Chapter 36. Valproate

Print: Chapter 36. Valproate

http://www.psychiatryonline.com/popup.aspx?aID=431827&print=yes…

1 of 14

10/05/2009 16:17

Print Close Window

Charles L. Bowden: Chapter 36. Valproate, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F.

Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.431823. Printed

5/10/2009 from www.psychiatryonline.com

Textbook of Psychopharmacology >

Chapter 36. Valproate

HISTORY AND DISCOVERY

Valproic acid was first synthesized by Burton in the United States in 1882 and subsequently was used as an organic solvent. The

drug’s antiepileptic properties were discovered serendipitously by Meunier in 1963 in France. Meunier used valproic acid as a

vehicle for other compounds that were being screened for antiepileptic activity. He found that compounds that did not have

antiepileptic properties when administered alone inhibited seizure activity when dissolved in valproic acid and concluded that the

antiepileptic activity was due to the solvent, valproic acid, rather than to the test drugs (Bowden and McElroy 1995; Fariello and

Smith 1989; Meunier et al. 1975).

Valproate was the first alternative mood stabilizer to be studied, with Lambert’s first research published in 1966 (Lambert et al.

1966). Valproate was first introduced as an antiepileptic in France in 1967. It has been used in Holland and Germany since 1968

and in the United Kingdom since 1973, and it became available in the United States in 1978. An enteric-coated formulation,

divalproex sodium, was introduced to the U.S. market in 1983. A formulation consisting of a capsule containing coated particles

of divalproex sodium was introduced in 1989. An extended-release formulation of divalproex was approved for migraine in 2001

and mania in 2006. Valproate was approved for treatment of mania in the United States in 1995. Valproate, either as divalproex

or as other formulations, is now approved for treatment of mania in most developed countries.

STRUCTURE–ACTIVITY RELATIONS

Valproic acid (dipropylacetic acid) is an eight-carbon, branched-chain carboxylic acid that is structurally distinct from other

antiepileptic and psychotropic compounds (Bocci and Beretta 1976; Levy et al. 2002) (Figure 36–1). Although straight-chain

acids have little or no antiepileptic activity, other branched-chain carboxylic acids have potencies similar to that of valproate in

antagonizing pentylenetetrazole-induced seizures. However, increasing the number of carbon atoms to nine introduces marked

sedative properties. The primary amide of valproic acid, valpromide, has been reported to be about twice as potent as the parent

compound.

FIGURE 36–1. Chemical structure of valproic acid (2-propyl-pentanoic acid).

PHARMACOLOGICAL PROFILE

Valproate blocks pentylenetetrazole-induced and maximal electroshock seizures in a variety of animals and suppresses

secondarily generalized seizures without affecting focal activity in chemically lesioned animals (Fariello and Smith 1989).

Valproate also has antikindling properties, preventing the spread of epileptiform activity in cats without affecting focal seizures

(Leveil and Nanquet 1977).

Studies in epilepsy and bipolar disorder indicate that divalproex causes a reduction in plasma levels of -aminobutyric acid

(GABA) and that plasma GABA levels positively correlate with the degree of improvement in manic symptomatology (Brennan et

1. 1984; Emrich et al. 1981). Animal studies also indicate that chronic valproate increases the expression of mRNA encoding the

67-kilodalton isoform of glutamate decarboxylase (GAD67) in the brain, thereby facilitating GABAergic transmission (Tremolizzo

et al. 2002). Valproate is incorporated into neuronal membranes in a saturable manner and appears to displace naturally

occurring branched-chain phospholipids (Siafaka-Kapadai et al. 1998). Chronic valproate reduces protein kinase C (PKC) activity

in manic patients (Hahn et al. 2005). Elevated PKC activity has been associated with manic patients and in animal models for

mania (Einat and Manji 2006). Valproate inhibits glycogen synthase kinase 3 (GSK-3) at concentrations present therapeutically.

The effect is indirect, linked to its capability to upregulate gene expression through inhibition of histone deacetylase (Harwood

and Agam 2003). In laboratory animals, valproate activates the extracellular signal-regulated kinase (ERK) pathway (Einat et al.

2003). Valproate increases the expression of the cytoprotective protein B-cell lymphoma/leukemia-2 gene ( bcl-2) in the central

nervous system in vivo and in cells of human neuronal origin (Gray et al. 2003). Valproate provided antioxidant effects, reversing

early DNA damage caused by amphetamine in an animal model of mania (Andreazza et al. 2007). Valproate and lithium both

reduce inositol biosynthesis. However, the mechanism of valproate action is unique, resulting from decreased myo-inositol

1-phosphate synthase inhibition (Shaltiel et al. 2004). Valproate and lithium both lengthen the period of circadian rhythms and

increase arrhythmicity in Drosophila. This action of the two drugs is of interest given recent data implicating sets of genes

associated with circadian rhythmicity in bipolar disorders (Dokucu et al. 2005). Therapeutic doses of either valproate or lithium

increase the antiapoptotic protein bcl-2 in anterior cingulate cortex, potentially providing a buffer against the destructive effects

of increased intracellular Ca2+ in bipolar disorder (Quiroz et al. 2008).

Despite primary differences in the initial modes of action of valproate and lithium, it is noteworthy that valproate and lithium

have substantial overlapping effects on neuronal systems involved in maintaining mood stability and alertness that have not

been observed in studies of similar systems with carbamazepine or atypical antipsychotic drugs. Whereas several of thePrint: Chapter 36. Valproate

http://www.psychiatryonline.com/popup.aspx?aID=431827&print=yes…

2 of 14

10/05/2009 16:17

above-reviewed systems are impacted by both lithium and valproate, only valproate inhibits histone deacetylase, which in turn

results in a gradual increase in the phosphorylation of Akt and GSK-3 (Harwood and Agam 2003). Valproate enhances

acetylated histone content, thereby preventing methionine-induced reelin promoter hypermethylation and normalizing

behavioral responses in a mouse model for schizophrenia-like behavior (Tremolizzo et al. 2005). Recent study of valproate as a

cancer chemotherapeutic agent may also be stimulated by its effects on cell proliferation through inhibition of histone

deacetylase (Andratschke et al. 2001).

Valproate increased corticotropin-releasing factor (CRF) mRNA expression in the cortex and reduced CRF type 1 receptor (CRF 1)

binding in the amygdala and cortex of nonstressed rats, suggesting that one of valproate’s effects in the brain is to dampen tone

in this pathway, which is associated with stress-linked psychopathology (Gilmor et al. 2003).

PHARMACOKINETICS AND DISPOSITION

Valproate is commercially available in the United States in five oral preparations: 1) divalproex sodium, an enteric-coated,

stable-coordination compound containing equal proportions of valproic acid and sodium valproate in a 1:1 molar ratio; 2)

valproic acid; 3) sodium valproate; 4) divalproex sodium sprinkle capsule (containing coated particles of divalproex sodium),

which can be ingested intact or pulled apart and contents sprinkled on food; and 5) an extended-release form of divalproex that

provides once-daily dosing and a substantially flatter peak-to-trough ratio. Sodium valproate is available for intravenous use

and, as such, has been demonstrated to provide reduction in manic symptoms within 1 day or less (Grunze et al. 1999).

Valproate can also be compounded in suppository form for rectal administration. The valproate ion is the common compound in

plasma.

The bioavailability of valproate approaches 100% with all preparations (Levy et al. 2002; Penry and Dean 1989; Wilder 1992). All

preparations taken orally, except divalproex sodium, are rapidly absorbed after oral ingestion. Sodium valproate and valproic

acid attain peak serum concentrations within 2 hours. Divalproex sodium reaches peak serum concentrations within 3–8 hours.

The extended-release form of divalproex has an earlier onset of absorption than divalproex sodium regular-release tablets and

approximately a 20% smaller difference in trough and peak serum levels than regular-release divalproex (Figure 36–2).

Absorption can also be delayed if the drug is taken with food.

FIGURE 36–2. Mean plasma valproate concentrations with different formulations.

aData derived from different studies after 500-mg doses.

DR = delayed-release; ER = extended-release.

Source. Abbott Laboratories, data on file.

Valproate is highly protein bound, predominantly to serum albumin and proportional to the albumin concentration. Although

patients with low levels of albumin have a higher fraction of unbound drug, the steady-state level of total drug is not altered.

