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Carbamazepine and Its -10,11-Epoxide Metabolite in Plasma and CSF: Relationship to Antidepressant Response

Carbamazepine and Its -10,11-Epoxide Metabolite in Plasma and CSF: Relationship to Antidepressant... Abstract • Levels of carbamazepine and its -10,11-epoxide metabolite were measured in plasma and CSF of affectively ill patients treated only with carbamazepine for an average of 33 days at an average dosage of 1,055 mg/day. The CSF levels of carbamazepine were 2.06 μ/mL (ie, 31% of plasma levels, which equaled 6.55 μ/mL); CSF -10,11-epoxide concentrations averaged 0.91 μ/mL in 18 subjects (63% of those found in plasma). Carbamazepine levels in plasma or CSF were not related to degree of antidepressant or antimanic response. In contrast, concentrations of the -10,11-epoxide metabolite were correlated with the degree of antidepressant response. This preliminary study suggests the possibility that the -10,11-epoxide metabolite of carbamazepine may be related to the degree of clinical efficacy in affectively ill patients and may thus possess active psychotropic properties in man in addition to its reported anticonvulsant effects in animals. (Arch Gen Psychiatry 1983;40:673-676) References 1. Post RM, Ballenger JC, Reus VI, et al: Effects of carbamazepine in mania and depression . Read before the 131st annual meeting of the American Psychiatric Association, Atlanta, 1978. 2. Ballenger JC, Post RM: Therapeutic effects of carbamazepine in affective illness: A preliminary report . Commun Psychopharmacol 1978;2: 159-175. 3. Ballenger JC, Post RM: Carbamazepine (Tegretol) in manic-depressive illness: A new treatment . Am J Psychiatry 1980;137:782-790. 4. Post RM, Ballenger JC, Hare TA, et al: Lack of effect of carbamazepine on gamma-aminobutyric acid in cerebrospinal fluid . Neurology 1980;30: 1008-1011.Crossref 5. Post RM, Ballenger JC, Uhde TW, et al: Efficacy of carbamazepine in manic-depressive illness: Implications for underlying mechanisms, in Post RM, Ballenger JC (eds): Neurobiology of the Mood Disorders, Baltimore, Williams & Wilkins Co, in press. 6. Okuma T, Kishimoto A, Inoue K, et al: Anti-manic and prophylactic effects of carbamazepine on manic-depressive psychosis . Folia Psychiatr Neurol Jpn 1973;27:283-297. 7. Okuma T, Inanaga K, Otsuki S, et al: Comparison of the antimanic efficacy of carbamazepine and chlorpromazine: A double-blind controlled study . Psychopharmacology 1979;66:211-217.Crossref 8. Bertilsson L: Clinical pharmacokinetics of carbamazepine . Clin Pharmacokinet 1978;3:128-143.Crossref 9. Frigerio A, Morselli PL: Carbamazepine: Biotransformation . Adv Neurol 1975;11:295-308. 10. Gagneux AR: The chemistry of carbamazepine , in Birkmayer W (ed): Epileptic Seizures—Behaviour—Pain . Bern, Switzerland, Hans Huber Publisher, 1976, pp 120-126. 11. Johannessen SI, Gerna M, Bakke J, et al: CSF concentrations and serum protein binding of carbamazepine and carbamazepine-10,11-epoxide in epileptic patients . Br J Clin Pharmacol 1976;3:575-582.Crossref 12. McKange L, Tyrer JH, Eadie MJ: Factors influencing simultaneous concentrations of carbamazepine and its epoxide in plasma . Ther Drug Monit 1981;3:63-70.Crossref 13. Eichelbaum M, Bertilsson L, Lund L, et al: Plasma levels of carbamazepine and carbamazepine-10,11-epoxide during treatment of epilepsy . Eur J Clin Pharmacol 1976;9:417-421.Crossref 14. Eichelbaum M, Bertilsson L, Rane A, et al: Autoinduction of carbamazepine metabolism in man , in Richens A, Woodford FP (eds): Anticonvulsant Drugs and Enzyme Induction . Amsterdam, Associated Scientific Publishers. 1976. pp. 147-158. 15. Meinardi H: Other antiepileptic drugs—carbamazepine , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 487-496. 