Daniel Carlat, MDDr. Carlat has disclosed that he has no significant relationships with or financial interests in any commercial companies pertaining to this educational activity.
Panic disorder is a much harder nut to crack than we give it credit for. We tend to get complacent about treating it, because so many patient appear to do well on the standard starting regimen of an SSRI with or without a benzodiazepine.
Unfortunately, achieving “panic-free” status—the standard outcome measure in short term studies—is rarely enough to bring patients back to normal functioning. Excellent treatment of panic disorder entails close attention to issues like diagnosis, optimal dosing, use of augmentation when appropriate, and awareness of the special usefulness of cognitive behavior therapy. In this issue of The Carlat Report, we review all these issues in the hopes of rejuvenating your enthusiasm for treating this “bread and butter” condition.
Higher doses aren’t always necessary, at least for SSRIs other than Paxil. This is good news for side effect management.
Before jumping into a discussion of medications, it’s important to review some simple elements of diagnosis. In anxiety disorders, diagnostic accuracy may seem unnecessary, because, let’s face it, SSRIs treat everything and anything with the slightest whiff of anxiety. But diagnosis is not just a DSM-4 sport; ideally, it helps us in choosing treatment and in figuring out when our patients are better.
The TCR diagnostic reminders for panic disorder include:
1) Document the typical panic attack in painstaking detail. A panic attack is a spasm of fear that may or may not be triggered by a particular situation. That spasm of fear has to be accompanied by at least 4 dramatic symptoms to qualify as a full-scale panic attack; less than 4 symptoms would qualify as a “limited-symptom” attack. Different sufferers present with different symptoms, which may have treatment implications. Those with respiratory symptoms (shortness of breath, a choking sensation) are more frequently women and benefit from breath retraining (see this month’s article on cognitive behavior therapy). Those with primarily cardiac symptoms may benefit from adjunctive beta-blockers. And so on.
2) Distinguish panic disorder from other anxiety disorders that include panic attacks as a common feature. The classic example here is the patient who says he has a panic attack “all day long”; such patients usually suffer from generalized anxiety disorder (GAD). Other common examples: the social phobic who only panics when feeling scrutinized by others, the simple phobic who panics in response to specific situations (eg., lightning, elevators), and the patient with PTSD who panics when reminded of a traumatic event. Recall that for panic disorder, only unprovoked, “out-of-the-blue” attacks need apply.
3) Document the degree and nature of agoraphobic avoidance. Almost all panickers suffer some degree of phobic avoidance, and this symptom will typically be the last to respond to treatment. Ask of all your anxious patients: “Has your anxiety caused you to avoid doing certain things or going certain places?” Document the degree of phobic avoidance, and make clear up front that this is a symptom you’ll be targeting.
A final point before launching into meds: Panic disorder is very hard to treat. In a Mass General Hospital Study of 105 patients with panic disorder on medication, the mean length of remission was only 9 months, and 60% of these patients relapsed despite being compliant with meds (1). The take home message here is that we are treating our panic patients for the long haul.
Now, what about our medications? First-line are the SSRIs and benzodiazepines, singly or in combination. Over time, we have all appreciated the need to start at very low doses for panic patients because of initial stimulation, basically at no more than half the “unit” dose, and for some particularly sensitive patients less than that, often in liquid form. While only three SSRIs currently have FDA panic indications (Paxil/Paxil CR, Zoloft, and Prozac) we know that all SSRIs work for panic, because the published evidence is there (2), and the clinical experience is even clearer.
But what doses should we shoot for? Only fixed dose studies can really tell us the answer here, because the more common flexible dose studies allow (and often require) investigators to creep up on the dosages as they see fit, often before a patient has the chance to respond to the original dose. The major fixed-dose trial of Paxil endorsed the 40 mg dose over 20 mg (3), but for the other SSRIs the story is murkier. In the two major fixed-dose trials of Zoloft for panic disorder (4,5), 50 mg a day was just as effective as 100 mg or 200 mg. Similarly, Celexa, which is approved for panic disorder in most European countries but not in the U.S., has been shown to be as effective at 20-30 mg Q day as at 40-60 mg (6). Finally, Prozac seems to be as effective at 20 mg daily as 60 mg daily (7). The bottom line is that higher doses aren’t always necessary, at least for the non-Paxil alternatives. This is good news, since side effects are clearly dose-dependent.