Only the unbound drug crosses the blood–brain barrier and is bioactive. Thus, when valproate is displaced from protein-binding

sites through drug interactions, the total drug concentration may not change; however, the pharmacologically active unbound

drug does increase and may produce signs and symptoms of toxicity. Moreover, when the plasma concentration of valproate

increases in response to increased dosing, the amount of unbound (active) valproate increases disproportionately and isPrint: Chapter 36. Valproate

http://www.psychiatryonline.com/popup.aspx?aID=431827&print=yes…

3 of 14

10/05/2009 16:17

metabolized, with an apparent increase in clearance of total drug, yielding lower-than-expected total plasma concentrations

(Levy et al. 2002; Wilder 1992) (Figure 36–3). In addition, valproate protein binding is increased by low-fat diets and decreased

by high-fat diets. Because of lower serum protein levels, women and elderly patients will generally have a higher proportion of

the active free moiety.

FIGURE 36–3. Total valproate (VPA) concentrations.

As the total concentration of VPA increases, protein-binding sites become saturated, and the percentage of unbound to bound VPA increases.

Source. Reprinted from Wilder BJ: “Pharmacokinetics of Valproate and Carbamazepine.” Journal of Clinical Psychopharmacology 12 (1,

suppl):64S–68S, 1992. Used with permission.

The concentration range generally required for good clinical effect in mania is approximately 45 to 125 g/mL (Bowden et al.

1996). Patients who tolerate higher serum levels, up to around 125 g/mL, may have greater improvement (Allen et al. 2006).

One open report suggests that patients with bipolar II conditions and cyclothymia may respond to serum valproate

concentrations of less than 50 g/mL (Jacobsen 1993).

Valproate is metabolized primarily in the liver by glucuronidation. In addition, oxidative pathways yield a large number of

metabolites, some of which have antiepileptic and/or toxic effects (Bocci and Beretta 1976; Levy et al. 2002; Penry and Dean

1989; Wilder 1992) (Figure 36–4). The oxidative pathways are mitochondrial -oxidation to 3-hydroxyvalproate,

3-oxo-valproate, and 2-en-valproate; and the cytochrome P450 microsomal metabolism to the toxic 4-en- and 2,4-en

metabolites. Less than 3% of valproate is excreted unchanged in the urine and feces. Valproate’s elimination half-life is typically

5–20 hours and can be altered by agents that affect the mitochondrial and/or microsomal enzyme systems responsible for its

metabolism.

FIGURE 36–4. Two pathways for metabolism of valproate (VPA).

VPA is metabolized within the mitochondria by the -oxidative pathway, which metabolizes medium- and long-chain fatty acids. This is the

major metabolic pathway used in patients taking VPA as monotherapy. VPA is also metabolized by the microsomal cytochrome P450 pathway,

which occurs outside the mitochondria; metabolism via this pathway is increased when VPA is administered in combination with

enzyme-inducing drugs (e.g., carbamazepine). 3 OH-VPA = 3-hydroxyvalproate; 3-OXO-VPA = 3-oxo-valproate; 2 VPA = 2-en-valproate

metabolite; 4 VPA = 4-en-valproate metabolite; 2,4 VPA = 2,4-en-valproate metabolite; t½ = half-life.

Source. Reprinted from Wilder BJ: “Pharmacokinetics of Valproate and Carbamazepine.” Journal of Clinical Psychopharmacology 12 (1,

suppl):64S–68S, 1992. Used with permission.

Treatment with valproate for bipolar disorder is usually begun at a dosage of 15–20 mg/kg/day. The drug can be “orally loaded”

at 20–30 mg/kg/day in patients with acute mania to induce more rapid response. The dosage of valproate is increased according

to the patient’s response and side effects, usually by 250–500 mg/day every 1–3 days, to serum concentrations of 45–125

g/mL. Of note, sedation, increased appetite, and reduction in white blood count and platelet count all become more frequent at

serum concentrations above 100 g/mL (Bowden 2000). During maintenance treatment, bipolar I patients whose serum levels

were between 75 and 100 g/mL had significantly longer time to intervention for a developing mood episode than did patients

with serum levels either lower or higher than this range (Keck et al. 2005).

INDICATIONS AND EFFICACY

The indications for valproate that are currently recognized by the U.S. Food and Drug Administration (FDA) are for the treatmentPrint: Chapter 36. Valproate

http://www.psychiatryonline.com/popup.aspx?aID=431827&print=yes…

4 of 14

10/05/2009 16:17

of manic episodes associated with bipolar disorder; for sole and adjunctive therapy in the treatment of simple and complex

absence seizures; for adjunctive therapy in multiple seizure types, including absence seizures; and for prophylaxis of migraine.

Controlled studies have also shown that valproate is effective in prevention of recurrence of mania in bipolar disorder (Tohen et

1. 2003) and in prolongation of the depression-free period compared with lithium (Gyulai et al. 2003). Controlled studies

additionally indicate that valproate is effective in generalized epilepsies, including generalized tonic–clonic and myoclonic

seizures, as well as in secondarily generalized tonic–clonic seizures, infantile spasms, photosensitive epilepsy, and febrile

seizures (Bourgeois 1989; Rimmer and Richens 1985).

Use in Bipolar Disorder

Acute Bipolar Mania

Numerous open studies and controlled trials (five placebo-controlled, one haloperidol-controlled, one lithium-controlled, and one

placebo- and lithium-controlled) indicate that valproate is effective in the treatment of acute mania (Bowden et al. 1994; McElroy

et al. 1993). In the controlled trials (Bowden et al. 1994, 2006; Brennan et al. 1984; Emrich et al. 1985; Freeman et al. 1992;

McElroy et al. 1996; Pope et al. 1991), valproate was superior to placebo and comparable to lithium and haloperidol in the

short-term treatment of acute mania. The most recent placebo-controlled study indicated that patients with more severe manic

symptoms experienced greater benefits from valproate relative to placebo compared with patients with milder manic

symptomatology (Bowden et al. 2006). In these studies, the antimanic response to valproate occurred as early as 5 days

following initiation of treatment.

In an open-label, rater-blind study of valproate administration via an oral loading dosage of 20 mg/kg/day to 19 patients with

acute mania, 10 (53%) of the patients had a significant response within 5 days of treatment, with minimal side effects (Keck et

1. 1993). Similarly, in a controlled comparison study with haloperidol, divalproex administered at 20 mg/kg/day produced rapid

antimanic and antipsychotic effects comparable to those of haloperidol (McElroy et al. 1996). Valproate and carbamazepine were

compared in a small (n = 30) blinded, randomized study in acute mania (Vasudev et al. 2000). Valproate provided greater

reduction in mania scores, produced earlier response, and was associated with fewer adverse effects than carbamazepine.

Intravenous valproate infused as 600 mg over 20 minutes yielded rapid improvement in 4 of 5 manic patients (Grunze et al.

1999). In the aggregate, studies of the past decade have extended the evidence of the efficacy of valproate and the breadth of

circumstances in which it can be effectively employed. The area of weakness in studies for valproate, as well as other antimanic

agents, is that there have been only open case series for patients with hypomania or cyclothymia (Jacobsen 1993).

Adjunctive Regimens in Mania

Valproate has been studied in an add-on design in mania with consistent evidence that addition either of valproate to an

antipsychotic (Muller-Oerlinghausen et al. 2000) or of an antipsychotic (olanzapine, quetiapine, risperidone, haloperidol) to

valproate (or lithium) resulted in approximately 20% higher rates of antimanic response than with the antipsychotic or valproate

alone (Tohen et al. 2002; Yatham 2003, 2005).

Patients treated with valproate plus lithium were significantly less likely to relapse over the course of a year than were patients

treated with lithium. Side effects were more common with the combination regimen (Solomon et al. 1997).

One of the combination studies enrolled both patients who had received treatment with either valproate or lithium at an

adequate dose for 2 weeks or longer and were still manic and patients who were manic without treatment, in which case both

risperidone or haloperidol and either lithium or valproate were started concurrently. No advantage for the combination treatment

occurred in the cotherapy group, whereas patients who had demonstrated unresponsiveness to valproate or lithium showed the

advantage of the add-on therapy. The results suggest that in most circumstances combination therapy should be limited to

patients who fail to respond to a relatively short period of adequate treatment with a first drug before adding the second (Sachs

et al. 2002).

