- Email: [email protected]
VALPROIC ACID AND RISPERIDONE
LETTERS TO THE EDITOR
use for psychosis, tic disorders, and Tourette’s syndrome, neuroleptics are commonly used for aggression and conduct disorder and in individuals with mental retardation (Green, 1995). Neuroleptics are usually given as an oral preparation once or more a day, often with some difficulty when a child is either unable to swallow the medication or noncompliant with the treatment. Despite the potential benefits of using depot preparations, they are used rarely in children (Barnes, 1991). A review of the literature revealed no papers addressing this issue in children and adolescents. We describe the use of haloperidol decanoate in an 11-yearold boy as an example of the use of a depot form of neuroleptic as an alternative. I.F. is an 11-year-old boy with a pervasive developmental disorder who has had behavior problems since his toddler years. These behavior problems were often extreme enough to require visits to the psychiatric emergency department or police intervention. Recently, his behavior problems escalated and hospitalization was necessary. He presented to the hospital with a 2- to 3-month episodic exacerbation of conflict with his mother. He showed significant hostility toward her, often attacking her physically. These episodes were often precipitated when she attempted to have him follow a more normal routine that interfered with his morbid preoccupation with “Dragon Ball Z,” a television series. Of the various medication combinations that had been tried, I.F.’s mother reported that haloperidol and clonidine were the most effective. These had been started because of I.F.’s history of Tourette’s syndrome. His mother also reported that the addition of trazodone for temper tantrums was successful. While the effectiveness of the medications was not in doubt (indeed, he fared well on the combination during the hospitalization), his compliance was poor. His mother frequently found pills in his room and in the bathroom. He stated that sometimes he did not take the medication. Lack of compliance was affecting not only his functioning at home, but also his mother’s ability to manage him. After discharge, he was noncompliant with the medications and he had to be readmitted 1 week later. Given the demonstrated effectiveness of the medications (and the few side effects noted, mainly mild sedation), we wanted to continue this regimen. The benefits and risks of haloperidol decanoate were explained to both the patient and his mother. The mother accepted the modality with few questions; the patient’s primary concerns were with pain associated with injection. He was reassured, and the medication was started. On the basis of his oral doses of haloperidol at the time (2–5 mg/day), we started with 50 mg of haloperidol decanoate via intramuscular injections. Approximately 3 months after initiation of haloperidol decanoate treatment (initial dose of 50 mg injected in the anterior femoral area, and two consecutive injections of 100 mg
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each in the same site at monthly intervals), the overall picture includes a decrease in violence and aggression, improved motivation, and decreased visits to the emergency department. No extrapyramidal side effects were noted, I.F.’s weight remained stable, and no side effects were reported. The only complaint he continues to relate is the “energy-draining pills” (trazodone). He remains perseverative and concrete, but his egocentricity and hostility lack the previously observed serious aggression. Because of improved adherence, explosive behavior is less frequent than when taking haloperidol orally. He seems to tolerate the decanoate form well, except for pain for 2 days at the site of the injection that is amenable to analgesics and occasional reports of sedation in school. To our knowledge, this is the first reported case of a prepubertal patient given a depot form of neuroleptic. In this case, compliance made the patient’s behavior increasingly stable. Such a formula could be useful in those cases in which a longterm prescription is contemplated and when compliance, or simply the difficulties of administering daily doses of a neuroleptic, is an issue. Issues of dosing, metabolism, and long-term effects need further consideration if these preparations are to be used more widely (Chouinard et al., 1989; Pabis et al., 1996). Norman Alessi, M.D. Iyad Alkhouri, M.D. Thomas Fluent, M.D. Paul Quinlan, D.O. Karen Williams, M.Ed. Division of Child and Adolescent Psychiatry Department of Psychiatry University of Michigan, Ann Arbor Barnes T (1991), Depot antipsychotic drugs and prevention of relapse. Clin Neuropharmacol 14(suppl 2):S1–S6 Chouinard G, Annable L, Campbell W (1989), A randomized clinical trial of haloperidol decanoate and fluphenazine decanoate in the outpatient treatment of schizophrenia. J Clin Psychopharmacol 9:247–253 Green WH (1995), Child and Adolescent Clinical Psychopharmacology. Baltimore: Williams & Wilkins Pabis DJ, Dorson PG, Crismon ML (1996), Evaluation of inpatient depot antipsychotic prescribing. Ann Pharmacother 30:1381–1386
VALPROIC ACID AND RISPERIDONE To the Editor: The combination of valproic acid and risperidone is frequently used for psychiatric patients, in particular those with mood disorders and aggressive behavior. Hepatotoxicity is a rare but potentially lethal side effect of valproic acid, particularly in children (Levy et al., 1990). We report a drug interaction between risperidone and valproic acid that led to significantly increased levels of valproic acid. No previous reports have been published about this interaction.
