0 1998 Martin Dunitz Ltd
InternationalJournal of Psychiatry in Clinical Practice 1998 Volume 2 Pages 53 -55
a
53
.
Clozapine-induced myoclonic seizures and valproic acid
Int J Psych Clin Pract Downloaded from informahealthcare.com by The University of Manchester on 11/06/14 For personal use only.
ENDER TANER, BEHCET COSAR AND ERDAL ISIK Department of Psychiatry, Gazi University Faculty of Medicine, Ankara, Turkey
Within a 3-year period, in 220 patients receiving clozapine, we observed myoctonic seizures in two who had no previous epileptic history. Seizures appeared at the titration phase at relatively low doses, and resolved with the addition of valproic acid, allowing further increases of the clozapine dose to therapeutic levels. (Int j Psych Clin Pract 1998; 2: 53 - 55)
Correspondence Address Dr Ender Tuner, Bagis sokak, No: 171, 06660, Kiipikesat, Ankara, Turkey Tel: +90 312 4259833 Fax: +90 312 2869029
Received 6 October 1997; revised 11 November 1997; accepted for publication 16 December 1997
Keywords myoclonic seizures clozapine
INTRODUCTION
C
lozapine is used for the treatment of refractory schizophrenia, but since agranulocytosis is an important side-effect, this agent is not a first-line drug, but is reserved for treatment-resistant patients.’ Another problem that is rarely encountered but which needs clinical intervention, is the risk of convulsions. Seizures have been reported in psychotic patients receiving clozapine, the vast majority being tonic-~lonic.~-~ Cases of myoclonic seizures during clozapine therapy have also been reported:-’ as well as in animal models.” In a study of 5629 patients, the incidence of generalized tonic-clonic seizures was reported as 1.3%,of whom only one patient had myoclonic seizures, the authors suggesting that this low frequency may represent an underestimate, not a reflection of the true freq~ency.’~ The actual frequency of myoclonic seizures with clozapine is not known. In some reports, electroencephalographic changes denoting epileptic activity have also been ~ h ~ ~ n Valproic . ~ . ~ acid - ~is~one v of ~ the ~ agents used for the treatment of clozapine-induced myoclonic seizure^.^*'^.'^ We would like to report two cases of clozapine-induced myoclonic seizures which have been successfully treated with valproic acid.
CASE 1 Mr B, a 21-year-old university student, with the DSM-1V diagnosis of undifferentiated type schizophrenia,16showed loosening of associations, circumstantiality, impaired social functioning, impaired sense of self, depersonalization, delusions of persecution and first-rank Schneiderian ’
schizophrenia vulproic acid
delusions (thought insertion, thought withdrawal). Haloperidol was used at therapeutic dose for one month. The response was so discouraging that the medication was changed to clozapine. Having increased the clozapine dose by 25 mg every two days, haloperidol was tapered off and discontinued within one week. When the clozapine dose reached 400 mgday, we recognized myoclonic seizures, which were repetitive jerks of the upper extremities and head the seizures resolved 20 min after an oral 10 mg dose of diazepam. We decreased the clozapine dosage to 300 mg/day and an EEG was performed. This showed basal activity with partial seizures. There was no previous history of partial or generalized seizures. We added valproic acid at a dose of 800 mgday and titrated the clozapine dose to 400 mg/day. No further seizures occurred. There was satisfactory recovery of the positive symptoms, especially the loosened associations. With these doses, the patient was discharged from the hospital. At the 6-month follow-up, there were no complaints; either of the psychotic symptoms or the seizures. The patient is still on weekly follow-up. ,
CASE 2 Mr S, a 23-year-old high school graduate, received a DSM1V diagnosis of disorganized-type schizophrenia.l6 His first symptoms had started 4 years previously, and he had been treated in different hospitals during that period. His complaints on admission were of hearing voices saying things like: ‘Eat human meat; kill yourself; cut yourself, and a sense of fear that he could not describe. On mental
Int J Psych Clin Pract Downloaded from informahealthcare.com by The University of Manchester on 11/06/14 For personal use only.
