SSRIs

August 1, 1996

Many of the advantages of the MAOIs are seen with selective serotonin reuptake inhibitors, which have become the drugs of choice in the treatment of panic disorder.

Many of the advantages of the MAOIs are seen with selective serotonin reuptake inhibitors, which have become the drugs of choice in the treatment of panic disorder.

Even though few large-scale, placebo-controlled studies are available (Oehrberg and coworkers; Den Boer and Westenberg 1988 and 1990; Black and others) SSRIs have essentially become a first-line treatment for panic disorder as reflected in uncontrolled trials (Gorman and others; Schneier and others) and clinical practice.

When compared to TCAs, SSRIs cause fewer anticholinergic effects and fewer cardiac effects, such as orthostatic hypotension, palpitations and dizziness. As mentioned previously, these latter two side effects can mimic a panic attack and frighten the patient. SSRIs cause less sedation and weight gain as compared with TCAs. When compared to MAOIs, SSRIs do not have the dietary constrictions and also cause less orthostatic hypotension. SSRIs do not have the abuse potential of the benzodiazepines.

The initial approach to the treatment of panic with SSRIs is listed in Table 3. As with TCAs and MAOIs, the primary treatment guideline is to start slowly (begin with a low dose such as 5 mg of fluoxetine [Prozac], 25 mg sertraline [Zoloft]) so as to avoid activation, but build up gradually to high doses to achieve a more complete blockade of the panic attacks. With complete blockade of the panic attack, the anticipatory anxiety will reduce and, based on the clinical experience of many including this author, the patient will be less reluctant to enter phobic situations. If the patients panic is blocked in these situations, the phobic avoidance may decrease. As noted above, benzodiazepines are frequently used in conjunction with SSRIs to avoid the activation. Besides activation, SSRI side effects that may be troublesome in the treatment of panic disorder are nausea, heartburn, diarrhea, insomnia, and sexual desire and performance problems.

Though paroxetine (Paxil) has been recently approved by the FDA for treatment of panic disorder, there are no studies to suggest that it has any special efficacy over the other SSRIs for this syndrome.

Combination Treatment

Although no controlled evidence exists for this approach, in many clinical settings a combination of a low-dose benzodiazepine and antidepressant is frequently given. In general, this combination is safe and beneficial as the drugs tend to complement each other by having differing effects on the aspects of panic disorder. Benzodiazepines block the activation of antidepressants in addition to alleviating anticipatory anxiety while antidepressants (which are slower to act) block the panic attack and also alleviate comorbid depressive symptoms.

The strategy is to hold the individual on low-dose benzodiazepines (e.g., alprazolam 0.25 to 0.5 mg tid or qid plus antidepressant) for four to eight weeks. When the patient's panic has abated and antidepressant levels are adequate, the benzodiazepine can be slowly withdrawn. For some individuals who experience symptom worsening upon withdrawal of the benzodiazepine, it may be necessary to continue the patient on the combination for longer periods of time.

For individuals who fail on monotherapy, a combination of TCA plus SSRI is occasionally used in the treatment of panic disorder (Coplan and colleagues). This requires an extremely cautious approach as SSRIs inhibit the hepatic cytochrome P450 2 D6 (as well as 3A4 and 1A2) system and interfere with the metabolism of TCAs, causing marked increases in TCA levels with the end result being severe cardiac toxicity. Though controversies exist as to the quantitative differences between the three SSRIs in elevating tricyclic levels (Preskorn and colleagues; Harvey and Preskorn; Nemeroff and others), it appears that fluoxetine and paroxetine elevate tricyclic levels more than sertraline does. Sertraline appears to have less inhibition of the hepatic TCA metabolism. For patients who receive a TCA-SSRI combination, TCA blood levels and electrocardiograms should be monitored frequently.

Alternative Treatments

Clonidine (Catapres) at doses of 0.2 to 0.5 mg per day has been found to have some effects in the treatment of panic disorder in one open (Liebowitz and colleagues 1981) and one double-blind crossover study (Hoehn-Saric). (The main effect of clonidine in the Hoehn-Saric study was a decrease of anxiety attacks and "psychic" symptoms. Somatic symptoms were least affected. The conditions of 17 percent of the patients became worse with the medication- Ed.) Its usage, either alone or in combination, however, appeared somewhat limited secondary to such side effects as drowsiness, sedation, fatigue, weakness and dizziness.

