Flumazenil Provocation of Panic Attacks Evidence for Altered
Benzodiazepine
Receptor Sensitivity in David J.
Panic Disorder
Nutt, DM, MRCP, MRCPsych; Paul Glue, MRCPsych; Chris Lawson, MRCPsych; Sue Wilson
\s=b\ The possibility that panic disorder might be due to abnormal activity of endogenous ligands of the benzodiazepine receptor was investigated with the use of the benzodiazepine antagonist flumazenil. Physiological and subjective psychological responses to this selective antagonist were measured in 10 patients with panic disorder and in 10 control subjects, by using a placebocontrolled crossover study design. Subjective anxiety responses after flumazenil infusion were significantly higher in the patient group with panic disorder than in the controls, and eight patients with panic disorder but no controls had panic attacks. This anxiogenic effect of flumazenil in the patients argues against the presence of endogenous anxiogenic (inverse agonist) ligands. Possible explanations include the differential production of an anxiolytic endogenous ligand or an altered benzodiazepine receptor "set-point." Such an abnormality may contribute to the pathogenesis of panic disorder. (Arch Gen Psychiatry. 1990;47:917-925)
Benzodiazepianxiety. nes They
well-established drugs in the treat¬ have an immediate therapeutic effect in anticipatory and in generalized anxiety." In high doses, they are also effective in treating panic disorder,6"8 although higher potency benzodiazepines, such as alprazo¬ lam, may be more efficacious in this condition.5,9 These drugs act at specific high-affinity receptors in the brain that are associated with 7-aminobutyric acid- (GABA-A) recep¬ tors.10,11 The benzodiazepine receptor has unique pharmaco¬ logical properties, in that it is acted on in a distinct way by three classes of ligands (for reviews, see Petersen,12 Haefely,13 Haefely et al,14 Braestrup et al,15 and Nutt16). Agonists (eg, diazepam) facilitate the inhibitory effects of GABA, re¬ sulting in their sedative, anxiolytic, and anticonvulsant ef¬ fects. The second class of ligands are called inverse agonists (eg, the ß-carboline FG 7142), and these produce opposite effects to the agonists, such as increased anxiety and arousal in humans.17,1S The third class are the antagonists (eg, fluma¬ zenil [Ro 15-1788])19,20 that block the effects of both agonists and inverse agonists, but that have few intrinsic effects are
ment of
themselves.21
It is possible that abnormalities of benzodiazepine receptor function may underlie anxiety disorders. There are three Accepted for publication June 28,1990. From the Reckitt & Colman Psychopharmacology Unit, School of Medical Sciences, Bristol, United Kingdom. Reprint requests to Reckitt & Colman Psychopharmacology Unit, School of Medical Sciences, University Walk, Bristol BS8 1TD, United Kingdom (Dr Nutt).
