Divalproex (Depakote) and valproic acid (Depakene) have been the most popular medications for treating bipolar disorder.  In fact, research does not find it better that lithium or carbamazepine.  Lithium results in far fewer successful suicides than either divalproex and carbamazepine.  Carbamazepine (Tegretol), while not superior to divalproex, is far less expensive and causes much less weight gain and other side-effects.  Valproic acid is just as good at treating bipolar illness as divalproex and is much less expensive because it is available as a generic.  However, valproic acid is rarely used by American psychiatrists.  Valproic acid does cause a higher rate of nausea in perhaps 15% of patients.  However, in view of the large cost savings of roughly $1000 per patient per year, it is worth trying out.

Valproic acid is much worse for the developing fetus than any other anti-manic agent.  Since pregnant women have lower carnitine and since valproic acid also lowers carnitine, I wonder if a supplement of L-carnitine during pregnancy might reduce the risk to brain damage to the developing fetus.  This has never been studied, although carnitine has been frequently used in valproic acid overdoses with benefit.

Divalproex (Depakote) = Placebo for Bipolar NOS Kids: A PC DB of 53 children 5-17 years old for up to five years found no difference with both improving. Offspring of bipolar parent with diagnosis Bipolar NOS or Cyclothymia. Findling RL, Calabrese JR, Youngstrom EA. Divalproex sodium vs. placebo in the treatment of youth at genetic high-risk for developing bipolar disorder. Program and abstracts of the Fifth International Conference on Bipolar Disorder; June 12-14, 2003; Pittsburgh, Pennsylvania. Abstract P64.

Divalproex No Better than Lithium for Bipolar Children: Youths (139) ages 5-17 years with bipolar I or II disorder were initially treated with Lithium and divalproex (DVPX). Then, in a DB PC study of 60 patients achieving remission criteria for four consecutive weeks, half were given either Lithium or DVPX for up to 76 weeks. The treatment groups did not differ in survival time until emerging symptoms of relapse (p = .55) or survival time until discontinuation for any reason (p = .72). Double-blind 18-month trial of lithium versus divalproex maintenance treatment in pediatric bipolar disorder. Findling RL, McNamara NK, et al. Case Western Reserve University. J Am Acad Child Adolesc Psychiatry. 2005 May;44(5):409-17. Ed: This is the study the University of Illinois should have done!  

Lithium vs. Divalproex of Mania: Anxious-Depressed Hardest to Help: 179 manic patients in PC DB. The anxious-depressed subtype did not respond to any treatment; the psychotic and classic subtypes responded similarly to lithium and to divalproex; and the irritable-dysphoric subtype responded better to divalproex than to lithium. Overall, divalproex improved impulsivity and hostility significantly more than placebo, and lithium or divalproex improved hyperactivity more than placebo. Swann AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD. Pattern of response to divalproex, lithium, or placebo in four naturalistic subtypes of mania. Neuropsychopharmacology. 2002;26:530-536.

Depakote Causes Polycystic Ovary Syndrome: All patients still on VPA (Depakote) had elevated serum androstenedione levels. Polycystic ovary syndrome was more common in patients on medication (38%; in 63% on VPA, in 25% on other medication) than in patients off medication (6%) or in controls (11%) (p = 0.005). Long-term reproductive endocrine health in young women with epilepsy during puberty. Mikkonen K, Vainionpaa LK, Pakarinen AJ, Knip M, Jarvela IY, Tapanainen JS, Isojarvi JI. University of Oulu. Neurology. 2004 Feb 10;62(3):445-50 

Depakene No Difference From Divalproex Except Nausea: 300 patients started on one or other. GI side-effects (A, N, V, dyspepsia) 29% vs. 15% with 6 of 150 stopping divalproex due to GI symptoms vs. 19 of 150 with valproic acid. Of 12 switched, all but 2 tolerated divalproex. No difference other side-effects or effectiveness. J Clin Psychiatry ’99;60:232, McLean. Ed: Valproic acid (Depakene) is much less expensive.

No Problem Switching Depakote to Depakene: Chart review of 22 patients switched to generic valproic acid showed them doing just as well. Tom Schwartz, SUNY, Syracuse, APA 5/30/98 Toronto.

