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Improvement of tardive dyskinesia following zopiclone treatment
Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 727–728
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p
Letter to the Editor (Case report) Improvement of tardive dyskinesia following zopiclone treatment 1. Introduction Tardive dyskinesia (TD) is a symptom characterized by involuntary, repetitive movements. It is considered to be a late-onset adverse effect of prolonged administration of neuroleptics. Many mechanisms have been proposed to explain how neuroleptics induce TD. The most prominent theory implicates postsynaptic dopamine receptor hypersensitivity (Rascol and Fabre, 2001). Nevertheless, this theory does not seem to fully explain a number of clinical and experimental observations (Blin et al., 1989; Sachdev, 2000). Several studies have suggested that a hypofunction of a gamma-amino butyric acid (GABA) inhibitory tonus plays an important role in the pathophysiology of TD (Andersson et al., 1989; Peixoto et al., 2003). However, human studies using GABA agonists have shown only minimal effects (Bhoopathi and Soares-Weiser, 2006; Soares et al., 2004). The authors report a case of significant improvement of TD in patients with schizophrenia following treatment with zopiclone. To our knowledge, this is the first report of such an effect for zopiclone. 2. Case reports 2.1. Case 1 Mr. A is a 32-year-old single male with a DSM-IV-TR diagnosis of schizophrenia, paranoid type, of 6 years duration. Beginning in 2003, he was convinced that colleagues were planning to hurt him. In September 2005, he was admitted to the outpatient psychiatry department of a hospital and received olanzapine 5 mg. In April 2006, marked TD was present, leading to an Abnormal Involuntary Movement Scale (AIMS) score of 20. He was switched to perospirone 8 mg/day. There was no improvement in his TD, so it was decided to switch his medication to sulpiride (150 mg/day). But his AIMS score remained 12. In October 2006, the patient took zopiclone prescribed for ondemand use of insomnia at noon on his own volition. Then, TD was reduced (AIMS score 4) 2 or 3 h after administration of zopiclone (20 mg/day). The effect of zopiclone lasted until time for bed. He also took zolpidem and other benzodiazepines according to self-judgment. The former was effective for TD, but made him too sleepy. The latter was ineffective for TD. In June 2007, a trial of reducing the dose of sulpiride led to an increase in the severity of TD, so the dose remained at 150 mg/day. At 1 year follow up, he remains asymptomatic with respect to abnormal movements (AIMS score 4). 2.2. Case 2 Mrs. H is a 59-year-old married female with a DSM-IV-TR diagnosis of schizophrenia, paranoid type, of 7 years duration. In December 2001, she expressed the delusional idea of persecution by her 0278-5846/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2009.02.016
neighbors and suffered from insomnia. In February 2002, she visited a psychiatry clinic and received multiple neuroleptics including a conventional antipsychotic. In April 2007, while she was on clocapramine (75 mg/day) and zotepine (50 mg/day), she developed perioral and jaw movements and dysphagia. Clocapramine was tapered off, and chlorpromazine (37.5 mg/day) and levodopa (100 mg/day) were administered. However, she showed no significant change in TD (AIMS score 20). In November 2007, levodopa was discontinued. She was switched to risperidone (1 mg/day). TD remained unchanged after the administration of risperidone. A switch to olanzapine did not change TD either. With her agreement, zopiclone was initiated (7.5 mg). Marked improvement of TD (AIMS score 4) without sleepiness was obtained at a dose of 15 mg. At a 6-month follow up, she remains asymptomatic with respect to abnormal movements (AIMS score 4). 