competing hypotheses: the first is that anxious patients may have an overproduction of an endogenous inverse agonist. Several candidates have been suggested, with the two most plausible being diazepam-binding inhibitor22 or its metabo¬ lite,23 and tribulin.24,25 The second possibility is that there is a functional deficit of an endogenous agonist. This could be an as yet unidentified substance, or a benzodiazepine, since com¬ pounds such as diazepam and desmethyldiazepam26"28 have been discovered in benzodiazepine-naive human brain. The third possibility is that the coupling between the benzodiaze¬ pine receptor and the GABA-A receptor is abnormal so that there is reduced GABA function. Such a shift in receptor function has been demonstrated by preclinical studies of ani¬ mals in benzodiazepine withdrawal.29^2 These reveal reduced efficacy of benzodiazepine agonists, increased efficacy of in¬ verse agonists, and the emergence of partial inverse agonist actions for antagonists, such as flumazenil and ZK 93426. It has been suggested that many if not all of the symptoms of clinical withdrawal from benzodiazepines could be due to such a shift and the consequential reduction of GABA-mediated inhibition.29^2 Anxiety, both somatic and psychological, is commonly seen in benzodiazepine withdrawal,29,33"36 as would be expected if GABA function was reduced. The present study set out to test these hypotheses by the administration of the antagonist flumazenil to patients with a discrete form of anxiety, panic disorder. We hypothesized that if anxiety was due to the presence of an endogenous inverse agonist, flumazenil should be anxiolytic in patients and neutral in controls. If the anxiety disorders were due to a deficit of an endogenous anxiolytic, then flumazenil should be anxiogenic in both patients with panic disorder and control subjects. If the receptor shift hypothesis was correct, then flumazenil should behave like an inverse agonist in anxious patients and as an inert antagonist in control subjects. SUBJECTS AND METHODS
Subjects Ten healthy volunteers and 10 patients with panic disorder or panic disorder with agoraphobia (DSM-III-R, American Psychiatric Asso¬ ciation, 1987) who were attending general psychiatric outpatient clinics were recruited. All subjects gave informed consent to the study, which was approved by the district ethical committee. All subjects had been completely benzodiazepine free for at least 3 months at the time of testing, and none had any regular use of these drugs in the past, with six being benzodiazepine naive. All subjects were free of other psychotropic medication for 3 weeks, and three had never had any. Before entering the study, all subjects were compre¬ hensively screened to ensure physical fitness. Nine patients and controls were age and sex matched; one pair was age matched only. Subjects were told of the nature of the project and that an attempt was being made to understand what, if any contribution, benzodiaze-
Downloaded From: http://archpsyc.jamanetwork.com/ by a New York University User on 05/27/2015
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80
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70
Sleepiness
60
Anxiety
60 50
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30
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10
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Benzodiazepine
Receptor Sensitivity in David J.
Panic Disorder
Nutt, DM, MRCP, MRCPsych; Paul Glue, MRCPsych; Chris Lawson, MRCPsych; Sue Wilson
\s=b\ The possibility that panic disorder might be due to abnormal activity of endogenous ligands of the benzodiazepine receptor was investigated with the use of the benzodiazepine antagonist flumazenil. Physiological and subjective psychological responses to this selective antagonist were measured in 10 patients with panic disorder and in 10 control subjects, by using a placebocontrolled crossover study design. Subjective anxiety responses after flumazenil infusion were significantly higher in the patient group with panic disorder than in the controls, and eight patients with panic disorder but no controls had panic attacks. This anxiogenic effect of flumazenil in the patients argues against the presence of endogenous anxiogenic (inverse agonist) ligands. Possible explanations include the differential production of an anxiolytic endogenous ligand or an altered benzodiazepine receptor "set-point." Such an abnormality may contribute to the pathogenesis of panic disorder. (Arch Gen Psychiatry. 1990;47:917-925)
Benzodiazepianxiety. nes They
well-established drugs in the treat¬ have an immediate therapeutic effect in anticipatory and in generalized anxiety." In high doses, they are also effective in treating panic disorder,6"8 although higher potency benzodiazepines, such as alprazo¬ lam, may be more efficacious in this condition.5,9 These drugs act at specific high-affinity receptors in the brain that are associated with 7-aminobutyric acid- (GABA-A) recep¬ tors.10,11 The benzodiazepine receptor has unique pharmaco¬ logical properties, in that it is acted on in a distinct way by three classes of ligands (for reviews, see Petersen,12 Haefely,13 Haefely et al,14 Braestrup et al,15 and Nutt16). Agonists (eg, diazepam) facilitate the inhibitory effects of GABA, re¬ sulting in their sedative, anxiolytic, and anticonvulsant ef¬ fects. The second class of ligands are called inverse agonists (eg, the ß-carboline FG 7142), and these produce opposite effects to the agonists, such as increased anxiety and arousal in humans.17,1S The third class are the antagonists (eg, fluma¬ zenil [Ro 15-1788])19,20 that block the effects of both agonists and inverse agonists, but that have few intrinsic effects are
ment of
themselves.21
It is possible that abnormalities of benzodiazepine receptor function may underlie anxiety disorders. There are three Accepted for publication June 28,1990. From the Reckitt & Colman Psychopharmacology Unit, School of Medical Sciences, Bristol, United Kingdom. Reprint requests to Reckitt & Colman Psychopharmacology Unit, School of Medical Sciences, University Walk, Bristol BS8 1TD, United Kingdom (Dr Nutt).