Both Divalproex (Depakote) & Lithium Failed in Maintenance: DB PC 52 weeks 372 pt after 3 month recovery from manic episode. U Texas authors try to tease out some advantages for divalproex by pointing to secondary measures. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Bowden CL, Calabrese JR, McElroy SL, Gyulai L, Wassef A, Petty F, Pope HG Jr, Chou JC, Keck PE Jr, Rhodes LJ, Swann AC, Hirschfeld RM, Wozniak PJ. Arch Gen Psychiatry 2000 May;57(5):481-9

Divalproex (Depakote) = Lithium in Acute Mania DB: In a DB PC study of 176 manics, half of whom had been unresponsive to lithium in past, the response rate was 48% with divalproex, 49% with lithium, and 25% with placebo. Efficacy of divalproex vs. lithium and placebo in the treatment of mania. The Depakote Mania Study Group. Bowden CL, Brugger AM, Swann AC, Calabrese JR, Janicak PG, Petty F, Dilsaver SC, Davis JM, Rush AJ, Small JG, et al. JAMA 1994 Mar 23-30;271(12):918-24

Valproate Once a Day Dosing Fine: In 12 seizure patients in a DB PC crossover trial, there was no difference between once a day and three times a day dosing. Monodose versus 3 daily doses of sodium valproate: a controlled trial. Gjerloff I, Arentsen J, Alving J, Secher BG. Acta Neurol Scand 1984 Feb;69(2):120-4. Ed: This study certainly suggests that the new extended release Depakote is pointless and simply a gimmick by the manufacturer to extend their patent protection and profits.

Depakote = Lithium Except More Weight, Alopecia, Tremor, Sedation, and Infection from Depakote: Patients abstracted from other studies. 12 months duration with 372 participants comparing lithium, divalproex and placebo. No reliable difference between the treatments, although there was a trend for divalproex to be more effective than lithium. No significant difference in the numbers of patients in receipt of divalproex compared with those in receipt of lithium who left the study because they suffered any mood episode. (RRR 22%; RR 0.78). There was insufficient information to allow sub-group analyses of rapid-cycling disorder. The divalproex group had significantly more tremor (RRI 223%; RR 3.23), weight gain (RRI 187%; RR 2.87) and alopecia (RRI 143%) than the placebo group. In comparison with the lithium, divalproex was associated with more frequent sedation (RRI 58%; RR 1.58) and infection (RRI 107%; RR 2.07), but less suffered thirst (RRR 62%; RR 0.38) and polyuria (RRR 57%; RR 0.43). U Oxford, Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Macritchie KA, Geddes JR, Scott J, Haslam DR, Goodwin GM. Cochrane Database Syst Rev 2001;(3):CD003196

Divalproex + Quetiapine > Divalproex in Teen DB: Thirty manic or mixed bipolar I adolescents (12-18 years) received an initial DVP dose of 20 mg/kg and were randomly assigned to 6 weeks of combination therapy with quetiapine, which was titrated to 450 mg/day. YMRS response 87% vs 53%. U Cinn. A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. Delbello MP, Schwiers ML, Rosenberg HL, Strakowski SM. J Am Acad Child Adolesc Psychiatry 2002 Oct;41(10):1216-23

Valproate + Anti-psychotic > Anti-psychotic Alone for Acute:136 acute mania rx haldol or perazine and DB PC 21 day trial add valproate. Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania: a prospective, randomized, double-blind, placebo-controlled, multicenter study. European Valproate Mania Study Group. Muller-Oerlinghausen B, Retzow A, Henn FA, Giedke H, Walden J. J Clin Psychopharmacol 2000 Apr;20(2):195-203

Valproate: Two cases of Parkinson’s disease after four years Rx reversed within 3 mo. of switch to carbamazepine. J Neurol 12/98

Divalproex loading OK: 59 pt. 1/3 rx divalproex 30mg/kg/d 1^st and 2^nd day then 20mg/kg/d. Others rx divalproex 250TID or lithium 300 TID. 3^rd day YMRS decr 10.3 for loading, 8.1 nonloading, 6.1 lithium. Blood level 3^rd day 83.8 v 41.8 for nonloading. No diff side-effects. Hirschfeld, J Clin Psych 99;60:815, U Tx Galveston

Valproate Good for Sex, Carbamazepine Bad: Val increases sex hormones and Carb does opposite with lower DHEA-S. 19% of 21 Valproate men reported improved sex functioning and 19% of 40 reported worse with Carbamazepine. Neurol 01;56:31

