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Long-term management of panic disorder
CURRENT THERAPEUTIC RESEARCH VOL. 54, NO. 6, DECEMBER1993
LONG-TERM MANAGEMENT OF PANIC DISORDER JUAN RAMON DE LA FUENTE Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
ABSTRACT Many patients with panic disorder respond to pharmacologic treatment with benzodiazepines, monoamine oxidase inhibitors, tricyclic and tetracyclic antidepressants, and selective serotonin reuptake inhibitors. In these patients, the dose of antipanic medication can be gradually tapered off and the drug eventually withdrawn. Patients with a prolonged duration of illness, severe and frequent attacks, attacks while receiving medication, secondary psychopathology, or continued avoidant or other maladaptive behavior may require chronic or lifelong drug therapy. Controlled clinical studies have demonstrated the sustained effectiveness of the drugs used to treat panic disorder. The side effects associated with long-term treatment are similar both in type and frequency to those observed with acute therapy. Discontinuation of any drug that has been used for a prolonged period of time can cause withdrawal symptoms in patients with panic disorder. Gradual tapering of the drug dose usually is helpful in reducing the risk of withdrawal symptoms, but particularly intense symptoms have been reported in patients treated with benzodiazepines toward the end of the dose-tapering period. Logarithmically derived dose-reduction strategies and concomitant cognitive behavioral and supportive therapy are useful in preventing symptoms during the later phases of discontinuation.
INTRODUCTION
The decision tree approach to the assessment of patients with panic disorder developed by Schatzberg and Ballenger 1 in 1991 remains valid today. Briefly, this approach calls for the assessment of symptoms, morbidity and comorbidity, frequency of attacks, and family history. The findings from this evaluation can then be used to identify patients who meet the criteria for pharmacologic treatment (Figure 1). 1 In patients who require drug therapy, acute treatment is initiated with benzodiazepines, particularly high-potency benzodiazepines (BZDs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), or possibly selective serotonin reuptake inhibitors (SSRIs). Controlled trials have shown that BZDs and TCAs are superior to placebo in the management of panic disorder. 2 Antipanic drug therapy is continued for approximately 6 months in patients who respond to treatment. The drug dose is then tapered off grad838
0011-393X/93/$3.50
JUAN RAMON DE LA FUENTE
Decision Tree: Assessment and Treatment of Panic Disorder Panic Disorder
(Current)
I
S . . . . dary
t
Assess symptoms, morbidity, frequency of attacks, comorbidity, and family history; meets criteria for treatment?
~"
Yes
No
I Acutetreatment:~'BZs'MAOIs'TCAs I
I Ob~rve I
J If responds, continue 6+ months l + I Meets guidelines? I Yes J'
No
[
Maint. . . . . .
I
lorogpe,ing1 I ReCap.......~...... I
I Resumetherapy and then maintain I
I No,e,ap............. I
..... I
Figure 1. Decision tree for the assessment of patients with panic disorder. (Reprinted, with permissioa, from Schatzberg and Ballenger.1)
ually. The antipanic medication is eventually discontinued. Treatment may have to be reinstituted and maintained in patients who experience relapse or recurrence of panic attacks. Other patients with panic disorder may require treatment for extended periods of time. Chronic maintenance therapy should be considered in patients in whom acute treatment is well tolerated and who have any of the following features: long duration of illness; severe and frequent attacks; recent panic attacks while on medication; secondary psychopathology, particularly pathology that is still present; or continued avoidant or other maladaptive behavior. The recognition that panic disorder is a chronic illness possibly requiring long-term therapy raises a number of issues that must be addressed. Among these are the stability of drug treatment over time, the long-term side effects of antipanic medications, and the effect of the duration of treatment on withdrawal syndromes or rebound phenomena. STABILITY OF DRUG TREATMENT
Controlled studies have demonstrated the sustained effectiveness of certain drugs used to treat panic disorder. In one recently published trial, 3 relief of the symptoms of panic disorder achieved with alprazolam and 839
LONG-TERM MANAGEMENT OF PANIC DISORDER
imipramine was maintained for up to 32 weeks. At the end of the study observation period (classifying dropouts as nonresponders) 62% of patients treated with alprazolam, 26% of those treated with imipramine, and 26% of those receiving placebo were free of panic attacks. A study by Curtis et al, 4 reported a higher rate of study retention in patients treated with alprazolam than in those who received placebo. Higher dropout rates with both imipramine and placebo, compared with alprazolam, have been a consistent finding in both acute and chronic investigations. In a follow-up of phase I of the Cross-National Collaborative Panic Study, antipanic t r e a t m e n t with alprazolam remained effective for 17 months. There was no evidence of the need for dose escalation to maintain a panic-free state. In fact, a tendency toward continued efficacy with a reduction of the alprazolam dose was seen. The mean daily dose 17 months after the start of the study was about one half that required in the acute phase (Figure 2). 5 Other data support these findings. 6 In the study by Curtis et al, 4 no evidence was found of the need to increase the alprazolam dose to maintain the therapeutic response over an 8-month period of treatment. The average number of tablets per day remained fairly constant during this time. SIDE EFFECTS
OF LONG-TERM TREATMENT
The unwanted side effects associated with maintenance therapy are a sig-
6-
5-
~
"~-.,o.,..