54
E Tuner et a1
State examination he showed posturing of the left hand, decrease in personal hygiene, extreme loosening of associations, anxiety and irritability, an impaired sense of self, auditory hallucinations (directing type), thought block and paranoid delusions. For the last four years, he had been treated with anti-psychotics, including haloperidol, chlorpromazine, thioridazine and fluphenazine, but no satisfactory results were obtained except temporary suppression of auditory hallucinations. He was taken by his mother to traditional religious healers and for the last two months he had been drug-free. The patient was hospitalized and clozapine was started. Increasing by 25 mg every two days, the dose was titrated up to 425 mg/day, when myoclonic seizures were recognized. These were repetitive jerks of the upper extremities; when he tried to walk, he fell down, without loss of consciousness. There was no history of epileptic seizures. The seizures ceased after oral administration of 10 mg diazepam. The clozapine dose was decreased to 300 mg/ day. Biochemical measures were normal, and an EEG performed on the next day was unremarkable. The clozapine dose was gradually increased to 425 mg/day, when seizures recurred; we added valproic acid at a dose of 600 mg/day, and the seizures ceased. The valproic acid dose was increased to 1000 mg/day, and clozapine to 550 mgday. The auditory hallucinations and delusions resolved completely and there was also some improvement in the stereotypic movements, hand posture, and loosening of associations. No other seizures were seen. The patient was discharged from hospital on this treatment regime. In the outpatient clinic, the clozapine dose has been increased to 600 mgday; the patient is still on follow-up, and is free from seizures.
seizures. Sajatovic and Meltze? have reported four myoclonic seizures, two of which were followed by tonicclonic seizures, in 148 patients treated with clozapine. As shown in earlier reports, some tonic-clonic seizures are preceded by myoclonic s e i z ~ r e s . 3 Myoclonic ~ ~ * ~ ~ * seizures ~~ can be missed if the patient is not well observed, especially in the titration phase, but it is important to diagnose them because they can be forerunners of a generalized seizure. This may be the explanation for the high variation in the frequency of myoclonic seizures quoted in different studies, but it needs to be tested in future investigations. For myoclonic seizures, temporary discontinuation of clozapine does not seem to be necessary, since we merely reduced the dose of clozapine, which decreased the time needed for the re-titration of the clozapine dosage. Before starting clozapine treatment, EEG evaluation of the patient for epileptic foci which might be induced by clozapine could be beneficial, to detect high-risk patients, but would not seem to be cost-effective. It is important to enquire about the medical history of the patient before treatment. If there is a history of seizures, pretreatment evaluation and investigation with EEG in the titration phase should help to determine whether seizures are likely to occur, but this point needs further research. In vulnerable patients, antiepileptic treatment could be started, namely valproic acid for myoclonic jerks." The combination of valproic acid with clozapine has fewer additional side-effects than carbamazepine (decrease in or phenytoin (which increases liver leucocyte enzymes and decreases clozapine level^).^^'^ One important reminder is that the combined use of classical antipsychoticswith clozapine in the titration phase leads to a theoretical and practical increased risk of epileptic seizures, and such medication combinations should ideally be discontinued before clozapine treatment.
DISCUSSION Although myoclonic jerks occurred in our two cases, the early improvement in the symptoms of schizophrenia were so encouraging that we could not have changed the clozapine treatment. However, the myoclonic jerks seen during clozapine treatment would have caused difficulty unless valproic acid had been added. The appearance of seizures has been associated with the dosage," and with relatively fast increases of the dose in the titration phase." Pacia and Devinsky evaluated 5629 patients and showed that seizures appeared both at low ( < 300 rnglday) and high doses ( > 600 mg/day)." The seizures they reported were all of the generalized tonicclonic type, only one preceding generalized tonic-clonic
KEY POINTS 0
0
0
0
Myoclonic seizures tend to occur at the titration phase of clozapine treatment Myoclonic seizures observed during clozapine treatment are effectively treated with valproic acid Myoclonic seizures are underdiagnosed clinically but can be a forerunner of generalized seizures Rather than temporary discontinuation, a reduction of the clozapine dose is sufficient to relieve myoclonic seizures
REFERENCES 1. Kaplan HI, Sadock BJ, Grobb JA (1995) Kaplan and Sadock's synopsis of psychiatry (Middle East edn.) (7th edn) 932-5. Mass Publishing, Giza.
2. Liukkonen J, Koponen HJ, Nousiainen U (1992) Clinical picture and long term course of epileptic seizures that occur during clozapine treatment. Psychiatry Res 44: 107-12.
Int J Psych Clin Pract Downloaded from informahealthcare.com by The University of Manchester on 11/06/14 For personal use only.
