International Journal of Psychiatry in Clinical Practice, 2007; 11(1): 76 78
CASE REPORT
Panic attacks after treatment with zuclopenthixol decanoate
ANIL SRIVASTAVA & JORGE SONI Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
Abstract The association between neuroleptics and anxiety is unclear: neuroleptics have been used to treat anxiety though may also themselves be anxiogenic. We present the case of a man who developed new onset panic attacks after treatment with zuclopenthixol decanoate, a commonly administered depot antipsychotic. We review the literature on the association between antipsychotics and anxiety and present possible pathophysiological mechanisms.
Key Words: Anxiety, panic attacks, zuclopenthixol decanoate, neuroleptics, antipsychotics
Introduction It is suggested that the pharamacotherapy of panic disorder involves, as first line treatment, SSRIs, often modified with the use of benzodiazepines [1]. The use of antipsychotics in panic attacks or disorder is more controversial and is not at present considered part of standard treatment. Indeed, the association between neuroleptics and anxiety is unclear: while some clinicians report that they are anxiolytic, others have reported the opposite. For instance, Takahashi et al. [2] reported on three cases of people with schizophrenia, one of whose panic attacks resolved after switching from risperidone (10 mg daily) to quetiapine, though Takahashi et al. [3] reported a patient with schizophrenia who experienced a cessation of panic attacks after switching to risperidone (3 mg daily) from haloperidol. There has been a report of new-onset panic attacks associated with the introduction of olanzapine (15 mg daily) [4] but, by contrast, a report on two cases of treatmentrefractory panic attacks suggested that starting olanzapine (between 10 and 12.5 mg daily) was of benefit [5], as it was in a woman with schizophrenia who experienced new onset panic attacks 20 weeks after being started on clozapine (400 mg daily) [6]. Dose may be of importance given Higuchi et al.’s [7] finding that there was a non-statistically significant trend towards higher chloropromazine-equivalent doses of neuroleptics among those who had schizophrenia and panic attacks compared to those with schizophrenia but without panic attacks. We present here the case of a man who developed new-onset
panic attacks following the introduction of a commonly administered depot antipsychotic and we review possible mechanisms. Case report A 70-year-old man with a discharge diagnosis of ‘Psychosis Not Otherwise Specified’ had been maintained successfully on trifluoperazine for many years, at a daily dose between 2.5 and 5 mg. He arrived at our hospital following an assault on his neighbours which was thought to be psychotically driven. Approximately 1 month prior to our seeing the patient in July 2004 he had been started on 100 mg of zuclopenthixol decanoate biweekly because of non-adherence with his trifluoperazine; he was on no other psychotropic medications. The patient noted that soon after starting this medication he began to experience panic attacks characterized by shortness of breath, a feeling of losing control including an inability to speak, tachycardia, diaphoresis, and a feeling of urinary urgency, with occasional incontinence, all lasting about a minute. Extensive medical investigation was conducted. An EKG suggested left ventricular hypertrophy, and a subsequent echocardiogram revealed a Grade IV left ventricle. However, he reported no other symptoms, including orthopnea or shortness of breath on exertion, which would suggest that this was anything other than an incidental finding. He was started on a number of cardiovascular medications, including carvedilol 3.125 mg b.i.d, ramipril 2.5 mg o.d.,
Correspondence: Anil Srivastava, Department of Psychiatry, University of Toronto, 250 College St., Toronto, Ontario, Canada M5T 1R8. Tel: /1 416 535 8501. E-mail: [email protected]
(Received 15 October 2005; accepted 29 March 2006) ISSN 1365-1501 print/ISSN 1471-1788 online # 2007 Taylor & Francis DOI: 10.1080/13651500600811446
