Therapeutic options in panic disorder

Eur Psychiatry (1995) 10. Suppl2,67s-70s 0 Elsevier,

Paris

Therapeutic options in panic disorder HGM Westenberg Department of Biological Psychiatry, Academic Hospital Utrecht, PO Box 85500, Vtrecht, NL-3508, The Netherlands

What are the management options for patients with panic disorder?

The principal management strategy for patients with panic attacks and agoraphobia has traditionally been behavioural therapy, but the delineation of panic disorder as a distinct diagnostic entity has stimulated psychopharmacological research on this psychiatric condition. As a result, the treatment of panic disorder has diversified. Effective pharmacological treatment of this disorder began with the antidepressant imipramine, but today a wide variety of efficacious agents are available for treating the symptoms of panic disorder. The four primary classes of agents for panic disorder are the tricyclic antidepressants (TCAs), the serotonin reuptake inhibitors (SSRIs), the monoamine oxidase inhibitors (MAOIs) and the high-potency benzodiazepines (BZs). Effective non-pharmacological treatments are primarily behavioural, although cognitive approaches have also been shown to be successful. The objectives of pharmacological therapy in panic disorder are three-fold: to block panic attacks, to decrease anticipatory anxiety, and to reduce phobic avoidance. What is the basis for the efficacy of the antidepressants in the treatment of panic disorder?

Among the TCAs, imipramine and clomipramine have been investigated most extensively for their therapeutic potential in panic disorder. Even in the absence of depressive symptoms these agents appear effective in reducing symptoms of panic anxiety and avoidance behaviour. However, not all TCAs and related agents are equally effective in the treatment of panic disorder. The

lack of activity of the antidepressant maprotiline on a variety of measurements - anxiety, panic frequency, performance behaviour - suggests that antidepressants that act on the serotonin (N-IT) system may be more effective than those whose action is confined to the noradrenergic system. Challenge studies with 5-HT selective agonists support the idea that the 5-HT neuronal systems are implicated in the generation of panic anxiety. MAOIs, particularly phenelzine, have been shown to be effective in panic disorder. However, their major disadvantage, at least with the older, non-selective agents, is their tendency to precipitate hypertensiveepisodes. Recent studies with selective MAO-A inhibitors have shown a reduced propensity for this side effect. Are there any data to support the hypothesis that agents which act selectively on the 5-HT neuronal system may be more effective in the treatment of panic disorder than other antidepressive agents?

A number of investigations have studied the efficacy of SSRIs in panic disorder and evidence for their antipanic activity is accumulating rapidly (table I). These studies, that for the most part have been conducted with fluvoxamine, have proven that SSRIs are effective in reducing symptoms of panic and anxiety. Most recently a multicentre, placebo-controlled study compared the SSRI, paroxetine, with the TCA, clomipramine, in 368 patients with panic disorder (DSM-III-R). Paroxetine and clomipramine were equally effective in reducing the panic attack frequency to zero after 12 weeks, but paroxetine appeared to have a more rapid onset of action (Lecrubier and The Panic Disorder Group, 1994). Paroxetine wassignificantly more effective in reducing

68s

HGM

Table I. Studies reporting

the efficacy

of serotonin

muptake

Westenberg

inhibitors

(SSRIs)

Trearment Evans et al (1986) den Boer er al (1987) den Boer and V@enberg (I 988) den Boer and Westenberg ( 1990) Black et al (1992) Hoehn Saric et al (1993) Woods et al (I 994) Gorman and Wolkow (1994) Bakish (1994)

Zim, imi, pla Flu, clam Flu, mapro Flu, lit, pla Flu, pla, ct Flu, pla Flu, pla Ser, pla Flu. imi. ula

Clam: clomipramine;ct:

imifeumine;mapro:

cognitive therapy; flu: fluvoxamine;imi:

in panic disorder. Number

of patients 25 50 44 60 75 50 191 320 54

maprouline;

Results Zim = imi z- pla Flu = clam Flu > mapro Flu>rit=pla Flu > ct > pla Flu > pla Flu > pla Ser > pla Flu = imi > pla

pla: placebo, tit: ritanserin; ser: sertraline; zim: zimeldine.

the number of panic attacks to zero at weeks 6 and 9 (fig 1). Also, paroxetine was significantly more effective than clomipramine in reducing the frequency of panic attacks by 2 50% at all time points (fig 2). Adverse events in all groupswere monitored (fig 3). In the clomipramine group tremor wasaprominent side effect, anddry mouth and sweatingwere adverseevents reportedin both the clomipramineandparoxetinegroups. Patients withdrew from the study due to lack of efficacy, or relapse,sideeffects, or a combination of lack of efficacy and side effects. There were significantly fewer withdrawals from the paroxetine group compared with either the clomipramine or the placebo groups(14 versus 23 verrur 3 1 patients,respectively).

panic andcarbondioxide canalso inducepanic attacks, although these are more likely in patients than in healthy controls. Recently, fragments of cholecystokinin (CCK), a neuropeptidepresentin the brain, were found to induce panic attacks in both patients and healthy controls, although larger dosesof CCK were required to elicit panic attacks in control subjects.Interestingly, if patients were pre-treated with the SSRI fluvoxamine before they were rechallengedwith CC& there was a significant decreasein the likelihood of a panic attack occurring. These results suggestthat the primary action of SSRIs is to reduce the frequency of panic attacks and the reduction in phobic anxiety is probably secondary.