Clozapine-induced myoclonic seizures 6 valproic acid
3. Sajatovic M, Meltzer HY (1996) Clozapine-induced myoclonus and generalised seizures. Biol Psychiatry 3 9 367 - 70. 4. Devinsky 0,Pacia SV (1994) Seizures during clozapine therapy. J Clin Psychiatry 55 (suppl B): 153-6. 5. Berman 1, Zalma A, DuRand CJ, Green A1 (1992) Clozapine induced myoclonic jerks and drop attacks (letter) J Clin Psychiatry 53: 329 - 30. 6. Gouzoulis E, Ozdaglar A, Kasper J (1993) Myoclonic seizures followed by grand-mal seizures during clozapine treatments. Am J Psychiatry 150 1128. 7. Brogmus KE, Lesh A (1995) Psychotropic drug-induced myoclonus (in German) Psyrhiatr Prax 2 2 77-9. 8. Liukkonen J, Koponen HJ, Kajander A (1992) Epileptic seizures during clozapine treatment. Clin Neurophamacol 15 (suppl 1) 226E. 9. Frank J, Ayd J (1995) Clozapine-induced myoclonic jerks and drop attacks. Int Drug Ther Newsletter 30 37-8. 10. Denney D, Stevens JR (1995) Clozapine and seizures. B i d Psychiatry 37: 427 - 33. 11. Welch J, Manschreck T, Redmond D (1994) Clozapine-induced seizures and EEG changes. J Neuropsychiatry Clin Neurosci 6: 250 - 6.
55
12. Mallow BA, Reese KB, Sato S et a1 (1994) Spectrum of EEG abnormality during clozapine treatment. Electroencephalogr Clin Neurophysiol 91: 205-11. 13. Littrell KH, Johnson CG, Schultz RE (1995) The phannacological management of clozapine related seizures. J Psychosoc Nurs Ment Health Service 3 3 42-3. 14. Pacia SV,Devinsky 0 (1994) Clozapine-related seizures: experience with 5629 patients. Neurology 44: 2247-9. 15. Meltzer HY, Ranjan R (1994) Valproic acid treatment of clozapine induced myoclonus. Am J Psychiatry 151: 1246-7. 16. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, (4th edn) (DSM-IV), Washington, D C APA. 17. Devinsky 0, Honigfeld G, Patin J (1991) Clozapine-related seizures. Neurology 41: 369-71. 18. Isik E (1997) Yeni antipisikotikler. In: Sizojreni (2nd edn) 162- 5. Kent Publishing, Ankara.
InternationalJournal of Psychiatry in Clinical Practice 1998 Volume 2 Pages 53 -55
a
53
.
Clozapine-induced myoclonic seizures and valproic acid
Int J Psych Clin Pract Downloaded from informahealthcare.com by The University of Manchester on 11/06/14 For personal use only.
ENDER TANER, BEHCET COSAR AND ERDAL ISIK Department of Psychiatry, Gazi University Faculty of Medicine, Ankara, Turkey
Within a 3-year period, in 220 patients receiving clozapine, we observed myoctonic seizures in two who had no previous epileptic history. Seizures appeared at the titration phase at relatively low doses, and resolved with the addition of valproic acid, allowing further increases of the clozapine dose to therapeutic levels. (Int j Psych Clin Pract 1998; 2: 53 - 55)
Correspondence Address Dr Ender Tuner, Bagis sokak, No: 171, 06660, Kiipikesat, Ankara, Turkey Tel: +90 312 4259833 Fax: +90 312 2869029
Received 6 October 1997; revised 11 November 1997; accepted for publication 16 December 1997
Keywords myoclonic seizures clozapine
INTRODUCTION
C
lozapine is used for the treatment of refractory schizophrenia, but since agranulocytosis is an important side-effect, this agent is not a first-line drug, but is reserved for treatment-resistant patients.’ Another problem that is rarely encountered but which needs clinical intervention, is the risk of convulsions. Seizures have been reported in psychotic patients receiving clozapine, the vast majority being tonic-~lonic.~-~ Cases of myoclonic seizures during clozapine therapy have also been reported:-’ as well as in animal models.” In a study of 5629 patients, the incidence of generalized tonic-clonic seizures was reported as 1.3%,of whom only one patient had myoclonic seizures, the authors suggesting that this low frequency may represent an underestimate, not a reflection of the true freq~ency.’~ The actual frequency of myoclonic seizures with clozapine is not known. In some reports, electroencephalographic changes denoting epileptic activity have also been ~ h ~ ~ n Valproic . ~ . ~ acid - ~is~one v of ~ the ~ agents used for the treatment of clozapine-induced myoclonic seizure^.^*'^.'^ We would like to report two cases of clozapine-induced myoclonic seizures which have been successfully treated with valproic acid.
