# 2004 Taylor & Francis
International Journal of Psychiatry in Clinical Practice 2004
Volume 8
Pages 127 /129 127
Case Report
Int J Psych Clin Pract Downloaded from informahealthcare.com by Universitat de Girona on 10/27/14 For personal use only.
Recurrent, persisting panic attacks after sudden discontinuation of mirtazapine treatment: A case report PIERRE-ANDRE´ FAUCHE`RE Clinique Romande de Re´adaptation, Sion, Switzerland
Correspondence Address Pierre-Andre´ Fauche`re, Clinique Romande de Re´adaptation, Av. Grand Champsec 90, CH1951 Sion, Switzerland Tel: /(41) 27 603 3030 Fax: /(41) 27 603 3031 E-mail: [email protected]
A 53-year-old woman with depressive symptoms and sleep problems, diagnosed as adjustment disorder with depressive reaction (ICD-10, F43.2), was treated with mirtazapine at a dose of 30 mg/day for a period of 10 weeks. In view of an imminent surgical intervention, the medication was than abruptly stopped. On the second day after discontinuation of mirtazapine, the patient developed a typical panic attack crisis with symptoms of palpitations, dyspnoea, retro-sternal pain, dizziness and nausea, blurred vision, anguish and fear of dying. During the next 5 days the patient suffered from severe, similar attacks recurring every 1 2 h, with each attack lasting about 20 min. Upon hospitalization and minor surgical intervention, the frequency and severity of symptoms regressed progressively, but the patient remained, with about one attack per week, not symptom free until the restitution of mirtazapine treatment at a dose of 30 mg/day. After re-introduction of mirtazapine panic attacks vanished, and during the entire follow-up period the patient remained symptom free. This case illustrates the risk of abrupt withdrawal of mirtazapine and indicates that, even after a medium-long therapy (10 weeks) with mirtazapine, progressive tapering-off of medication is advisable. (Int J Psych Clin Pract 2004; 8: 127 129)
/
/
Received 9 April 2003; accepted for publication 19 February 2004
Keywords recurrent sudden discontinuation of mirtazapine treatment
INTRODUCTION
M
irtazapine is a representative of a new class (NASSA) of antidepressant drugs (AD) that originates from a research of a conceptually novel approach to the treatment of depression. By the virtue of a direct and combined, specific action on a-adrenergic (a2-presynaptic) and 5-HT ( 5-HT2, 5-HT3) receptors mirtazapine promotes noradrenaline (NA) release and enhances serotoninergic transmission in the brain. Large, international, controlled clinical studies have demonstrated its clinical efficacy and, by comparison to conventional AD, clearly improved safety. Few cases of withdrawal reactions were, however, reported after disconti-
persisting panic attacks case report
nuation of mirtazapine treatment,1,2 among which was also one case with panic attacks.3 We wish to report here another case of persisting, recurrent panic attacks, which developed after sudden discontinuation of mirtazapine in a patient with no previous own or family history of anxiety disorders.
CASE REPORT The patient was a 53-year-old woman of Portuguese origin, married and having two adult children. She was admitted to the re-adaptation hospital for the rehabilitation of her right
DOI: 10.1080/13651500410006134
Int J Psych Clin Pract Downloaded from informahealthcare.com by Universitat de Girona on 10/27/14 For personal use only.