Maintenance Treatment of Bipolar Disorder

Several recent studies address the question of maintenance of effect in mania. A 12-week randomized, blinded comparison of

valproate and olanzapine showed equivalent efficacy on mania for the two treatments (Zajecka et al. 2002). A 47-week study of

the two drugs reported low rates of completion for both treatments (15% vs. 16%), with earlier symptomatic remission with

olanzapine but equivalent efficacy for the two drugs over the remaining portion of the study. For both drugs, patients who were

in remission at the end of week 3 of treatment were significantly more likely to complete the 47-week trial than those not in

remission (divalproex: 26.2% vs. 11.1%; olanzapine: 20.3% vs. 10.6%; P = 0.001). This finding indicates that acute treatment

response to a drug (either valproate or olanzapine) during a manic episode is predictive of effective treatment with the same

drug in maintenance therapy. In both studies, weight gain was greater with olanzapine than with divalproex, and divalproex was

associated with a significant reduction in cholesterol levels, compared with an increase in cholesterol levels with olanzapine

(Tohen et al. 2003; Zajecka et al. 2002).

One large (n = 372) double-blind, placebo-controlled maintenance monotherapy study of valproate has been published (Bowden

et al. 2000). Patients who recovered with open treatment with either divalproex or lithium were randomly assigned to

maintenance treatment with divalproex, lithium, or placebo. The divalproex group did not differ significantly from the placebo

group in time to any mood episode (P = 0.06), in part because the rate of relapse into mania with placebo was lower than

anticipated. On most secondary outcome measures, divalproex was superior to placebo, with lower rates of discontinuation for

either any recurrent mood episode or a depressive episode (Bowden 2004). Divalproex was superior to lithium on some

comparisons, including longer duration of successful prophylaxis in the study and less deterioration in depressive symptom

scores. Among the subset of patients treated with divalproex in the open acute phase, those subsequently randomized to

divalproex had significantly longer times to recurrence of any mood episode ( P = 0.05) or a depressive episode (P = 0.03), and

the proportion of patients who completed the 1-year study without developing either a manic or a depressive episode was

significantly higher for divalproex than for placebo (41% vs. 13%; P = 0.01). This is the only study published to date that hasPrint: Chapter 36. Valproate

http://www.psychiatryonline.com/popup.aspx?aID=431827&print=yes…

5 of 14

10/05/2009 16:17

allowed a statistical test of the relationship between acute-episode response to treatment and maintenance treatment outcomes

(Bowden et al. 2000). A secondary post hoc review of the study employing relative risk analysis found that patients treated with

divalproex were significantly less likely than those treated with placebo to have prematurely left the study because of a mood

episode (relative risk [RR] = 0.63, 95% confidence interval [CI] = 0.44–0.90) (Macritchie et al. 2001). A post hoc analysis of

time to any mood episode or early discontinuation for any reason, a measure of effectiveness that has been incorporated in

recent maintenance studies in bipolar disorder, indicated a significant advantage for divalproex over lithium ( P >0.004) (Bowden

2003a).

A randomized open comparison of valpromide (the primary amide of valproic acid) and lithium for an 18-month period reported

good efficacy for both drugs, with somewhat more favorable results among valpromide-treated patients (Lambert and Venaud

1992). The mean number of recurrent affective episodes per patient during the maintenance period was 0.61 in the

lithium-treated group and 0.51 in the valpromide-treated group.

A separate study comparing valproate and lithium in a randomized, blinded trial of rapid-cycling patients reported that only

one-quarter of patients enrolled met criteria for an acute bimodal response to either drug, with fewer than 25% of those

randomized retaining benefits without relapse for the 20-month maintenance period. The results indicate that monotherapy

regimens with either mood stabilizer are unlikely to be effective in any more than a small minority of rapid-cycling patients

(Calabrese et al. 2005).

Acute Bipolar Depression

An 8-week randomized, placebo-controlled, blinded study reported that divalproex-treated subjects experienced significantly

greater improvement than placebo-treated patients in both depressive and anxious symptomatology, based on Hamilton Rating

Scale for Depression (Ham-D) and Hamilton Anxiety Scale (Ham-A) scores (Davis et al. 2005). In a 6-week randomized, blinded

study in bipolar depression, divalproex was superior to placebo, with a large effect size advantage (Cohen’s d = 0.81). Primary

improvement was on core mood symptoms rather than on anxiety or insomnia (Ghaemi et al. 2007). In an 8-week double-blind

study of bipolar I or II depressed patients, 43% of patients treated with divalproex recovered, compared with 27% of patients

treated with placebo. However, change in the total Ham-D score did not differ significantly between divalproex and placebo,

although the depressed mood item favored divalproex at weeks 2, 4, and 5 (Sachs et al. 2001). In a 1-year randomized,

double-blind study of initially manic bipolar patients, divalproex was more effective than lithium or placebo in delaying time to

clinical depression. In those subjects who developed depression, divalproex plus paroxetine or sertraline was superior to either

antidepressant alone in treatment of the depression (Gyulai et al. 2003).

In summary, several relatively small studies suggest some antidepressant properties for valproate both in acute depression and

in prophylaxis; however, adequately powered studies have not yet been conducted.

Bipolar Disorder in Children and Adolescents

Open trials of valproate report moderate to marked improvement in manic youth ages 8–18 years (Deltito et al. 1998; Mandoki

1993; Papatheodorou and Kutcher 1993; Wagner et al. 2002). Kowatch et al. (2000) studied 42 bipolar I manic patients (ages

9–18 years) who were treated for 6 weeks with divalproex, lithium, or carbamazepine in a randomized open study. Overall, 61%

achieved 50% or greater improvement, which did not differ significantly across the groups. The effect size for improvement was

greater for divalproex-treated patients than for lithium-treated or carbamazepine-treated patients (divalproex = 1.63, lithium =

1.06, carbamazepine = 1.00). A 6-month open study of valproate as monotherapy for 34 pediatric subjects with mixed mania

reported high treatment completion rates and effectiveness of the drug (Pavuluri et al. 2005). Because the available data are

limited to findings from open trials, valproate’s comparative efficacy and effectiveness remain to be established.

One double-blind, randomized, placebo-controlled study has been conducted in youth ages 8–10 years who met criteria for

oppositional defiant disorder or conduct disorder and had experienced temper and mood liability but did not meet the full criteria

for bipolar disorder. By the end of phase 1, 8 of 10 patients who received divalproex had responded, compared with none on

placebo. Of the 15 patients who completed both phases, 12 had superior responses to divalproex (Donovan et al. 2000).

Bipolar Disorder in the Elderly

Open trials (Narayan and Nelson 1997; Risinger et al. 1994) and one randomized, placebo-controlled study (Porsteinsson et al.

2001) reported benefits of valproate for irritable, agitated symptoms of dementia and for mania in elderly patients with bipolar

disorder (Kahn et al. 1988; McFarland et al. 1990). The studies are difficult to summarize, as the authors did not utilize consistent

terminology to report the behavioral disturbances of interest. For example, the terms behavioral disturbance, aggression,

agitation, hostility, and impulsivity have all been used to describe effects of valproate on a symptom set that deals with the

hyperactive and irritable dimensions of mania in the elderly (Narayan and Nelson 1997; Tariot et al. 1998). In a randomized,

blinded study of 56 nursing home patients with agitation and dementia treated with either placebo or individualized doses of

divalproex, when several covariates were taken into account, the drug/placebo difference in Brief Psychiatric Rating Scale

Agitation scores became statistically significant (P = 0.05). Sixty-eight percent of patients on divalproex were rated as showing

reduced agitation on the Clinical Global Impression Scale, versus 52% on placebo ( P = 0.06 in the adjusted analysis). Side

effects occurred in 68% of the divalproex group versus 33% of the placebo group ( P = 0.03) and were generally rated as mild.

This placebo-controlled study, despite some limitations, suggests possible short-term efficacy, tolerability, and safety of

divalproex for agitation in dementia and supports further placebo-controlled studies (Porsteinsson et al. 2001). Patients with

dementia are most frequently institutionalized for agitation and behavioral disturbances. A smaller randomized,

placebo-controlled study using a fixed dose (valproate 480 mg/day) that may have been inadequate failed to find any difference

between valproate and placebo groups.