]
:>,
4-
E
3-
Total • long-term
ed means) n = 142
Patients never off "~'~
alprazolam n ~47= ",,-~,~,~, n ,.~,,~.~
21-
0
]
i
r
Beginning of Therapy
End Short-term Therapy
End Long-term Therapy
Poststudy Interview (17 mo)
(2 mo)
(8 too)
Figure 2. Doses of alprazolam in long-term antipanic treatment. (From Black et al.5) 840
JUAN RAMON DE LA FUENTE
nificant concern in patients with chronic panic disorder. Eight-month follow-up data from a subgroup of 400 panic disorder patients receiving alprazolam, imipramine, or placebo showed no unexpected side effects with any of these treatments. The frequency and pattern of side effects during chronic drug administration was essentially similar to that during acute therapy. Many of the drugs used to manage panic disorder also are used to treat depression. Thus clinical experience in the long-term management of depression has been helpful in identifying the risks associated with the chronic treatment of panic disorder. Weight gain, hypertensive crisis, and hyperpyretic reactions are among the important potential complications that can occur in patients with panic disorder who receive MAOIs. TCAs can cause weight gain and anorgasmia. Weight gain also can occur with the use of tetracyclic antidepressants. Dependence and cognitive deficits are the risks of greatest concern in patients receiving long-term benzodiazepine therapy. DISCONTINUATION OF TREATMENT
Discontinuation of any drug used to treat panic disorder for a prolonged period of time will have some effect on the patient. 7 Rebound hypomania, for example, has been reported with the discontinuation of MAOIs in patients with depression and in those with obsessive-compulsive disorder. Discontinuation of TCAs has been associated with a rebound cholinergic syndrome, with hypomanic reactions noted in patients treated for depression. Rebound anxiety and insomnia are the principal withdrawal symptoms associated with discontinuation of long-term benzodiazepine therapy, while rebound cholinergic effects and rebound depression have been reported after withdrawal of SSRIs (table). In addition to the symptoms that may appear after discontinuation of the various antipanic medications, re-emergence of the original panic disorder symptoms can occur. With some drugs, the effects of withdrawal appear within a very short time after therapy is stopped. Withdrawal symptoms in patients receiving long-term therapy with alprazolam or imipramine tend to become more intense toward the end of Table. Discontinuation risks of drug treatment.
MAOIs: TCAs: BZDs: SSRIs:
Rebound hypomania (depression, obsessive-compulsive disorder) Rebound cholinergic symptoms and hypomanic reactions (depression) Withdrawal symptoms, rebound anxiety, and insomnia Cholinergic rebound, rebound depression
MAOIs = monoamine oxidase inhibitors; TCAs = tricyclic antidepressants; BZDs = benzodiazepines; SSRIs = selective serotonin reuptake inhibitors. 841
LONG-TERMMANAGEMENTOF PANICDISORDER
the drug-tapering process. Lowering the doses of these drugs generally precipitates few side effects or rebound phenomena until the dose has been reduced to more than 50% of its original level. At that time, withdrawal symptoms and the re-emergence of panic disorder symptoms are most likely to be seen. A number of techniques have been suggested for minimizing the risk of withdrawal symptoms when benzodiazepines are discontinued. Among these is a logarithmically derived dose-reduction strategy that calls for a 10% decrease in the dose every 4 to 7 days. Evidence suggests that clonazepam or another long-acting benzodiazepine can be substituted for a shorter-acting benzodiazepine at the end of the dose-tapering period, s However, because the long-acting benzodiazepine eventually must be withdrawn as well, this approach may not be an adequate solution to the problem of drug withdrawal. The anticonvulsant carbamazepine has been reported to relieve withdrawal symptoms,9 but experience with this agent is limited and the rationale for its use is questionable. Cognitive behavioral and supportive therapy may be the best approach for preventing drug withdrawal symptoms during the final phase of discontinuation. CONCLUSIONS
