Skip to main content
SpringerLink
Log in

Valproic Acid

A Review of its Pharmacology and Therapeutic Potential in Indications Other than Epilepsy

  • Drug Evaluation
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Synopsis

Valproic acid, a simple branched-chain fatty acid, was originally developed for the treatment of epilepsy, but also has mood-stabilising, anxiolytic, antimigraine and antinociceptive effects, and has been evaluated in the management of various other disorders, particularly psychiatric conditions.

Valproic acid has been shown to be effective in patients with bipolar and schizoaffective disorders, including those resistant to lithium and carbamazepine. Response was achieved in approximately 50 to 70% of patients treated with valproic acid monotherapy for acute manic episodes in noncomparative and placebo-controlled studies. Long term prophylaxis against recurrent manic and depressive episodes has been demonstrated in approximately 65 to 70% of patients receiving the drug as monotherapy or in combination with other drugs in non-comparative studies. Moreover, valproic acid appears to be effective in rapid-cycling patients and those with mixed or dysphoric mania or neurological abnormalities, who tend to respond poorly to lithium. Evidence from preliminary studies and case reports suggests that valproic acid may prove useful for management of other psychiatric conditions, including panic attacks and aggressive behaviour.

Valproic acid was found to provide prophylaxis against migraine with or without aura, and also showed promise in the treatment of acute migraine attacks, and as prophylaxis against refractory chronic daily headache. Preliminary findings suggest that valproic acid may be of value in the management of severe refractory pain, including trigeminal neuralgia, lancinating pain, and neuropathic pain associated with advanced cancer.

Valproic acid is generally well tolerated, does not induce hepatic drug metabolism and has a low propensity for interactions with psychotropic agents. However, as has been observed with several other antiepileptic drugs, it is teratogenic and can cause elevated hepatic enzyme levels and rare, fatal hepatotoxicity. Weight gain and alopecia are relatively common.

Thus, while few comparative data are available, valproic acid has demonstrated considerable potential as a first-line therapy for the management of bipolar or schizoaffective disorder, particularly for patients resistant to, or intolerant of, lithium or carbamazepine and those with rapid cycling or mixed mania. It has also shown potential in the treatment of refractory migraine and other types of chronic headache. Further studies are warranted in other psychiatric conditions, including panic attacks, and in severe refractory pain.

Pharmacology

In addition to its anticonvulsant activity, valproic acid has demonstrated anxiolytic, mood-stabilising, antimigraine and antinociceptive effects. These activities appear to be mediated, at least in part, by its effects on γ-aminobutyric acid (GABA) -mediated neurotransmission. Valproic acid increases CNS concentrations of GABA, possibly by increasing its synthesis and/or inhibiting its catabolism. Valproic acid has also been reported to decrease neurotransmission by the excitatory amino acids γ-hydroxybutyric, aspartic and glutamic acids, to inhibit cell firing induced by N-methyl-D-aspartate, and to exert a direct neuronal membrane depressant effect, via modulation of sodium and potassium conductance. Moreover, it may also modulate noradrenergic and serotonergic neurotransmission. Valproic acid has also been reported to alter circadian rhythms in animals, possibly via effects on GABAergic functions, and this may be important in its mood-stabilising and antimigraine effects.

As with other antiepileptic drugs, valproic acid has been shown to adversely affect psychomotor performance, but it appears to cause less psychomotor and cognitive impairment than phenobarbital (phenobarbitone) or phenytoin.

Oral formulations of valproic acid are almost completely absorbed after administration, and dose-proportional peak plasma concentrations are attained within 1 to 3 hours (uncoated tablets), 3 to 5 hours (enteric-coated tablets) or 5 to 10 hours (controlled-release tablets). Administration with food decreases the rate, but not the extent, of absorption. Maximum plasma concentrations range from 25 to 100 mg/L following administration of 250 to 1000mg doses, in uncoated tablet or capsule form. The apparent volume of distribution (Vd) is small (0.1 to 0.4 L/kg) and plasma protein binding is approximately 90% in healthy persons, although the unbound proportion increases at total plasma valproic acid concentrations >80 mg/L. Metabolism occurs by at least 5 major pathways, and the drug is eliminated by renal and faecal routes, mostly (97%) in metabolised form. Plasma clearance ranges from 0.4 to 0.6 L/h, and plasma elimination half-life (t½β) from 9 to 16 hours, in healthy volunteers. Plasma clearance of valproate is enhanced by coadministration with hepatic enzyme-inducing drugs, resulting in decreased t½β. Plasma protein binding was decreased in pregnancy and in patients with impaired renal function or diabetes mellitus, while decreased clearance of unbound valproate was noted in patients with alcoholic cirrhosis of the liver. The t½β, Vd and proportion of unbound valproate were increased in neonates, while plasma clearance was increased and t½β decreased in children. In the elderly, unbound valproate concentrations were increased, as a result of decreased clearance and plasma protein binding.

Therapeutic Potential

Valproic acid has been shown to be effective and well tolerated in the treatment of patients with bipolar and schizoaffective disorders, including those resistant to lithium and carbamazepine. When given alone or (more commonly) in combination with other agents in noncomparative studies, it provided prophylaxis against recurrent manic and depressive episodes for prolonged periods in approximately 65 to 70% of patients. A small number of comparative and noncomparative studies have shown that valproic acid monotherapy is effective in controlling acute manic episodes in approximately 50 to 70% of patients, and efficacy comparable to that of lithium was demonstrated in one double-blind, placebo-controlled study involving 179 patients. Moreover, oral loading to reach therapeutic concentrations within 24 hours achieved control of acute mania within 5 days. Valproic acid was more effective in mania than depression, and appeared particularly effective in patients with rapid-cycling bipolar disorder, dysphoric or mixed mania, electro-encephalographic abnormalities or psychiatric illness following closed head injury. Evidence from preliminary studies and case reports suggests that valproic acid may prove useful in the treatment of other psychiatric disorders, including panic attacks and aggressive behaviour.

