Clonazepam for panic disorders and agitation

REJEAN FONTAINE, M.D., F.R.C.P.(C)

Clonazepam for panic disorders and agitation Anxiety disorders with recurrent panic attacks, such as the DSM-III categories of panic disorder and agoraphobia with panic attacks, have become very interesting topics to clinicians and researchers during the last decade. With DSM-III, the classic anxiety neurosis described at the tum of the century has been subdivided into panic disorder and generalized anxiety disorder. I Panic disorder is characterized by the presence of recurrent panic attacks. At least three such attacks must have occurred within a three-week period for this diagnosis to be made. As the Figure shows, the incidence of panic disorder ranges between 0.4% and 1.0%, more females than males have the disorder, and it is a disorder that tends to be chronic. Adding patients with the DSM-III diagnosis of agoraphobia with panic attacks at least doubles the incidence. About half the patients become disabled, mostly because of avoidance behavior. As they have panic attacks, they begin to avoid going to work; as a result, they lose their job. The same thing occurs with family and interpersonal relationships, as avoidance leads to diminished functioning. Other medical complications may also ensue, such as abuse of alcohol or drugs in an attempt to control symptoms. Because the complications are so common, the treating physician often must assess and treat both the illness and the complications. 2

Treatment The optimal treatment of panic disorder is, obviously, a combination of psychotherapy and medication, and the most widely accepted drug for treatment in the U.S. and Canada is imipramine. 3 In Europe, imipramine and monoamine oxidase inhibitors are widely used in this disorder.

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However, several problems, particularly anticholinergic side effects, limit the usefulness of antidepressants in patients with panic disorder. These side effects present more of a problem in such patients than they do in depressed patients. 4 An additional problem is the risk of suicide with these drugs, which can be lethal in overdose. Most patients with panic disorder are treated as outpatients, and with I to 2 g of imipramine a patient can kill herself following some disappointment or bad news. These problems led us to look for alternative treatments for patients having recurrent panic attacks. Initially, we found that alprazolam, a potent benzodiazepine, was effica-

Anxiety neurosis (ICD-9) AfterRDC and DSM-III subdivision

Generalized anxiety disorder 2.5%-3% 1female: 1 male 15% are disabled Diffuse anxiety

Panic disorder 0.4-1 % 3.5 female: 1 male 50% are disabled Recurrent panic attacks

FIGURE--Characteristics ofgeneralized anxiety and panic disorder.

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Panic and agitation

Table 1-HSCL-90 self-ratings: Baseline and After Clonazepam Treatment Baseline evaluation mean (SE)

After clonazepam treatment

t-value (df = 9)

Anxiety

(0-40)

22.4 (2.7)

7.9 (1.3)

5.8

<.001

Phobic anxiety

(0-28)

18.3 (2.4)

5.7 (2.5)

5.0

<.001

Panic attacks

(0-12)

9.3(1.1)

2.7 (0.8)

5.8

<.001

!

cious in such patients. 5 Because this drug has certain shortcomings associated with its relatively short half-life, we went on to study c1onazepam, another potent benzodiazepine. The combination of c1onazepam's high potency with its long half-life, which decreases the likelihood of withdrawal symptoms including rebound phenomena, provided the rationale for our study.• The clinical use of c10nazepam is increasingly documented. 6 When we looked at the clinical literature on c1onazepam, however, we found that its antianxiety properties have as yet to be investigated. This was surprising, since animal studies 7 clearly have shown c10nazepam to be a highly potent agent in several anticonflict tests, and these are the tests that would predict a drug's effect on various anxiety symptoms.

Design We studied the use of c10nazepam in eight women and two men with a DSM-III diagnosis of panic disorder or agoraphobia with panic attacks. The female-to-male ratio was about the same as is usually found for this disorder. Their mean age was 33 years, with a range from 27 to 42 years, and the mean length of illness was seven years, ranging from one to 21 years. Although antidepressants are usually thought ofas the treatment ofchoice for panic disorder, only one patient was on an antidepressant when she came to us. Seven were on low potency benzodiazepines, and three were not taking any medication. The study began with a gradual discontinuation of all medication, followed by a washout phase of one to two weeks, at the end of which we performed EEG studies. In the treatment phase, we gave a flexible dosage of c1onazepam, beginning with 0.5 mg at supper and bedtime, to be increased by 0.5 mg every three days until the next visit or a

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P (2-talled)

maximum of 2 mg. Treatment was continued for three months, with the dosage adjusted upward as needed, to a maximum of 3 to 6 mg daily for most patients. Assessments performed at the end of the washout period included the Hamilton Anxiety Scale and the selfrating Hopkins Symptom Check List (SCL-90).' These were repeated on a monthly basis and at the end of the treatment period.