Bipolar Disorder With Alcoholism

Bipolar disorder is often associated with comorbid substance use disorders, particularly alcoholism. In the largest prospective,

blinded, placebo-controlled study, 59 bipolar I patients with alcohol dependence were treated with lithium carbonate andPrint: Chapter 36. Valproate

http://www.psychiatryonline.com/popup.aspx?aID=431827&print=yes…

6 of 14

10/05/2009 16:17

psychosocial interventions for 24 weeks, with half randomly assigned to receive adjunctive valproate. The addition of valproate

was associated with significantly fewer heavy drinking days, fewer drinks per heavy drinking day, and fewer drinks per drinking

day. Higher serum valproate concentrations were correlated with improved alcohol use outcomes. Both manic and depressive

symptoms improved equivalently (Salloum et al. 2005).

In a 12-week double-blind, placebo-controlled trial, divalproex was associated with a significantly smaller percentage of

individuals relapsing to heavy drinking, but there were no significant differences in other alcohol-related outcomes. There were

significantly greater decreases in irritability in the divalproex-treated group and a trend toward greater decreases on measures

of lability and verbal assault. There were no significant between-group differences on measures of impulsivity (Brady et al.

2002).

Bipolar Disorder Comorbid With Borderline Personality Disorder

Frankenburg and Zanarini (2002) conducted a placebo-controlled, double-blind study of divalproex sodium in 30 female subjects

ages 18–40 years who met Revised Diagnostic Interview for Borderlines (Zanarini et al. 1989) and DSM-IV (American Psychiatric

Association 1994) criteria for borderline personality disorder and DSM-IV criteria for bipolar II disorder. Subjects were randomly

assigned to divalproex or placebo in a 2:1 manner. Treatment duration was 6 months. Divalproex was significantly superior to

placebo in diminishing interpersonal sensitivity and anger/hostility as well as overall aggression. Adverse effects were

infrequent (Frankenburg and Zanarini 2002).

Potential Predictors of Positive Response to Valproate Versus Lithium

Mixed mania

Patients treated with divalproex who had mixed manic presentations had greater improvement in manic symptoms with

divalproex than with lithium treatment in two randomized studies, one of which was placebo controlled (Bowden 1995; Freeman

et al. 1992; Swann et al. 1997). Patients with mixed manic and pure manic symptoms who received divalproex had equivalent

improvement, thereby indicating a lack of differential effectiveness of divalproex for the two subtypes (Swann et al. 1997). By

contrast, during maintenance treatment, patients with mixed mania had equivalent responses to divalproex or lithium, with

evidence of higher adverse effects as a function of illness features of mixed mania, compared with rates of adverse effects in

patients with euphoric mania (Bowden et al. 2005). The results suggest that mixed manic states require more complex regimens

than monotherapies for effective long-term management.

Mania with irritability

Results from a large randomized, double-blind study of manic patients showed that valproate was significantly superior to

placebo in reducing symptoms of hostility, whereas lithium was not. Similarly, among patients with an irritable subtype of mania,

divalproex reduced overall manic symptomatology, whereas lithium did not. By contrast, both valproate and lithium were

effective in reducing impulsivity and hyperactivity (Swann et al. 2002). These results are consistent with studies of valproate for

irritability in patients with personality disorders and for secondary manic states (Hollander et al. 2003; Kavoussi and Coccaro

1998; Noaghiul et al. 1998).

Irritability in manic patients has been associated with greater likelihood of response to divalproex than to lithium (Swann et al.

2002) and carbamazepine (Vasudev et al. 2000). Irritability has been the most consistently differentiating symptom favoring

divalproex benefit in patients with disorders other than bipolar disorder—namely, Cluster B personality disorders (including

borderline personality disorder) and schizophrenia (Casey et al. 2003; Frankenburg and Zanarini 2002; Hollander et al. 2003;

Swann et al. 2002).

Prior nonresponse to lithium

Manic patients with a history of nonresponse to lithium who were randomly assigned to divalproex showed significantly greater

improvement than patients who were randomized to lithium (Bowden et al. 1994). These data are consistent with reports of the

efficacy of divalproex among patients selected for nonresponse to lithium (Pope et al. 1991).

High lifetime number of episodes

Divalproex was significantly more effective than lithium among manic patients with more than 10 episodes of illness (Swann et

1. 1999) or more than 2 depressive episodes (Swann et al. 2000).

Rapid cycling

One blinded, randomized study reported that manic patients with a rapid-cycling illness course showed improvement in manic

symptoms that was similar to the improvement seen in the entire patient cohort (Chamberlain et al. 1987).

In an open study of valproate in patients with rapid-cycling bipolar I or II disorder who were followed for a mean of 17.2

months, 52 of 58 (90%) had a marked or moderate antimanic response, 88 of 94 (94%) had a prophylactic antimanic response,

13 of 15 (87%) had an acute anti–mixed state response, and 17 of 18 (94%) had a prophylactic anti–mixed state response

(Calabrese et al. 1993). A comparison of bipolar I rapid-cycling patients treated with divalproex, lithium, or the combination

found that both drugs were highly effective acutely among patients entering into a manic episode but only moderately effective

among initially depressed patients (Calabrese et al. 2005). As discussed in the section on maintenance treatment, a longer-term

maintenance study comparing divalproex and lithium reported low rates of response (both acute and sustained) for both

treatments (Calabrese et al. 2005). Although reasons for the somewhat discrepant responses reported by the same group of

investigators are not clear, in the aggregate the data suggest that rapid-cycling bipolar disorder is difficult to treat effectively

with any monotherapy regimen.

In a double-blind, placebo-controlled trial of valproate in acutely manic bipolar patients, the 12 patients whose symptoms

responded to valproate did not differ with respect to frequency of rapid cycling from the 5 valproate-treated patients whoPrint: Chapter 36. Valproate

http://www.psychiatryonline.com/popup.aspx?aID=431827&print=yes…

7 of 14

10/05/2009 16:17

showed no response (McElroy et al. 1991).

Migraine in bipolar disorder

The prevalence of migraine is increased in persons with bipolar disorder, particularly bipolar II disorders. Valproate has been

shown to be effective in the prophylaxis of migraine. The dosage of valproate is lower for migraine than for bipolar disorders,

generally in the range of 500–1,000 mg/day (Freitag et al. 2002).

Other Potential Uses

Cotherapy in Schizophrenia

The use of valproate among patients with schizophrenia has increased, with one report indicating that over a third received

valproate during hospitalization (Citrome et al. 2000; Wassef et al. 2000, 2001). A 4-week randomized, double-blind study of 242

schizophrenic patients who received risperidone or olanzapine alone, or divalproex plus the antipsychotic drug, indicated

significantly greater improvement in Positive and Negative Syndrome Scale (PANSS)—Total and PANSS positive subscale scores

among combination therapy patients from day 3 through day 21, but not at day 28. Platelet count was lower with combination

therapy, and cholesterol levels increased with olanzapine or risperidone, compared with the significantly lower levels seen with

antipsychotic plus divalproex. Weight gain did not differ between olanzapine and divalproex plus olanzapine; weight gain was

greater with divalproex plus risperidone (7.5 pounds) than with risperidone (4.2 pounds) (Casey et al. 2003). A small ( n = 12)

randomized, blinded study also indicated greater global improvement and improvement in negative symptoms for patients who

were receiving divalproex plus haloperidol than for those who were receiving haloperidol alone (Wassef et al. 2000). Divalproex

appeared to be effective as adjunctive therapy for schizoaffective disorder in a retrospective study of 20 patients with

schizoaffective disorder, bipolar type (Bogan et al. 2000).

Substance Use Disorders

Open-label studies have demonstrated the efficacy of valproic acid in reducing both cocaine craving and rates of relapse. The rate

of relapse to cocaine in 55 patients treated with valproic acid was related to serum levels: patients who had serum levels of >50

g/ml had lower rates of relapse as compared to those whose levels were <50 g/ml. A direct relationship was also noted

between serum levels and a decrease in number of days of cocaine use and improved levels of subjective functioning (Myrick et

1. 2003).