In several studies, mostly in small numbers of patients, valproic acid provided prophylaxis against migraine with or without aura, including that resistant to standard therapies, decreasing the frequency of attacks versus baseline or placebo. Valproic acid was also reported to be effective in 58% of acute migraine attacks, and to provide prophylaxis against refractory chronic daily headache in 2 small noncomparative studies.

Preliminary data, mostly from nonblinded case series, suggest that valproic acid may prove useful in the management of severe refractory pain, including trigeminal neuralgia, lancinating pain and neuropathic pain associated with advanced cancer.

Tolerability

The majority of tolerability data on valproic acid are derived from patients receiving the drug for management of epilepsy. However, the pattern of adverse events appears similar in epileptic and nonepileptic indications. The most common adverse effects are gastrointestinal disturbances (dyspepsia, nausea, anorexia, particularly at the start of therapy), weight gain, CNS effects (tremor, drowsiness, ataxia) and transient hair loss. Enteric coated formulations of valproic acid are associated with a considerably lower incidence of gastrointestinal adverse events (3 to 6% of patients) than uncoated preparations. Elevated liver enzymes and hyperammonaemia are relatively common in patients receiving valproic acid, but are not usually clinically significant. However, fatal hepatotoxicity, which is more common in patients <2 years old, and those receiving polytherapy, occurs rarely. Other serious adverse events include haemorrhagic pancreatitis, which is sometimes fatal, and haematological disorders (thrombocytopenia, leucopenia, disturbance of platelet function).

Use of valproic acid during pregnancy is associated with an increased risk of birth defects, particularly spina bifida, as observed with several other antiepileptic agents.

Drug Interactions

Valproic acid can increase the plasma concentrations of coadministered drugs by inhibiting their metabolism and/or by displacement from plasma protein binding sites. Such interactions have been reported to occur between valproic acid and phenytoin, phenobarbital, carbamazepine, ethosuximide, lamotrigine, felbamate, diazepam and warfarin.

Coadministration of drugs that induce hepatic drug metabolism (e.g. phenytoin, carbamazepine, phenobarbital, primidone) can decrease plasma concentrations of valproic acid. Adjustment of valproic acid dosage may therefore be necessary when such drugs are initiated or withdrawn. Salicylates increase free and total plasma valproate concentrations by inhibition of valproate metabolism and displacement of valproate from plasma binding sites. In contrast with other antiepileptic agents, valproic acid does not impair the efficacy of oral contraceptives.

Dosage and administration

Enteric-coated and controlled-release preparations of valproic acid are usually Administration administered once or twice daily, and uncoated tablets 3 to 4 times daily. Tablets or capsules should be swallowed whole with or after food, in order to minimise gastrointestinal disturbance.

Valproic acid is usually initiated at a low dosage (e.g. 500 to 1000 mg/day), which is titrated upwards until response is achieved or dose-limiting adverse events are noted. However a higher initial dose of 20 mg/kg/day was effective and well tolerated for achieving control of acute manic episodes in hospitalised patients. Plasma valproate concentrations of approximately 50 to 100 mg/L are generally required to achieve a good therapeutic effect.

Valproic acid should not be given to patients with hepatic disease or significant hepatic dysfunction. Patients aged ≤2 years and/or receiving cotherapy with several antiepileptic drugs are at increased risk of developing hepatotoxicity, as are those with genetic disorders of metabolism (carnitine or ornithine carbamoyl-transferase deficiency, family history of severe hepatic disease), or severe epilepsy associated with cerebral lesions, mental retardation or other hereditary pathology.

Elderly patients may require a lower dosage of valproic acid. Dosage adjustments based on total plasma drug concentrations should be made with caution in the elderly and patients with renal dysfunction or uncompensated diabetes mellitus, as the unbound fraction of valproic acid is increased in such patients.

Use of valproic acid during pregnancy should be avoided if possible, because of an increased risk of neural tube defects. Platelet count and coagulation parameters should be monitored before therapy, at periodic intervals during therapy, and before elective surgery in patients receiving valproic acid.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Davis R, Peters DH, McTavish D. Valproic acid. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy. Drugs 1994; 47: 332–72

    PubMed  CAS  Google Scholar 

  2. Chapman A, Keane PE, Meldrum BS, et al. Mechanism of anticonvulsant action of valproate. Prog Neurobiol 1982; 19: 315–59

    PubMed  CAS  Google Scholar 

  3. Löscher W. Effects of the antiepileptic drug valproate on metabolism and function of inhibitory and excitatory amino acids in the brain. Neurochem Res 1993; 18: 485–502

    PubMed  Google Scholar 

  4. Kuruvilla A, Uretsky NJ. Effect of sodium valproate on motor function regulated by the activation of GABA receptors. Psychopharmacology 1981; 72: 167–72

    PubMed  CAS  Google Scholar 

  5. Cao BJ, Peng NA. Magnesium valproate attenuates hyperactivity induced by dexamphetamine-chlordiazepoxide mixture in rodents. Eur J Pharmacol 1993; 237: 177–81

    PubMed  CAS  Google Scholar 

  6. Linnoila M, Viukari M, Hietala O. Effect of sodium valproate on tardive dyskinesia. Br J Psychiatry 1976; 129: 114–9

    PubMed  CAS  Google Scholar 

  7. Teruel AF, Boix F, Escorihuela RM, et al. Sodium valproate reduces immobility in the behavioural ‘despair’ test in rats. Eur J Pharmacol 1988; 152: 1–7

    Google Scholar 

  8. Keck Jr PE, Taylor VE, Tugrul KC, et al. Valproate treatment of panic disorder and lactate-induced panic attacks. Biol Psychiatry 1993; 33: 542–6

    PubMed  Google Scholar 

  9. Frank Y. Visual event related potentials after methylphenidate and sodium valproate in children with attention deficit hyperactivity disorder. Clin Electroencephalogr 1993; 24: 19–24