Results The results presented are primarily in terms of the Anxiety and Phobic-Anxiety factors and the index for panic attacks ofthe SCL-90" a scale widely used to measure symptomatic improvement in drug trials. We examined each patient's score for anxiety factor, phobic anxiety factor, and panic attack index. The score for each of these factors represents a combined score of from three to ten SCL-90 items.' There was no premature termination; all patients stayed in the study for a full three months of treatment. As Table I shows, there was a statistically significant improvement for the three types of symptoms that are predominant with these patients. If we look at panic attacks, for example, the factor score dropped from 9.3 down to 2.7. Using the two-tailed test, all the symptoms were clearly improved. In addition, verbal reports from our patients indicated a substantial improvement over their previous treatment, which probably explains why there were no dropouts. Panic attacks are very abrupt, very acute outbursts of anxiety-in many ways like seizures. In most cases they occur spontaneously; people do not feel them coming, and they last, in most cases, usually less than half an hour. Termination is also relatively abrupt, and usually leaves the patient in a state of some difficulty with concentration, feeling tired and unable to carry out regular activities. These similarities are noteworthy, in view ofthe apparent effectiveness ofthis anticonvulsive agent, c1onazepam, in blocking panic attacks.' Phobic anxiety was also significantly reduced with c1onazepam. The issue that is very important here is that as the panic attacks are blocked or suppressed with c1onazepam, eventually patients begin to be able to go back to the feared situations or to use much less avoidance behavior. In other words, first c10nazepam works very quickly in the first week or so as an antipanic agent and then the patients gain back their confidence. Overall, eight of the ten patients im-

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PSYCHOSOMATICS

proved moderately to markedly and two remained symptomatic. The side effects experienced with these patients were normal with the regimen described previously. Three patients reported mild sedation and had to increase the dosage more slowly than every three days. Two patients reported mild ataxia, and did not seem to develop tolerance to the ataxia; after several weeks they remained somewhat ataxic, but never to a degree that would interfere with their functioning. Discussion These findings indicate clearly the antipanic, antiphobic, and anxiolytic effect of c10nazepam and the rapidity with which improvement occurs, as previously reported." Clonazepam thus differs from the classical benzodiazepines such as diazepam or chlordiazepoxide, which have been shown to be of limited efficacy in these disorders. 10 A recent study by Noyes and associates" suggests that diazepam has some effect on panic attacks and in the treatment of panic disorder. However, it appears that low or medium potency benzodiazepines, such as chlordiazepoxide and diazepam, may improve anxiety symptoms but that they do not really block the panic attacks; therefore, patients will tend not to expose themselves to fear-provoking situations as much as they would when taking a more potent benzodiazepine such as c1onazepam. Thus, c1onazepam-as was found previously with imipramine-has a clear antipanic effect,

Table 3-Comparison of Alprazolam and Clonazepam In Panic Disorder Alprazolam

Clonazepam

Half-life (hr)

12-15

>24

Withdrawal reactions

+++

+

Regimen 5 to 9 mg/d

aiD

BID or single dose

which leads eventually to an antiphobic effect. Significantly, most patients did not experience side effects and they have tolerated c10nazepam well. This differs from the lesser tolerance seen in epileptic patients taking c1onazepam: and the difference may be explained by the high degree of arousal characteristic of patients suffering from panic disorders. Clonazepam has a long half life of 20 to 40 hours in humans· and both radioligand and autoradiographic studies have shown that among the presently available benzodiazepines, c10nazepam has the greatest affinity for benzodiazepine receptors. 12 In terms of distribution, 47% of the drug is bound to protein, as compared with 19% for diazepam" Thus c10nazepam is a potent benzodiazepine because of its particular pharmacokinetic profile, but also because of its direct binding effect on Table 2-Drug Treatment of Panic Disorder: Comparison of Potent benzodiazepine receptors. And these Benzodiazepines vs Tricyclics two properties certainly make c1onazepam a benzodiazepine different from the others, combining, as it does, Potent benzodiazepines Klein's protocol potency with a long half-life. (alprazolam or (imipramine or Since the ten-patient trial reported clonazepam) desipramine) here, we have used c10nazepam in at Previous history of least 60 other patients in an open alcohol or drug abuse - or + study, with similar results. We have found that treatment of panic disorder Side effects Minimal Significant in must usually continue for six to eight over 30% of months to allow patients sufficient cases time to behaviorally desensitize themOverdose Sedation; sleep Sleep; coma selves. The medication may then be or death gradually discontinued over a four-toWithdrawal syndrome six-week period. With gradual disupon drug cessation +++ + continuation there have been no major problems such as seizures, delirium,