Panic disorder is a benign disease in approximately 30% to 40% of afflicted patients. Symptoms in these patients respond well to antipanic medication and remain suppressed when the drug is withdrawn. In some patients, however, panic disorder is a chronic condition. The optimal duration of treatment in such patients has not been established, but some patients may require chronic therapy. Because there is no evidence of the development of tolerance with the long-term use of antipanic drugs, total elimination of treatment is not necessarily desirable in all patients. If a patient is functioning well and experiencing no serious side effects, it may be best to continue treatment. References: 1. Schatzberg AF, Ballenger JC. Decisions for the clinician in the treatment of panic disorder; when to treat, which treatment to use and how long to treat. J Clin Psychiatry 1991; 52(Suppl 2):26-31. 2. Cross National Collaborative Panic Study, second phase investigators. Drug treatment of panic disorder. Comparative efficacy of alprazolam, imipramine and placebo. Br J Psychiatry 1993; 160:191-202. 3. Schweizer E, Rickels K, Weiss S, et al. Maintenance drug treatment of panic disorder I, results of a prospective placebo-controlled comparison of alprazolam and imipramine. Arch Gen Psychiatry 1993; 50:51-60. 842
JUANRAMONDE LAFUENTE
4. Curtis GC, Massana J, Udina C, et al. Maintenance drug therapy of panic disorder. J Psychiatr Res (in press). 5. Black DW, Wesrer R, Bowers W, Gabel J. A comparison of fluvoxamine cognitive therapy, and placebo in the treatment of panic disorder. Arch Gen Psychiatry 1993; 50:44-50. 6. Nagy LM, Krystal JH, Woods SW, et al. Clinical and medication outcome after shortterm alprazolam and behavioral group treatment in panic disorder. Arch Gen Psychiatry 1989; 46:993-999. 7. King D, Nicolini H, de la Fuente JR. Abuse and withdrawal of panic treatment drugs. Psychiatr Ann 1990; 20(9):525-528. 8. Herman JB, Rosenbaum JF, Brotman AW. The alprazolam to clonazepam switch for the treatment of panic disorder. J Clin Psychopharmacol 1987; 7:175-178. 9. Klein E, Uhde TW, Post RM. Preliminary evidence for the utility of carbamazepine in alprazolam withdrawal. A m J Psychiatry 1986; 143:235-236.
843
LONG-TERM MANAGEMENT OF PANIC DISORDER JUAN RAMON DE LA FUENTE Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
ABSTRACT Many patients with panic disorder respond to pharmacologic treatment with benzodiazepines, monoamine oxidase inhibitors, tricyclic and tetracyclic antidepressants, and selective serotonin reuptake inhibitors. In these patients, the dose of antipanic medication can be gradually tapered off and the drug eventually withdrawn. Patients with a prolonged duration of illness, severe and frequent attacks, attacks while receiving medication, secondary psychopathology, or continued avoidant or other maladaptive behavior may require chronic or lifelong drug therapy. Controlled clinical studies have demonstrated the sustained effectiveness of the drugs used to treat panic disorder. The side effects associated with long-term treatment are similar both in type and frequency to those observed with acute therapy. Discontinuation of any drug that has been used for a prolonged period of time can cause withdrawal symptoms in patients with panic disorder. Gradual tapering of the drug dose usually is helpful in reducing the risk of withdrawal symptoms, but particularly intense symptoms have been reported in patients treated with benzodiazepines toward the end of the dose-tapering period. Logarithmically derived dose-reduction strategies and concomitant cognitive behavioral and supportive therapy are useful in preventing symptoms during the later phases of discontinuation.
INTRODUCTION
The decision tree approach to the assessment of patients with panic disorder developed by Schatzberg and Ballenger 1 in 1991 remains valid today. Briefly, this approach calls for the assessment of symptoms, morbidity and comorbidity, frequency of attacks, and family history. The findings from this evaluation can then be used to identify patients who meet the criteria for pharmacologic treatment (Figure 1). 1 In patients who require drug therapy, acute treatment is initiated with benzodiazepines, particularly high-potency benzodiazepines (BZDs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), or possibly selective serotonin reuptake inhibitors (SSRIs). Controlled trials have shown that BZDs and TCAs are superior to placebo in the management of panic disorder. 2 Antipanic drug therapy is continued for approximately 6 months in patients who respond to treatment. The drug dose is then tapered off grad838
0011-393X/93/$3.50
JUAN RAMON DE LA FUENTE
Decision Tree: Assessment and Treatment of Panic Disorder Panic Disorder
(Current)
I
S . . . . dary
t
Assess symptoms, morbidity, frequency of attacks, comorbidity, and family history; meets criteria for treatment?