Calcium channel blockers have found some success in the treatment of panic disorder. Goldstein noted some success for both diltiazem (Cardizem) (60 mg per day) and verapamil (Calan) (80 mg per day), and in a double-blind crossover study, Klein and Uhde noted some benefit for seven of 11 patients treated with verapamil. Because of the possibility of cardiac side effects, EKG, blood pressure and pulse should be monitored. Similarly, because of these effects, combination treatment with calcium channel blockers should be cautiously undertaken.

Anticonvulsants have recently gained some attention in panic disorder. Though an initial double-blind placebo controlled study found carbamazepine (Tegretol) ineffective for panic disorder, Tondo and colleagues noted improvement in 20 of 34 patients treated with 170 to 500 mg per day of carbamazepine for two to 12 months. Open and double-blind crossover studies with valproate have yielded some success in panic disorder (Lum and colleagues; Woodman and Noyes). Despite the small numbers, doses of valproate in the range of 1,000 to 2,000 mg per day have decreased the length and intensity of panic attacks with minimal side effects.

Length of Treatment

It is pretty clear that panic disorder is a life-long problem as 50 percent of patients suffer continuous symptoms despite adequate treatment (Peselow and colleagues). Though no firm evidence exists, many clinicians feel that patients who respond should be maintained on the treatment for nine months to two years (Coplan and others 1996). After this length of time, discontinuation can be considered.

Fyer and colleagues found high rates of relapse if the drug is withdrawn quickly. Consequently, a slow taper (from three to six months) is often indicated. Chances for a patient to be successfully withdrawn from medication completely are small. It has been often felt that cognitive behavioral therapy (CBT) in conjunction with pharmacotherapy may help with the discontinuation process and decrease the possibility of relapse (Black and others). In the event of relapse upon discontinuation, the medication should be restarted and continued over the same interval.

Cognitive-Behavioral Therapy

Cognitive-behavioral therapy is often considered an effective treatment for panic disorder (Barlow and others 1984, 1989). There are those who regard it as a first-line treatment for panic disorder with some considering it to be as or more effective than medication (Clark and others). Though this is highly controversial, it is clear that for individuals with phobic avoidance in conjunction with the panic, CBT's use of imagery and in vivo exposure has been found to benefit this specific population.

As noted, for those with incomplete response to medication, a trial of cognitive therapy (including thought restructuring, relaxation training and in vivo exposure to phobic situations) and education about the illness is often helpful for both acute and long-term treatment. Though there are virtually no data regarding the combined approach, medications appear to offer rapid symptom relief from the panic attack while CBT offers an array of long-term coping skills.

Conclusion

During the last 15 years, we have gained extensive knowledge regarding the pharmacological management of panic disorder. We have discovered new agents and learned new strategies. Pharmacologic treatment of panic disorder is extremely effective, with treatment failures being related to inadequate dosage, lack of initial careful management or inadequate length of treatment as the major factors of nonresponse. All of this knowledge has led to more beneficial outcomes for patients with panic disorder.

Table 1DSM-IV Criteria fora Panic Attack

A discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes:

  • Palpitations, pounding heart or accelerated heart rate (tachycardia)
  • Sweating
  • Trembling or shaking
  • Sensations of shortness of breath or smothering
  • Feeling of choking
  • Chest pain or discomfort
  • Nausea or abdominal distress
  • Feeling dizzy, unsteady, lightheaded or faint
  • Derealization (feelings of unreality) or depersonalization (being detached from oneself)
  • Fear of losing control or "going crazy"
  • Fear of dying
  • Paresthesia (numbness or tingling sensations)
  • Chills or hot flushesDSM-IV Criteria for Panic Disorder
  • Recurrent unexpected panic attacks and
  • At least one of the attacks has been followed by one month or more of one (or more) of the following: a. Persistent concern about having additional attacks
    b. Worry about the implications of the attack or its consequences (e.g., losing control, having a heart attack, "going crazy")
    c. A significant change in behavior related to the attacks