J . A M . AC A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 8 , AU G U S T 2 0 0 1
LETTERS TO THE EDITOR
The patient, a 10-year-old boy, was referred to our clinic because of mood swings with increasingly aggressive behavior toward his caregivers. Treatment with valproic acid was initiated, and the dose was gradually titrated up to 1,750 mg/day. The medication was well tolerated, and the valproate serum levels (143 mg/L) remained within therapeutic range (50–150 mg/L). Liver enzymes remained within normal limits. After being treated with 1,750 mg/day for 10 days with only mild improvement of symptoms, risperidone 2 mg/day was added, which was increased to 3 mg/day on day 4. On the fifth day after risperidone was started, the patient’s symptoms had further improved but the valproic acid level had risen well above the therapeutic range to 191 mg/L. Decreasing the dose of valproic acid to 1,000 mg/day led to normalization of the level to 108 mg/L within 3 days, and stabilization thereafter. The patient continued to take the same doses of valproic acid and risperidone and eventually achieved good behavioral control. The addition of risperidone to valproic acid produced a significant increase in the steady-state concentrations of valproic acid. Risperidone is metabolized by cytochrome P-450 2D6, and in vitro studies show it to be only a relatively weak inhibitor of this enzyme, while in vivo studies have not shown evidence of enzyme inhibition (Prior et al., 1999). Valproic acid is mainly glucuronidized by hepatic enzymes, while hepatotoxic metabolites formed by catabolyzation through the cytochrome P-450 account for less than 10% of the dose (Levy et al., 1990). Therefore, risperidone is not expected to have a significant effect on the clearance of valproic acid. Alternatively, the high proteinbinding capacity of risperidone could lead to a competition for protein-binding with the high protein-binding capacity of valproic acid, leading to displacement of valproic acid from plasma protein-binding sites. Pieter Joost van Wattum, M.D. Child Study Center Yale University School of Medicine New Haven, CT Levy RH, Rettenmeier AW, Anderson GD et al. (1990), Effects of polytherapy with phenytoin, carbamazepine, and stiripentol? on formation of 4ene-valproate, a hepatotoxic metabolite of valproic acid. Clin Pharmacol Ther 48:225–235 Prior TI, Chue TS, Tibbo P, Baker BG (1999), Drug metabolism and atypical antipsychotics. Eur Neuropsychopharmacol 9:301–309
Commentary: This is the first report of a pharmacokinetic interaction between valproic acid and risperidone. Careful monitoring of the serum concentration of valproate after the addition of risperidone allowed the author to promptly identify a substantial elevation in valproate level even in the absence of clinical signs of drug toxicity. Valproic acid is primarily metabolized by the endomitochondrial β-oxidation pathways and only in smaller
J . A M . AC A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 8 , AU G U S T 2 0 0 1
part by the microsomal oxidase enzymes containing cytochrome P-450 2D6 (Wilder, 1992). Risperidone is metabolized by 2D6, upon which it also exerts a mild inhibitory effect (Mannens et al., 1993). Although the 2D6 route is a relatively minor metabolic pathway for valproic acid, it is not clinically insignificant. In fact, drugs that induce 2D6, such as phenytoin and carbamazepine, have been found to reduce valproate serum levels by about 30% (Wilder, 1992). It is possible that at the high doses of valproate used in the case reported in this letter, even a slight inhibition of a secondary metabolic pathway such as the 2D6 might have caused a significant increase in drug level. A more likely explanation, however, is a displacement of valproate by risperidone from plasma proteins, also described in the letter. Valproate is highly bound to plasma proteins, and displacement leads to impaired clearance, higher serum levels, and increase in the unbound portion of drug (“free drug”), which is available for pharmacological action. This change in the ratio between protein-bound and unbound drug further increases the likelihood of adverse events. A similar interaction is known to occur between valproate and acetylsalicylic acid (Goulden et al., 1987) or naproxen (Grimaldi et al., 1984). For valproate, the usual therapeutic range of serum concentrations for the treatment of mania is 50 to 125 μg/mL (Bowden et al., 1996). Higher levels are more