Panic attacks after treatment with zuclopenthixol decanoate and aspirin 81 mg o.d. Because of his complaints of urinary urgency during these attacks, urinalysis was performed which was negative for infection or other abnormalities; a pelvic ultrasound did reveal mild prostatic hypertrophy, though a post-void residual was unremarkable. The patient had preexisting diabetes mellitus, but during the times of his attacks, his blood glucose had always been within the normal range. In short, his medical history was felt to be non-contributory to his new-onset panic attacks. Because of the episodic nature of the symptoms, and their quick onset and relatively rapid dissolution, consideration to panic attacks, rather than generalized anxiety, was felt to be appropriate. He had no complaints of pain or other somatic symptoms between episodes; the onset of a somatoform disorder therefore seemed unlikely. Although the patient remained frustrated at times by his continued stay in hospital, there was no evidence of a particularly depressed or irritable mood. Indeed, with respect to psychiatric symptoms no abnormalities were noted during his stay other than the above anxiety. Discussion Serotonin has been implicated in panic disorder: current thought centres on the role of serotonin in inhibiting the locus coeruleus, a source of norepinephrine [8], where this latter neurotransmitter is involved in many of the typical symptoms of panic attacks such as tachycardia [9]. Serotonin may also be involved in regulation of the periaqueductal grey region [10] and in the modulation of inhibition to the amygdala [11], both implicated in anxiety. Neuroleptics both atypicals and typicals may block serotonin receptors [12]. Dopamine has also been implicated. For example, a study that examined plasma homovanillic acid levels, a metabolite of dopamine that is believed to reflect central levels, noted that they were significantly lower among the 22 with panic disorder compared with 18 controls [13]. As all effective antipsychotics act on dopamine receptors, such a finding suggests that antipsychoticinduced blockade of dopamine may modulate anxiety. The nigrostriatal pathway may be involved. In a study that examined the relationship between Parkinson’s disease and panic attacks it was observed that panic attacks were exclusively present during periods where motor function was impaired and that after the ingestion of a new dose of levodopa, panic attack symptoms disappeared; the authors suggested that a lack of striatal dopamine could lead to disinhibition of the locus coeruleus and thereby precipitate panic attacks [14]. Takahashi et al. [2] postulated that quetiapine was effective in ameliorating panic attacks because of its transient, versus prolonged, D2 receptor occupancy; if this were the case though, the same should be true of clozapine
77
given its transient D2 occupancy [15], though it too has been associated with panic attacks [6]. The presence of extrapyramidal symptoms suggests a high degree of dopamine receptor occupancy [16]; in the case above, no such symptoms or signs were noted. Neuroleptics have been implicated previously in panic attacks; this is the first reported association with zuclopenthixol decanoate, a commonly administered depot antipsychotic. It does not appear, given the case reports above and the present observation, that either so-called atypicals or typical antipsychotics are more or less likely to produce panic attacks in patients. We have presented possible mechanisms that point to an anxiogenic role for antipsychotics and though this is our observation based on the above case report, we have also noted that clinically the role of antipsychotics in anxiety remains unclear. Certainly, however, while the therapeutic use of antispsychotics in anxiety awaits further investigation, we would emphasize that it is important that clinicians are aware of the potential side effect of neuroleptic-induced panic attacks and not simply assume the presence of co-morbidity. Key points . The association between neuroleptics and anxiety is unclear: some reports indicate they are anxiolytic while others suggest that they are anxiogenic . We report the case of a man who started on zuclopenthixol decanoate and developed new onset panic attacks . Antipsychotics may be anxiogenic through their blockade of serotonin and dopamine, which in turn might disinhibit the locus ceruleus . It does not appear that either atypical or typical antipsychotics, or particular medications within those classes, are more or less likely to produce or alleviate anxiety . Clinicians should be aware of the potential for antipsychotic-induced anxiety and not simply assume the presence of co-morbidity Statement of interest The authors have no conflict of interest with any commercial or other associations in connection with the submitted article.