Mania Secondary to Head Trauma or Organic Brain Syndromes

Evidence suggesting that secondary or complicated mania responds well to valproate is mixed. In an open study of 56

valproate-treated patients with mania, response was associated with the presence of nonparoxysmal abnormalities on the

electroencephalogram but not with neurological soft signs or abnormalities on computed axial tomography scans of brain

(McElroy et al. 1988). Nevertheless, there was a trend for responders to have histories of closed-head injury antedating the

onset of their affective symptoms (Pope et al. 1988). Furthermore, case reports described successful valproate treatment of

organic brain syndromes with affective features (Kahn et al. 1988) and mental retardation in patients with bipolar disorder or

bipolar symptoms (Kastner et al. 1990; Sovner 1989).

Impulsive Aggression

Valproate has been reported to be effective in reducing impulsive aggression among patients with personality disorders. In the

one randomized, placebo-controlled, double-blind study that has been reported, 249 patients with Cluster B personality

disorders, intermittent explosive disorder, or posttraumatic stress disorder were treated for 12 weeks with divalproex or

placebo. Divalproex did not differ from placebo among all subjects, but among the 96 Cluster B patients, aggression and

irritability scores were improved significantly over the course of the study (Hollander et al. 2003). These results are consistent

with smaller open trials of valproate for impulsive aggression (Kavoussi and Coccaro 1998).

SIDE EFFECTS AND TOXICOLOGY

Valproate has been extensively used over several decades; thus, its adverse-effect profile is well characterized (DeVane 2003;

Prevey et al. 1996). Patients treated for epilepsy are more likely to experience adverse events than patients being treated for

migraine or mania, consequent to generally higher doses of valproate and more complex drug regimens in epilepsy (DeVane

2003). In a large 1-year placebo-controlled study in bipolar disorder, tremor and reported weight gain were the only symptoms

more commonly seen with divalproex than placebo (Prevey et al. 1996).

Gastrointestinal Effects

The most common gastrointestinal effects include nausea, vomiting, diarrhea, dyspepsia and anorexia. These are dose

dependent, are usually encountered at the start of treatment, and are often transient (DeVane 2003). Immediate-release

formulations of valproate are more likely to cause adverse events compared with the extended-release and enteric-coated

formulations (Horn and Cunanan 2003; Zarate et al. 2000).

Tremor

Tremor consequent to valproate resembles benign essential tremor and is more frequently seen in patients with seizure disorder

than in patients with bipolar disorder (DeVane 2003). Tremor may respond to a reduction in dosage or treatment with

propranolol. Extended-release or enteric-coated formulations may lessen the frequency of tremor (Wilder et al. 1983; Zarate et

1. 2000).

Sedation

Mild to moderate sedation is common, usually at the initiation of treatment. This adverse event is dose dependent and may be

minimized by dosage reduction, slower titration, use of extended-release formulations, and taking all medication at bedtime.Print: Chapter 36. Valproate

http://www.psychiatryonline.com/popup.aspx?aID=431827&print=yes…

8 of 14

10/05/2009 16:17

Hair Loss

Loss of hair can occur with valproate, possibly consequent to chelation of trace metals by valproate in the intestines and to its

effects on histone deacetylase, which result in interference with rapidly dividing cells. As with many other characteristic side

effects, lowering dosage can control this effect in some patients. Valproate ingestion should be spaced several hours before or

after ingestion of vitamin preparations, supplemental zinc, folate, and biotin, which appear able to reverse this adverse effect in

some patients (Bowden 2003b; Hurd et al. 1984).

Pancreatitis

Valproate is associated with infrequent idiosyncratic acute pancreatitis. In three migraine trials, the rates of elevation of amylase

were similar between the valproate and placebo groups (Pellock et al. 2002). Therefore, precautionary amylase levels provide

little benefit in predicting pancreatitis. Psychiatrists should be guided by clinical symptoms of pancreatitis.

Hematological Effects

Leukopenia and thrombocytopenia are directly related to higher valproate serum level, usually 100 g/mL (Acharya and Bussel

1996). Thrombocytopenia is usually mild and rarely associated with bleeding complications. Management consists of dosage

reduction. Platelet counts below 75,000/mm (Casey et al. 2003) should also be regularly reassessed, since levels below this are

more often associated with bruising or bleeding.

Hepatotoxicity

The risk of liver toxicity is largely limited to patients younger than 2 years of age, because hepatic function is immature until age

2. In long-term study of divalproex, full-dosage regimens for 1 year were associated with improvements in laboratory indices of

hepatic function, and no hepatotoxicity was reported in the 187 patients treated with divalproex (Bowden et al. 2000). Similar

results were reported in a 47-week study of divalproex in bipolar disorder (Tohen et al. 2003).

A risk factor for the development of hepatotoxicity is the concomitant administration of anticonvulsants such as carbamazepine,

which cause induction of enzymes involved in the metabolism of valproate, leading to increased concentrations of an active and

hepatotoxic metabolite, 2-propyl-4-pentenoic acid.

Weight Gain

Weight gain ranging from 3–24 pounds is seen in 3%–20% of patients treated with valproic acid over a time course that has

ranged from 3 to 12 months (Bowden 2003b). In a 47-week study, divalproex (dosage range = 500–2,500 mg/day) resulted in

less weight gain in manic and mixed-manic patients than olanzapine (1.22 kg vs. 2.79 kg) (Tohen et al. 2003). In a 3-week trial

in manic patients, weight gain as a side effect was seen in 10% of valproate-treated patients and in 25% of olanzapine-treated

patients (Zajecka et al. 2002). Valproate serum levels greater than 125 g/mL are more likely to cause weight gain than those

below this level (Bowden et al. 2000). If increased appetite and weight gain occur, valproate dosage should be lowered so long

as clinical effectiveness is maintained, or alternatively should be discontinued and replaced by regimens without risks of weight

gain.

Cognitive Dulling

Valproate has infrequent adverse effects on cognitive functioning, and it improves cognition in some patients (Prevey et al.

1996). In a 20-week randomized, observer-blinded, parallel-group trial, the addition of valproate to carbamazepine resulted in

improvement on short-term verbal memory (Aldenkamp et al. 2000). No adverse cognitive effects with the use of valproate were

seen in a group of elderly patients (mean age = 77 years) (Craig and Tallis 1994).

Lipid-Lowering Effects

Several studies indicate that valproate reduces total cholesterol and low-density lipoprotein (LDL) and high-density lipoprotein

(HDL) cholesterol levels and protects against the adverse effects of some antipsychotic drugs on lipid function. An open case

series found no changes in lipid profiles in children receiving long-term valproate (Geda et al. 2002). Valproate significantly

lowered total and LDL cholesterol in comparison with phenobarbital and carbamazepine in a study of children with epilepsy

(Ylmaz et al. 2001). In a 47-week study in manic and mixed-manic patients, valproate reduced cholesterol levels (Tohen et al.

1995). In patients with schizophrenia, valproate adjunctive to olanzapine or risperidone resulted in lowered cholesterol levels

(Casey et al. 2003). The cholesterol-lowering effect of valproate is apparent even in short 3-week trials in acute mania. For the

full sample in the randomized, blinded study, total cholesterol decreased significantly more in the divalproex group than in the

placebo group (–13.47 mg/dL vs. –2.46 mg/dL; P = 0.001). Stratification by baseline total cholesterol levels ( 200 mg/dL vs.

<200 mg/dL) indicated that reduction with divalproex compared with placebo was limited to the stratum with higher mean

baseline values (–18.6mg/dL vs. –6.5 mg/dL, respectively) (Bowden et al. 2006). In a 12-week comparison of divalproex and

olanzapine in bipolar disorder patients, cholesterol and LDL levels fell with valproate use, compared with significant increases in

olanzapine-treated patients (Zajecka and Weisler 2000).

Polycystic Ovarian Syndrome

Polycystic ovarian syndrome (PCOS) occurs in 4%–12% of women and is the leading cause of ovulatory infertility. PCOS appears

to have a higher incidence in women with epilepsy; PCOS was found in 20% of 50 women with temporal lobe epilepsy and in

25% of 20 women with complex partial seizures, most of whom were unmedicated (Ernst and Goldberg 2002).

