Ó
2000 Martin Dunitz Ltd
International Journal of Psychiatry in Clinical Practice 2000 Volume 4 Pages 241 ± 243
241
Risperidone treatment of neuroleptic-induced tardive extrapyramidal symptoms
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of Montreal on 12/02/14 For personal use only.
1
TAKAMI SUENAGA , 1 YASUTAKA TAWARA , 1 SHINICHIRO GOTO , 1 SHIN-ICHI KOUHATA , 1 ARIYUKI KAGAYA , 1 JUN HORIGUCHI , 2 YUSUKE YAMANAKA and 1 SHIGETO YAMAWAKI 1
Department of Psychiatry and Neurosciences, Hiroshima University School of Medicine; 2 Yamanaka Neuro-psychiat ric Clinic, Hiroshima, Japan
Tardive extrapyrami dal symptoms (EPS) induced by neuroleptic treatment, and particularly EPS which persist after withdrawal of the drugs, are clinically serious problems. We describe a patient with four types of tardive and persistent EPS such as dystonia, dyskinesia, choreatic movemen t and myoclonus, induced by haloperidol . These EPS were remarkabl y inhibited by 3 mg/day risperidone. This is the first published case demonstrating simultaneou s developmen t of these four types of tardive EPS induced by a neuroleptic and then reduced by low-dose risperidone treatment. (Int J Psych Clin Pract 2000; 4: 241 ± 243)
Correspondence Address Prof. Shigeto Yamawaki, Department of Psychiatry and Neurosciences, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan Tel: +81-82-257-520 7 Fax: +81-82-257-520 9
Received 8 April 1999; accepted for publication 15 December 1999
Keywords tardive extrapyramidal symptoms 5-HT2A receptor
INTRODUCTION
R
isperidone is an atypical antipsychotic agent which acts on dopaminergic and serotonergic neurotransmitter systems, with a relatively low risk of developing EPS, compared to typical neuroleptics such as haloperidol. Jeste et al1 reported that administering 4 ±12 mg/day risperidone for 10 weeks to schizophrenic patients induced significant reductions in dystonia, parkinsonism and dyskinesia. Chouinard et 2 al reported that at doses of 6 ±16 mg/day, risperidone displayed a marked antidyskinetic effect compared with placebo. This effect was more pronounced in patients with severe dyskinesia. We describe a case demonstrating various types of tardive EPS such as dystonia, dyskinesia, choreatic movement and myoclonus, which were improved by administration of a low dose of risperidone (3 mg/day); the improved state has persisted for 11 months.
risperidone
CASE HISTORY The patient, who had no family history of movement disorders, began to suffer from auditory hallucinations at the age of 21. When she was 25 years old, she was diagnosed with schizophrenia, and haloperidol (maximum 6 mg/day) administration was started. 1 After 22 years, tremor and rigidity began to appear at the age of 27, and so the dosages of both haloperidol and biperiden were reduced (from 6 to 0.75, and from 2 to 1 mg/day, respectively). Then the parkinsonism faded. Figure 1 shows the clinical course and drug treatment before she visited our hospital. Six months later, however, at the age of 28, dystonia appeared on both arms. Three months after this, biperiden was stopped and 2 mg/day trihexyphenidyl was begun, with 0.75 mg/day haloperidol. Nevertheless, a couple of weeks later, other EPS such as knitting her eyebrows, blepharospasms, oral dyskinesia, dystonia in the tongue, neck and both arms, and choreatic
242
T Suenaga et al
Haloperidol Biperiden
0.75
1.5
6
3
0.75 2
1
(mg/day) 1
DISCUSSION
50
Promethazine Clonazepam
4
2
2
Trihexyphenidyl
0.5
Sodium valproate Carbamazepine
1 400 200
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of Montreal on 12/02/14 For personal use only.
tremor, rigidity dystonia, dyskinesia, choreaticmovement, myoclonus 25
26
27
28
months since she was discharged, the patient is still in good condition and there is no sign of EPS; she regularly takes only 2 mg/day risperidone.