And benzodiazepines? They work faster than SSRIs and just as well, but noone feels particularly good about prescribing them because of the potential for addiction. There’s a feeling among psychiatrists that high potency benzodiazepines are more effective for panic than low potency agents, but this is probably false; witness a study comparing valium (average dose 43 mg/day) with xanax (4.9 mg/day) for panic, which showed equal efficacy and tolerability (8). The big news on benzos is not really news, but rather a reassuring endorsement of what most of us do all the time. Goddard and colleagues (9) randomly assigned 50 panic disorder patients to two groups: Zoloft plus placebo and Zoloft plus Klonipin 0.5 TID. The Zoloft/Klonipin group responded dramatically faster than the Zoloft/Placebo group. Furthermore, after 4 weeks of treatment, patients were tapered off Klonipin without major problems. We all wish our patients would taper off Klonipin so easily, but they don’t, because most of them would have never met the strict entry criteria for clinical trials.
Don’t forget about non-SSRIs. In this month’s Q & A Dr. Pollack discusses some of the evidence on newer agents, so I won’t upstage him here. But a word on tricyclics (TCAs) and monoamine oxidase inhibitors (MAOIs). The surprising story to many here is that among TCAs imipramine is not the gold-standard of panic treatment, but rather clomipramine (Anafranil), which beats imipramine in head-to-head trials (10). This presumably reflects the serotonin and panic connection. Finally, you can’t throw up your hands until you’ve pulled out an MAOI, preferably Nardil (phenelzine) which should be pushed as high as 90 mg/day to give it a good trial.
Basic stuff? You bet. That’s how we keep our patients well.
TCR VERDICT: In Panic: The treatment is long, the dose is low
1.Pollack MH, Otto MW, Worthington JJ. Predictors of time to relapse in a longitudinal study of panic disorder. Annual Meeting of the American College of Neuropharmacology, San Juan, Puerto Rico, 1994. 2. Rosenbaum JF, Pollack MH, Fredman SJ. The Pharmacotherapy of Panic Disorder. In Panic Disorder and Its Treatment, Ed. Rosenbaum JF and Pollack MH, 1998, Marcel Dekker, New York. 3. Ballenger JC, Wheadon DE, Steiner M, et. al. Double-blind, fixed dose, placebo-controlled study of paroxetine in the treatment of panic disorder. Am J Psychiatry 1998; 155:36-42. 4. Londborg PD, Wolkow R, Smith WT, et al. Sertraline in the treatment of panic disorder. A multi-site, double-blind, placebo-controlled, fixed-dose investigation. Br J Psychiatry 1998;173:54-60. 5. Sheikh JI, Londborg P, Clary CM. The efficacy of sertraline in panic disorder: combined results from two fixed-dose studies. Int Clin Psychopharmacol 2000;15:335-342. 6. Lepola UM, Wade AG, Leinonen EV. A controlled, prospective, 1-year trial of citalopram in the treatment of panic disorder. J Clin Psychiatry 1998;59:528-34. 7. Michelson D, Allgulander C, Dantendorfer K. Efficacy of usual antidepressant dosing regimens of fluoxetne in panic disorder. Br J Psychiatry 2001 Dec;179:514-8. 8. Noyes R, Burrows GD, Reich JH. Diazepam versus alprazolam for the treatment of panic disorder. J Clin Psychiatry 1996; 57:349-355. 9. Goddard AW et al. Early coadministration of clonazepam with sertraline for panic disorder. Arch Gen Psychiatry 2001;58:681-686. 10. Modigh K, Westberg P, Eriksson E. Superiority of clomipramine over imipramine in the treatment of panic disorder: a placebo-controlled trial. J Clin Psychopharmacol 1992; 12:251-261.