128
P-A Fauche`re
arm, which was fractured after an accident at home about 2 months prior to the admission. Upon routine psychiatric examination, the patient presented symptoms of moderately severe depression and prominent sleep problems. In her history, except brief depressive reaction after the death of her father when she was 18 years old, there were no particularities. She claimed to have been always in a good health until the accident at her home and the fracture of her arm complicated by a lesion of the distal part of the brachial plexus. The anamnesis revealed no psychiatric problems in her family history either. The patient was diagnosed as adjustment disorder with depressive reaction (F 43.2) according to the ICD.10 classification and prescribed mirtazapine at a dose of 30 mg once daily. Bromazepam 1.5. mg/day, which she received for several weeks already, was kept as concomitant medication. During the 5 weeks of her hospitalization the patient recovered well and the depressive symptoms regressed favourably. She was discharged from the hospital with the maintenance medication including mirtazapine 30 mg/day and oxazepam 15 mg/day. The otherwise very compliant patient stopped taking oxazepam after consultation with her treating physician about 10 days thereafter without any problem. One month later (10 weeks after the start of the mirtazapine treatment) she stopped taking mirtazapine in view of an imminent minor surgical intervention on her arm and anaesthesia. Two days thereafter the patient developed a typical panic attack crisis with symptoms of anguish and fear of dying, dyspnoea, retro-sternal constriction, palpitations, blurred vision, dizziness and nausea. The attacks lasted about 20 min and recurred in intervals of about 1 /2 h for the next 5 days, when she was hospitalized. During the time interval between the onset of symptoms and hospitalization she was prescribed flurazepam 20 mg/nocte and probably another benzodiazepine as reserve medication. During the period of hospitalization and the following surgical intervention (revision of the brachial plexus) the symptoms ameliorated with progressive regression of the severity and frequency of panic attacks. Although the patient was not entirely symptom free she did not receive any particular treatment for her panic attacks and was discharged from hospital with flurazepam at a dose of 15 mg in the evening as only psychotropic medication. In the period following the discharge from the hospital, the patient experienced recurrent panic attacks, which were, however, somewhat less severe and less frequent (one to two per week) than initially. Nevertheless, she slowly developed an anticipatory anxiety and presented herself for psychiatric consultation 18 days later, when mirtazapine 30 mg once daily was re-introduced into the therapy. Flurazepam 30 mg/nocte was prescribed as reserve medication. Following the re-introduction of mirtazapine the patient experienced another four attacks, but there were no further panic episodes thereafter. The patient, still kept on the maintenance therapy with mirtazapine because
of the residual depressive symptomatology, is free of any anxiety symptoms since that time.
DISCUSSION To the best of our knowledge only one case of panic attacks after sudden discontinuation of mirtazapine has been reported in the literature until now.3 However, this case, described by Klesmer et al, differed from the case we report here in that the treatment with mirtazapine lasted several years prior to the abrupt stop of the therapy. Also, since mirtazapine was re-introduced to the therapy of this patient shortly after the onset of the panic attack symptoms, the possible evolution of the withdrawal pathology remains unknown. In our case the duration of therapy with mirtazapine was less than 3 months, therefore the treatment could be considered as a still short-term therapy. Another interesting aspect of our case is the persistence of the withdrawal reaction. The patient has experienced recurrent episodes of panic attacks over a period of few months, even though anxiety features or pre- disposing factors suggesting latent panic disorder or anxiety could not be identified in either patient’ s own or family history. As in the case of Klesmer et al , the fact that the re-introduction of mirtazapine therapy led to complete resolution of the panic attacks and anticipatory anxiety suggests that the whole pathology has been provoked solely by mirtazapine withdrawal. The underlying mechanism of this withdrawal reaction is unclear. Generally, dysregulation of noradrenergic and serotoninergic systems has been implicated in the origin of panic disorder. Mirtazapine is a drug with a direct action on various receptors, with major agonistic effects on presynaptic, a2-adrenergic and antagonistic effects on serotoninergic 5-HT2 and 5-HT3 receptors. Without doubt, the repeated treatment with mirtazapine produces changes in the density and affinity of these receptors and, thus, decreased or increased reactivity of the systems to the incoming internal and external stimuli. It is therefore possible that the acute withdrawal from mirtazapine results in an inbalance of the regulatory, inhibitory and excitatory control of l. coeruleus (noradrenergic) and median raphe´ (serotoninergic) neurons, which are considered responsible for the mediation of anxiety symptoms. Whatever the underlying mechanism of the panic disorder resulting from the abrupt discontinuation of mirtazapine treatment might be, our and already reported cases of hypomania,1 serotonin syndrome-like symptoms including anxiety2 and panic attack,3 indicate, that progressive tapering-off of mirtazapine treatment is necessary even after rather short-lasting treatment. At present, however, the guidelines for the rate of discontinuation to be adopted in the practice do not exist.