Age
Figure 1 Clinical course and drug treatment before admission. Above: time course of individual use of medication; below, change s in severity of parkinsonism and tardive EPS.
movement from the left fingers to the forearm suddenly appeared. These EPS continued, and did not improve, despite stopping the administration of both haloperidol and trihexyphenidyl. Five months later, the patient was prescribed 50 mg/day promethazine, 0.5 ±1 mg/day clonazepam, 2 ±4 mg/day trihexyphenidyl, 400 mg/day sodium valproate and 200 mg/day carbamazepine, but there was no change. She was examined by brain magnetic resonance imaging (MRI) and computed tomography (CT) and diagnosed as normal. After a further 4 months, she was admitted to Hiroshima University Hospital. She was found to meet criteria for DSM-IV schizophrenia3 and exhibited many kinds of tardive EPS induced by haloperidol. We also found myoclonus on both upper arms. She was given no drugs for 11 days, and we observed during this period that both the psychiatric and neurological symptoms had stabilized. On the twelfth day, we began to prescribe 1 mg/day risperidone, and increased this over a couple of days to 3 mg/day. This caused a rapid decrease in blepharospasms, tongue dystonia and left hand ±finger choreatic movement. Knitting her eyebrows, oral dyskinesia, dystonia in the neck and both forearms, and myoclonus on the upper arms showed drastic improvement on both subjective and objective findings. By the 24th day in the hospital, scores 4 on the Abnormal Involuntary Movement Scale (AIMS) and 5 Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS) improved from 31 to 16, and from 13 to 8, respectively. Furthermore, scores on the Positive And Negative Syndrome Scale (PANSS) 6 improved: Positive Scale from 16 to 12, Negative Scale from 19 to 17. General Psychopathology Scale improved from 38 to 34 and Brief 7 Psychiatric Rating Scale (BPRS) improved from 43 to 35. Her stable condition regarding both psychiatric symptoms and involuntary movements allowed her to be discharged from hospital on the 37th day. Although it has been 11
This patient showed various kinds of tardive EPS which could have been induced by haloperidol, and a low dose of risperidone was effective in reducing all of those involuntary movements. To our knowledge, there is no previous report of a single patient showing these four types of tardive EPS, induced by neuroleptics, almost all at the same time, although there are a couple of reports8 ,9 of complex movement disorders induced by fluoxetine or antiparkinsonian medication. There are several reports of 1 ,1 0 risperidone improving tardive dystonia or tardive 2 ,1 1 dyskinesia; however, there has been no report of tardive myoclonus or tardive choreatic movement responding to risperidone; this is the first case to demonstrate concurrent effects of risperidone against all four different types of tardive EPS. Risperidone has a high affinity for the 5-hydroxytryptamine (5-HT2A) receptor and dopamine-2 (D2) receptor. Recently, risperidone has been shown to be both slightly more clinically effective than typical antipsychotics in the treatment of chronic schizophrenia, and better 12 tolerated. It has been postulated that this enhanced efficacy may be due to 5-HT2A receptor blockade. Kapur and Remington 1 3 hypothesized that 5-HT2A receptor blockade has a protective effect against extrapyramidal side-effects that is lost at D2 occupancies above a certain 14 threshold. Knabel et al associate more than 70% of D2 occupancy by risperidone with the need for prophylactic anticholinergic medication and the appearance of extra15 pyramidal side-effects. Travis et al reported that there was no relationship between treatment response and 5-HT2A receptor occupancy in any cortical region; however, their results indicate that significant 5-HT2A occupancy is seen with doses of risperidone as low as 3 mg/day, suggesting that the use of atypicals in low doses may lead
KEY POINTS
· · · ·
Various tardive EPS such as dystonia, dyskinesia, choreatic movement and myoclonus developed in a schizophrenic woman under haloperidol treatment. These tardive EPS continued despite stopping the haloperidol treatment. A low dose of risperidone reduced all of those EPS. This effect may be related to the unique balance between D2 and 5-HT2A receptor blockade induced by risperidone.
Risperidone treatment of extrapyramidal symptoms
to favourable 5-HT2A occupancy ratio, which could optimize clinical response and minimize extrapyramidal side-effects. A 5-HT2A antagonistic action of risperidone may inhibit the neuronal activity in the serotonergic system; it may also release the dopaminergic system from the inhibitory action produced by the serotonergic
243
1 0 ,1 3
system. Thus, we consider that a low dose of risperidone (3 mg/day in our hospital and 2 mg/day on line) could maintain the unique and good balance between D2 and 5-HT2A receptor blockade. Further research is clearly necessary, because the pathophysiology of various EPS is still poorly understood.
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of Montreal on 12/02/14 For personal use only.
