anxiety
Disorder
Kessler et al. Arch Gen Psychiatry. 1995;52:1048.
Kessler et al. Arch Gen Psychiatry. 1994;51:8.
PTSD Generalized
Anxiety
Disorder
Panic
Disorder

Outcome of Panic Disorder at
Long-Term Follow-up
Persistence of Rate (%) Range (%)
Panic attacks 46 17-70
Phobic avoidance 69 36-82
Functional impairment 50 39-67
Roy-Byrne & Cowley, 1995

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
• 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)
• 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

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

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

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
• 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.)
• 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
• 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)
• 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
• 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
• 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

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

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

•Effective as AD in panic
Alprazolam
•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)

• Labeled as anticonvulsant
Clonazepam
• As effective as alprazolam for panic; issue of potency for antipanic
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
• 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

Average PDSS scores
2.5
2
1.5
1
0.5
0
End-Point (LVCF) Analysis of Panic Disorder Severity
Scale Scores for Each Group
Week
00
†
*
Week
01
*
Week
02
Week
03
*
Week
04
*
Week
05
Clonazepam Taper
Phase
Week
06
Week
07
Week
08
* Together the Clonazepam groups differ from the Placebo group at p< .05
† Clonazepam groups differ from each other at p

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
• 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
• Valproate and gabapentin effective for nonictal
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
• Maximize dose
Disorder
• Combine antidepressant and benzodiazepine
• Administer cognitive-behavioral therapy
• Attend to psychosocial issues
.

Strategies for Refractory Anxiety
• Augmentation
– Anticonvulsants
• Gabapentin
• Valproate
• Topiramate
– Beta blocker
– Buspirone
– Clonidine/Guanfacine
– Pindolol
–Dopaminergic agonists
(e.g., Ropinirole) for
social phobia
– Cyproheptadine
Disorders
• Combined SSRI/TCA
• Alternative
antidepressant
– Clomipramine
– MAOI
• Other
– Inositol
–Kava-kava
– Atypical neuroleptics

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 selfadministered
(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
Acute Phase
Responder Status
Acute Phase
Responders
Acute Phase
Non-responders
8%
Sustained
Response
Continuation Phase
Responder Status
Lost response
Converted to responder
Continued non-response
non response
46%
54%
92%
0% 20% 40% 60% 80% 100%
Responder = > 30% decrease CAPS and CGI-S = 1 or 2
Londborg et al. J Clin Psychiatry, in press.

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.

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

Patients
(%)
Paroxetine Long-Term GAD Treatment
% Remission
Phase I: Single-Blind Phase II: Double-Blind
80 Paroxetine 20-50 mg
(N=599 responders)
70
Randomization
60
50
40
30
20
10
0
* P

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