Given that antidepressants which act on the 5-HT system are effective in the treatment of panic disorder, and the aim of treatment is to reduce panic attacks, anxiety, and avoidance, is there any evidence suggestinga primary action of SSRIs?

How doestreatment with BZs compare with that of antidepressants?

Panic attacks can be spontaneous,provoked by a situation or provoked in the laboratory. Professor Klein mentioned earlier that lactate can induce anxiety and

. l

*

p-0.041, p9LOSi.

pwoxetlw paroxellm

n n

The conventional opinion was that BZs were ineffective in panic disorder, but recent studies with highpotency BZs have demonstrated that at sufficiently high dosestheseagentscan reduce panic and phobic avoidance. They have the advantage of rapid relief of symptomswhereasmost antidepressantstend to have a

clomipnmlne placebo

Fig 1. Reduction in the number of full panic attacks to zero in patients treated with paroxetine, clomipramine or placebo.

Fig 2. Reduction

in the number of full panic attacks by >_ 50% in patients treated with paroxetine, clomipnunine or placebo.

Therapeutic

Patients

69s

options in panic disorder

60 lomipramine

to4 50

(n=121) ~--- -1

40 30 20 IO 0

* gender Fig 3. Emergent

specific

event

adverse events occurring

in > 10% patients treated with paroxetine,

delayed onset of action. However, the antipanic effects of BZs are achieved at the expense of daytime sedation, and a serious disadvantage of these agents is the risk of withdrawal and rebound phenomenon when the treatment is stopped. Chairman’s commentary I wanted to comment on the important design implications of having a three-armed trial when evaluating psychotherapy. An important point often overlooked when performing such trials, is the need for a placebo group. For instance, in an early trial on depression, the effect of cognitive therapy was compared with imipramine and appeared to give better results. However, there was no placebo group and therefore comparisons of imipramine and placebo were not possible. There was a placebo group in the National Institute of Mental Health collaborative depression trial (Elkin et al, 1989) and the results indicated that imipramine was better than placebo, whereas cognitive therapy was similar to placebo. A recent placebo-controlled study on social phobia compared phenelzine and cognitive behavioural group therapy (Liebowitz and Heimberg, 1995). The study showed that cognitive therapy was better than placebo, but that phenelzine was better than cognitive therapy. Without three treatment arms it is not possible to determine the relative merits of various treatments. Dr Westenberg Such a three-armed trial has been performed with the

clomipramine

or placebo

SSRI fluvoxamine in panic disorder patients (table I). Black et al (1992) compared the efficacy of fluvoxamine with cognitive therapy and placebo. They found fluvoxamine to be superior to both placebo and cognitive therapy and that it also produced improvement earlier than cognitive therapy. References Bakish D. The use of the reversible monoamine oxidase-A inhibitor brofaromine in social phobia complicated by panic disorder with or without agoraphobia. J C/in Psychopharmacnl 1994; 14:74-5 Black B, Uhde TW, Tancer ME. Fluoxetine for the treatment of social phobia. .I Clirz Psychophumtacol 1992; 12:293-5 den Boer JA, Westenberg HGM, Kamerbeek WD, Verhoeven WM, Kahn RS. Effect of serotonin uptake inhibitors in anxiety disorders; a double-blind comparison of clomipramine and fluvoxamine. Int Clin Psychophurmucol 1987;2:2 I-32 den Boer JA, Westenberg HGM. Effect of serotonin and noradrenaline uptake inhibitors in panic disorders; a double-blind comparative study with fluvoxamine and maprotiline. hlf Clin Psychophu1?nuc01 1988;3:59-74 den Boer JA, Westenberg HGM. Serotonin function in panic disorder, a double-blind placebo-controlled study with fluvoxamine and ritanserin. Psychopharmucol 1990; 102:85-94 Elkin 1, Shea MT, Watkins JT et ~1. National Institute of Mental Health Treatment of Depression Collaborative Research Program; General Effectiveness of Treatments. Arch Gen Psychiafry 1989;46:971-82 Evans L, Kenardy J, Schneider P, Hoey H. Effect of a selective serotonin uptake inhibitor in agoraphobia with panic attacks. Acts Psychiatr Stand 1986;73:49-53 Gorman J, Wolkow R. Sertraline as a treatment for panic disorder. Neuropsychopharmuco,I 1994; 10: 197s Hoehn Saric R, McLeod DR, Hipsley A. Effect of fluvoxamine on

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panic disorder. J Clin Psychophamaco11993;5:321-6 Lecrubier, The Panic Disorder Group. A double-blind placebo controlled study of paroxetine and clomipramine in the treatment of panic disorder. AEP, Copenhagen 18-22 Sepfl994 Liebowitz MR. Heir&erg RG. Treatment of social phobia. In: Heh berg RG. Liebowitz MR. Hope G, Scbneier F, eds. Socialphobia

awessment and treatment. New York: Guilford Press, 1995;in press Woods S, Black D, Brown S, Asnis G, Potkin S, Hameedi F. Fluvoxamine in the treatment of panic disorder in out-patients: a doubleblind, placebo-controlled study. Neuropsychophmacof 1994;10:1033 diagnosis,