    PubMed  Google Scholar 

  10. Jacome DE. EEG features in basilar artery migraine. Headache 1987; 27: 80–3

    PubMed  CAS  Google Scholar 

  11. Gordon CR, Kuritzky A, Doweck I, et al. Vestibulo-ocular reflex in migraine patients. The effect of sodium valproate. Headache 1993; 33: 129–32

    PubMed  CAS  Google Scholar 

  12. Löscher W. Valproate induced changes in GABA metabolism st the subcellular level. Biochem Pharmacol 1981; 30: 1364–6

    PubMed  Google Scholar 

  13. Phillips NI, Fowler LJ. The effects of sodium valproate on γ-aminobutyrate metabolism and behaviour in naive and ethanolamine-O-sulphate pretreated rats and mice. Biochem Pharmacol 1982; 31: 2257–61

    PubMed  CAS  Google Scholar 

  14. Taberner PV, Charington CB, Unwin JW. Effects of GAD and GABA-T inhibitors on GAB A metabolism in vivo. Brain Res Bull 1980; 5 Suppl. 2: 621–5

    CAS  Google Scholar 

  15. Van der Laan JW, De Boer T, Bruinvels J. Di-n-propylacetate and GABA degradation. Preferential inhibition of succinic semialdehyde dehydrogenase and indirect inhibition of GABA-transaminase. J Neurochem 1979; 32: 1769–80

    PubMed  Google Scholar 

  16. Zeise ML, Kasparow S, Zieglgansberger W. Valproate suppresses N-methyl-D-aspartate-evoked, transient depolarizations in the rat neocortex in vitro. Brain Res 1991; 544: 345–8

    PubMed  CAS  Google Scholar 

  17. Gent JP., Phillips NI. Sodium di-n-propylacetate (valproate) potential responses to GABA and muscinol on single central neurons. Brain Res 1980; 197: 275–8

    PubMed  CAS  Google Scholar 

  18. MacDonald RL, Bergey GK. Valproic acid augments GABA-mediated postsynaptic inhibition in cultured mammalian neurons. Brain Res 1979; 170: 558–62

    PubMed  CAS  Google Scholar 

  19. Motohashi N. GABA receptor alterations after chronic lithiumin comparison with carbamazepine and sodium valproate. Clin Neuropharmacol 1990; 13: 207–8

    Google Scholar 

  20. Vayer P, Cash CD, Maitre M. Is the anticonvulsant mechanism of valproate linked to its interaction with the cerebral γ-hydroxybutyrate system? Trends Pharmacol Ther 1988; 9: 127–9

    CAS  Google Scholar 

  21. Whittle SR, Turner SJ. Effects of anticonvulsants on the formation of γ-hydroxybutyrate from γ-aminobutyrate in rat brain. J Neurochem 1982; 38: 848–51

    PubMed  CAS  Google Scholar 

  22. McLean MJ, MacDonald RL. Sodium valproate, but not ethosuximide, produces use- and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture. J Pharmacol Exp Ther 1986; 237: 1001–11

    PubMed  CAS  Google Scholar 

  23. Zona C, Avoli M. Effects induced by the antiepileptic drug valproic acid upon the ionic currents recorded in rat neocortical neurons in cell culture. Exp Brain Res 1990; 81: 313–7

    PubMed  CAS  Google Scholar 

  24. Van den Berg RJ, Kok P, Voskuyl RA. Valproate and sodium currents in cultured hippocampal neurons. Exp Brain Res 1993; 93: 279–87

    PubMed  Google Scholar 

  25. Slater GE, Johnson D. Sodium valproate increases potassium conductance in aplysia neurones. Epilepsia 1978; 19: 379–84

    PubMed  CAS  Google Scholar 

  26. Waiden J, Altrup U, Reith H, et al. Valproate induced increase of transmembraneous potassium currents [abstract]. Second World Congress of Biological Psychiatry 1978: 248

  27. Waiden J, Altrup U, Reith H, et al. Effects of valproate on early and late potassium currents of single neurons. Eur Neuropsychopharmac 1993; 3: 137–41

    Google Scholar 

  28. Maitre L, Baltzer V, Mondadori C. Psychopharmacological and behavioural effects of anti-epileptic drugs in animals. In: Emrich HM, Okuma T, Müller AA, editors. Anticonvulsants in affective disorders. Amsterdam: Elsevier Science Publishers, 1984: 3–13

    Google Scholar 

  29. Gean P-W, Huang C-C, Hung C-R, et al. Valproic acid suppresses the synaptic response mediated by the NMDA receptors in rat amygdalar slices. Brain Res Bull 1994; 33: 333–6

    PubMed  CAS  Google Scholar 

  30. Nagaki S, Kato N, Minatogawa Y, et al. Effects of anticonvulsants and gamma-aminobutyric acid (GABA)-mimetic drugs on immunoreactive somatostatin and GABA contents in the rat brain. Life Sci 1990; 46: 1587–95

    PubMed  CAS  Google Scholar 

  31. Post RM, Weiss SRB, Chuang D-M. Mechanisms of action of anticonvulsants in affective disorders. Comparisons with lithium. J Clin Psychopharmacol 1992; 12 Suppl.: 23S–5S

    PubMed  CAS  Google Scholar 

  32. Brodie MJ, McPhail E, Macphee GJA, et al. Psychomotor impairment and anticonvulsant therapy in adult epileptic patients. Eur J Clin Pharmacol 1987; 31: 65835–60

    Google Scholar 

  33. Lesser RP, Luders H, Wylllie E, et al. Mental deterioration in epilepsy. Epilepsia 1986; 27 Suppl. 2: S105–23

    PubMed  Google Scholar 

  34. Berretini WH, Post RM. GABA in affective illness. In: Post RM, Ballenger JC, editors. Neurobiology of mood disorders. Baltimore: Williams & Wilkins, 1984: 673–85