competing hypotheses: the first is that anxious patients may have an overproduction of an endogenous inverse agonist. Several candidates have been suggested, with the two most plausible being diazepam-binding inhibitor22 or its metabo¬ lite,23 and tribulin.24,25 The second possibility is that there is a functional deficit of an endogenous agonist. This could be an as yet unidentified substance, or a benzodiazepine, since com¬ pounds such as diazepam and desmethyldiazepam26"28 have been discovered in benzodiazepine-naive human brain. The third possibility is that the coupling between the benzodiaze¬ pine receptor and the GABA-A receptor is abnormal so that there is reduced GABA function. Such a shift in receptor function has been demonstrated by preclinical studies of ani¬ mals in benzodiazepine withdrawal.29^2 These reveal reduced efficacy of benzodiazepine agonists, increased efficacy of in¬ verse agonists, and the emergence of partial inverse agonist actions for antagonists, such as flumazenil and ZK 93426. It has been suggested that many if not all of the symptoms of clinical withdrawal from benzodiazepines could be due to such a shift and the consequential reduction of GABA-mediated inhibition.29^2 Anxiety, both somatic and psychological, is commonly seen in benzodiazepine withdrawal,29,33"36 as would be expected if GABA function was reduced. The present study set out to test these hypotheses by the administration of the antagonist flumazenil to patients with a discrete form of anxiety, panic disorder. We hypothesized that if anxiety was due to the presence of an endogenous inverse agonist, flumazenil should be anxiolytic in patients and neutral in controls. If the anxiety disorders were due to a deficit of an endogenous anxiolytic, then flumazenil should be anxiogenic in both patients with panic disorder and control subjects. If the receptor shift hypothesis was correct, then flumazenil should behave like an inverse agonist in anxious patients and as an inert antagonist in control subjects. SUBJECTS AND METHODS
Subjects Ten healthy volunteers and 10 patients with panic disorder or panic disorder with agoraphobia (DSM-III-R, American Psychiatric Asso¬ ciation, 1987) who were attending general psychiatric outpatient clinics were recruited. All subjects gave informed consent to the study, which was approved by the district ethical committee. All subjects had been completely benzodiazepine free for at least 3 months at the time of testing, and none had any regular use of these drugs in the past, with six being benzodiazepine naive. All subjects were free of other psychotropic medication for 3 weeks, and three had never had any. Before entering the study, all subjects were compre¬ hensively screened to ensure physical fitness. Nine patients and controls were age and sex matched; one pair was age matched only. Subjects were told of the nature of the project and that an attempt was being made to understand what, if any contribution, benzodiaze-
Downloaded From: http://archpsyc.jamanetwork.com/ by a New York University User on 05/27/2015
80
80
70
70
Sleepiness
60
Anxiety
60 50
50
40
40
30
30
20
20
10
10
0
o
-10
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-I
-10 -J
- — -1— — — — — — — — — — — — — — — — — —I 25 30 35 40 45 50 20 10 15 0 5
Time, min
Time, min 10·
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-20
50-
Alertness
-30
40
-40
30-
-50
20
-60
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-70
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5
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15
20
25
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40
45
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Time, min
Time, min 80
80
70
701 Gastrointestinal Symptoms
60
— — — — — — — — — — —I— — —'—I 20 25 30 35 40 45 50 15
Tachycardia
60
50
50
40
40
30
30-
20
20-
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— — — —