References [1] Bakker A, van Balkom AJLM, Stein DJ. Evidence based pharmacotherapy of panic disorder. Int J Neuropsychopharmacol 2005;8(3):473. [2] Takahashi H, Sugita T, Yoshida K, Higuchi H, Shimizu T. Effect of quetiapine in the treatment of panic attacks in patients with schizophrenia: 3 case reports. J Neuropsychiatry Clin Neurosci 2004;16:113 5. /
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[3] Takahashi H, Higuchi H, Shimizu T. Full remission of panic attacks in a schizophrenic patient after switching from haloperidol to risperidone. J Neuropsychiatry Clin Neurosci 2001;13:113 4. [4] Mandalos G, Szarek B. New onset panic attacks in a patient treated with olanzapine. J Clin Psychopharmacol 1999; 19(2):191. [5] Etxebeste M, Aragues E, Pablo M, Pacheco L. Olanzapine and panic attacks. Am J Psychiatry 2000;157(4):659 60. [6] Bressan RA, Monteiro VBM, Dias CC. Panic disorder associated with clozapine. Am J Psychiatry 2000;157(12): 2056. [7] Higuchi H, Kamata M, Yoshimoto M, Shimisu T, Hishikawa Y. Panic attacks in patients with chronic schizophrenia: a complication of long-term neuroleptic treatment. Psychiatry Clin Neurosci 1999;53:91 4. [8] Aston-Jones G, Akaoka H, Charlety P, Chouvet G. Serotonin selectively attenuates glutamate-evoked activation of noradrenergic locus coeruleus neurons. J Neurosci 1991; 11:760 9. [9] Gorman J, Kent JM, Sullivan GM, Coplan J. Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry 2000;157:493 505. [10] Viana MB, Graeff FG, Loschmann PA. Kainate microinjection into the dorsal raphe nucleus induces 5-HT release in the amygdala and periaqueductal gray. Pharmacol Biochem Behav 1997;58:167 72. /
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[11] Stutzmann GE, LeDoux JE. GABAergic antagonists block the inhibitory effects of serotonin in the lateral amygdala: a mechanism for modulation of sensory inputs related to fear conditioning. J Neurosci 1999;19(RC8):1 4. [12] Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D1, D-2 and serotonin-2 pKi values. J Pharmacol Exper Ther 1989;251:238 46. [13] Wingerson D, Cowley DS, Kramer GL, Petty F, Roy-Byrne PP. Effect of benzodiazepines on plasma levels of homovanillic acid in anxious patients and control subjects. Psychiatry Res 1996;65:53 9. [14] Vazquez A, Jimenez-Jimenez FJ, Garcia-Ruiz P, Garcia-Urra D. ‘‘Panic attacks’’ in Parkinson’s disease: A long term complication of levodopatherapy. Acta Neurol Scand 1993; 87:14 8. [15] Kapur S, Seeman P. Does Fast Dissociation From the dopamine D2 receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 2001;158: 360 9. [16] Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Arch Gen Psychiatry 1992;49:538 44. /
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CASE REPORT
Panic attacks after treatment with zuclopenthixol decanoate
ANIL SRIVASTAVA & JORGE SONI Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
Abstract The association between neuroleptics and anxiety is unclear: neuroleptics have been used to treat anxiety though may also themselves be anxiogenic. We present the case of a man who developed new onset panic attacks after treatment with zuclopenthixol decanoate, a commonly administered depot antipsychotic. We review the literature on the association between antipsychotics and anxiety and present possible pathophysiological mechanisms.
Key Words: Anxiety, panic attacks, zuclopenthixol decanoate, neuroleptics, antipsychotics
Introduction It is suggested that the pharamacotherapy of panic disorder involves, as first line treatment, SSRIs, often modified with the use of benzodiazepines [1]. The use of antipsychotics in panic attacks or disorder is more controversial and is not at present considered part of standard treatment. Indeed, the association between neuroleptics and anxiety is unclear: while some clinicians report that they are anxiolytic, others have reported the opposite. For instance, Takahashi et al. [2] reported on three cases of people with schizophrenia, one of whose panic attacks resolved after switching from risperidone (10 mg daily) to quetiapine, though Takahashi et al. [3] reported a patient with schizophrenia who experienced a cessation of panic attacks after switching to risperidone (3 mg daily) from haloperidol. There has been a report of new-onset panic attacks associated with the introduction of olanzapine (15 mg daily) [4] but, by contrast, a report on two cases of treatmentrefractory panic attacks suggested that starting olanzapine (between 10 and 12.5 mg daily) was of benefit [5], as it was in a woman with schizophrenia who experienced new onset panic attacks 20 weeks after being started on clozapine (400 mg daily) [6]. Dose may be of importance given Higuchi et al.’s [7] finding that there was a non-statistically significant trend towards higher chloropromazine-equivalent doses of neuroleptics among those who had schizophrenia and panic attacks compared to those with schizophrenia but without panic attacks. We present here the case of a man who developed new-onset
panic attacks following the introduction of a commonly administered depot antipsychotic and we review possible mechanisms. Case report A 70-year-old man with a discharge diagnosis of ‘Psychosis Not Otherwise Specified’ had been maintained successfully on trifluoperazine for many years, at a daily dose between 2.5 and 5 mg. He arrived at our hospital following an assault on his neighbours which was thought to be psychotically driven. Approximately 1 month prior to our seeing the patient in July 2004 he had been started on 100 mg of zuclopenthixol decanoate biweekly because of non-adherence with his trifluoperazine; he was on no other psychotropic medications. The patient noted that soon after starting this medication he began to experience panic attacks characterized by shortness of breath, a feeling of losing control including an inability to speak, tachycardia, diaphoresis, and a feeling of urinary urgency, with occasional incontinence, all lasting about a minute. Extensive medical investigation was conducted. An EKG suggested left ventricular hypertrophy, and a subsequent echocardiogram revealed a Grade IV left ventricle. However, he reported no other symptoms, including orthopnea or shortness of breath on exertion, which would suggest that this was anything other than an incidental finding. He was started on a number of cardiovascular medications, including carvedilol 3.125 mg b.i.d, ramipril 2.5 mg o.d.,