    Google Scholar 

  35. Lloyd KG, Morselli PL. Psychopharmacology of GABAergic drugs. In: Meltzer HY, editor. Psychopharmacology: the third generation of progress. New York: Raven Press, 1987: 183–95

    Google Scholar 

  36. Sanger DJ. Minireview. GABA and the behavioural effects of anxiolytic drugs. Life Sci 1985; 36: 1503–13

    PubMed  CAS  Google Scholar 

  37. Chou JC-Y. Recent advances in the treatment of acute mania. J Clin Psychopharmacol 1991; 11: 3–21

    PubMed  CAS  Google Scholar 

  38. Borsook D, Richardson GS, Moore-Ede MC, et al. GABA and circadian timekeeping. Implications for manic-depression and sleep disorders. Med Hypotheses 1986; 19: 185–98

    PubMed  CAS  Google Scholar 

  39. Ostrow D, Halaris A, Dysken M, et al. State dependence of noradrenergic activity in a rapidly cycling bipolar patient. J Clin Psychiatry 1984; 45: 306–9

    PubMed  CAS  Google Scholar 

  40. Post RM, Stoddard FJ, Gillin JC, et al. Alterations in motor activity, sleep, and biochemistry in a cycling manic-depressive patient. Arch Gen Psychiatry 1977; 43: 470–7

    Google Scholar 

  41. Siever LJ, Kahn RS, Lawlor BA, et al. Critical issues in defining the role of serotonin in psychiatric disorders. Pharmacol Rev 1991; 43: 509–25

    PubMed  CAS  Google Scholar 

  42. Hering R, Kuritzky A. Sodium valproate in the treatment of cluster headache. An open clinical trial. Cephalalgia 1989; 9: 195–8

    PubMed  CAS  Google Scholar 

  43. Hering R, Kuritzky A. Sodium valproate in the prophylactic treatment of migraine. A double-blind study versus placebo. Cephalalgia 1992; 12: 81–4

    PubMed  CAS  Google Scholar 

  44. Mathew NT. Valproate in the prophylaxis of migraine. Cephalalgia 1992; 12: 67–8

    PubMed  CAS  Google Scholar 

  45. Mathew NT, Ali S. Valproate in the treatment of persistent chronic daily headache. An open label study. Headache 1991; 31: 71–4

    PubMed  CAS  Google Scholar 

  46. Horrobin DF. Prevention of migraine by reducing prolactin levels? Lancet 1974; 1: 777

    Google Scholar 

  47. Hering R, Gilad I, Laron Z, et al. Effect of sodium valproate on the secretion of prolactin, cortisol and growth hormone in migraine patients. Cephalalgia 1992; 12: 257–8

    PubMed  CAS  Google Scholar 

  48. Stein JM, Warfield CA. Herpes zoster and postherpetic neuralgia. Hosp Pract 1982; 17: 96A–96O

    CAS  Google Scholar 

  49. Hitchcock E, Teixera M. Anticonvulsant activation of pain suppressive systems. Appl Neurophys 1982; 45: 582–93

    CAS  Google Scholar 

  50. Zaccara G, Messori A, Moroni F. Clinical pharmacokinetics of valproic acid-1988. Clin Pharmacokinet 1988; 15: 367–89

    PubMed  CAS  Google Scholar 

  51. Prien RF, Potter WZ. NIMH Workshop Report on treatment of bipolar disorder. Psychopharmacol Bull 1990; 26: 409–27

    PubMed  CAS  Google Scholar 

  52. Brown R. U.S. experience with valproate in manic depressive illness. A multicenter trial. J Clin Psychiatry 1989; 50 Suppl.: 13–6

    PubMed  Google Scholar 

  53. Calabrese JR, Woyshville MJ, Kimmel SE, et al. Predictors of valproate response in bipolar rapid cycling. J Clin Psychopharmacol 1993; 13: 280–3

    PubMed  CAS  Google Scholar 

  54. Emrich HM, Wolf R. Valproate treatment of mania. Prog Neuropsych Biol Psychiatry 1992; 16: 691–701

    CAS  Google Scholar 

  55. Emrich HM, von Zerssen D, Kissling W, et al. Effect of sodium valproate on mania. The GABA-hypothesis of affective disorders. Arch Psychiat Nervenkr 1980; 229: 1–16

    PubMed  CAS  Google Scholar 

  56. Fogelson DL, Jacobson S, Sternbach H. A retrospective study of valproate in private psychiatric practice. Ann Clin Psychiatry 1991; 3: 315–20

    Google Scholar 

  57. Guscott R. Clinical experience with valproic acid in 22 patients with refractory bipolar mood disorder [correspondence]. Can J Psychiatry 1992; 37: 590

    PubMed  CAS  Google Scholar 

  58. Hayes SG. Long-term use of valproate in primary psychiatric disorders. J Clin Psychiatry 1989; 50 Suppl.: 35–9

    PubMed  Google Scholar 

  59. Jacobsen FM. Low-dose valproate: a new treatment for cyclothymia, mild rapid cycling disorders, and premenstrual syndrome. J Clin Psychiatry 1993; 54: 229–4

    PubMed  CAS  Google Scholar 

  60. Lambert PA. Acute and prophylactic therapies of patients with affective disorders using valpromide (dipropylacetamide). In: Emrich HM et al., editors. Anticonvulsants in affective disorders. Amsterdam: Elsevier Science Publishers, 1984

    Google Scholar 

  61. McCoy L, Votolato NA, Schwarzkopf SB, et al. Clinical correlates of valproate augmentation in refractory bipolar disorder. Ann Clin Psychiatry 1993; 5: 29–33

    PubMed  CAS  Google Scholar 

  62. McElroy SL, Keck Jr PE, Pope Jr HG, et al. Valproate in primary psychiatric disorders. Literature review and clinical experience in a private psychiatric hospital. In: McElroy SL, Pope Jr HG, editors. Use of anticonvulsants in psychiatry: recent advances. Clifton, New Jersey: Oxford Health Care, 1988

