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Antiplatelet therapy in ischaemic events
THE LANCET
Replication of zolpidem test for catatonia in an adolescent SIR—Thomas and colleagues (March 8, p 702)1 in a case study showed in one patient that zolpidem, a selective ␥-aminobutyric acid A (GABA-A) agonist with an indication as a hypnotic, can relieve the motor and behavioural symptoms of catatonia in direct correlation to its circulating blood concentration. They suggest that enhancing GABA activity may reverse the abnormal basal-gangliadopaminergic activity that may underlie the clinical picture of catatonia. We attempted to replicate these findings in an adolescent with autism who developed catatonia. A 14-year-old boy with a 6-month history of progressive loss of dexterity and selective mutism developed a movement disorder. He had not previously taken any medication and presented with features of: Parkinson’s disease with a mask-like face, festinant gait, and muscle rigidity; and choreoathetoid movements of his arms and legs, grimacing, and posturing. He also showed waxy flexibility and the psychological pillow. He fulfilled Diagnostic and Statistical Manual IV criteria for catatonia. Our investigations excluded organic causes of catatonia. We obtained consent from his parents. We used the Modified Roger’s rating scale 2 to assess his baseline catatonic features. We administered an oral dose of 7·5 mg zolpidem. Zolpidem plasma concentrations were measured every 30 min with coincidental rating assessments. The plasma concentrations of zolpidem peaked at 0·17 mg/L, falling to half this value at 2 h. The catatonia score fell from 27 to 18 during this time, but continued to improve with a score of ten at 4 h. Clinically, there was striking improvement with the resolution of motor symptoms. We did not replicate the cut-off for relapse as 0·9 mg/L reported by Thomas and colleagues. 1 Indeed, the improvements were sustained for 24 h. Danielle and co-workers 3 reported that zolpidem treatment among elderly patients with Parkinson’s disease caused improvements in rigidity and bradykinesia that lasted for 2–4 h. The reason for the prolonged response in our case is not clear, but the overall amelioration of symptoms cannot be explained by the natural course of catatonia. Zolpidem seems to be a safe and effective pharmacological test for catatonia. This drug could be especially helpful in the primary psychiatric diagnosis by
1914
enabling the interview of a previously mute patient whose history is unclear. *Z F Z aw, G D L Bates *Department of Child and Adolescent Psychiatry, Brimingham Children’s Hospital NHS Trust, Ladywood, Birmingham B16 8ET, UK
1
2
3
Thomas P, Rascle C, Mastain B, Maron M, Vaiva G. Test for catatonia with zolpidem. Lancet 1997; 349: 702. Lund CE, Mortimer AM, Rogers D, McKenna PJ. Motor volitional and behavioural disorders in schizophrenia. 1: Assessment using the modified Rogers Scale. B J Psychiatry 1991; 158: 323–27. Daniele A, Albanese A, Gainotti G, Gregori B, Bartolomeo P. Zolpidem in Parkinson’s disease. Lancet 1997; 349: 1222–23.
Antiplatelet therapy in ischaemic events SIR—Verheugt in the opening paragraph of his May commentary1 asserts that the efficacy of dipyridamole as an antiplatelet drug is doubtful. In doing so he ignores the recently published report of the Second European Stroke Prevention Trial (ESPS 2)2 which has confirmed definitively the efficacy of dipyridamole, in a modified release formulation at doses known to prevent thromboembolism, in the secondary prevention of ischaemic stroke and transient ischaemic attack. Dipyridamole was shown to be as efficacious as aspirin in preventing second stroke and furthermore when coadministered with aspirin led to an impressive doubling of the risk reduction to 37%, a result shown to be highly statistically significant. Furthermore, dipyridamole (Persantin Retard, 200 mg) has recently been approved in this indication in the UK. D M Humphreys Boehringer Ingelheim Limited, Bracknell, Berkshire RG12 8YS, UK
1 2
Verheugt FWA. In search of a superaspirin for the heart. Lancet 1997; 349: 1409–10. Diener H, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: 1–13.