~"
Yes
No
I Acutetreatment:~'BZs'MAOIs'TCAs I
I Ob~rve I
J If responds, continue 6+ months l + I Meets guidelines? I Yes J'
No
[
Maint. . . . . .
I
lorogpe,ing1 I ReCap.......~...... I
I Resumetherapy and then maintain I
I No,e,ap............. I
..... I
Figure 1. Decision tree for the assessment of patients with panic disorder. (Reprinted, with permissioa, from Schatzberg and Ballenger.1)
ually. The antipanic medication is eventually discontinued. Treatment may have to be reinstituted and maintained in patients who experience relapse or recurrence of panic attacks. Other patients with panic disorder may require treatment for extended periods of time. Chronic maintenance therapy should be considered in patients in whom acute treatment is well tolerated and who have any of the following features: long duration of illness; severe and frequent attacks; recent panic attacks while on medication; secondary psychopathology, particularly pathology that is still present; or continued avoidant or other maladaptive behavior. The recognition that panic disorder is a chronic illness possibly requiring long-term therapy raises a number of issues that must be addressed. Among these are the stability of drug treatment over time, the long-term side effects of antipanic medications, and the effect of the duration of treatment on withdrawal syndromes or rebound phenomena. STABILITY OF DRUG TREATMENT
Controlled studies have demonstrated the sustained effectiveness of certain drugs used to treat panic disorder. In one recently published trial, 3 relief of the symptoms of panic disorder achieved with alprazolam and 839
LONG-TERM MANAGEMENT OF PANIC DISORDER
imipramine was maintained for up to 32 weeks. At the end of the study observation period (classifying dropouts as nonresponders) 62% of patients treated with alprazolam, 26% of those treated with imipramine, and 26% of those receiving placebo were free of panic attacks. A study by Curtis et al, 4 reported a higher rate of study retention in patients treated with alprazolam than in those who received placebo. Higher dropout rates with both imipramine and placebo, compared with alprazolam, have been a consistent finding in both acute and chronic investigations. In a follow-up of phase I of the Cross-National Collaborative Panic Study, antipanic t r e a t m e n t with alprazolam remained effective for 17 months. There was no evidence of the need for dose escalation to maintain a panic-free state. In fact, a tendency toward continued efficacy with a reduction of the alprazolam dose was seen. The mean daily dose 17 months after the start of the study was about one half that required in the acute phase (Figure 2). 5 Other data support these findings. 6 In the study by Curtis et al, 4 no evidence was found of the need to increase the alprazolam dose to maintain the therapeutic response over an 8-month period of treatment. The average number of tablets per day remained fairly constant during this time. SIDE EFFECTS
OF LONG-TERM TREATMENT
The unwanted side effects associated with maintenance therapy are a sig-
6-
5-
~
"~-.,o.,..
]
:>,
4-
E
3-
Total • long-term
ed means) n = 142
Patients never off "~'~
alprazolam n ~47= ",,-~,~,~, n ,.~,,~.~
21-
0
]
i
r
Beginning of Therapy
End Short-term Therapy
End Long-term Therapy
Poststudy Interview (17 mo)
(2 mo)
(8 too)
Figure 2. Doses of alprazolam in long-term antipanic treatment. (From Black et al.5) 840
JUAN RAMON DE LA FUENTE
nificant concern in patients with chronic panic disorder. Eight-month follow-up data from a subgroup of 400 panic disorder patients receiving alprazolam, imipramine, or placebo showed no unexpected side effects with any of these treatments. The frequency and pattern of side effects during chronic drug administration was essentially similar to that during acute therapy. Many of the drugs used to manage panic disorder also are used to treat depression. Thus clinical experience in the long-term management of depression has been helpful in identifying the risks associated with the chronic treatment of panic disorder. Weight gain, hypertensive crisis, and hyperpyretic reactions are among the important potential complications that can occur in patients with panic disorder who receive MAOIs. TCAs can cause weight gain and anorgasmia. Weight gain also can occur with the use of tetracyclic antidepressants. Dependence and cognitive deficits are the risks of greatest concern in patients receiving long-term benzodiazepine therapy. DISCONTINUATION OF TREATMENT
Discontinuation of any drug used to treat panic disorder for a prolonged period of time will have some effect on the patient. 7 Rebound hypomania, for example, has been reported with the discontinuation of MAOIs in patients with depression and in those with obsessive-compulsive disorder. Discontinuation of TCAs has been associated with a rebound cholinergic syndrome, with hypomanic reactions noted in patients treated for depression. Rebound anxiety and insomnia are the principal withdrawal symptoms associated with discontinuation of long-term benzodiazepine therapy, while rebound cholinergic effects and rebound depression have been reported after withdrawal of SSRIs (table). In addition to the symptoms that may appear after discontinuation of the various antipanic medications, re-emergence of the original panic disorder symptoms can occur. With some drugs, the effects of withdrawal appear within a very short time after therapy is stopped. Withdrawal symptoms in patients receiving long-term therapy with alprazolam or imipramine tend to become more intense toward the end of Table. Discontinuation risks of drug treatment.