3. Discussion Zopiclone is a cyclopyrrolone and a commonly used hypnosedative. It induces sleep by enhancing the inhibitory effects of gammaaminobutyric acid (GABA) on neuroexcitation by its agonist activity at the GABA-A receptor complex (Holm and Goa, 2000). Until today, an improvement of TD following zopiclone treatment has not been reported in human studies. Nevertheless, animal studies support our clinical observation. Peixoto et al. (2005) observed improvement of an oral dyskinesia model treated with GABA-A agonist in Wistar rats. In the same study, diazepam, one of the benzodiazepine drugs did not modify oral dyskinesia at any dose tested. In our case 1, the patient also took benzodiazepines but no improvement was experienced. Benzodiazepines also act at the GABAA receptor complex. But these drugs facilitate GABA transmission through modulation of GABA-A receptors, depending on GABA availability (Dubnick et al., 1983). In a previous animal study, reserpine which decreases GABA content in total brain (Abet et al., 1989; Lane et al., 1976) was used to induce oral dyskinesia. Direct agonistic activity of GABA-A receptor might cause the differences of improvement in TD between zopiclone and benzodiazepines. Indeed, zopiclone has been prescribed as hypnotic. However, patients were not overcome with sleepiness in our cases. While undergoing long-term treatment for schizophrenia, both patients were also prescribed benzodiazepines. So, cross-tolerance may occur between benzodiazepines and zopiclone (Cohen and Sanger, 1994). In case 1, the patient took zolpidem, which has agonist activity at GABA-A receptor complex like zopiclone. Zolpidem was also effective for TD but made the patient too sleepy. Most benzodiazepines show a nonselective affinity for GABA-A receptors (Sanger, 1998), and zopiclone is similar in this respect. In contrast, zolpidem has a particularly high affinity for GABA-A receptors containing alpha-1 subunits. An affinity for alpha-1 subunits might cause the differences in levels of sleepiness between zopiclone and zolpidem. The finding that zopiclone improved TD supports the involvement of GABA related mechanisms in the pathophysiology of TD. However, all the antipsychotics used in these clinical cases have dopamine D2
728
Letter to the Editor (Case report)
antagonism. In our case 1, the fact that a trial of reducing the dose of sulpiride led to an increase in the severity of TD suggests there might be postsynaptic dopamine receptor hypersensitivity. Although one unifying theory may ultimately be discovered, current understanding suggests that several of these mechanisms may coexist to produce TD. 4. Conclusion We report two cases of significant improvement of TD after the administration of zopiclone, a GABA-A agonist. To our knowledge, this is the first report of such an effect for zopiclone. However, TD may recur in withdrawal from zopiclone. To avoid the development of tolerance caused by a long-term treatment, it is preferable to set the drug holiday or prescribe for on-demand use. Controlled studies are needed to shed light on the benefit of zopiclone treatment in patients suffering from TD. References Andersson U, Haggstrom JE, Levin ED, Bondesson U, Valverius M, Gunne LM. Reduced glutamate decarboxylase activity in the subthalamic nucleus in patients with tardive dyskinesia. Mov Disord 1989;4:37–46. Bhoopathi PS, Soares-Weiser K. Benzodiazepines for neuroleptic-induced tardive dyskinesia. Cochrane Database Syst Rev 2006;3:CD000205. Blin J, Baron JC, Cambon H, Bonnet AM, Dubois B, Loc'h C. Striatal dopamine D2 receptors in tardive dyskinesia: PET study. J Neurol Neurosurg Psychiatry 1989;52:1248–52. Cohen C, Sanger DJ. Tolerance, cross-tolerance and dependence measured by operant responding in rats treated with triazolam via osmotic pumps. Psychopharmacology 1994;115:86–94.
Dubnick B, Lippa AS, Klepner CA, Colpet J, Greenblatt EN, Beer B. The separation of 3Hbenzodiazepine binding sites in brain and of benzodiazepine pharmacological properties. Pharmacol Biochem Behav 1983;18:311–8. Holm KJ, Goa KL. Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia. Drugs 2000;59:865–89. Lane JD, Smith JE, Shea PA, McBride WJ. Neurochemical changes following the administration of depleters of biogenic monoamine. Life Sci 1976:1663–8. Peixoto MF, Abílio VC, Silva RH, Frussa-Filho R. Effects of valproic acid on an animal model of tardive dyskinesia. Behav Brain Res 2003;142:229–33. Peixoto MF, Araujo NP, Silva RH, Castro JP, Fukushiro DF, Faria RR. Effects of gabaergic drugs on reserpine-induced oral dyskinesia. Behav Brain Res 2005;160:51–9. Rascol O, Fabre N. Dyskinesia: L-DOPA-induced and tardive dyskinesia. Clin Neuropharmacol 2001;24:313–23. Sachdev OS. The current status of tardive dyskinesia. Aust N Z J Psychiatry 2000;34:355–69. Soares K, Rathbone J, Deeks J. Gamma-aminobutyric acid agonists for neurolepticinduced tardive dyskinesia. Cochrane Database Syst Rev 2004;4:CD000203.