REFERENCES 1. Jeste DV, Klausner M, Brecher M, et al (1997) A clinical evaluation of risperidone in the treatment of schizophrenia: a 10-week, open-label/multicenter trial. Psychopharmac ol 131: 239 ±47. 2. Chouinard G, Jones B, Remington G, et al (1993) A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmaco l 13: 25 ±40. 3. American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association. 4. Guy W (ed) (1976) ECDEU Assessment Manual for Psychopharmacolog y 534-537. Publication ADM 76-338. Washington, DC: US Department of Health, Education and Welfare. 5. Inada T, Yagi G (1996) Current topics in neuroleptic-induced extrapyramidal symptoms in Japan. Keio J Med 45: 95 ±9. 6. Kay SR, Fiszbein A, Opler LA (1987) The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophreni a Bull 13: 261 ±76. 7. Overall JE, Gorham DR (1962) Brief Psychiatric Rating Scale. Psychol Rep 10: 799 ±812. 8. Bharucha KJ, Sethi KD (1996) Complex movement disorders induced by fluoxetine. Mov Disord 11: 324 ±6.
9. Luquin MR, Scipioni O, Vaamonde J, et al (1992) Levodopainduced dyskinesias in Parkinson's disease: clinical and pharmacological classification. Mov Disord 7: 117 ±24. 10. Yoshida K, Higuchi H, Hishikawa Y (1998) Marked improvement of tardive dystonia after replacing haloperidol with risperidone in a schizophrenic patient. Clin Neuropharmaco l 21: 68 ±9. 11. Kopala LC, Honer WG (1994) Schizophrenia and severe tardive dyskinesia responsive to risperidone. J Clin Psychopharma col 14: 430 ±1. 12. Peuskens J, on behalf of the Risperidone Study Group (1995) Risperidone in the treatment of patients with chronic schizophrenia: A multi-national, multi-center, double-blind parallelgroup study versus haloperidol. Br J Psychiatry 166: 712 ±26. 13. Kapur S, Remington G (1996) Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry 153: 466 ± 76. 14. Knabel MB, Heinz A, Raedler T, et al (1997) Extrapyramidal side effects with risperidone and haloperidol at comparable D2 receptor occupancy levels. Psychiatry Res 75: 91 ±101. 15. Travis MJ (1997) Clozapine: A review. J Serotonin Res 4: 125 ± 44.
2000 Martin Dunitz Ltd
International Journal of Psychiatry in Clinical Practice 2000 Volume 4 Pages 241 ± 243
241
Risperidone treatment of neuroleptic-induced tardive extrapyramidal symptoms
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of Montreal on 12/02/14 For personal use only.
1
TAKAMI SUENAGA , 1 YASUTAKA TAWARA , 1 SHINICHIRO GOTO , 1 SHIN-ICHI KOUHATA , 1 ARIYUKI KAGAYA , 1 JUN HORIGUCHI , 2 YUSUKE YAMANAKA and 1 SHIGETO YAMAWAKI 1
Department of Psychiatry and Neurosciences, Hiroshima University School of Medicine; 2 Yamanaka Neuro-psychiat ric Clinic, Hiroshima, Japan
Tardive extrapyrami dal symptoms (EPS) induced by neuroleptic treatment, and particularly EPS which persist after withdrawal of the drugs, are clinically serious problems. We describe a patient with four types of tardive and persistent EPS such as dystonia, dyskinesia, choreatic movemen t and myoclonus, induced by haloperidol . These EPS were remarkabl y inhibited by 3 mg/day risperidone. This is the first published case demonstrating simultaneou s developmen t of these four types of tardive EPS induced by a neuroleptic and then reduced by low-dose risperidone treatment. (Int J Psych Clin Pract 2000; 4: 241 ± 243)
Correspondence Address Prof. Shigeto Yamawaki, Department of Psychiatry and Neurosciences, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan Tel: +81-82-257-520 7 Fax: +81-82-257-520 9
Received 8 April 1999; accepted for publication 15 December 1999
Keywords tardive extrapyramidal symptoms 5-HT2A receptor
INTRODUCTION
R
isperidone is an atypical antipsychotic agent which acts on dopaminergic and serotonergic neurotransmitter systems, with a relatively low risk of developing EPS, compared to typical neuroleptics such as haloperidol. Jeste et al1 reported that administering 4 ±12 mg/day risperidone for 10 weeks to schizophrenic patients induced significant reductions in dystonia, parkinsonism and dyskinesia. Chouinard et 2 al reported that at doses of 6 ±16 mg/day, risperidone displayed a marked antidyskinetic effect compared with placebo. This effect was more pronounced in patients with severe dyskinesia. We describe a case demonstrating various types of tardive EPS such as dystonia, dyskinesia, choreatic movement and myoclonus, which were improved by administration of a low dose of risperidone (3 mg/day); the improved state has persisted for 11 months.