The prevalence of menstrual disturbances is high in women with bipolar disorder, irrespective of medication received, probably

representing a dysfunction of the hypothalamic-pituitary-gonadal axis. A study of 10 lithium-treated, 10 valproate-treated, and 2

carbamazepine-treated women with bipolar disorder found a high frequency of menstrual dysfunction in all groups. Ultrasound

identified an increased number of ovarian follicles in 1 of the lithium-treated patients but no increases in any valproate-treated

patient. PCOS did not occur in any of the patients. Hormonal assessment of estrone, luteinizing hormone, follicle-stimulatingPrint: Chapter 36. Valproate

http://www.psychiatryonline.com/popup.aspx?aID=431827&print=yes…

9 of 14

10/05/2009 16:17

hormone, testosterone, and dehydroepiandrosterone (DHEA) yielded no abnormal values in any patient (Rasgon et al. 2000).

In the cross-sectional National Institute of Mental Health Systematic Treatment Enhancement Program for Bipolar Disorder

(STEP-BD) program, new-onset menstrual cycle irregularities and hyperandrogenism occurred in 10.5% of 86 women treated

with valproate as a component of their prior treatment regimen before entering the STEP-BD study (Joffe et al. 2006a). A

follow-up study of 7 women who had developed valproate-associated PCOS reported that PCOS reproductive features remitted in

3 of the 4 patients who discontinued valproate and persisted in all 3 patients who remained on valproate (Joffe et al. 2006b). No

changes in polycystic ovarian morphology were associated with valproate in either study.

A study evaluating four groups of women with epilepsy—an untreated group, a carbamazepine-treated group, a valproate-treated

group, and a group receiving more than one antiepileptic agent—found no differences in rates of PCOS among the drug-treated

groups (Bauer et al. 2000). Valproate did not alter endocrine measures indicative of PCOS in a 12- to 15-month study in rhesus

monkeys (Ferin et al. 2003). Obesity may be a mechanistic pathway whereby valproate (and potentially other drugs) predisposes

women to PCOS. It is advisable to treat weight gain as a risk factor for possible development of PCOS and intervene as needed to

avoid clinically significant weight gain.

Use During Pregnancy and Lactation

Birth Defects

Valproate is associated with an increased incidence of birth defects, including neural tube defects, craniofacial anomalies, limb

abnormalities, and cardiovascular anomalies, if infants are exposed to valproic acid in the first 10 weeks of gestation (Kinrys et

1. 2003; Samren et al. 1997). Neural tube defects, the most serious of the congenital anomalies, occur in 1%–4% of such

infants. Prenatal exposure to valproate prior to the closure of the neural tube, during the fourth of week of gestation, leads to a

prevalence of spina bifida in 1%–2% of infants, a 10–20 times greater rate than in the general population (Kinrys et al. 2003).

Most of the available data involved patients with epilepsy, who are generally treated with higher doses of valproate than the

doses employed for bipolar disorder and migraine and who are often concurrently treated with other teratogenic anticonvulsants

(Bowden 2003b). The risk of malformations is increased with higher dosages and higher serum levels of valproate, as well as

with concomitant use of other anticonvulsants (due to higher concentration of 2-propyl-4-pentenoic acid, a teratogenic agent); is

possibly decreased with supplemental folic acid; and is definitely reduced with lower dosages of valproate (Bowden 2003b).

Because alternate treatment strategies lacking teratogenic risk may work to effectively manage bipolar symptoms, valproate

should generally be discontinued if conception is desired and during the early course of pregnancy if it occurs.

Breast-Feeding

Valproate is minimally present in breast milk. Piontek et al. (2000) reported that among six mother–infant pairs, serum valproate

levels in the infants ranged from 0.9% to 2.3% of the mother’s serum level, with absolute serum levels of 0.7–1.56 g/mL. The

valproate concentration in an infant was 1.5% of the maternal concentration (Wisner and Perel 1998).

Overdose

Regarding overdose, recovery from coma has occurred with serum valproate concentrations of greater than 2,000 g/mL. In

addition, serum valproate concentrations have been reduced by hemodialysis and hemoperfusion, and valproate-induced coma

has been reversed with naloxone (Rimmer and Richens 1985). It is generally not necessary to perform routine blood monitoring

of hematological and hepatic function in patients receiving valproate (Willmore et al. 1991). Superior to routine laboratory

screening is educating the patient about the signs and symptoms of organ system dysfunction and instructing the patient to

report these symptoms if they occur, in conjunction with careful monitoring of the patient’s clinical status.

DRUG–DRUG INTERACTIONS

Because valproate is highly protein bound and extensively metabolized by the liver, a number of potential drug–drug interactions

may occur with other protein-bound or metabolized drugs (Fogel 1988; Levy et al. 2002; Rall and Schleifer 1985; Rimmer and

Richens 1985). Thus, free fraction concentrations of valproate in serum can be increased and valproate toxicity can be

precipitated by coadministration of other highly protein-bound drugs (e.g., aspirin) that can displace valproate from its

protein-binding sites.

Because valproate tends to inhibit drug oxidation—it is the only major antiepileptic that does not induce hepatic microsomal

enzymes—serum concentrations of a number of metabolized drugs can be increased by the coadministration of valproate.

Valproate has been reported to increase serum concentrations of phenobarbital, phenytoin, and tricyclic antidepressants.

Conversely, the metabolism of valproate can be increased, and valproate serum concentrations subsequently decreased, by

coadministration of microsomal enzyme–inducing drugs such as carbamazepine. Drugs that inhibit metabolism may increase

valproate concentrations in serum. Fluoxetine, for instance, has been reported to boost valproate concentrations (Sovner and

Davis 1991).

The competitive inhibition by valproate of excretion of lamotrigine via glucuronidation requires that lamotrigine be started at a

lower dosage, usually 25 mg every other day, and increased more cautiously. Steady-state dosage of lamotrigine used with

valproate is also generally lower, but not in all patients.

CONCLUSION

The broad spectrum of efficacy in bipolar spectrum disorders and generally good tolerability of valproate make it a foundation of

treatment for many patients with bipolar disorders. For optimal results, most patients should be treated with a formulation that

permits single daily dosing and has the lowest peak-to-trough serum level, which in the United States currently is

extended-release divalproex. Although onset of action of valproate is prompt with loading-dose strategies, given the paramount

importance of tolerability and adherence of bipolar patients to long-term treatment regimens, gradual dosage increase is

preferable for all but severely manic states.Print: Chapter 36. Valproate

http://www.psychiatryonline.com/popup.aspx?aID=431827&print=yes…

10 of 14

10/05/2009 16:17

During maintenance treatment, it is often important to reduce dosage if adverse effects persist. Valproate alleviates and is

prophylactic principally for manic symptoms, although prophylactic benefits for depression are now relatively well established. A

history of many episodes or current irritability may be a particularly strong indicator of a favorable response to valproate.

Although some patients may have acute and sustained remission with valproate monotherapy, many patients are more

effectively treated with combinations, including other mood stabilizers and adjunctive medications. All current medications with

established or putative roles can be combined with valproate.

Although valproate is now approved for mania in most countries, well-designed studies that advance clinical knowledge continue

to be conducted with this drug. Additionally, scientific information coming from studies in patients with migraine, epilepsy, and

other psychiatric disorders will continue to provide useful, reliable information, especially regarding prescribing practices and

adverse-effect profiles and management.

REFERENCES

Acharya S, Bussel JB: Hematologic toxicity of sodium valproate. J Pediatr Neurol 14:303–307, 1996

Aldenkamp AP, Baker G, Mulder OG, et al: A multicenter, randomized clinical study to evaluate the effect on cognitive function of

topiramate compared with valproate as add-on therapy to carbamazepine in patients with partial-onset seizures. Epilepsia

41:1167–1178, 2000 [PubMed]

Allen MH, Hirschfeld RM, Wozniak PJ, et al: Linear relationship of valproate serum concentration to response and optimal serum

levels for acute mania. Am J Psychiatry 163:272–275, 2006 [Full Text] [PubMed]

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC, American

Psychiatric Association, 1994

Andratschke N, Grosu AL, Molis M, et al: Perspectives in the treatment of malignant gliomas in adults. Anticancer Res

21:3541–3550, 2001 [PubMed]

Andreazza AC, Frey BN, Stertz L, et al: Effects of lithium and valproate on DNA damage and oxidative stress markers in an animal

model of mania. Bipolar Disord 9:16, 2007

Bauer J, Jarre A, Klingmüller D, et al: Polycystic ovary syndrome in patients with focal epilepsy: a study in 93 women. Epilepsy

Res 41:163–167, 2000 [PubMed]

Bocci U, Beretta G: Esperienze sugli alcoolisti e tossicomania con dipropilacetate di sodio. Lavoro Neuropsichiatrico 58:51–61,

1976

Bogan AM, Brown ES, Suppes T: Efficacy of divalproex therapy for schizoaffective disorder. J Clin Psychopharmacol 20:520–522,

2000 [PubMed]

Bourgeois B: Valproate: clinical use, in Antiepileptic Drugs, 3rd Edition. Edited by Levy RH, Dreifuss FE, Mattson RH, et al. New

York, Raven, 1989, pp 633–642

Bowden CL: Predictors of response to divalproex and lithium. J Clin Psychiatry 56:25–30, 1995 [PubMed]

Bowden CL: Valproate in mania, in Bipolar Medications: Mechanisms of Action. Edited by Manji HK, Bowden CL, Belmaker RH.