Imipramine
Start with 10 mg for 1 day
Then 20 mg for 2 days
Then 30 mg for 2 days
Then 40 mg for 1-2 days
Then 50 mg for 1-2 days
Give 75-100 mg for 1 week (week 2)
Give 125-150 mg for 1 week (week 3)
Give 175-200 mg for 1 week (week 4)

Increase to 250-300 mg range as clinically indicated

Nortriptyline
Start with 10 mg for 1-2 days
Then 20 mg for 2-3 days
Then 30 mg for 2-3 days
Then 40 mg for 2-3 days
Then 50 mg for 2-3 days

Give 75 mg for 1 week (week 3)
Give 100 mg for 1 week (week 4)

Increase to 125-150 mg range as clinically indicated

  • MAOIs

Start with 15 mg phenelzine for 1-3 days

Then 30 mg phenelzine for 3-4 days

Then 45 mg phenelzine for 1 week (week 2)

Increase to 60-90 mg range as clinically indicated

Overall length of antidepressant treatment is a minimum of 6-8 weeks

(See also Table 3)

  • Table 3Practical Approach to Treatment of Panic (Cont.)SSRIs

Fluoxetine
Start with 5 mg fluoxetine (or in extreme cases use liquid form and give 1/2-1 cc or 2-4 mg) over 1 week and then increase to 10 mg for 1 week, 15-20 mg for 1-3 weeks up to a relative maximum of 40-60 mg. Because of possibility of activation it is often necessary to start with coexistent fluoxetine + a benzodiazepine, the latter for alleviating anticipatory anxiety. In general, due to long half-life of fluoxetine, an 8- to 12-week treatment period is necessary.

Paroxetine
Start with 1/2 pill (10 mg) for 2-6 days and then increase to 20 mg for 1-2 weeks. If no or incomplete response, may increase by 10 mg weekly up to a maximum of 50 mg. Treat for 8-12 weeks.

Sertraline
Start with 25 mg (1/2 pill) for 2-6 days and if no side effects, increase dose to 50 mg for 1 week. Increase over 2nd and 3rd week to 75-100 mg range and hold for 1-2 weeks. If no significant response, increase to 150 mg for 2 weeks and if necessary increase up to 200 mg. Treat for 8-12 weeks. May need an adjunctive benzodiazepine to treat anticipatory anxiety but activation effect is not as strong as with fluoxetine.

References:

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  • All of the following medical conditions are considered part of the differential diagnosis of panic disorder except: a. coronary artery disease
    b. metastatic cancer
    c. irritable bowel syndrome
    d. epilepsy
    e. vestibular dysfunction

  • Select the correct statement a. Tricyclic antidepressants are generally considered the treatment of choice in panic disorder.
    b. Paroxetine (Paxil), which was recently approved by the FDA for the treatment of panic disorder, has been shown to be clearly more efficacious than sertraline (Zoloft) or fluoxetine (Prozac) in reducing the frequency of panic attacks.
    c. Double-blind studies have confirmed the efficacy of the antidepressant/benzodiazepine combination in the initial treatment of panic disorder.
    d. Despite adequate pharmacologic treatment, panic disorder is a lifelong illness and as many as 50% of individuals will have relapses.
    e. Cognitive behavioral treatment has clearly been shown to be inferior to drug therapy in the treatment of panic disorder.

  • A panic attack may be characterized by all of the following symptoms except: a. headaches
    b. palpitations
    c. nausea
    d. derealization/depersonalization
    e. sweating

  • All of the following statements are true except: a. In the initial treatment of panic disorder it is best to start at a low dose of medication to avoid side effects such as palpitations and agitation, which may frighten the patient and mimic a panic attack.
    b. Depression, social phobia, and substance abuse are often comorbid in panic disorder patients.
    c. Long-term usage of benzodiazepines in the treatment of panic disorder is never indicated.
    d. At least one-third of individuals with panic disorder develop avoidance (agoraphobia) to places where previous panic attacks have begun.
    e. The rationale for using a benzodiazepine/antidepressant combination in the initial phase of panic disorder is that the benzodiazepine will work quickly on the anticipatory anxiety while antidepressants act more slowly to block the panic attacks and also alleviate comorbid depressive symptoms when present.

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