    Google Scholar 

  63. Puzynski S, Klosiewicz L. Valproic acid amide as a prophylactic agent in affective and schizoaffective disorders. Psychopharmacol Bull 1984; 20: 151–9

    PubMed  CAS  Google Scholar 

  64. Semadeni GW. Etude clinique de l’effet normothymique du dipropylacétamide. Acta Psychiatr Belg 1976; 76: 458–66

    PubMed  CAS  Google Scholar 

  65. Perris C. The heuristic value of a distinction between bipolar and unipolar affective disorders. In: Angst J, editor. Classification and prediction of outcome of depression. Stuttgart/New York: FK Schattaeur Verlag, 1974: 75–84

    Google Scholar 

  66. Dunner DL, Gershon ES, Goodwin FK. Heritable factors in the severity of affective illness. Biol Psychiatry 1976; 11: 31–42

    PubMed  CAS  Google Scholar 

  67. World Health Organisation. International Classification of Diseases, 9th Rev. Geneva: World Health Organisation, 1978

    Google Scholar 

  68. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd ed., rev. Washington DC: American Psychiatric Association, 1987

    Google Scholar 

  69. Spitzer RL, Endicott J, Robbins E. Research diagnostic criteria for a selected group of functional disorders. 2nd ed., New York: New York State Psychiatric Institute, 1975

    Google Scholar 

  70. McElroy SL, Keck Jr PE. Treatment guidelines for valproate in bipolar and schizoaffective disorders. Can J Psychiatry 1993; 38 Suppl. 2: S62–6

    PubMed  CAS  Google Scholar 

  71. Pope Jr HG, McElroy SL, Keck Jr PE, et al. Valproate in the treatment of acute mania. Arch Gen Psychiatry 1991; 48: 62–8

    PubMed  Google Scholar 

  72. Jefferson JW. Lithium. A therapeutic magic wand. J Clin Psychiatry 1989; 50: 81–6

    PubMed  CAS  Google Scholar 

  73. Lipowski ZJ. Delirium in the elderly patient. N Engl J Med 1989; 320: 578–81

    PubMed  CAS  Google Scholar 

  74. Post RM. Emerging perspectives on valproate in affective disorders. J Clin Psychiatry 1989; 50 Suppl. 3: 3–9

    PubMed  Google Scholar 

  75. McFarland BH, Miller MR, Straumfjord AA. Valproate use in the older manic patient. J Clin Psychiatry 1990; 51: 479–81

    PubMed  CAS  Google Scholar 

  76. Clothier JL, Pazzaglia PJ, Freeman TW, et al. Plasma level response characteristics of valproate in the treatment of manic syndrome. Ann Clin Psychiatry 1991; 3: 321–4

    Google Scholar 

  77. Keck Jr PE, McElroy SL, Tugrul KC, et al. Valproate oral loading in the treatment of acute mania. J Clin Psychiatry 1993; 54: 305–8

    PubMed  Google Scholar 

  78. McElroy SL, Keck Jr PE, Pope Jr HG, et al. Correlates of anti-manic response to valproate. Psychopharmacol Bull 1991; 27: 127–33

    PubMed  CAS  Google Scholar 

  79. Bowden CL, Brugger AM, Swann AC, et al. Efficacy of divalproex sodium vs lithium and placebo in the treatment of mania. JAMA 1994; 271: 918–24

    PubMed  CAS  Google Scholar 

  80. Freeman TW, Clothier JL, Pazzaglia PJ, et al. A double-blind comparison of valproate and lithium in the treatment of acute mania. Am J Psychiatry 1992; 149: 108–11

    PubMed  CAS  Google Scholar 

  81. McElroy SL, Keck Jr PE, Tugrul KC, et al. Valproate as a loading treatment in acute mania. Neuropsychobiology 1993; 27: 146–9

    PubMed  CAS  Google Scholar 

  82. Calabrese JR, Delucchi GA. Spectrum of efficacy of valproate in 55 patients with rapid cycling bipolar disorder. Am J Psychiatry 1990; 147: 431–4

    PubMed  CAS  Google Scholar 

  83. Dilsaver SC, Swann AC, Shoaib AM, et al. Depressive mania associated with nonresponse to antimanic agents. Am J Psychiatry 1993; 150: 1548–51

    PubMed  CAS  Google Scholar 

  84. Dilsaver SC, Swann AC, Shoaib AM, et al. The manic syndrome. Factors which may predict a patient’s response to lithium, carbamazepine and valproate. J Psychiatry Neurosci 1993; 18: 61–6

    PubMed  CAS  Google Scholar 

  85. Potter WZ, Bowden CL. Introduction. J Clin Psychopharmacol 1992; 12: Suppl. 1: 2S–6S

    PubMed  CAS  Google Scholar 

  86. Calabrese JR, Delucchi GA. Phenomenology of rapid cycling manic depression and its treatment with valproate. J Clin Psychiatry 1989; 50 Suppl.: 30–4

    PubMed  Google Scholar 

  87. Dunner DL, Fieve RR. Clinical factors in lithium prophylaxis failure. Arch Gen Psychiatry 1974; 30: 229–33

    PubMed  CAS  Google Scholar 

  88. Dunner DL, Patrick V, Fieve RR. Rapid-cycling manic depressive patients. Compr Psychiatry 1977; 18: 561–6

    PubMed  CAS  Google Scholar 

  89. McElroy SL, Keck Jr PE, Pope Jr HG, et al. Valproate in the treatment of rapid-cycling bipolar disorder. J Clin Psychopharmacol 1988; 8: 275–9

    PubMed  CAS  Google Scholar 

  90. Sharma V, Persad E, Mazmanian D, et al. Treatment of rapid cycling bipolar disorder with combination therapy of valproate and lithium. Can J Psychiatry 1993; 38: 137–9

