Serotonin Selective Reuptake Inhibitors

Kessler et al. Arch Gen Psychiatry. 1995;52:1048.
Kessler et al. Arch Gen Psychiatry. 1994;51:8.

Any Anxiety

Disorder

Social

Anxiety

Disorder

PTSD

Generalized

Anxiety

Disorder

Panic

Disorder

(

)

Prevalence of Anxiety

Disorders

Outcome of Panic

Disorder at Long-Term

Follow-up

Persistence of

Rate (%) Range (%)

Panic attacks

17-70

Phobic avoidance

36-82

Functional impairment

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

Post-treatment

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

Pre-treatment

Standard

drinks/week

140

IES

Alcohol use

IES

score

Sertraline In Comorbid

PTSD

And Alcoholism

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

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

(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

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

• 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

End-Point (LVCF) Analysis of Panic Disorder Severity

Scale Scores for Each Group

0.5

1.5

2.5

Week

Paroxetine + Placebo
Paroxetine + Clonazepam

Paroxetine + Clonazepame w/taper

†
*

* 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

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 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

• 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/Guanfacin

– Pindolol

– D

opaminergic agonists

(e.g., Ropinirole) for

social phobia

– Cyproheptadine

• 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 self-

administered

(

TherapyWorks manuals 800-228-

0752///http://www.psychcorp.com)

• CBT may facilitate medication discontinuation

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

Londborg et al. J Clin Psychiatry, in press.

46%

54%

92%

20%

40%

60%

80%

100%

Acute Phase

Responders

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

Acute Phase Response Category

Acute Phase

Non-responders

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

-2

-4

-6

-8

-10

-12

-14
-16

-18

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.

Placebo (N=274)

Paroxetine (N=285)

Paroxetine 20-50 mg

(N=599 responders)

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

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

Document Outline