Sudden discontinuation of mirtazapine
Int J Psych Clin Pract Downloaded from informahealthcare.com by Universitat de Girona on 10/27/14 For personal use only.
CONCLUSION
129
KEY POINTS
Few cases of withdrawal reactions, including one case of a panic attack, have been already reported in the literature. Our case of persisting, recurrent panic attacks which developed after abrupt discontinuation of rather short-term (10 weeks) mirtazapine treatment, further illustrates the risks of the sudden stop of mirtazapine therapy. The withdrawal reactions probably result from a disbalance of noradrenergic and serotoninergic transmission, caused by treatment-induced receptor sensitivity changes. However, irrespective of the underlying mechanism of the undesired pathological reactions, our and other cases suggest that abrupt withdrawal from mirtazapine treatment is risky and should be avoided.
. Mirtazapine is a new generation antidepressant with confirmed clinical efficacy and generally improved safety in comparison to conventional antidepressants . However, a few cases of withdrawal reactions of various type after sudden discontinuation of mirtazapine treatment have been reported recently, suggesting that caution is needed if therapy with mirtazapine has to be stopped . The case of persisting recurrent panic attacks after rather short-term treatment with mirtazapine further illustrates the risks of abrupt discontinuation of treatment with this antidepressant . The guidelines for the discontinuation rate to be adopted in practice do not, however, exist at present. In any case, abrupt withdrawal from therapy with mirtazapine should be avoided
ACKNOWLEDGEMENTS Thanks for advice to Prof. Dr. A. Delini-Stula, ADI International Institute for Advancement of Drug Development Ltd, Mittlerestrasse 2, CH-4056 Basle, Switzerland.
REFERENCES 1. 2.
McCall C, Callender J (1999) Mirtazapine withdrawal causing hypomania. Br J Psychiatry 175: 390. Benazzi F (1998) Mirtazapine withdrawal symptoms. Can J Psychiatry 43: 525.
3.
Klesmer J, Sarcevic A, Fomari V (2000) Panic attacks during discontinuation of mirtazapine. Can J Psychiatry 45: 570.
International Journal of Psychiatry in Clinical Practice 2004
Volume 8
Pages 127 /129 127
Case Report
Int J Psych Clin Pract Downloaded from informahealthcare.com by Universitat de Girona on 10/27/14 For personal use only.
Recurrent, persisting panic attacks after sudden discontinuation of mirtazapine treatment: A case report PIERRE-ANDRE´ FAUCHE`RE Clinique Romande de Re´adaptation, Sion, Switzerland
Correspondence Address Pierre-Andre´ Fauche`re, Clinique Romande de Re´adaptation, Av. Grand Champsec 90, CH1951 Sion, Switzerland Tel: /(41) 27 603 3030 Fax: /(41) 27 603 3031 E-mail: [email protected]
A 53-year-old woman with depressive symptoms and sleep problems, diagnosed as adjustment disorder with depressive reaction (ICD-10, F43.2), was treated with mirtazapine at a dose of 30 mg/day for a period of 10 weeks. In view of an imminent surgical intervention, the medication was than abruptly stopped. On the second day after discontinuation of mirtazapine, the patient developed a typical panic attack crisis with symptoms of palpitations, dyspnoea, retro-sternal pain, dizziness and nausea, blurred vision, anguish and fear of dying. During the next 5 days the patient suffered from severe, similar attacks recurring every 1 2 h, with each attack lasting about 20 min. Upon hospitalization and minor surgical intervention, the frequency and severity of symptoms regressed progressively, but the patient remained, with about one attack per week, not symptom free until the restitution of mirtazapine treatment at a dose of 30 mg/day. After re-introduction of mirtazapine panic attacks vanished, and during the entire follow-up period the patient remained symptom free. This case illustrates the risk of abrupt withdrawal of mirtazapine and indicates that, even after a medium-long therapy (10 weeks) with mirtazapine, progressive tapering-off of medication is advisable. (Int J Psych Clin Pract 2004; 8: 127 129)
/
/
Received 9 April 2003; accepted for publication 19 February 2004
Keywords recurrent sudden discontinuation of mirtazapine treatment
INTRODUCTION
M
irtazapine is a representative of a new class (NASSA) of antidepressant drugs (AD) that originates from a research of a conceptually novel approach to the treatment of depression. By the virtue of a direct and combined, specific action on a-adrenergic (a2-presynaptic) and 5-HT ( 5-HT2, 5-HT3) receptors mirtazapine promotes noradrenaline (NA) release and enhances serotoninergic transmission in the brain. Large, international, controlled clinical studies have demonstrated its clinical efficacy and, by comparison to conventional AD, clearly improved safety. Few cases of withdrawal reactions were, however, reported after disconti-
persisting panic attacks case report
nuation of mirtazapine treatment,1,2 among which was also one case with panic attacks.3 We wish to report here another case of persisting, recurrent panic attacks, which developed after sudden discontinuation of mirtazapine in a patient with no previous own or family history of anxiety disorders.