likely to cause neurological toxicity, with tremor, hyperactivity, and drowsiness. However, the most dangerous side effects of valproate, liver toxicity and thrombocytopenia, are not dose-dependent and not more likely to occur at higher plasma levels than at lower ones. A final comment relates to the clinical and research implications of the complexity of drug pharmacokinetics and metabolism, also considering the considerable individual variability among patients. On one hand, this complexity should humble us as clinicians and, in general, discourage the use of combined pharmacological treatments if simpler alternatives exist. On the other hand, it should spur more research on the pharmacokinetic, metabolic, and pharmacodynamic interactions between drugs in those cases in which a clear rationale for combined use can be identified. Benedetto Vitiello, M.D. National Institute of Mental Health Bethesda, MD Bowden CL, Janicak PG, Orsulak P et al. (1996), Relation of serum valproate concentration to response in mania. Am J Psychiatry 153:765–770 Goulden KJ, Dooley JM, Camfield PR, Fraser AD (1987), Clinical valproate toxicity induced by acetylsalicylic acid. Neurology 37:1392–1394 Grimaldi R, Lechini S, Crema F, Perucca E (1984), In vivo protein binding interaction between valproic acid and naproxen. Eur J Drug Metab Pharmacokinet 9:359–363 Mannens G, Huang M-L, Meuldermans W, Hendrickx J, Woestenborghs R, Heykants J (1993), Absorption, metabolism and excretion of risperidone in humans: a summary. Drug Metab Dispos 21:1134–1141 Wilder BJ (1992), Pharmacokinetics of valproate and carbamazepine. J Clin Psychopharmacol 12:64S–68S
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use for psychosis, tic disorders, and Tourette’s syndrome, neuroleptics are commonly used for aggression and conduct disorder and in individuals with mental retardation (Green, 1995). Neuroleptics are usually given as an oral preparation once or more a day, often with some difficulty when a child is either unable to swallow the medication or noncompliant with the treatment. Despite the potential benefits of using depot preparations, they are used rarely in children (Barnes, 1991). A review of the literature revealed no papers addressing this issue in children and adolescents. We describe the use of haloperidol decanoate in an 11-yearold boy as an example of the use of a depot form of neuroleptic as an alternative. I.F. is an 11-year-old boy with a pervasive developmental disorder who has had behavior problems since his toddler years. These behavior problems were often extreme enough to require visits to the psychiatric emergency department or police intervention. Recently, his behavior problems escalated and hospitalization was necessary. He presented to the hospital with a 2- to 3-month episodic exacerbation of conflict with his mother. He showed significant hostility toward her, often attacking her physically. These episodes were often precipitated when she attempted to have him follow a more normal routine that interfered with his morbid preoccupation with “Dragon Ball Z,” a television series. Of the various medication combinations that had been tried, I.F.’s mother reported that haloperidol and clonidine were the most effective. These had been started because of I.F.’s history of Tourette’s syndrome. His mother also reported that the addition of trazodone for temper tantrums was successful. While the effectiveness of the medications was not in doubt (indeed, he fared well on the combination during the hospitalization), his compliance was poor. His mother frequently found pills in his room and in the bathroom. He stated that sometimes he did not take the medication. Lack of compliance was affecting not only his functioning at home, but also his mother’s ability to manage him. After discharge, he was noncompliant with the medications and he had to be readmitted 1 week later. Given the demonstrated effectiveness of the medications (and the few side effects noted, mainly mild sedation), we wanted to continue this regimen. The benefits and risks of haloperidol decanoate were explained to both the patient and his mother. The mother accepted the modality with few questions; the patient’s primary concerns were with pain associated with injection. He was reassured, and the medication was started. On the basis of his oral doses of haloperidol at the time (2–5 mg/day), we started with 50 mg of haloperidol decanoate via intramuscular injections. Approximately 3 months after initiation of haloperidol decanoate treatment (initial dose of 50 mg injected in the anterior femoral area, and two consecutive injections of 100 mg