    PubMed  CAS  Google Scholar 

  91. Emrich HM, Dose M, von Zerssen D. The use of sodium valproate, carbamazepine and oxcarbarbazepine in patients with affective disorders. J Affect Dis 1985; 8: 243–50

    PubMed  CAS  Google Scholar 

  92. Pope Jr HG, McElroy SL, Satlin A, et al. Head injury, bipolar disorder and response to valproate. Compr Psychiatry 1988; 29: 34–8

    PubMed  Google Scholar 

  93. Sharma V, Persad E. Augmentation of valproate with lithium in a case of rapid cycling affective disorder. Can J Psychiatry 1992; 37: 584–5

    PubMed  CAS  Google Scholar 

  94. Butchart A. Combined anticonvulsant therapy in the treatment of mania. A case report. Aust J Hosp Pharm 1993; 23: 51

    Google Scholar 

  95. Keck Jr PE, McElroy SL, Vuckovic A, et al. Combined valproate and carbamazepine treatment of bipolar disorder. J Psychiatr Clin Neurosci 1992; 4: 319–22

    Google Scholar 

  96. Ketter TA, Pazzaglia PJ, Post RM. Synergy of carbamazepine and valproic acid in affective illness: case report and review of the literature. J Clin Psychopharmacol 1992; 12: 276–81

    PubMed  CAS  Google Scholar 

  97. Schnetzler JP, Préaubert G, Schnetzler F. L’association acide valproïque-diazepam (1) comme alternative au traitement neuroleptique. Ann Med Psychol 1988; 146: 325–39

    CAS  Google Scholar 

  98. Corrigan FM. Sodium valproate augmentation of fluoxetine or fluvoxamine effects. Biol Psychiatry 1992; 31: 1172–83

    Google Scholar 

  99. Primeau F, Fontaine R, Beauclair L. Valproic acid and panic disorder. Can J Psychiatry 1990; 35: 248–50

    PubMed  CAS  Google Scholar 

  100. Lum M, Fontaine R, Elie R, et al. Divalproex sodium’s antipanic effect in panic disorder. A placebo-controlled study. Biol Psychiatry 1990; 27: 279A

    Google Scholar 

  101. Kastner T, Finesmith R, Walsh K. Long-term administration of valproic acid in the treatment of affective symptoms in people with mental retardation. J Clin Psychopharmacol 1993; 13: 448–51

    PubMed  CAS  Google Scholar 

  102. Giakas WJ, Seibyl JP, Mazure CM. Valproate in the treatment of temper outbursts [letter]. J Clin Psychiatry 1990; 51: 525

    PubMed  CAS  Google Scholar 

  103. Syzmanski HV, Olympia J. Divalproex in posttraumatic stress disorder. Am J Psychiatry 1991; 148: 1086

    Google Scholar 

  104. Mazure C, Druss BG, Cellar JS. Valproate treatment of older psychotic patients with organic mental syndromes and behaviour dyscontrol. J Am Geriatr Soc 1992; 40: 914–6

    PubMed  CAS  Google Scholar 

  105. Mattes JA. Valproic acid for nonaffective aggression in the mentally retarded. J Nerv Ment Dis 1992; 180: 601–2

    PubMed  CAS  Google Scholar 

  106. Herridge PL, Pope Jr. HG. Treatment of bulimia and rapid-cycling bipolar disorder with sodium valproate: a case report. J Clin Psychopharmacol 1985; 5: 229–30

    PubMed  CAS  Google Scholar 

  107. Tachibana N, Sugita Y, Teshima Y, et al. A case of anorexia nervosa associated with epileptic seizures showing favorable responses to sodium valproate and clonazepam. Jpn J Psychiatry Neurol 1989; 43: 77–84

    PubMed  CAS  Google Scholar 

  108. Kemp LI. Sodium valproate as an antidepressant. Br J Psychiatry 1992; 160: 121–3

    PubMed  CAS  Google Scholar 

  109. Mitchell P. Valproate for rapid-cycling unipolar affective disorder. J Nerv Ment Dis 1991; 179: 503–4

    PubMed  CAS  Google Scholar 

  110. Pies R, Adler DA, Ehrenberg BL. Sleep disorders and depression with atypical features. Response to valproate. J Clin Psychopharmacol 1989; 9: 352–7

    PubMed  CAS  Google Scholar 

  111. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias, and facial pain. Cephalalgia 1988; 8 Suppl. 7: 1–96

    Google Scholar 

  112. Moore KL. Valproate in the treatment of refractory recurrent headaches. A retrospective analysis of 207 patients. Headache Q 1992; 3: 323–5

    Google Scholar 

  113. Sianard-Gainko J, Lenaerts M, Bastings E, et al. Sodium valproate in severe migraine and tension-type headache. Clinical efficacy and correlations with blood levels. Cephalalgia 1993; 13 Suppl. 13: 176

    Google Scholar 

  114. Sorensen KV Valproate. A new drug in migraine prophylaxis. Acta Neurol Scand 1988; 78: 346–8

    PubMed  CAS  Google Scholar 

  115. Jensen R, Brinck T, Olesen J. Sodium valproate has a prophylactic effect in migraine without aura. A triple-blind, placebocontrolled crossover study. Neurology 1994; 44: 647–51

    PubMed  CAS  Google Scholar 

  116. Mathew NT, Saper JR, Silberstein SD, et al. Migraine prophylaxis with divalproex sodium. Arch Neurol. In press

  117. Hering R, Steiner TJ. Sodium valproate in the treatment of acute migraine attacks [abstract]. Cephalalgia 1993; 13 Suppl. 13: 98

    Google Scholar 

  118. Desai N, Shah K, Gandhi I. Baclofen sodium valproate combination in carbamazepin resistant trigeminal neuralgia. A double blind clinical trial. 5th International Headache Congress: 1991 Jun 30–Jul 3; Washington DC