16. Christiansen J, Dam M: Influence of phenobarbital and diphenylhydantoin on plasma carbamazepine levels in patients with epilepsy . Ada Neurol Scand 1973;49:543-546.Crossref 17. Hooper WD, Dubetz DK, Eadie MJ, et al: Preliminary observations on the clinical pharmacology of carbamazepine (Tegretol) . Proc Aust Assoc Neurol 1974;11:189-198. 18. Johannessen SI, Strandjord RE: The concentration of carbamazepine (Tegretol) in serum and in cerebrospinal fluid in patients with epilepsy . Acta Neurol Scand 1972;48:445-446. 19. Morselli PL, Bossi L, Gerna M: Pharmacokinetic studies with carbamazepine in epileptic patients , in Birkmayer W (ed): Epileptic Seizures—Behaviour—Pain . Bern, Switzerland, Hans Huber Publisher, 1976, pp 141-150. 20. Schneider H: Carbamazepine: The influence of other antiepileptic drugs on its serum level , in Schneider H, Janz D, Gardner-Thorpe C, et al (eds): Clinical Pharmacology of Antiepileptic Drugs . New York, Springer-Verlag. 1975. pp. 189-195. 21. Morselli PL: Carbamazepine: Absorption, distribution and excretion . Adv Neurol 1975;11:279-293. 22. Rane A, Hojer B, Wilson JT: Kinetics of carbamazepine and its 10,11-epoxide metabolite in children . Clin Pharmacol Ther 1976;19:276283. 23. Pynnonen S, Sillanpaa M, Frey H et al: Carbamazepine and its 10,11-epoxide in children and adults with epilepsy . Eur J Clin Pharmacol 1977;11:129-133.Crossref 24. Cereghino JJ, Van Meter JC, Broch JT, et al: Preliminary observations of serum carbamazapine concentration in epileptic patients . Neurology 1973;23:357-366.Crossref 25. Tomson T, Tybring G, Bertilsson L, et al: Carbamazepine therapy in trigeminal neuralgia: Clinical effects in relation to plasma concentration . Arch Neurol 1980;37:699-703.Crossref 26. Monaco F, Riccio A, Benna P, et al: Further observation on carbamazepine plasma levels in epileptic patients: Relationships with therapeutic and side effects . Neurology 1976;26:936-943.Crossref 27. Spitzer R, Endicott J, Robins E: Research diagnostic criteria: Rationale and reliability . Arch Gen Psychiatry 1978;35:773-782.Crossref 28. Cereghino JJ: Serum carbamazepine concentration and clinical control . Adv Neurol 1975;11:309-329. 29. Dam M, Christiansen J: Interaction of propoxyphene with carbamazepine . Lancet 1977;2:509.Crossref 30. Goodwin FK, Post RM, Dunner DL, et al: Cerebrospinal fluid amine metabolites in affective illness: The probenecid technique . Am J Psychiatry 1973;130:73-79. 31. Kutt H: Carbamazepine: Chemistry and methods of determinations . Adv Neurol 1975;11:249-260. 32. Westenberg GHG, Van der Kleijn E, Oei TT, et al: Kinetics of carbamazepine and carbamazepine in epoxide determined by use of plasma and saliva . Clin Pharmacol Ther 1978;23:320-328. 33. Friis ML, Christiansen J: Carbamazepine, carbamazepine-10,11-epoxide and phenytoin concentrations in brain tissue of epileptic children . Acta Neurol Scand 1978;58:104-108.Crossref 34. Morselli PL, Barruzzi A, Gerna M, et al: Carbamazepine and carbamazepine-10,11-epoxide concentrations in human brain . Br J Clin Pharmacol 1977;4:535-540.Crossref 35. Johannessen SI, Barruzzi A, Gomeni R, et al: Further observations on carbamazepine and carbamazepine-10,11-epoxide kinetics in epileptic patients , in Gardner-Thorpe C, Janz D, Meinardi H, et al (eds): Antiepileptic Drug Monitoring . London, Pitman Publishing Ltd, 1977, pp 110-127. 36. Faigle JW, Feldmann FK, Baltzer V: Anticonvulsant effect of carbamazepine: An attempt to distinguish between the potency of the parent drug and its epoxide metabolite , in Gardner-Thorpe C, Janz D, Meinardi H, et al (eds): Antiepileptic Drug Monitoring . London, Pitman Publishing Ltd, 1977, pp 104-109. 37. Bertilsson L, Hojer B, Tybring G, et al: Autoinduction of carbamazepine metabolism in children examined by a stable isotope technique . Clin Pharmacol Ther 1980;27:83-88.Crossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of General Psychiatry American Medical Association

Carbamazepine and Its -10,11-Epoxide Metabolite in Plasma and CSF: Relationship to Antidepressant Response