CASE 1 Mr B, a 21-year-old university student, with the DSM-1V diagnosis of undifferentiated type schizophrenia,16showed loosening of associations, circumstantiality, impaired social functioning, impaired sense of self, depersonalization, delusions of persecution and first-rank Schneiderian ’
schizophrenia vulproic acid
delusions (thought insertion, thought withdrawal). Haloperidol was used at therapeutic dose for one month. The response was so discouraging that the medication was changed to clozapine. Having increased the clozapine dose by 25 mg every two days, haloperidol was tapered off and discontinued within one week. When the clozapine dose reached 400 mgday, we recognized myoclonic seizures, which were repetitive jerks of the upper extremities and head the seizures resolved 20 min after an oral 10 mg dose of diazepam. We decreased the clozapine dosage to 300 mg/day and an EEG was performed. This showed basal activity with partial seizures. There was no previous history of partial or generalized seizures. We added valproic acid at a dose of 800 mgday and titrated the clozapine dose to 400 mg/day. No further seizures occurred. There was satisfactory recovery of the positive symptoms, especially the loosened associations. With these doses, the patient was discharged from the hospital. At the 6-month follow-up, there were no complaints; either of the psychotic symptoms or the seizures. The patient is still on weekly follow-up. ,
CASE 2 Mr S, a 23-year-old high school graduate, received a DSM1V diagnosis of disorganized-type schizophrenia.l6 His first symptoms had started 4 years previously, and he had been treated in different hospitals during that period. His complaints on admission were of hearing voices saying things like: ‘Eat human meat; kill yourself; cut yourself, and a sense of fear that he could not describe. On mental
Int J Psych Clin Pract Downloaded from informahealthcare.com by The University of Manchester on 11/06/14 For personal use only.
54
E Tuner et a1
State examination he showed posturing of the left hand, decrease in personal hygiene, extreme loosening of associations, anxiety and irritability, an impaired sense of self, auditory hallucinations (directing type), thought block and paranoid delusions. For the last four years, he had been treated with anti-psychotics, including haloperidol, chlorpromazine, thioridazine and fluphenazine, but no satisfactory results were obtained except temporary suppression of auditory hallucinations. He was taken by his mother to traditional religious healers and for the last two months he had been drug-free. The patient was hospitalized and clozapine was started. Increasing by 25 mg every two days, the dose was titrated up to 425 mg/day, when myoclonic seizures were recognized. These were repetitive jerks of the upper extremities; when he tried to walk, he fell down, without loss of consciousness. There was no history of epileptic seizures. The seizures ceased after oral administration of 10 mg diazepam. The clozapine dose was decreased to 300 mg/ day. Biochemical measures were normal, and an EEG performed on the next day was unremarkable. The clozapine dose was gradually increased to 425 mg/day, when seizures recurred; we added valproic acid at a dose of 600 mg/day, and the seizures ceased. The valproic acid dose was increased to 1000 mg/day, and clozapine to 550 mgday. The auditory hallucinations and delusions resolved completely and there was also some improvement in the stereotypic movements, hand posture, and loosening of associations. No other seizures were seen. The patient was discharged from hospital on this treatment regime. In the outpatient clinic, the clozapine dose has been increased to 600 mgday; the patient is still on follow-up, and is free from seizures.
seizures. Sajatovic and Meltze? have reported four myoclonic seizures, two of which were followed by tonicclonic seizures, in 148 patients treated with clozapine. As shown in earlier reports, some tonic-clonic seizures are preceded by myoclonic s e i z ~ r e s . 3 Myoclonic ~ ~ * ~ ~ * seizures ~~ can be missed if the patient is not well observed, especially in the titration phase, but it is important to diagnose them because they can be forerunners of a generalized seizure. This may be the explanation for the high variation in the frequency of myoclonic seizures quoted in different studies, but it needs to be tested in future investigations. For myoclonic seizures, temporary discontinuation of clozapine does not seem to be necessary, since we merely reduced the dose of clozapine, which decreased the time needed for the re-titration of the clozapine dosage. Before starting clozapine treatment, EEG evaluation of the patient for epileptic foci which might be induced by clozapine could be beneficial, to detect high-risk patients, but would not seem to be cost-effective. It is important to enquire about the medical history of the patient before treatment. If there is a history of seizures, pretreatment evaluation and investigation with EEG in the titration phase should help to determine whether seizures are likely to occur, but this point needs further research. In vulnerable patients, antiepileptic treatment could be started, namely valproic acid for myoclonic jerks." The combination of valproic acid with clozapine has fewer additional side-effects than carbamazepine (decrease in or phenytoin (which increases liver leucocyte enzymes and decreases clozapine level^).^^'^ One important reminder is that the combined use of classical antipsychoticswith clozapine in the titration phase leads to a theoretical and practical increased risk of epileptic seizures, and such medication combinations should ideally be discontinued before clozapine treatment.