    Google Scholar 

  119. Peiris JB, Perera GLS, Devendra SV, et al. Sodium valproate in trigeminal neuralgia. Med J Aust 1990; 2: 278

    Google Scholar 

  120. Raftery H. The management of post herpetic pain using sodium valproate and amitriptyline. J Ir Med Assoc 1979; 72: 399–401

    CAS  Google Scholar 

  121. Swerdlow M, Cundill JG. Anticonvulsant drugs used in the treatment of lancinating pain. A comparison. Anaesthesia 1981; 36: 1129–32

    PubMed  CAS  Google Scholar 

  122. Snare AJ, Tett SE, Kaye K, et al. Sodium valproate. Retrospective analysis of neuropathic pain control in patients with advanced cancer. J Pharm Technol 1993; 9: 114–7

    Google Scholar 

  123. Skelton WP, Skelton NR. Nutritional depletion polyneuropathy and valproic acid. Arch Intern Med 1993; 153: 902–3

    PubMed  Google Scholar 

  124. Schmidt, D. Adverse effects of valproate. Epilepsia 1984; 25 Suppl. 1. S44–9

    PubMed  Google Scholar 

  125. Dreifuss FE, Santilli N, Langer DH, et al. Valproic acid hepatic fatalities: a retrospective review. Neurology 1987; 37: 379–85

    PubMed  CAS  Google Scholar 

  126. Dreifuss FE, Langer DH, Moline KA, et al. Valproic acid hepatic fatalities. II. US experience since 1984. Neurology 1989; 39: 201–7

    PubMed  CAS  Google Scholar 

  127. Hawkins E, Brewer E. Case 4. Renal toxicity induced by valproic acid (Depakene). Pediatric Pathology 1993; 13: 863–8

    PubMed  CAS  Google Scholar 

  128. Landau J, Baulac M, Durand G, et al. Impairment of consciousness induced by valproate treatment following neurosurgical operation. Acta Neurochir (Wien) 1993; 125: 92–6

    CAS  Google Scholar 

  129. Bilo L, Meo R, Nappi C, et al. Reproductive endocrine disorders in women with primary generalized epilepsy. Epilepsia 1988; 29: 612–9

    PubMed  CAS  Google Scholar 

  130. Herzog AG, Seibel MM, Schomer DL, et al. Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. Arch Neurol 1986; 43: 341–6

    PubMed  CAS  Google Scholar 

  131. Isojärvi JIT, Laatikainen TJ, Pakarinen AJ, et al. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 1993; 329: 1383–488

    PubMed  Google Scholar 

  132. Omtzigt JGC, Los FJ, Grobbee DE, et al. The risk of spina bifida aperta after first-trimester exposure to valproate in a prenatal cohort. Neurology 1992; 42 Suppl. 5: 119–25

    PubMed  CAS  Google Scholar 

  133. Dalessio DJ. Current concepts: seizure disorders and pregnancy. N Engl J Med 1985; 312: 559–63

    PubMed  CAS  Google Scholar 

  134. Rosa FW. Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med 1991; 324: 674–7

    PubMed  CAS  Google Scholar 

  135. Nau H, Ralf-Siegbert H, Ehlers K. Valproic acid-induced neural tube defects in mouse and human: aspects of chirality, alternative drug development, pharmacokinetics and possible mechanisms. Pharmacol Toxicol 1991; 69: 310–21

    PubMed  CAS  Google Scholar 

  136. Dansky LV, Rosenblatt DS, Andermann E. Mechanisms of teratogenesis: folic acid and antiepileptic therapy. Neurology 1992; 42 Suppl. 5: 32–42

    PubMed  CAS  Google Scholar 

  137. Sanofi-Winthrop. Sodium valproate technical brochure, 2nd edition, Guildford, UK, 1992

  138. Hulsman J. Hyperammonaemia and the use of antiepileptic drugs, including valproate. In: Chadwick, editor. Proceedings of the Fourth International Symposium on Sodium Valproate and Epilepsy, International Congress and Symposium Series No. 152. London: Royal Society of Medicine Services, 1989: 163–8

    Google Scholar 

  139. Patsalos PN, Wilson SJ, Popovic M, et al. The prevalence of valproic acid-associated hyperammonaemia in patients with intractable epilepsy resident at the Chalfont Centre for Epilepsy. J Epilepsy 1993; 6: 228–32

    Google Scholar 

  140. Behgi E, Bizzi A, Codegoni AM, et al. Valproate, carnitine metabolism, and biochemical indicators of liver function. Epilepsia 1990; 33: 346–52

    Google Scholar 

  141. Kossak BD, Schmidt-Sommerfeld E, Schoeller DA, et al. Impaired fatty acid oxidation in children on valproic acid and the effect of 1-carnitine. Neurology 1993; 43: 2362–8

    PubMed  CAS  Google Scholar 

  142. Dreifuss FE, Langer DH. Side effects of valproate. Am J Med 1988; 84 Suppl 1A: 34–41

    PubMed  CAS  Google Scholar 

  143. Asconapé JJ, Penry JK, Dreifuss FE, et al. Valproate-associated pancreatitis. Epilepsia 1993; 34: 177–83

    PubMed  Google Scholar 

  144. May RB, Sunder TR. Hematological manifestations of long-term valproate therapy. Epilepsia 1993; 34: 1098–101

    PubMed  CAS  Google Scholar 

  145. Mortensen PB, Hansen HE, Pedersen B, et al. Acute valproate intoxication: biochemical investigations and hemodialysis treatment. Int J Clin Pharmacol Ther Toxicol 1983; 21: 64–8

    PubMed  CAS  Google Scholar 

  146. Dupuis RE, Lichtman SN, Pollack GM. Acute valproic acid overdose. Clinical course and pharmacokinetic disposition of valproic acid and metabolites. Drug Saf 1990; 5: 65–71