Washington, DC, American Psychiatric Press, 2000, pp 357–365

Bowden CL: Acute and maintenance treatment with mood stabilizers. Int J Neuropsychopharmacol 6:269–275, 2003a

Bowden CL: Valproate. Bipolar Disord 5:189–202, 2003b

Bowden CL: Relationship of acute mania symptomatology to maintenance treatment response. Curr Psychiatry Rep 6:473–477,

2004 [PubMed]

Bowden CL, McElroy SL: History of the development of valproate for treatment of bipolar disorder. J Clin Psychiatry 56:3–5, 1995

[PubMed]

Bowden CL, Brugger AM, Swann AC, et al: Efficacy of divalproex vs lithium and placebo in the treatment of mania. JAMA

271:918–924, 1994 [PubMed]

Bowden CL, Janicak PG, Orsulak P, et al: Relation of serum valproate concentration to response in mania. Am J Psychiatry

153:765–770, 1996 [Full Text] [PubMed]

Bowden CL, Calabrese JR, McElroy SL, et al: A randomized, placebo-controlled 12-month trial of divalproex and lithium in

treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Arch Gen Psychiatry 57:481–489, 2000

[PubMed]

Bowden CL, Collins MA, McElroy SL, et al: Relationship of mania symptomatology to maintenance treatment response with

divalproex, lithium or placebo. Neuropsychopharmacology 30:323–330, 2005

Bowden CL, Swann AC, Calabrese JR, et al: A randomized, placebo-controlled, multicenter study of valproex sodium extended

release in the treatment of acute mania. J Clin Psychiatry 67:1501–1510, 2006 [PubMed]

Brady KT, Myrick H, Henderson S, et al: The use of divalproex in alcohol relapse prevention: a pilot study. Drug Alcohol Depend

67:323–330, 2002 [PubMed]

Brennan MJW, Sandyk R, Borseek D: Use of sodium-valproate in the management of affective disorders: basic and clinical

aspects, in Anticonvulsants in Affective Disorders. Edited by Emrich HM, Okuma T, Muller AA. Amsterdam, The Netherlands,

Excerpta Medica, 1984, pp 56–65

Calabrese JR, Woyshville MJ, Kimmel SE, et al: Predictors of valproate response in bipolar rapid cycling. J Clin PsychopharmacolPrint: Chapter 36. Valproate

http://www.psychiatryonline.com/popup.aspx?aID=431827&print=yes…

11 of 14

10/05/2009 16:17

13:280–283, 1993 [PubMed]

Calabrese JR, Shelton MD, Rapport DJ, et al: A 20-month, double-blind, maintenance trial of lithium versus divalproex in

rapid-cycling bipolar disorder. Am J Psychiatry 162:2152–2161, 2005 [Full Text] [PubMed]

Casey DE, Daniel DG, Wassef AA, et al: Effect of divalproex combined with olanzapine or risperidone in patients with an acute

exacerbation of schizophrenia. Neuropsychopharmacology 28:182–192, 2003 [PubMed]

Chamberlain B, Ervin FR, Pihl RO, et al: The effect of raising or lowering tryptophan levels on aggression in vervet monkeys.

Pharmacol Biochem Behav 28:503–510, 1987 [PubMed]

Citrome L, Levine J, Allingham B: Changes in use of valproate and other mood stabilizers for patients with schizophrenia from

1994 to 1998. Psychiatr Serv 51:634–638, 2000 [Full Text] [PubMed]

Craig I, Tallis R: Impact of valproate and phenytoin on cognitive function in elderly patients: results of a single-blind randomized

comparative study. Epilepsia 35:381–390, 1994 [PubMed]

Davis LL, Bartolucci A, Petty F: Divalproex in the treatment of bipolar depression: a placebo-controlled study. J Affect Disord

85:259–266, 2005 [PubMed]

Deltito JA, Levitan J, Damore J, et al: Naturalistic experience with the use of divalproex sodium on an in-patient unit for

adolescent psychiatric patients. Acta Psychiatr Scand 97:236–240, 1998 [PubMed]

DeVane CL: Pharmacokinetics, drug interactions and tolerability of valproate. Psychopharmacol Bull 37 (suppl):25–42, 2003

Dokucu M, Yu L, Taghert P: Lithium- and valproate-induced alterations in circadian locomotor behavior in Drosophila.

Neuropsychopharmacology 30:2216–2224, 2005 [PubMed]

Donovan SJ, Stewart JW, Nunes EV, et al: Divalproex treatment for youth with explosive temper and mood lability: a

double-blind, placebo-controlled crossover design. Am J Psychiatry 157:818–820, 2000 [Full Text] [PubMed]

Einat H, Manji HK: Cellular plasticity cascades: genes-to-behavior pathways in animal models of bipolar disorder. Biol Psychiatry

59:1160–1171, 2006 [PubMed]

Einat H, Yuan P, Gould TD, et al: The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J

Neurosci 23:7311–7316, 2003 [PubMed]

Emrich HM, von Zerssen DKW, Moller HJ: On a possible role of GABA in mania: therapeutic efficacy of sodium valproate. Adv

Biochem Psychopharmacol 26:287–296, 1981 [PubMed]

Emrich HM, Dose M, von Zerssen D: The use of sodium valproate, carbamazepine, and oxcarbazepine in patients with affective

disorders. J Affect Disord 8:243–250, 1985 [PubMed]

Ernst CL, Goldberg JF: The reproductive safety profile of mood stabilizers, atypical antipsychotics, and broad-spectrum

psychotropics. J Clin Psychiatry 63 (suppl):42–55, 2002

Fariello R, Smith MC: Valproate: mechanisms of action, in Antiepileptic Drugs, 3rd Edition. Edited by Levy RH, Dreifuss FE,

Mattson RH, et al. New York, Raven, 1989, pp 567–575

Ferin M, Morrell M, Xiao E, et al: Endocrine and metabolic responses to long-term monotherapy with the antiepileptic drug

valproate in the normally cycling rhesus monkey. J Clin Endocrinol Metab 88:2908–2915, 2003 [PubMed]

Fogel BS: Combining anticonvulsants with conventional psychopharmacologic agents, in Use of Anticonvulsants in Psychiatry:

Recent Advances. Edited by McElroy SL, Pope HG Jr. Clifton, NJ, Oxford Health Care, 1988, pp 77–94

Frankenburg FR, Zanarini MC: Divalproex sodium treatment of women with borderline personality disorder and bipolar II

disorder: a double-blind placebo-controlled pilot study. J Clin Psychiatry 63:442–446, 2002 [PubMed]

Freeman TW, Clothier JL, Pazzaglia P, et al: A double-blind comparison of valproate and lithium in the treatment of acute mania.

Am J Psychiatry 149:108–111, 1992 [PubMed]

Freitag FG, Collins SD, Carlson HA, et al: A randomized trail of divalproex sodium extended-release tablets in migraine

prophylaxis. Neurology 58:1652–1659, 2002 [PubMed]

Geda G, Casken H, Icagasioglu D: Serum lipids with B-12 and folic acid levels in children receiving long term valproate therapy.