DISCUSSION Although myoclonic jerks occurred in our two cases, the early improvement in the symptoms of schizophrenia were so encouraging that we could not have changed the clozapine treatment. However, the myoclonic jerks seen during clozapine treatment would have caused difficulty unless valproic acid had been added. The appearance of seizures has been associated with the dosage," and with relatively fast increases of the dose in the titration phase." Pacia and Devinsky evaluated 5629 patients and showed that seizures appeared both at low ( < 300 rnglday) and high doses ( > 600 mg/day)." The seizures they reported were all of the generalized tonicclonic type, only one preceding generalized tonic-clonic
KEY POINTS 0
0
0
0
Myoclonic seizures tend to occur at the titration phase of clozapine treatment Myoclonic seizures observed during clozapine treatment are effectively treated with valproic acid Myoclonic seizures are underdiagnosed clinically but can be a forerunner of generalized seizures Rather than temporary discontinuation, a reduction of the clozapine dose is sufficient to relieve myoclonic seizures
REFERENCES 1. Kaplan HI, Sadock BJ, Grobb JA (1995) Kaplan and Sadock's synopsis of psychiatry (Middle East edn.) (7th edn) 932-5. Mass Publishing, Giza.
2. Liukkonen J, Koponen HJ, Nousiainen U (1992) Clinical picture and long term course of epileptic seizures that occur during clozapine treatment. Psychiatry Res 44: 107-12.
Int J Psych Clin Pract Downloaded from informahealthcare.com by The University of Manchester on 11/06/14 For personal use only.
Clozapine-induced myoclonic seizures 6 valproic acid
3. Sajatovic M, Meltzer HY (1996) Clozapine-induced myoclonus and generalised seizures. Biol Psychiatry 3 9 367 - 70. 4. Devinsky 0,Pacia SV (1994) Seizures during clozapine therapy. J Clin Psychiatry 55 (suppl B): 153-6. 5. Berman 1, Zalma A, DuRand CJ, Green A1 (1992) Clozapine induced myoclonic jerks and drop attacks (letter) J Clin Psychiatry 53: 329 - 30. 6. Gouzoulis E, Ozdaglar A, Kasper J (1993) Myoclonic seizures followed by grand-mal seizures during clozapine treatments. Am J Psychiatry 150 1128. 7. Brogmus KE, Lesh A (1995) Psychotropic drug-induced myoclonus (in German) Psyrhiatr Prax 2 2 77-9. 8. Liukkonen J, Koponen HJ, Kajander A (1992) Epileptic seizures during clozapine treatment. Clin Neurophamacol 15 (suppl 1) 226E. 9. Frank J, Ayd J (1995) Clozapine-induced myoclonic jerks and drop attacks. Int Drug Ther Newsletter 30 37-8. 10. Denney D, Stevens JR (1995) Clozapine and seizures. B i d Psychiatry 37: 427 - 33. 11. Welch J, Manschreck T, Redmond D (1994) Clozapine-induced seizures and EEG changes. J Neuropsychiatry Clin Neurosci 6: 250 - 6.
55
12. Mallow BA, Reese KB, Sato S et a1 (1994) Spectrum of EEG abnormality during clozapine treatment. Electroencephalogr Clin Neurophysiol 91: 205-11. 13. Littrell KH, Johnson CG, Schultz RE (1995) The phannacological management of clozapine related seizures. J Psychosoc Nurs Ment Health Service 3 3 42-3. 14. Pacia SV,Devinsky 0 (1994) Clozapine-related seizures: experience with 5629 patients. Neurology 44: 2247-9. 15. Meltzer HY, Ranjan R (1994) Valproic acid treatment of clozapine induced myoclonus. Am J Psychiatry 151: 1246-7. 16. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, (4th edn) (DSM-IV), Washington, D C APA. 17. Devinsky 0, Honigfeld G, Patin J (1991) Clozapine-related seizures. Neurology 41: 369-71. 18. Isik E (1997) Yeni antipisikotikler. In: Sizojreni (2nd edn) 162- 5. Kent Publishing, Ankara.