Norio Sugawara Department of Psychiatry, Hirosaki-Aiseikai Hospital, 1-6-2 Kitazono, Hirosaki City, Aomori, 036-8151, Japan Corresponding author. Fax: +81 172 34 7112. E-mail address: [email protected]. Norio Yasui-Furukori Sunao Kaneko Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki City, Japan 9 January 2009
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p
Letter to the Editor (Case report) Improvement of tardive dyskinesia following zopiclone treatment 1. Introduction Tardive dyskinesia (TD) is a symptom characterized by involuntary, repetitive movements. It is considered to be a late-onset adverse effect of prolonged administration of neuroleptics. Many mechanisms have been proposed to explain how neuroleptics induce TD. The most prominent theory implicates postsynaptic dopamine receptor hypersensitivity (Rascol and Fabre, 2001). Nevertheless, this theory does not seem to fully explain a number of clinical and experimental observations (Blin et al., 1989; Sachdev, 2000). Several studies have suggested that a hypofunction of a gamma-amino butyric acid (GABA) inhibitory tonus plays an important role in the pathophysiology of TD (Andersson et al., 1989; Peixoto et al., 2003). However, human studies using GABA agonists have shown only minimal effects (Bhoopathi and Soares-Weiser, 2006; Soares et al., 2004). The authors report a case of significant improvement of TD in patients with schizophrenia following treatment with zopiclone. To our knowledge, this is the first report of such an effect for zopiclone. 2. Case reports 2.1. Case 1 Mr. A is a 32-year-old single male with a DSM-IV-TR diagnosis of schizophrenia, paranoid type, of 6 years duration. Beginning in 2003, he was convinced that colleagues were planning to hurt him. In September 2005, he was admitted to the outpatient psychiatry department of a hospital and received olanzapine 5 mg. In April 2006, marked TD was present, leading to an Abnormal Involuntary Movement Scale (AIMS) score of 20. He was switched to perospirone 8 mg/day. There was no improvement in his TD, so it was decided to switch his medication to sulpiride (150 mg/day). But his AIMS score remained 12. In October 2006, the patient took zopiclone prescribed for ondemand use of insomnia at noon on his own volition. Then, TD was reduced (AIMS score 4) 2 or 3 h after administration of zopiclone (20 mg/day). The effect of zopiclone lasted until time for bed. He also took zolpidem and other benzodiazepines according to self-judgment. The former was effective for TD, but made him too sleepy. The latter was ineffective for TD. In June 2007, a trial of reducing the dose of sulpiride led to an increase in the severity of TD, so the dose remained at 150 mg/day. At 1 year follow up, he remains asymptomatic with respect to abnormal movements (AIMS score 4). 2.2. Case 2 Mrs. H is a 59-year-old married female with a DSM-IV-TR diagnosis of schizophrenia, paranoid type, of 7 years duration. In December 2001, she expressed the delusional idea of persecution by her 0278-5846/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2009.02.016
neighbors and suffered from insomnia. In February 2002, she visited a psychiatry clinic and received multiple neuroleptics including a conventional antipsychotic. In April 2007, while she was on clocapramine (75 mg/day) and zotepine (50 mg/day), she developed perioral and jaw movements and dysphagia. Clocapramine was tapered off, and chlorpromazine (37.5 mg/day) and levodopa (100 mg/day) were administered. However, she showed no significant change in TD (AIMS score 20). In November 2007, levodopa was discontinued. She was switched to risperidone (1 mg/day). TD remained unchanged after the administration of risperidone. A switch to olanzapine did not change TD either. With her agreement, zopiclone was initiated (7.5 mg). Marked improvement of TD (AIMS score 4) without sleepiness was obtained at a dose of 15 mg. At a 6-month follow up, she remains asymptomatic with respect to abnormal movements (AIMS score 4). 