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Publisher
American Medical Association
Copyright
Copyright © 1983 American Medical Association. All Rights Reserved.
ISSN
0003-990X
eISSN
1598-3636
DOI
10.1001/archpsyc.1983.04390010083010
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Abstract

Abstract • Levels of carbamazepine and its -10,11-epoxide metabolite were measured in plasma and CSF of affectively ill patients treated only with carbamazepine for an average of 33 days at an average dosage of 1,055 mg/day. The CSF levels of carbamazepine were 2.06 μ/mL (ie, 31% of plasma levels, which equaled 6.55 μ/mL); CSF -10,11-epoxide concentrations averaged 0.91 μ/mL in 18 subjects (63% of those found in plasma). Carbamazepine levels in plasma or CSF were not related to degree of antidepressant or antimanic response. In contrast, concentrations of the -10,11-epoxide metabolite were correlated with the degree of antidepressant response. This preliminary study suggests the possibility that the -10,11-epoxide metabolite of carbamazepine may be related to the degree of clinical efficacy in affectively ill patients and may thus possess active psychotropic properties in man in addition to its reported anticonvulsant effects in animals. (Arch Gen Psychiatry 1983;40:673-676) References 1. Post RM, Ballenger JC, Reus VI, et al: Effects of carbamazepine in mania and depression . Read before the 131st annual meeting of the American Psychiatric Association, Atlanta, 1978. 2. Ballenger JC, Post RM: Therapeutic effects of carbamazepine in affective illness: A preliminary report . Commun Psychopharmacol 1978;2: 159-175. 3. Ballenger JC, Post RM: Carbamazepine (Tegretol) in manic-depressive illness: A new treatment . Am J Psychiatry 1980;137:782-790. 4. Post RM, Ballenger JC, Hare TA, et al: Lack of effect of carbamazepine on gamma-aminobutyric acid in cerebrospinal fluid . Neurology 1980;30: 1008-1011.Crossref 5. Post RM, Ballenger JC, Uhde TW, et al: Efficacy of carbamazepine in manic-depressive illness: Implications for underlying mechanisms, in Post RM, Ballenger JC (eds): Neurobiology of the Mood Disorders, Baltimore, Williams & Wilkins Co, in press. 6. Okuma T, Kishimoto A, Inoue K, et al: Anti-manic and prophylactic effects of carbamazepine on manic-depressive psychosis . Folia Psychiatr Neurol Jpn 1973;27:283-297. 7. Okuma T, Inanaga K, Otsuki S, et al: Comparison of the antimanic efficacy of carbamazepine and chlorpromazine: A double-blind controlled study . Psychopharmacology 1979;66:211-217.Crossref 8. Bertilsson L: Clinical pharmacokinetics of carbamazepine . Clin Pharmacokinet 1978;3:128-143.Crossref 9. Frigerio A, Morselli PL: Carbamazepine: Biotransformation . Adv Neurol 1975;11:295-308. 10. Gagneux AR: The chemistry of carbamazepine , in Birkmayer W (ed): Epileptic Seizures—Behaviour—Pain . Bern, Switzerland, Hans Huber Publisher, 1976, pp 120-126. 11. Johannessen SI, Gerna M, Bakke J, et al: CSF concentrations and serum protein binding of carbamazepine and carbamazepine-10,11-epoxide in epileptic patients . Br J Clin Pharmacol 1976;3:575-582.Crossref 12. McKange L, Tyrer JH, Eadie MJ: Factors influencing simultaneous concentrations of carbamazepine and its epoxide in plasma . Ther Drug Monit 1981;3:63-70.Crossref 13. Eichelbaum M, Bertilsson L, Lund L, et al: Plasma levels of carbamazepine and carbamazepine-10,11-epoxide during treatment of epilepsy . Eur J Clin Pharmacol 1976;9:417-421.Crossref 14. Eichelbaum M, Bertilsson L, Rane A, et al: Autoinduction of carbamazepine metabolism in man , in Richens A, Woodford FP (eds): Anticonvulsant Drugs and Enzyme Induction . Amsterdam, Associated Scientific Publishers. 1976. pp. 147-158. 15. Meinardi H: Other antiepileptic drugs—carbamazepine , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 487-496. 