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Panic and agitation

or psychoses. Mild rebound anxiety seems to be the only problem that has occurred during withdrawal. This is in spite of the fact that several patients with panic disorder have been found to have epileptiform discharges on the BEG. In fact, we reviewed these data recently and found that at least one third of our patients with panic disorder have epileptiform discharges. Thus it is interesting that when we stopped the benzodiazepine, which was the only drug given to these patients, none developed seizures. The pros and cons of using a potent benzodiazepine such as clonazepam or alprazolam vs using imipramine or desipramine are outlined in Table 2. Because of concerns about habituation with benzodiazepines, imipramine remains the tteabnent of choice for patients with a history of alcohol or drug abuse. On the other hand, imipramine may be expected to produce significantly more side effects and is also more dangerous if taken in overdose. While we might be concerned about the potential for a withdrawal syndrome upon termination of treatment with a potent benzodiazepine, this would seem to be less of a con-

cern with clonazepam than with alprazolam. If we compare the two potent benzodiazepines reported to have a therapeutic effect in panic disorder (Table 3), we can see that the half-life is different for the two drugs, which implies less of a withdrawal reaction in the case of clonazepam and also more dosage flexibility in that clonazepam could be given bid or in a single daily dose, whereas with alprazolam most of our patients are on a qid regimen. We have subsequently used clonazepam to treat severe anxiety and agitation in both adolescents and adults, and it has been well tolerated and efficacious in dosages of 6 to 12 mgld. In several cases its use enabled us to avoid using neuroleptics, which could induce tardive dyskinesia or parkinsonian side effects. In conclusion, clonazepam as seen with our results here seems to be an efficacious antipanic and antiphobic agent and we feel that it provides an alternative treatment for patients suffering from severe anxiety with recurrent panic attacks. It has less side effects than tricyclics and is less risky in case of overdose. 0

REFERENCES 1. Diagnostic and Statistical Manual of Mental Disorders. ed 3. Washington, DC. American Psychiatric Association, 1980. 2. Fontaine R, Beaudry P: Panic anacks and panic disorders. Can Fam Phy-

sician30:1383-1388,l984. 3. Zitrin CM. Klein OF. Woerner MG, et al: Treatment of phobias: I. Comparison of imipramine, hydrochloride and placebo. Arch Gen Psychiatry 40:125-138.1983. 4. Zitrin CM, Klein OF. Woerner MG: Behavior therapy, supportive psychotherapy, imipramine and phobias. Arch Gen Psychiatry 35:307-16, 1978. 5. Chouinard G, Annable l, Fontaine R. et al: Alprazolam in the treatment of generalized anxiety and panic disorders: A double-blind, placebo-controlled study. Psychopharmacology 77:229-233, 1982. 6. Browne TR: Clonazepam. N Engl J Med 15:812-816, 1978. 7. Sepinwall J. Cook l: Behavioral pharmacology of antianxiety drugs. in

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Iversen ll, Iversen SO. Snyder SH (eds): Handbook of Psychopharmacology. New York, Plenum, 1978, pp345-393. 8. Oerogatis lR, Lipman RS. Covi L: SCl-90: An outpatient psychiatric rating scale-Preliminary report. Psychopharmacol Bu1/9: 13-22, 1973. 9. Fontaine R, Chouinard G: Antipanic effect of clonazepam. Am J Psychiatry 141:149, 1984. 10. McNair OM. Kahn RJ: Imipramine compared with a benzodiazepine for agoraphobia in anxiety, in Klein OF, Raskin JO (eds): Anxiety: New ResearCh andChanging Concepts. New York, Raven Press, 1981, pp 69-81. 11. Noyes R Jr. Anderson OJ, Clancy J, et al: Oiazepam and propranolol in panic disorder and agoraphobia. Arch Gen Psychiatry 41 :287-292, 1984. 12. Mohler H, Richards JG: Benzodiazepine receptors in the central nervous system, in Costa E (ed): The Benzodiazepines: From Molecular Biology to Clinical Practice. New York, Raven Press, 1983, pp 93-116.

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Panel Discussion Dr. Penry: For how long did you continue to treat your patients?

blocked all along that she has been able to go back to the subway and various open places that she had been avoiding for years.

Dr. Fontaine: Treatment with an antidepressant for this condition continues for at least six to eight months and, in some patients, up to ten months. Once you get good pharmacologic control of the panic attacks, the patient needs time to gain back his confidence and to begin to return to situations that are feared or that have been avoided. By doing this, he will desensitize himself progressively. Most patients do not need systematic desensitization as we used to do in the early 1970s. Most will be able to desensitize themselves progressively while their symptoms are under control with medication, and only a subgroup, perhaps 20%, will need a special form of psychotherapy to help them to desensitize themselves. After six to eight months of treatment we decrease the dosage gradually over four to six weeks.