Author’s reply SIR—In the antiplatelet trialists’ overview1 to which I refer in my commentary, the efficacy of dipyridamole monotherapy on the combined endpoint vascular death, stroke, or myocardial infarction in ten small trials is only marginal (87 endpoints in the 719 dipyridamole patients versus 113 in the 755 controls,
19% reduction, p=0·13) and, therefore, doubtful. In the large ESPS 2 trial1 the efficacy of dipyridamole monotherapy given in an unusually high dose (400 mg daily) on total ischaemic events (stroke, myocardial infarction, or sudden death) was similar to that of placebo (271/1654 for dipyridamole monotherapy versus 307/1649 for placebo, 12% reduction, p=0·10), although the primary endpoint stroke was significantly reduced (211 for dipyridamole alone versus 250 for placebo, 16% reduction, p=0·04). Since in my first paragraph I deal with the protection of cardiovascular disease patients against ischaemic events, the efficacy of dipyridamole on cardiovascular outcome is still doubtful even after the well conducted ESPS 2 trial. Freek W A Verheugt 540 Department of Cardiology, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, Netherlands
1
2
Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308: 81–106. Diener HC, Cunha L, Forbes C, Silenius J, Smets P, Lowenthal A. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: 1–13.
AIDS epidemic in Kaliningrad SIR—A team of Finnish epidemiologists and virologists, together with experts from the Pasteur Institute in St Petersburg, have investigated the incidence of HIV in Kaliningrad, an enclave of Russian territory at the Baltic Sea between Lithuania and Poland. During the past 10 years, only a few cases of HIV infection had been reported. However, since June, 1996, more than 1200 cases have been detected in Kaliningrad’s population of about half a million inhabitants—April, 1996, eight cases, October, 1996, 190 cases, and March 1996, 168 cases. A conservative estimate puts the total number of infected people in the area to between 2000 and 3000. It seems doubtful that effective preventive measures can be taken to prevent a second wave of infections. HIV infection seems to be associated with the use of intravenous drugs, mainly a locally produced and popular opiate extract. The production and distribution of this drug facilitates the rapid spread of HIV infection once an
Vol 349 • June 28, 1997
Replication of zolpidem test for catatonia in an adolescent SIR—Thomas and colleagues (March 8, p 702)1 in a case study showed in one patient that zolpidem, a selective ␥-aminobutyric acid A (GABA-A) agonist with an indication as a hypnotic, can relieve the motor and behavioural symptoms of catatonia in direct correlation to its circulating blood concentration. They suggest that enhancing GABA activity may reverse the abnormal basal-gangliadopaminergic activity that may underlie the clinical picture of catatonia. We attempted to replicate these findings in an adolescent with autism who developed catatonia. A 14-year-old boy with a 6-month history of progressive loss of dexterity and selective mutism developed a movement disorder. He had not previously taken any medication and presented with features of: Parkinson’s disease with a mask-like face, festinant gait, and muscle rigidity; and choreoathetoid movements of his arms and legs, grimacing, and posturing. He also showed waxy flexibility and the psychological pillow. He fulfilled Diagnostic and Statistical Manual IV criteria for catatonia. Our investigations excluded organic causes of catatonia. We obtained consent from his parents. We used the Modified Roger’s rating scale 2 to assess his baseline catatonic features. We administered an oral dose of 7·5 mg zolpidem. Zolpidem plasma concentrations were measured every 30 min with coincidental rating assessments. The plasma concentrations of zolpidem peaked at 0·17 mg/L, falling to half this value at 2 h. The catatonia score fell from 27 to 18 during this time, but continued to improve with a score of ten at 4 h. Clinically, there was striking improvement with the resolution of motor symptoms. We did not replicate the cut-off for relapse as 0·9 mg/L reported by Thomas and colleagues. 1 Indeed, the improvements were sustained for 24 h. Danielle and co-workers 3 reported that zolpidem treatment among elderly patients with Parkinson’s disease caused improvements in rigidity and bradykinesia that lasted for 2–4 h. The reason for the prolonged response in our case is not clear, but the overall amelioration of symptoms cannot be explained by the natural course of catatonia. Zolpidem seems to be a safe and effective pharmacological test for catatonia. This drug could be especially helpful in the primary psychiatric diagnosis by
1914
enabling the interview of a previously mute patient whose history is unclear. *Z F Z aw, G D L Bates *Department of Child and Adolescent Psychiatry, Brimingham Children’s Hospital NHS Trust, Ladywood, Birmingham B16 8ET, UK
1
2
3
Thomas P, Rascle C, Mastain B, Maron M, Vaiva G. Test for catatonia with zolpidem. Lancet 1997; 349: 702. Lund CE, Mortimer AM, Rogers D, McKenna PJ. Motor volitional and behavioural disorders in schizophrenia. 1: Assessment using the modified Rogers Scale. B J Psychiatry 1991; 158: 323–27. Daniele A, Albanese A, Gainotti G, Gregori B, Bartolomeo P. Zolpidem in Parkinson’s disease. Lancet 1997; 349: 1222–23.