16. Christiansen J, Dam M: Influence of phenobarbital and diphenylhydantoin on plasma carbamazepine levels in patients with epilepsy . Ada Neurol Scand 1973;49:543-546.Crossref 17. Hooper WD, Dubetz DK, Eadie MJ, et al: Preliminary observations on the clinical pharmacology of carbamazepine (Tegretol) . Proc Aust Assoc Neurol 1974;11:189-198. 18. Johannessen SI, Strandjord RE: The concentration of carbamazepine (Tegretol) in serum and in cerebrospinal fluid in patients with epilepsy . Acta Neurol Scand 1972;48:445-446. 19. Morselli PL, Bossi L, Gerna M: Pharmacokinetic studies with carbamazepine in epileptic patients , in Birkmayer W (ed): Epileptic Seizures—Behaviour—Pain . Bern, Switzerland, Hans Huber Publisher, 1976, pp 141-150. 20. Schneider H: Carbamazepine: The influence of other antiepileptic drugs on its serum level , in Schneider H, Janz D, Gardner-Thorpe C, et al (eds): Clinical Pharmacology of Antiepileptic Drugs . New York, Springer-Verlag. 1975. pp. 189-195. 21. Morselli PL: Carbamazepine: Absorption, distribution and excretion . Adv Neurol 1975;11:279-293. 22. Rane A, Hojer B, Wilson JT: Kinetics of carbamazepine and its 10,11-epoxide metabolite in children . Clin Pharmacol Ther 1976;19:276283. 23. Pynnonen S, Sillanpaa M, Frey H et al: Carbamazepine and its 10,11-epoxide in children and adults with epilepsy . Eur J Clin Pharmacol 1977;11:129-133.Crossref 24. Cereghino JJ, Van Meter JC, Broch JT, et al: Preliminary observations of serum carbamazapine concentration in epileptic patients . Neurology 1973;23:357-366.Crossref 25. Tomson T, Tybring G, Bertilsson L, et al: Carbamazepine therapy in trigeminal neuralgia: Clinical effects in relation to plasma concentration . Arch Neurol 1980;37:699-703.Crossref 26. Monaco F, Riccio A, Benna P, et al: Further observation on carbamazepine plasma levels in epileptic patients: Relationships with therapeutic and side effects . Neurology 1976;26:936-943.Crossref 27. Spitzer R, Endicott J, Robins E: Research diagnostic criteria: Rationale and reliability . Arch Gen Psychiatry 1978;35:773-782.Crossref 28. Cereghino JJ: Serum carbamazepine concentration and clinical control . Adv Neurol 1975;11:309-329. 29. Dam M, Christiansen J: Interaction of propoxyphene with carbamazepine . Lancet 1977;2:509.Crossref 30. Goodwin FK, Post RM, Dunner DL, et al: Cerebrospinal fluid amine metabolites in affective illness: The probenecid technique . Am J Psychiatry 1973;130:73-79. 31. Kutt H: Carbamazepine: Chemistry and methods of determinations . Adv Neurol 1975;11:249-260. 32. Westenberg GHG, Van der Kleijn E, Oei TT, et al: Kinetics of carbamazepine and carbamazepine in epoxide determined by use of plasma and saliva . Clin Pharmacol Ther 1978;23:320-328. 33. Friis ML, Christiansen J: Carbamazepine, carbamazepine-10,11-epoxide and phenytoin concentrations in brain tissue of epileptic children . Acta Neurol Scand 1978;58:104-108.Crossref 34. Morselli PL, Barruzzi A, Gerna M, et al: Carbamazepine and carbamazepine-10,11-epoxide concentrations in human brain . Br J Clin Pharmacol 1977;4:535-540.Crossref 35. Johannessen SI, Barruzzi A, Gomeni R, et al: Further observations on carbamazepine and carbamazepine-10,11-epoxide kinetics in epileptic patients , in Gardner-Thorpe C, Janz D, Meinardi H, et al (eds): Antiepileptic Drug Monitoring . London, Pitman Publishing Ltd, 1977, pp 110-127. 36. Faigle JW, Feldmann FK, Baltzer V: Anticonvulsant effect of carbamazepine: An attempt to distinguish between the potency of the parent drug and its epoxide metabolite , in Gardner-Thorpe C, Janz D, Meinardi H, et al (eds): Antiepileptic Drug Monitoring . London, Pitman Publishing Ltd, 1977, pp 104-109. 37. Bertilsson L, Hojer B, Tybring G, et al: Autoinduction of carbamazepine metabolism in children examined by a stable isotope technique . Clin Pharmacol Ther 1980;27:83-88.Crossref

Journal

Archives of General PsychiatryAmerican Medical Association

Published: Jun 1, 1983

References