866
each in the same site at monthly intervals), the overall picture includes a decrease in violence and aggression, improved motivation, and decreased visits to the emergency department. No extrapyramidal side effects were noted, I.F.’s weight remained stable, and no side effects were reported. The only complaint he continues to relate is the “energy-draining pills” (trazodone). He remains perseverative and concrete, but his egocentricity and hostility lack the previously observed serious aggression. Because of improved adherence, explosive behavior is less frequent than when taking haloperidol orally. He seems to tolerate the decanoate form well, except for pain for 2 days at the site of the injection that is amenable to analgesics and occasional reports of sedation in school. To our knowledge, this is the first reported case of a prepubertal patient given a depot form of neuroleptic. In this case, compliance made the patient’s behavior increasingly stable. Such a formula could be useful in those cases in which a longterm prescription is contemplated and when compliance, or simply the difficulties of administering daily doses of a neuroleptic, is an issue. Issues of dosing, metabolism, and long-term effects need further consideration if these preparations are to be used more widely (Chouinard et al., 1989; Pabis et al., 1996). Norman Alessi, M.D. Iyad Alkhouri, M.D. Thomas Fluent, M.D. Paul Quinlan, D.O. Karen Williams, M.Ed. Division of Child and Adolescent Psychiatry Department of Psychiatry University of Michigan, Ann Arbor Barnes T (1991), Depot antipsychotic drugs and prevention of relapse. Clin Neuropharmacol 14(suppl 2):S1–S6 Chouinard G, Annable L, Campbell W (1989), A randomized clinical trial of haloperidol decanoate and fluphenazine decanoate in the outpatient treatment of schizophrenia. J Clin Psychopharmacol 9:247–253 Green WH (1995), Child and Adolescent Clinical Psychopharmacology. Baltimore: Williams & Wilkins Pabis DJ, Dorson PG, Crismon ML (1996), Evaluation of inpatient depot antipsychotic prescribing. Ann Pharmacother 30:1381–1386
VALPROIC ACID AND RISPERIDONE To the Editor: The combination of valproic acid and risperidone is frequently used for psychiatric patients, in particular those with mood disorders and aggressive behavior. Hepatotoxicity is a rare but potentially lethal side effect of valproic acid, particularly in children (Levy et al., 1990). We report a drug interaction between risperidone and valproic acid that led to significantly increased levels of valproic acid. No previous reports have been published about this interaction.
J . A M . AC A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 8 , AU G U S T 2 0 0 1
LETTERS TO THE EDITOR
The patient, a 10-year-old boy, was referred to our clinic because of mood swings with increasingly aggressive behavior toward his caregivers. Treatment with valproic acid was initiated, and the dose was gradually titrated up to 1,750 mg/day. The medication was well tolerated, and the valproate serum levels (143 mg/L) remained within therapeutic range (50–150 mg/L). Liver enzymes remained within normal limits. After being treated with 1,750 mg/day for 10 days with only mild improvement of symptoms, risperidone 2 mg/day was added, which was increased to 3 mg/day on day 4. On the fifth day after risperidone was started, the patient’s symptoms had further improved but the valproic acid level had risen well above the therapeutic range to 191 mg/L. Decreasing the dose of valproic acid to 1,000 mg/day led to normalization of the level to 108 mg/L within 3 days, and stabilization thereafter. The patient continued to take the same doses of valproic acid and risperidone and eventually achieved good behavioral control. The addition of risperidone to valproic acid produced a significant increase in the steady-state concentrations of valproic acid. Risperidone is metabolized by cytochrome P-450 2D6, and in vitro studies show it to be only a relatively weak inhibitor of this enzyme, while in vivo studies have not shown evidence of enzyme inhibition (Prior et al., 1999). Valproic acid is mainly glucuronidized by hepatic enzymes, while hepatotoxic metabolites formed by catabolyzation through the cytochrome P-450 account for less than 10% of the dose (Levy et al., 