CASE REPORT The patient was a 53-year-old woman of Portuguese origin, married and having two adult children. She was admitted to the re-adaptation hospital for the rehabilitation of her right
DOI: 10.1080/13651500410006134
Int J Psych Clin Pract Downloaded from informahealthcare.com by Universitat de Girona on 10/27/14 For personal use only.
128
P-A Fauche`re
arm, which was fractured after an accident at home about 2 months prior to the admission. Upon routine psychiatric examination, the patient presented symptoms of moderately severe depression and prominent sleep problems. In her history, except brief depressive reaction after the death of her father when she was 18 years old, there were no particularities. She claimed to have been always in a good health until the accident at her home and the fracture of her arm complicated by a lesion of the distal part of the brachial plexus. The anamnesis revealed no psychiatric problems in her family history either. The patient was diagnosed as adjustment disorder with depressive reaction (F 43.2) according to the ICD.10 classification and prescribed mirtazapine at a dose of 30 mg once daily. Bromazepam 1.5. mg/day, which she received for several weeks already, was kept as concomitant medication. During the 5 weeks of her hospitalization the patient recovered well and the depressive symptoms regressed favourably. She was discharged from the hospital with the maintenance medication including mirtazapine 30 mg/day and oxazepam 15 mg/day. The otherwise very compliant patient stopped taking oxazepam after consultation with her treating physician about 10 days thereafter without any problem. One month later (10 weeks after the start of the mirtazapine treatment) she stopped taking mirtazapine in view of an imminent minor surgical intervention on her arm and anaesthesia. Two days thereafter the patient developed a typical panic attack crisis with symptoms of anguish and fear of dying, dyspnoea, retro-sternal constriction, palpitations, blurred vision, dizziness and nausea. The attacks lasted about 20 min and recurred in intervals of about 1 /2 h for the next 5 days, when she was hospitalized. During the time interval between the onset of symptoms and hospitalization she was prescribed flurazepam 20 mg/nocte and probably another benzodiazepine as reserve medication. During the period of hospitalization and the following surgical intervention (revision of the brachial plexus) the symptoms ameliorated with progressive regression of the severity and frequency of panic attacks. Although the patient was not entirely symptom free she did not receive any particular treatment for her panic attacks and was discharged from hospital with flurazepam at a dose of 15 mg in the evening as only psychotropic medication. In the period following the discharge from the hospital, the patient experienced recurrent panic attacks, which were, however, somewhat less severe and less frequent (one to two per week) than initially. Nevertheless, she slowly developed an anticipatory anxiety and presented herself for psychiatric consultation 18 days later, when mirtazapine 30 mg once daily was re-introduced into the therapy. Flurazepam 30 mg/nocte was prescribed as reserve medication. Following the re-introduction of mirtazapine the patient experienced another four attacks, but there were no further panic episodes thereafter. The patient, still kept on the maintenance therapy with mirtazapine because
of the residual depressive symptomatology, is free of any anxiety symptoms since that time.