MAOIs: TCAs: BZDs: SSRIs:
Rebound hypomania (depression, obsessive-compulsive disorder) Rebound cholinergic symptoms and hypomanic reactions (depression) Withdrawal symptoms, rebound anxiety, and insomnia Cholinergic rebound, rebound depression
MAOIs = monoamine oxidase inhibitors; TCAs = tricyclic antidepressants; BZDs = benzodiazepines; SSRIs = selective serotonin reuptake inhibitors. 841
LONG-TERMMANAGEMENTOF PANICDISORDER
the drug-tapering process. Lowering the doses of these drugs generally precipitates few side effects or rebound phenomena until the dose has been reduced to more than 50% of its original level. At that time, withdrawal symptoms and the re-emergence of panic disorder symptoms are most likely to be seen. A number of techniques have been suggested for minimizing the risk of withdrawal symptoms when benzodiazepines are discontinued. Among these is a logarithmically derived dose-reduction strategy that calls for a 10% decrease in the dose every 4 to 7 days. Evidence suggests that clonazepam or another long-acting benzodiazepine can be substituted for a shorter-acting benzodiazepine at the end of the dose-tapering period, s However, because the long-acting benzodiazepine eventually must be withdrawn as well, this approach may not be an adequate solution to the problem of drug withdrawal. The anticonvulsant carbamazepine has been reported to relieve withdrawal symptoms,9 but experience with this agent is limited and the rationale for its use is questionable. Cognitive behavioral and supportive therapy may be the best approach for preventing drug withdrawal symptoms during the final phase of discontinuation. CONCLUSIONS
Panic disorder is a benign disease in approximately 30% to 40% of afflicted patients. Symptoms in these patients respond well to antipanic medication and remain suppressed when the drug is withdrawn. In some patients, however, panic disorder is a chronic condition. The optimal duration of treatment in such patients has not been established, but some patients may require chronic therapy. Because there is no evidence of the development of tolerance with the long-term use of antipanic drugs, total elimination of treatment is not necessarily desirable in all patients. If a patient is functioning well and experiencing no serious side effects, it may be best to continue treatment. References: 1. Schatzberg AF, Ballenger JC. Decisions for the clinician in the treatment of panic disorder; when to treat, which treatment to use and how long to treat. J Clin Psychiatry 1991; 52(Suppl 2):26-31. 2. Cross National Collaborative Panic Study, second phase investigators. Drug treatment of panic disorder. Comparative efficacy of alprazolam, imipramine and placebo. Br J Psychiatry 1993; 160:191-202. 3. Schweizer E, Rickels K, Weiss S, et al. Maintenance drug treatment of panic disorder I, results of a prospective placebo-controlled comparison of alprazolam and imipramine. Arch Gen Psychiatry 1993; 50:51-60. 842
JUANRAMONDE LAFUENTE
4. Curtis GC, Massana J, Udina C, et al. Maintenance drug therapy of panic disorder. J Psychiatr Res (in press). 5. Black DW, Wesrer R, Bowers W, Gabel J. A comparison of fluvoxamine cognitive therapy, and placebo in the treatment of panic disorder. Arch Gen Psychiatry 1993; 50:44-50. 6. Nagy LM, Krystal JH, Woods SW, et al. Clinical and medication outcome after shortterm alprazolam and behavioral group treatment in panic disorder. Arch Gen Psychiatry 1989; 46:993-999. 7. King D, Nicolini H, de la Fuente JR. Abuse and withdrawal of panic treatment drugs. Psychiatr Ann 1990; 20(9):525-528. 8. Herman JB, Rosenbaum JF, Brotman AW. The alprazolam to clonazepam switch for the treatment of panic disorder. J Clin Psychopharmacol 1987; 7:175-178. 9. Klein E, Uhde TW, Post RM. Preliminary evidence for the utility of carbamazepine in alprazolam withdrawal. A m J Psychiatry 1986; 143:235-236.
843