Valproate Adjunct Improves Anti-Psychotic: European study 136 acute manic 3 week DB PC. All on haldol and/or perazine. Those on valproate improved faster despite using less anti-psychotic. The combination of neuroleptic and valproate proved superior to neuroleptics in attempts to alleviate manic symptoms. The proportion of responders (a 50% improvement rate shown on the YMRS) was higher for the combination with valproate than for the group receiving only neuroleptics (70% vs. 46%). J Clin Psychopharmacol 2000 Apr;20(2):195-203, Berlin

Divalproex Helps Borderline-BADs: 30 women comorbid for BAD and Borderline treated DB PC for 6 months to blood level of 50-100 microg/ml. Symptoms decreased 35% vs 15% for placebo. Improvements in interpersonal sensitivity and anger/hostility and overt aggression. High (65%) drop out rate in study for both, esp after 3 months. Harvd (Abbott), J Clin Psych 02;63:442.

Valproate Thrombocytopenia Common: 39 adult inpt on divalproex up to 12 months. Patients over 60 yo rx 1900-2225mg/d, under 60 1400-1855 to levels 70-90 microg/mL 54% elderly and 13% nonelderly had platelet count <100,000/mm3. Only one had d/c’d due to low level. No mention of any symptoms and other studies suggest no need to monitor. Average elderly dropped from 300,000 to 150,000 and non-elderly 300,000 to 200,000. T Trannel, Am J Psychiatry 01:158:128, U Hawaii

Valproate Polycystic Ovaries with Wt Gain and Anovulation: The mechanism by which valproate may induce polycystic ovarian syndrome is unknown, but could possibly be secondary to valproate-induced weight gain or direct interference with steroid metabolism. Is valproate pharmacotherapy associated with polycystic ovaries? Chappell KA, Markowitz JS, Jackson CW. Ann Pharmacother 1999 Nov;33(11):1211-6

Valproate Obesity (59% averaged 46# gain) and Polycystic Ovaries Common: Twenty-two received valproate monotherapy and 43 received carbamazepine monotherapy. In addition to clinical examination, vaginal ultrasonography was performed to determine ovarian size, and the concentrations of serum sex hormones, insulin, insulin-like growth factor 1, and the insulin-like growth factor-binding proteins 1 and 3 (IGFBP-1 and IGFBP-3) were measured. Fifty-nine percent of the women on valproate were obese, and in a retrospective analysis an indisputable weight gain (mean, 21 kg; range, 8-49 kg) was found in 50% of the women taking valproate. Fourteen (64%) of the women on valproate had polycystic ovaries, hyperandrogenism, or both. Obesity and endocrine disorders in women taking valproate for epilepsy. Isojarvi JI, Laatikainen TJ, Knip M, Pakarinen AJ, Juntunen KT, Myllyla VV. Ann Neurol 1996 May;39(5):579-84

Valproate Weight Gain 13# vs Lamotrigine 1#: 133 epilepsy pt 32 weeks. Valproate 13# +/- 8#, lamotrigine 1# +/-12 Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy. Biton V, Mirza W, Montouris G, Vuong A, Hammer AE, Barrett PS. Neurology 2001 Jan 23;56(2):172-7

Valproate Weight Gain in Only 20% Seizure Patients, Carbamazepine preferred: 480 pts in study 2-5 years. For the control of secondarily generalized tonic-clonic seizures, carbamazepine and valproate were comparably effective (in 136 patients and 138 patients, respectively). For complex partial seizures, four of five outcome measures favored carbamazepine (100 patients) over valproate (106 patients): the total number of seizures (2.7 vs. 7.6, P = 0.05), the number of seizures per month (0.9 vs. 2.2, P = 0.01), the time to the first seizure (P less than 0.02), and the seizure-rating score (P = 0.04). Carbamazepine was also superior according to a composite score that combined scores for the control of seizures and for adverse effects (P less than 0.001). Valproate was associated more frequently than carbamazepine with a weight gain of more than 5.5 kg (12 lb) (20% vs. 8%), with hair loss or change in texture (12% vs. 6%), and with tremor (45% vs. 22%). Rash was more often associated with carbamazepine (11% vs. 1%). A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group. Mattson RH, Cramer JA, Collins JF. N Engl J Med 1992 Sep 10;327(11):765-71