DISCUSSION To the best of our knowledge only one case of panic attacks after sudden discontinuation of mirtazapine has been reported in the literature until now.3 However, this case, described by Klesmer et al, differed from the case we report here in that the treatment with mirtazapine lasted several years prior to the abrupt stop of the therapy. Also, since mirtazapine was re-introduced to the therapy of this patient shortly after the onset of the panic attack symptoms, the possible evolution of the withdrawal pathology remains unknown. In our case the duration of therapy with mirtazapine was less than 3 months, therefore the treatment could be considered as a still short-term therapy. Another interesting aspect of our case is the persistence of the withdrawal reaction. The patient has experienced recurrent episodes of panic attacks over a period of few months, even though anxiety features or pre- disposing factors suggesting latent panic disorder or anxiety could not be identified in either patient’ s own or family history. As in the case of Klesmer et al , the fact that the re-introduction of mirtazapine therapy led to complete resolution of the panic attacks and anticipatory anxiety suggests that the whole pathology has been provoked solely by mirtazapine withdrawal. The underlying mechanism of this withdrawal reaction is unclear. Generally, dysregulation of noradrenergic and serotoninergic systems has been implicated in the origin of panic disorder. Mirtazapine is a drug with a direct action on various receptors, with major agonistic effects on presynaptic, a2-adrenergic and antagonistic effects on serotoninergic 5-HT2 and 5-HT3 receptors. Without doubt, the repeated treatment with mirtazapine produces changes in the density and affinity of these receptors and, thus, decreased or increased reactivity of the systems to the incoming internal and external stimuli. It is therefore possible that the acute withdrawal from mirtazapine results in an inbalance of the regulatory, inhibitory and excitatory control of l. coeruleus (noradrenergic) and median raphe´ (serotoninergic) neurons, which are considered responsible for the mediation of anxiety symptoms. Whatever the underlying mechanism of the panic disorder resulting from the abrupt discontinuation of mirtazapine treatment might be, our and already reported cases of hypomania,1 serotonin syndrome-like symptoms including anxiety2 and panic attack,3 indicate, that progressive tapering-off of mirtazapine treatment is necessary even after rather short-lasting treatment. At present, however, the guidelines for the rate of discontinuation to be adopted in the practice do not exist.
Sudden discontinuation of mirtazapine
Int J Psych Clin Pract Downloaded from informahealthcare.com by Universitat de Girona on 10/27/14 For personal use only.
CONCLUSION
129
KEY POINTS
Few cases of withdrawal reactions, including one case of a panic attack, have been already reported in the literature. Our case of persisting, recurrent panic attacks which developed after abrupt discontinuation of rather short-term (10 weeks) mirtazapine treatment, further illustrates the risks of the sudden stop of mirtazapine therapy. The withdrawal reactions probably result from a disbalance of noradrenergic and serotoninergic transmission, caused by treatment-induced receptor sensitivity changes. However, irrespective of the underlying mechanism of the undesired pathological reactions, our and other cases suggest that abrupt withdrawal from mirtazapine treatment is risky and should be avoided.
. Mirtazapine is a new generation antidepressant with confirmed clinical efficacy and generally improved safety in comparison to conventional antidepressants . However, a few cases of withdrawal reactions of various type after sudden discontinuation of mirtazapine treatment have been reported recently, suggesting that caution is needed if therapy with mirtazapine has to be stopped . The case of persisting recurrent panic attacks after rather short-term treatment with mirtazapine further illustrates the risks of abrupt discontinuation of treatment with this antidepressant . The guidelines for the discontinuation rate to be adopted in practice do not, however, exist at present. In any case, abrupt withdrawal from therapy with mirtazapine should be avoided
ACKNOWLEDGEMENTS Thanks for advice to Prof. Dr. A. Delini-Stula, ADI International Institute for Advancement of Drug Development Ltd, Mittlerestrasse 2, CH-4056 Basle, Switzerland.
REFERENCES 1. 2.
McCall C, Callender J (1999) Mirtazapine withdrawal causing hypomania. Br J Psychiatry 175: 390. Benazzi F (1998) Mirtazapine withdrawal symptoms. Can J Psychiatry 43: 525.
3.
Klesmer J, Sarcevic A, Fomari V (2000) Panic attacks during discontinuation of mirtazapine. Can J Psychiatry 45: 570.