risperidone
CASE HISTORY The patient, who had no family history of movement disorders, began to suffer from auditory hallucinations at the age of 21. When she was 25 years old, she was diagnosed with schizophrenia, and haloperidol (maximum 6 mg/day) administration was started. 1 After 22 years, tremor and rigidity began to appear at the age of 27, and so the dosages of both haloperidol and biperiden were reduced (from 6 to 0.75, and from 2 to 1 mg/day, respectively). Then the parkinsonism faded. Figure 1 shows the clinical course and drug treatment before she visited our hospital. Six months later, however, at the age of 28, dystonia appeared on both arms. Three months after this, biperiden was stopped and 2 mg/day trihexyphenidyl was begun, with 0.75 mg/day haloperidol. Nevertheless, a couple of weeks later, other EPS such as knitting her eyebrows, blepharospasms, oral dyskinesia, dystonia in the tongue, neck and both arms, and choreatic
242
T Suenaga et al
Haloperidol Biperiden
0.75
1.5
6
3
0.75 2
1
(mg/day) 1
DISCUSSION
50
Promethazine Clonazepam
4
2
2
Trihexyphenidyl
0.5
Sodium valproate Carbamazepine
1 400 200
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of Montreal on 12/02/14 For personal use only.
tremor, rigidity dystonia, dyskinesia, choreaticmovement, myoclonus 25
26
27
28
months since she was discharged, the patient is still in good condition and there is no sign of EPS; she regularly takes only 2 mg/day risperidone.
Age
Figure 1 Clinical course and drug treatment before admission. Above: time course of individual use of medication; below, change s in severity of parkinsonism and tardive EPS.
movement from the left fingers to the forearm suddenly appeared. These EPS continued, and did not improve, despite stopping the administration of both haloperidol and trihexyphenidyl. Five months later, the patient was prescribed 50 mg/day promethazine, 0.5 ±1 mg/day clonazepam, 2 ±4 mg/day trihexyphenidyl, 400 mg/day sodium valproate and 200 mg/day carbamazepine, but there was no change. She was examined by brain magnetic resonance imaging (MRI) and computed tomography (CT) and diagnosed as normal. After a further 4 months, she was admitted to Hiroshima University Hospital. She was found to meet criteria for DSM-IV schizophrenia3 and exhibited many kinds of tardive EPS induced by haloperidol. We also found myoclonus on both upper arms. She was given no drugs for 11 days, and we observed during this period that both the psychiatric and neurological symptoms had stabilized. On the twelfth day, we began to prescribe 1 mg/day risperidone, and increased this over a couple of days to 3 mg/day. This caused a rapid decrease in blepharospasms, tongue dystonia and left hand ±finger choreatic movement. Knitting her eyebrows, oral dyskinesia, dystonia in the neck and both forearms, and myoclonus on the upper arms showed drastic improvement on both subjective and objective findings. By the 24th day in the hospital, scores 4 on the Abnormal Involuntary Movement Scale (AIMS) and 5 Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS) improved from 31 to 16, and from 13 to 8, respectively. Furthermore, scores on the Positive And Negative Syndrome Scale (PANSS) 6 improved: Positive Scale from 16 to 12, Negative Scale from 19 to 17. General Psychopathology Scale improved from 38 to 34 and Brief 7 Psychiatric Rating Scale (BPRS) improved from 43 to 35. Her stable condition regarding both psychiatric symptoms and involuntary movements allowed her to be discharged from hospital on the 37th day. Although it has been 11
This patient showed various kinds of tardive EPS which could have been induced by haloperidol, and a low dose of risperidone was effective in reducing all of those involuntary movements. To our knowledge, there is no previous report of a single patient showing these four types of tardive EPS, induced by neuroleptics, almost all at the same time, although there are a couple of reports8 ,9 of complex movement disorders induced by fluoxetine or antiparkinsonian medication. There are several reports of 1 ,1 0 risperidone improving tardive dystonia or tardive 2 ,1 1 dyskinesia; however, there has been no report of tardive myoclonus or tardive choreatic movement responding to risperidone; this is the first case to demonstrate concurrent effects of risperidone against all four different types