Antiplatelet therapy in ischaemic events SIR—Verheugt in the opening paragraph of his May commentary1 asserts that the efficacy of dipyridamole as an antiplatelet drug is doubtful. In doing so he ignores the recently published report of the Second European Stroke Prevention Trial (ESPS 2)2 which has confirmed definitively the efficacy of dipyridamole, in a modified release formulation at doses known to prevent thromboembolism, in the secondary prevention of ischaemic stroke and transient ischaemic attack. Dipyridamole was shown to be as efficacious as aspirin in preventing second stroke and furthermore when coadministered with aspirin led to an impressive doubling of the risk reduction to 37%, a result shown to be highly statistically significant. Furthermore, dipyridamole (Persantin Retard, 200 mg) has recently been approved in this indication in the UK. D M Humphreys Boehringer Ingelheim Limited, Bracknell, Berkshire RG12 8YS, UK
1 2
Verheugt FWA. In search of a superaspirin for the heart. Lancet 1997; 349: 1409–10. Diener H, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: 1–13.
Author’s reply SIR—In the antiplatelet trialists’ overview1 to which I refer in my commentary, the efficacy of dipyridamole monotherapy on the combined endpoint vascular death, stroke, or myocardial infarction in ten small trials is only marginal (87 endpoints in the 719 dipyridamole patients versus 113 in the 755 controls,
19% reduction, p=0·13) and, therefore, doubtful. In the large ESPS 2 trial1 the efficacy of dipyridamole monotherapy given in an unusually high dose (400 mg daily) on total ischaemic events (stroke, myocardial infarction, or sudden death) was similar to that of placebo (271/1654 for dipyridamole monotherapy versus 307/1649 for placebo, 12% reduction, p=0·10), although the primary endpoint stroke was significantly reduced (211 for dipyridamole alone versus 250 for placebo, 16% reduction, p=0·04). Since in my first paragraph I deal with the protection of cardiovascular disease patients against ischaemic events, the efficacy of dipyridamole on cardiovascular outcome is still doubtful even after the well conducted ESPS 2 trial. Freek W A Verheugt 540 Department of Cardiology, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, Netherlands
1
2
Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308: 81–106. Diener HC, Cunha L, Forbes C, Silenius J, Smets P, Lowenthal A. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: 1–13.
AIDS epidemic in Kaliningrad SIR—A team of Finnish epidemiologists and virologists, together with experts from the Pasteur Institute in St Petersburg, have investigated the incidence of HIV in Kaliningrad, an enclave of Russian territory at the Baltic Sea between Lithuania and Poland. During the past 10 years, only a few cases of HIV infection had been reported. However, since June, 1996, more than 1200 cases have been detected in Kaliningrad’s population of about half a million inhabitants—April, 1996, eight cases, October, 1996, 190 cases, and March 1996, 168 cases. A conservative estimate puts the total number of infected people in the area to between 2000 and 3000. It seems doubtful that effective preventive measures can be taken to prevent a second wave of infections. HIV infection seems to be associated with the use of intravenous drugs, mainly a locally produced and popular opiate extract. The production and distribution of this drug facilitates the rapid spread of HIV infection once an
Vol 349 • June 28, 1997