1990). Therefore, risperidone is not expected to have a significant effect on the clearance of valproic acid. Alternatively, the high proteinbinding capacity of risperidone could lead to a competition for protein-binding with the high protein-binding capacity of valproic acid, leading to displacement of valproic acid from plasma protein-binding sites. Pieter Joost van Wattum, M.D. Child Study Center Yale University School of Medicine New Haven, CT Levy RH, Rettenmeier AW, Anderson GD et al. (1990), Effects of polytherapy with phenytoin, carbamazepine, and stiripentol? on formation of 4ene-valproate, a hepatotoxic metabolite of valproic acid. Clin Pharmacol Ther 48:225–235 Prior TI, Chue TS, Tibbo P, Baker BG (1999), Drug metabolism and atypical antipsychotics. Eur Neuropsychopharmacol 9:301–309
Commentary: This is the first report of a pharmacokinetic interaction between valproic acid and risperidone. Careful monitoring of the serum concentration of valproate after the addition of risperidone allowed the author to promptly identify a substantial elevation in valproate level even in the absence of clinical signs of drug toxicity. Valproic acid is primarily metabolized by the endomitochondrial β-oxidation pathways and only in smaller
J . A M . AC A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 8 , AU G U S T 2 0 0 1
part by the microsomal oxidase enzymes containing cytochrome P-450 2D6 (Wilder, 1992). Risperidone is metabolized by 2D6, upon which it also exerts a mild inhibitory effect (Mannens et al., 1993). Although the 2D6 route is a relatively minor metabolic pathway for valproic acid, it is not clinically insignificant. In fact, drugs that induce 2D6, such as phenytoin and carbamazepine, have been found to reduce valproate serum levels by about 30% (Wilder, 1992). It is possible that at the high doses of valproate used in the case reported in this letter, even a slight inhibition of a secondary metabolic pathway such as the 2D6 might have caused a significant increase in drug level. A more likely explanation, however, is a displacement of valproate by risperidone from plasma proteins, also described in the letter. Valproate is highly bound to plasma proteins, and displacement leads to impaired clearance, higher serum levels, and increase in the unbound portion of drug (“free drug”), which is available for pharmacological action. This change in the ratio between protein-bound and unbound drug further increases the likelihood of adverse events. A similar interaction is known to occur between valproate and acetylsalicylic acid (Goulden et al., 1987) or naproxen (Grimaldi et al., 1984). For valproate, the usual therapeutic range of serum concentrations for the treatment of mania is 50 to 125 μg/mL (Bowden et al., 1996). Higher levels are more likely to cause neurological toxicity, with tremor, hyperactivity, and drowsiness. However, the most dangerous side effects of valproate, liver toxicity and thrombocytopenia, are not dose-dependent and not more likely to occur at higher plasma levels than at lower ones. A final comment relates to the clinical and research implications of the complexity of drug pharmacokinetics and metabolism, also considering the considerable individual variability among patients. On one hand, this complexity should humble us as clinicians and, in general, discourage the use of combined pharmacological treatments if simpler alternatives exist. On the other hand, it should spur more research on the pharmacokinetic, metabolic, and pharmacodynamic interactions between drugs in those cases in which a clear rationale for combined use can be identified. Benedetto Vitiello, M.D. National Institute of Mental Health Bethesda, MD Bowden CL, Janicak PG, Orsulak P et al. (1996), Relation of serum valproate concentration to response in mania. Am J Psychiatry 153:765–770 Goulden KJ, Dooley JM, Camfield PR, Fraser AD (1987), Clinical valproate toxicity induced by acetylsalicylic acid. Neurology 37:1392–1394 Grimaldi R, Lechini S, Crema F, Perucca E (1984), In vivo protein binding interaction between valproic acid and naproxen. Eur J Drug Metab Pharmacokinet 9:359–363 Mannens G, Huang M-L, Meuldermans W, Hendrickx J, Woestenborghs R, Heykants J (1993), Absorption, metabolism and excretion of risperidone in humans: a summary. Drug Metab Dispos 21:1134–1141 Wilder BJ (1992), Pharmacokinetics of valproate and carbamazepine. J Clin Psychopharmacol 12:64S–68S
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