    PubMed  CAS  Google Scholar 

  147. Tank JE, Palmer BF. Simultaneous ‘in series’ hemodialysis and hemoperfusion in the management of valproic acid overdose. Am J Kidney Dis 1993; 22: 341–4

    PubMed  CAS  Google Scholar 

  148. Alberto G, Erickson T, Popiel R, et al. Central nervous system manifestations of a valproic acid overdose responsive to naloxone. Ann Emerg Med 1989; 18: 889–91

    PubMed  CAS  Google Scholar 

  149. Farrar HC, Herold DA, Reed MD. Acute valproic acid intoxication: enhanced drug clearance with oral-activated charcoal. Crit Care Med 1993; 21: 299–301

    PubMed  CAS  Google Scholar 

  150. Levy RH, Koch KM. Drug interactions with valproic acid. Drugs 1982; 24: 543–56

    PubMed  CAS  Google Scholar 

  151. McKee PJW, Blacklaw J, Butler E, et al. Variability and clinical relevance of the interaction between sodium valproate and carbamazepine in epileptic patients. Epilepsy Res 1992; 11: 193–8

    PubMed  CAS  Google Scholar 

  152. Jeavons PM, Clark JE, Maheswari MC. Treatment of generalized epilepsies of childhood and adolescence with sodium valproate (‘Epilim’). Dev Med Child Neurol 1977; 19: 9–25

    PubMed  CAS  Google Scholar 

  153. Lai M-L, Huang J-D. Dual effect of valproic acid on the pharmacokinetics of phenytoin. Biopharm Drug Dispos 1993; 14: 365–70

    PubMed  CAS  Google Scholar 

  154. Crawford P, Chadwick D, Cleland P, et al. The lack of effect of sodium valproate on the pharmacokinetics of oral contraceptive steroids. Contraception 1986; 33: 23–9

    PubMed  CAS  Google Scholar 

  155. Perucca E, Grimaldi R, Gatti G, et al. Pharmacokinetics of valproic acid in the elderly. Br J Clin Pharmacol 1984; 17: 665–9

    PubMed  CAS  Google Scholar 

  156. Sonnen AEH. Sodium valproate and the contraceptive pill. Br J Clin Pract 1983; 27 Suppl.: 31–6

    Google Scholar 

  157. Abbott FS, Kassam J, Orr JM, et al. The effect of aspirin on valproic acid metabolism. Clin Pharmacol Ther 1986; 40: 94–100

    PubMed  CAS  Google Scholar 

  158. Goulden KJ, Dooley JM, Camfield PR, et al. Clinical valproate toxicity induced by acetylsalicylic acid. Neurology 1987; 37: 1392–4

    PubMed  CAS  Google Scholar 

  159. Orr JM, Abbott FS, Farrell K, et al. Interaction between valproic acid and aspirin in epileptic children: serum protein binding and metabolic effects. Clin Pharmacol Ther 1982; 31: 642–9

    PubMed  CAS  Google Scholar 

  160. Urien S, Albengres E, Tillement JP. Serum protein binding of valproic acid in healthy subjects and in patients with liver disease. Int J Clin Pharmacol Ther Toxicol 1981; 19: 319–25

    PubMed  CAS  Google Scholar 

  161. Sovner R, Davis JM. A potential drug interaction between fluoxetine and valproic acid [correspondence]. J Clin Psychopharmacol 1991; 11: 389

    PubMed  CAS  Google Scholar 

  162. Abbott Laboratories. Divalproex sodium prescribing information. Chicago, 1992

  163. Potter WZ, Ketter TA. Pharmacological issues in the treatment of bipolar disorder. Focus on mood-stabilizing compounds. Can J Psychiatry 1993; 38 Suppl. 2: S51–6

    PubMed  CAS  Google Scholar 

  164. Gerner RH, Stanton A. Algorithm for patient management of acute manic states. Lithium, valproate or carbamazepine. J Clin Psychopharmacol 1992; 12 Suppl.: 57S–63S

    PubMed  CAS  Google Scholar 

  165. Frankenburg FR, Tohen M, Cohen BM, et al. Long-term response to carbamazepine. A retrospective study. J Clin Psychopharmacol 1988; 8: 130–2

    PubMed  CAS  Google Scholar 

  166. Keck Jr PE, McElroy SL, Nemeroff CB. Anticonvulsants in the treatment of bipolar disorder. J Neuropsychiatry Clin Neurosci 1992; 4: 395–405

    PubMed  Google Scholar 

  167. Post RM, Leverich GS, Rosoff AS, et al. Carbamazepine prophylaxis in refractory affective disorders. A focus on long-term follow-up. J Clin Psychopharmacol 1990; 10: 318–27

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Julia A. Balfour & Harriet M. Bryson

Authors
  1. Julia A. Balfour
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Harriet M. Bryson
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Various sections of the manuscript reviewed by: C.L. Bowden, Division of Biological Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA; A.G. Chapman, Department of Neurology, Institute of Psychiatry, University of London, London, England; S.C. Dilsaver, Harris County Psychiatric Center, Houston, Texas, USA; H.M. Emrich, Psychiatric Clinic, Medical School, Hannover, Germany; R. Hering, Department of Neurology, Sapir Medical Center, Kfar-Saba, Israel; J.I.T. Isojärvi, Department of Neurology, University of Oulu, Oulu, Finland; R. Jensen, Department of Neurology, Rigshospitalet, Copenhagen, Denmark; P.E. Keck Jr, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; J.N. Lickiss, Palliative Care Service, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; R.M. Post, Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland, USA; V. Sharma, Mood Disorders Unit, London Psychiatric Hospital, London, Ontario, Canada; T.J. Steiner, Academic Unit of Neuroscience, Charing Cross and Westminster Medical School, University of London, London, England.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Balfour, J.A., Bryson, H.M. Valproic Acid. CNS Drugs 2, 144–173 (1994). https://doi.org/10.2165/00023210-199402020-00007

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00023210-199402020-00007

Keywords

Search

Navigation