3. Discussion Zopiclone is a cyclopyrrolone and a commonly used hypnosedative. It induces sleep by enhancing the inhibitory effects of gammaaminobutyric acid (GABA) on neuroexcitation by its agonist activity at the GABA-A receptor complex (Holm and Goa, 2000). Until today, an improvement of TD following zopiclone treatment has not been reported in human studies. Nevertheless, animal studies support our clinical observation. Peixoto et al. (2005) observed improvement of an oral dyskinesia model treated with GABA-A agonist in Wistar rats. In the same study, diazepam, one of the benzodiazepine drugs did not modify oral dyskinesia at any dose tested. In our case 1, the patient also took benzodiazepines but no improvement was experienced. Benzodiazepines also act at the GABAA receptor complex. But these drugs facilitate GABA transmission through modulation of GABA-A receptors, depending on GABA availability (Dubnick et al., 1983). In a previous animal study, reserpine which decreases GABA content in total brain (Abet et al., 1989; Lane et al., 1976) was used to induce oral dyskinesia. Direct agonistic activity of GABA-A receptor might cause the differences of improvement in TD between zopiclone and benzodiazepines. Indeed, zopiclone has been prescribed as hypnotic. However, patients were not overcome with sleepiness in our cases. While undergoing long-term treatment for schizophrenia, both patients were also prescribed benzodiazepines. So, cross-tolerance may occur between benzodiazepines and zopiclone (Cohen and Sanger, 1994). In case 1, the patient took zolpidem, which has agonist activity at GABA-A receptor complex like zopiclone. Zolpidem was also effective for TD but made the patient too sleepy. Most benzodiazepines show a nonselective affinity for GABA-A receptors (Sanger, 1998), and zopiclone is similar in this respect. In contrast, zolpidem has a particularly high affinity for GABA-A receptors containing alpha-1 subunits. An affinity for alpha-1 subunits might cause the differences in levels of sleepiness between zopiclone and zolpidem. The finding that zopiclone improved TD supports the involvement of GABA related mechanisms in the pathophysiology of TD. However, all the antipsychotics used in these clinical cases have dopamine D2
728
Letter to the Editor (Case report)
antagonism. In our case 1, the fact that a trial of reducing the dose of sulpiride led to an increase in the severity of TD suggests there might be postsynaptic dopamine receptor hypersensitivity. Although one unifying theory may ultimately be discovered, current understanding suggests that several of these mechanisms may coexist to produce TD. 4. Conclusion We report two cases of significant improvement of TD after the administration of zopiclone, a GABA-A agonist. To our knowledge, this is the first report of such an effect for zopiclone. However, TD may recur in withdrawal from zopiclone. To avoid the development of tolerance caused by a long-term treatment, it is preferable to set the drug holiday or prescribe for on-demand use. Controlled studies are needed to shed light on the benefit of zopiclone treatment in patients suffering from TD. References Andersson U, Haggstrom JE, Levin ED, Bondesson U, Valverius M, Gunne LM. Reduced glutamate decarboxylase activity in the subthalamic nucleus in patients with tardive dyskinesia. Mov Disord 1989;4:37–46. Bhoopathi PS, Soares-Weiser K. Benzodiazepines for neuroleptic-induced tardive dyskinesia. Cochrane Database Syst Rev 2006;3:CD000205. Blin J, Baron JC, Cambon H, Bonnet AM, Dubois B, Loc'h C. Striatal dopamine D2 receptors in tardive dyskinesia: PET study. J Neurol Neurosurg Psychiatry 1989;52:1248–52. Cohen C, Sanger DJ. Tolerance, cross-tolerance and dependence measured by operant responding in rats treated with triazolam via osmotic pumps. Psychopharmacology 1994;115:86–94.
Dubnick B, Lippa AS, Klepner CA, Colpet J, Greenblatt EN, Beer B. The separation of 3Hbenzodiazepine binding sites in brain and of benzodiazepine pharmacological properties. Pharmacol Biochem Behav 1983;18:311–8. Holm KJ, Goa KL. Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia. Drugs 2000;59:865–89. Lane JD, Smith JE, Shea PA, McBride WJ. Neurochemical changes following the administration of depleters of biogenic monoamine. Life Sci 1976:1663–8. Peixoto MF, Abílio VC, Silva RH, Frussa-Filho R. Effects of valproic acid on an animal model of tardive dyskinesia. Behav Brain Res 2003;142:229–33. Peixoto MF, Araujo NP, Silva RH, Castro JP, Fukushiro DF, Faria RR. Effects of gabaergic drugs on reserpine-induced oral dyskinesia. Behav Brain Res 2005;160:51–9. Rascol O, Fabre N. Dyskinesia: L-DOPA-induced and tardive dyskinesia. Clin Neuropharmacol 2001;24:313–23. Sachdev OS. The current status of tardive dyskinesia. Aust N Z J Psychiatry 2000;34:355–69. Soares K, Rathbone J, Deeks J. Gamma-aminobutyric acid agonists for neurolepticinduced tardive dyskinesia. Cochrane Database Syst Rev 2004;4:CD000203.
Norio Sugawara Department of Psychiatry, Hirosaki-Aiseikai Hospital, 1-6-2 Kitazono, Hirosaki City, Aomori, 036-8151, Japan Corresponding author. Fax: +81 172 34 7112. E-mail address: [email protected]. Norio Yasui-Furukori Sunao Kaneko Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki City, Japan 9 January 2009