Correspondence: Anil Srivastava, Department of Psychiatry, University of Toronto, 250 College St., Toronto, Ontario, Canada M5T 1R8. Tel: /1 416 535 8501. E-mail: [email protected]
(Received 15 October 2005; accepted 29 March 2006) ISSN 1365-1501 print/ISSN 1471-1788 online # 2007 Taylor & Francis DOI: 10.1080/13651500600811446
Panic attacks after treatment with zuclopenthixol decanoate and aspirin 81 mg o.d. Because of his complaints of urinary urgency during these attacks, urinalysis was performed which was negative for infection or other abnormalities; a pelvic ultrasound did reveal mild prostatic hypertrophy, though a post-void residual was unremarkable. The patient had preexisting diabetes mellitus, but during the times of his attacks, his blood glucose had always been within the normal range. In short, his medical history was felt to be non-contributory to his new-onset panic attacks. Because of the episodic nature of the symptoms, and their quick onset and relatively rapid dissolution, consideration to panic attacks, rather than generalized anxiety, was felt to be appropriate. He had no complaints of pain or other somatic symptoms between episodes; the onset of a somatoform disorder therefore seemed unlikely. Although the patient remained frustrated at times by his continued stay in hospital, there was no evidence of a particularly depressed or irritable mood. Indeed, with respect to psychiatric symptoms no abnormalities were noted during his stay other than the above anxiety. Discussion Serotonin has been implicated in panic disorder: current thought centres on the role of serotonin in inhibiting the locus coeruleus, a source of norepinephrine [8], where this latter neurotransmitter is involved in many of the typical symptoms of panic attacks such as tachycardia [9]. Serotonin may also be involved in regulation of the periaqueductal grey region [10] and in the modulation of inhibition to the amygdala [11], both implicated in anxiety. Neuroleptics both atypicals and typicals may block serotonin receptors [12]. Dopamine has also been implicated. For example, a study that examined plasma homovanillic acid levels, a metabolite of dopamine that is believed to reflect central levels, noted that they were significantly lower among the 22 with panic disorder compared with 18 controls [13]. As all effective antipsychotics act on dopamine receptors, such a finding suggests that antipsychoticinduced blockade of dopamine may modulate anxiety. The nigrostriatal pathway may be involved. In a study that examined the relationship between Parkinson’s disease and panic attacks it was observed that panic attacks were exclusively present during periods where motor function was impaired and that after the ingestion of a new dose of levodopa, panic attack symptoms disappeared; the authors suggested that a lack of striatal dopamine could lead to disinhibition of the locus coeruleus and thereby precipitate panic attacks [14]. Takahashi et al. [2] postulated that quetiapine was effective in ameliorating panic attacks because of its transient, versus prolonged, D2 receptor occupancy; if this were the case though, the same should be true of clozapine
77
given its transient D2 occupancy [15], though it too has been associated with panic attacks [6]. The presence of extrapyramidal symptoms suggests a high degree of dopamine receptor occupancy [16]; in the case above, no such symptoms or signs were noted. Neuroleptics have been implicated previously in panic attacks; this is the first reported association with zuclopenthixol decanoate, a commonly administered depot antipsychotic. It does not appear, given the case reports above and the present observation, that either so-called atypicals or typical antipsychotics are more or less likely to produce panic attacks in patients. We have presented possible mechanisms that point to an anxiogenic role for antipsychotics and though this is our observation based on the above case report, we have also noted that clinically the role of antipsychotics in anxiety remains unclear. Certainly, however, while the therapeutic use of antispsychotics in anxiety awaits further investigation, we would emphasize that it is important that clinicians are aware of the potential side effect of neuroleptic-induced panic attacks and not simply assume the presence of co-morbidity. Key points . The association between neuroleptics and anxiety is unclear: some reports indicate they are anxiolytic while others suggest that they are anxiogenic . We report the case of a man who started on zuclopenthixol decanoate and developed new onset panic attacks . Antipsychotics may be anxiogenic through their blockade of serotonin and dopamine, which in turn might disinhibit the locus ceruleus . It does not appear that either atypical or typical antipsychotics, or particular medications within those classes, are more or less likely to produce or alleviate anxiety . Clinicians should be aware of the potential for antipsychotic-induced anxiety and not simply assume the presence of co-morbidity Statement of interest The authors have no conflict of interest with any commercial or other associations in connection with the submitted article.