of tardive EPS. Risperidone has a high affinity for the 5-hydroxytryptamine (5-HT2A) receptor and dopamine-2 (D2) receptor. Recently, risperidone has been shown to be both slightly more clinically effective than typical antipsychotics in the treatment of chronic schizophrenia, and better 12 tolerated. It has been postulated that this enhanced efficacy may be due to 5-HT2A receptor blockade. Kapur and Remington 1 3 hypothesized that 5-HT2A receptor blockade has a protective effect against extrapyramidal side-effects that is lost at D2 occupancies above a certain 14 threshold. Knabel et al associate more than 70% of D2 occupancy by risperidone with the need for prophylactic anticholinergic medication and the appearance of extra15 pyramidal side-effects. Travis et al reported that there was no relationship between treatment response and 5-HT2A receptor occupancy in any cortical region; however, their results indicate that significant 5-HT2A occupancy is seen with doses of risperidone as low as 3 mg/day, suggesting that the use of atypicals in low doses may lead
KEY POINTS
· · · ·
Various tardive EPS such as dystonia, dyskinesia, choreatic movement and myoclonus developed in a schizophrenic woman under haloperidol treatment. These tardive EPS continued despite stopping the haloperidol treatment. A low dose of risperidone reduced all of those EPS. This effect may be related to the unique balance between D2 and 5-HT2A receptor blockade induced by risperidone.
Risperidone treatment of extrapyramidal symptoms
to favourable 5-HT2A occupancy ratio, which could optimize clinical response and minimize extrapyramidal side-effects. A 5-HT2A antagonistic action of risperidone may inhibit the neuronal activity in the serotonergic system; it may also release the dopaminergic system from the inhibitory action produced by the serotonergic
243
1 0 ,1 3
system. Thus, we consider that a low dose of risperidone (3 mg/day in our hospital and 2 mg/day on line) could maintain the unique and good balance between D2 and 5-HT2A receptor blockade. Further research is clearly necessary, because the pathophysiology of various EPS is still poorly understood.
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of Montreal on 12/02/14 For personal use only.
REFERENCES 1. Jeste DV, Klausner M, Brecher M, et al (1997) A clinical evaluation of risperidone in the treatment of schizophrenia: a 10-week, open-label/multicenter trial. Psychopharmac ol 131: 239 ±47. 2. Chouinard G, Jones B, Remington G, et al (1993) A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmaco l 13: 25 ±40. 3. American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association. 4. Guy W (ed) (1976) ECDEU Assessment Manual for Psychopharmacolog y 534-537. Publication ADM 76-338. Washington, DC: US Department of Health, Education and Welfare. 5. Inada T, Yagi G (1996) Current topics in neuroleptic-induced extrapyramidal symptoms in Japan. Keio J Med 45: 95 ±9. 6. Kay SR, Fiszbein A, Opler LA (1987) The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophreni a Bull 13: 261 ±76. 7. Overall JE, Gorham DR (1962) Brief Psychiatric Rating Scale. Psychol Rep 10: 799 ±812. 8. Bharucha KJ, Sethi KD (1996) Complex movement disorders induced by fluoxetine. Mov Disord 11: 324 ±6.
9. Luquin MR, Scipioni O, Vaamonde J, et al (1992) Levodopainduced dyskinesias in Parkinson's disease: clinical and pharmacological classification. Mov Disord 7: 117 ±24. 10. Yoshida K, Higuchi H, Hishikawa Y (1998) Marked improvement of tardive dystonia after replacing haloperidol with risperidone in a schizophrenic patient. Clin Neuropharmaco l 21: 68 ±9. 11. Kopala LC, Honer WG (1994) Schizophrenia and severe tardive dyskinesia responsive to risperidone. J Clin Psychopharma col 14: 430 ±1. 12. Peuskens J, on behalf of the Risperidone Study Group (1995) Risperidone in the treatment of patients with chronic schizophrenia: A multi-national, multi-center, double-blind parallelgroup study versus haloperidol. Br J Psychiatry 166: 712 ±26. 13. Kapur S, Remington G (1996) Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry 153: 466 ± 76. 14. Knabel MB, Heinz A, Raedler T, et al (1997) Extrapyramidal side effects with risperidone and haloperidol at comparable D2 receptor occupancy levels. Psychiatry Res 75: 91 ±101. 15. Travis MJ (1997) Clozapine: A review. J Serotonin Res 4: 125 ± 44.