Dr. Penry: What was the highest dosage you used? You mentioned 4 mg. Did you go higher than that in any of the patients?

Dr. Fontaine: I have one case where I went up to to mg; otherwise, the maximum was 8 mg. As I mentioned, an increase to this level always occurs during the first four to six weeks of treatment if we have to do it. And it may be related to the way patients metabolize the medication. I Knowing that further dosage increases are not necessary after this initial period is helpful in terms of avoiding abuse. If a patient started to increase the dosage I would question the indication and I would possibly switch to another treatment, such as an antidepressant.

Dr. Penry: Were there any relapses of the anxiety attacks or panic attacks while patients were under treatment?

Dr. Fontaine: No. Following the treatment, however, we expect that about 20% to 25% will relapse during the first year after treatment. It is interesting to note that we usually reach the therapeutic dosage with a given patient during the first month of treatment, and after that the patient maintains control of his symptoms without any further dosage increase. I have one case in mind in which we went to 4 mg/d during the first month and even after eight months of treatment, just before beginning to stop the drug gradually, the patient is still on the 4 mg and has had her panics so well

Dr. Chouinard: In the considerable number of patients we have seen, there has been little tendency to abuse c1onazepam. Obviously, we do not prescribe a benzodiazepine to those who have a tendency to abuse drugs. We find that most patients adjust their dosage relatively well and decrease the drug as soon as their manic symptoms subside.

Dr. Fontaine: One of the characteristics of clonazepam in that respect that makes it an interesting medication for adolescents, for example, is the fact that it does not cause a rush effect. People take it and say it doesn't do much really, unless they take it under their tongue. If they take it under their (continued)

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Panic and agitation

tongue, then they may feel some effects within an hour. But otherwise, patients do not feel a drastic effect as will be felt with the other benzodiazepines within an hour after taking them orally. This is related to the relatively low lipophilicity of clonazepam. 2

populations. While your patients were adults disabled by their phobias, children who are functioning well enough to attend school might be expected to respond differently. Did any of your patients have obsessive-compulsive behavior?

Dr. Fontaine: No, we excluded such patients. But you Dr. Penry: Over the long term did any of these individuals

concerned. In the other case, the patient became a little euphoric, but hardly hypomanic. She would not buy excessively or spend a lot of time on the phone, but she was feeling good and relieved from all the situations that she was afraid of and I sensed that it was a little bit too much. As I followed her, however, she always reassured me that she was doing very well on the medication and that I should not be concerned. She was not getting into any trouble and was doing well on her job. After a few months of treatment, she slowly came back to a more normal state according to both her own report and that of her husband.

have raised a very interesting issue. As you know, with children imipramine has been used more and more in school phobia or in those who have separation anxiety. It would be interesting to see how clonazepam works in these patients. If you look at other psychotropic drugs that are given to children, clonazepam is much less toxic than most. In terms of behavioral complications, we should not lose sight of the fact that most of our panic disorder patients have been sick for several years, and by the time we see them they usually have developed numerous problems secondary to their disorder-problems with drug abuse, losing theirjobs, often being in trouble in their family, avoiding most social activities, and so on. So the treatment of these patients should begin as early as possible in order not to give the complications a chance to set in. And it is possible that general practitioners will be more comfortable using a benzadiazepine to treat these people as compared with an antidepressant with outpatients, for example, where the risk of overdose is always present.

Dr. Chouinard: I think the most striking thing we have

Dr. Penry: Did you discover any drug interactions during

found is that the paradoxical behavioral reactions reported in children when clonazepam is used as an antiepileptic agent hardly exist when it is used in adults for psychiatric disorders. It is well known that some drugs have a paradoxical effect in children. Methylphenidate, for example, which is usually a stimulant in adults, may paradoxically help hyperactive children.

the treatment period of three to 12 months?

develop any new behavior disorders on chronic therapy, such as sudden changes in mood or ability to conform?

Dr. Fontaine: There were two cases in which we didn't know if the patient was a little euphoric. When we asked the husband ofone patient what was happening, he said that she

had been like this at times premorbidly, so we were not too

Dr. Penry: Ofcourse, drugs may act differently in different

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Dr. Fontaine: None of clinical relevance.

REFERENCES 1. Mavissakalian M. Perel J: Imipramine in the treatment of agoraphobia: Dose-response relationships. Am J Psychiatry 142: 1032-1 036. 1985. 2. Greenblatt OJ. Shader RI: Clinical pharmacokinetics of the benzodiazepines. in Smith DE, Wesson DR (eds): The Benzodiazepines: Current Standards for Medical Practice. Lancaster, England. MTP Press. 1985. pp43-58.

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