References [1] Bakker A, van Balkom AJLM, Stein DJ. Evidence based pharmacotherapy of panic disorder. Int J Neuropsychopharmacol 2005;8(3):473. [2] Takahashi H, Sugita T, Yoshida K, Higuchi H, Shimizu T. Effect of quetiapine in the treatment of panic attacks in patients with schizophrenia: 3 case reports. J Neuropsychiatry Clin Neurosci 2004;16:113 5. /
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78
A. Srivastava & J. Soni
[3] Takahashi H, Higuchi H, Shimizu T. Full remission of panic attacks in a schizophrenic patient after switching from haloperidol to risperidone. J Neuropsychiatry Clin Neurosci 2001;13:113 4. [4] Mandalos G, Szarek B. New onset panic attacks in a patient treated with olanzapine. J Clin Psychopharmacol 1999; 19(2):191. [5] Etxebeste M, Aragues E, Pablo M, Pacheco L. Olanzapine and panic attacks. Am J Psychiatry 2000;157(4):659 60. [6] Bressan RA, Monteiro VBM, Dias CC. Panic disorder associated with clozapine. Am J Psychiatry 2000;157(12): 2056. [7] Higuchi H, Kamata M, Yoshimoto M, Shimisu T, Hishikawa Y. Panic attacks in patients with chronic schizophrenia: a complication of long-term neuroleptic treatment. Psychiatry Clin Neurosci 1999;53:91 4. [8] Aston-Jones G, Akaoka H, Charlety P, Chouvet G. Serotonin selectively attenuates glutamate-evoked activation of noradrenergic locus coeruleus neurons. J Neurosci 1991; 11:760 9. [9] Gorman J, Kent JM, Sullivan GM, Coplan J. Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry 2000;157:493 505. [10] Viana MB, Graeff FG, Loschmann PA. Kainate microinjection into the dorsal raphe nucleus induces 5-HT release in the amygdala and periaqueductal gray. Pharmacol Biochem Behav 1997;58:167 72. /
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[11] Stutzmann GE, LeDoux JE. GABAergic antagonists block the inhibitory effects of serotonin in the lateral amygdala: a mechanism for modulation of sensory inputs related to fear conditioning. J Neurosci 1999;19(RC8):1 4. [12] Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D1, D-2 and serotonin-2 pKi values. J Pharmacol Exper Ther 1989;251:238 46. [13] Wingerson D, Cowley DS, Kramer GL, Petty F, Roy-Byrne PP. Effect of benzodiazepines on plasma levels of homovanillic acid in anxious patients and control subjects. Psychiatry Res 1996;65:53 9. [14] Vazquez A, Jimenez-Jimenez FJ, Garcia-Ruiz P, Garcia-Urra D. ‘‘Panic attacks’’ in Parkinson’s disease: A long term complication of levodopatherapy. Acta Neurol Scand 1993; 87:14 8. [15] Kapur S, Seeman P. Does Fast Dissociation From the dopamine D2 receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 2001;158: 360 9. [16] Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Arch Gen Psychiatry 1992;49:538 44. /
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