Acta Neurol Belg 102:122–126, 2002 [PubMed]

Ghaemi NS, Gilmer WS, Goldberg JF, et al. Divalproex in the treatment of acute bipolar depression: a preliminary double-blind,

randomized, placebo-controlled pilot study. J Clin Psychiatry 68:1840–1844, 2007 [PubMed]

Gilmor M, Skelton K, Nemeroff C, et al: The effects of chronic treatment with the mood stabilizers valproic acid and lithium on

corticotrophin-releasing factor neuronal systems. J Pharmacol Exp Ther 305:434–439, 2003 [PubMed]

Gray NA, Zhou R, Du J, et al: The use of mood stabilizers as plasticity enhancers in the treatment of neuropsychiatric disorders. J

Clin Psychiatry 64 (suppl):3–17, 2003

Grunze H, Erfurth A, Amann B, et al: Intravenous valproate loading in acutely manic and depressed bipolar I patients. J Clin

Psychopharmacol 19:303–309, 1999 [PubMed]

Gyulai L, Bowden CL, McElroy SL, et al: Maintenance efficacy of divalproex in the prevention of bipolar depression.

Neuropsychopharmacology 28:1374–1382, 2003 [PubMed]

Hahn CG, Umapathy, Wagn HY, et al: Lithium and valproic acid treatments reduce PKC activation and receptor-G protein coupling

in platelets of bipolar manic patients. J Psychiatr Res 39:35–63, 2005Print: Chapter 36. Valproate

http://www.psychiatryonline.com/popup.aspx?aID=431827&print=yes…

12 of 14

10/05/2009 16:17

Harwood AJ, Agam G: Search for a common mechanism of mood stabilizers. Biochem Pharmacol 66:179–189, 2003 [PubMed]

Hollander E, Tracy KA, Swann AC, et al: Divalproex in the treatment of impulsive aggression: efficacy in Cluster B personality

disorders. Neuropsychopharmacology 28:1186–1197, 2003 [PubMed]

Horn RL, Cunanan C: Safety and efficacy of switching psychiatric patients from a delayed-release to an extended-release

formulation of divalproex sodium. J Clin Psychopharmacol 23:176–181, 2003

Hurd RW, Van Rinsvelt HA, Wilder BJ, et al: Selenium, zinc, and copper changes with valproic acid: possible relation to drug side

effects. Neurology 34:1393–1395, 1984 [PubMed]

Jacobsen FM: Low dose valproate: a new treatment for cyclothymia, mild rapid cycling disorders, and premenstrual syndrome. J

Clin Psychiatry 54:229–234, 1993 [PubMed]

Joffe H, Cohen LS, Suppes T, et al: Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism in women

with bipolar disorder. Biol Psychiatry 59:1078–1086, 2006a

Joffe H, Cohen LS, Suppes T, et al: Longitudinal follow-up of reproductive and metabolic features of valproate-associated

polycystic ovarian syndrome features: a preliminary report. Biol Psychiatry 60:1378–1381, 2006b

Kahn D, Stevenson E, Douglas CJ: Effect of sodium valproate in three patients with organic brain syndromes. Am J Psychiatry

145:1010–1011, 1988 [PubMed]

Kastner T, Friedman DL, Plummer AT, et al: Valproic acid for the treatment of children with mental retardation and mood

symptomatology. Pediatrics 86:467–472, 1990 [PubMed]

Kavoussi RJ, Coccaro EF: Divalproex sodium for impulsive aggressive behavior in patients with personality disorder. J Clin

Psychiatry 59:676–680, 1998 [PubMed]

Keck PE Jr, McElroy SL, Tugrul KC, et al: Valproate oral loading in the treatment of acute mania. J Clin Psychiatry 54:305–308,

1993 [PubMed]

Keck PE Jr, Bowden CL, Meinhold JM, et al: Relationship between serum valproate and lithium levels and efficacy and tolerability

in bipolar maintenance therapy. Int J Psychiatry Clin Pract 9:271–277, 2005

Kinrys G, Pollack MH, Simon NM, et al: Valproic acid for the treatment of social anxiety disorder. Int Clin Psychopharmacol

18:169–172, 2003 [PubMed]

Kowatch RA, Suppes T, Carmody TJ, et al: Effect size of lithium, divalproex sodium, and carbamazepine in children and

adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 39:713–720, 2000 [PubMed]

Lambert PA, Venaud G: Comparative study of valpromide versus lithium as prophylactic treatment in affective disorders. Nervure

5:57–65, 1992

Lambert PA, Cavaz G, Borselli S, et al: Action neuropsychotrope d’un nouvel anti-epileptique: le depamide. Ann Med Psychol

1:707–710, 1966

Leveil V, Nanquet R: A study of the action of valproic acid on the kindling effect. Epilepsia 18:229–234, 1977

Levy RH, Mattson RH, Meldrum BS, et al (eds): Antiepileptic Drugs, 5th Edition. New York, Lippincott Williams & Wilkins, 2002

Macritchie KA, Geddes JR, Scott J, et al: Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder.

Cochrane Database Syst Rev (3):CD003196, 2001

Mandoki MW: Valproate-lithium combination and verapamil as treatments of bipolar disorder in children and adolescents

(abstract). Neuropsychopharmacology 9 (suppl):183S, 1993

McElroy SL, Pope HG Jr, Keck PE Jr: Treatment of psychiatric disorders with valproate: a series of 73 cases. Psychiatrie

Psychobiologie 3:81–85, 1988

McElroy SL, Keck PE, Pope HG, et al: Correlates of antimanic response to valproate. Psychopharmacol Bull 27:127–133, 1991

[PubMed]

McElroy SL, Keck PE, Tugrul KC, et al: Valproate as a loading treatment in acute mania. Neuropsychobiology 27:146–149, 1993

[PubMed]

McElroy SL, Keck PE, Stanton SP, et al: A randomized comparison of divalproex oral loading versus haloperidol in the initial

treatment of acute psychotic mania. J Clin Psychiatry 57:142–146, 1996 [PubMed]

McFarland BH, Miller MR, Straumfjord AA: Valproate use in the older manic patient. J Clin Psychiatry 51:479–481, 1990 [PubMed]

Meunier H, Carraz G, Meunier V, et al: Proprietes pharmacodynamiques de l’acide n-propylacetique. Therapie 18:435–438, 1975

Muller-Oerlinghausen B, Retzow A, Henn FA, et al: Valproate as an adjunct to neuroleptic medication for the treatment of acute

episodes of mania: a prospective, randomized, double-blind, placebo-controlled, multicenter study. J Clin Psychopharmacol

20:195–203, 2000 [PubMed]

Myrick H, Malcolm R, Raymond A: The use of antiepileptics in the treatment of addictive disorders. Prim Psychiatry 10:59–63,

2003

Narayan N, Nelson J: Treatment of dementia with behavioral disturbance using divalproex or a combination of divalproex and a

neuroleptic. J Clin Psychiatry 58:351–354, 1997 [PubMed]

Noaghiul S, Narayan M, Nelson JC: Divalproex treatment of mania in elderly patients. Am J Geriatr Psychiatry 6:257–262, 1998Print: Chapter 36. Valproate

http://www.psychiatryonline.com/popup.aspx?aID=431827&print=yes…

13 of 14

10/05/2009 16:17

[PubMed]

Papatheodorou G, Kutcher SP: Divalproex sodium treatment in late adolescent and young adult acute mania. Psychopharmacol

Bull 29:213–219, 1993 [PubMed]

Pavuluri MN, Henry DB, Carbray JA, et al: Divalproex sodium for pediatric mixed mania: a 6-month prospective trial. Bipolar

Disord 7:266–273, 2005 [PubMed]

Pellock JM, Wilder BJ, Deaton R, et al: Acute pancreatitis coincident with valproate use: a critical review. Epilepsia

43:1421–1424, 2002 [PubMed]

Penry JK, Dean JC: The scope and use of valproate in epilepsy. J Clin Psychiatry 50 (suppl):17–22, 1989

Piontek CM, Baab S, Peindl KS, et al: Serum valproate levels in 6 breastfeeding mother-infant pairs. J Clin Psychiatry 61:170–172,

2000 [PubMed]

Pope HG Jr, McElroy SL, Satlin A, et al: Head injury, bipolar disorder, and response to valproate. Compr Psychiatry 29:34–38,

1988 [PubMed]

Pope HG Jr, McElroy SL, Keck PE Jr, et al: Valproate in the treatment of acute mania: a placebo-controlled study. Arch Gen

Psychiatry 48:62–68, 1991 [PubMed]

Porsteinsson AP, Tariot PN, Erb R, et al: Placebo-controlled study of divalproex sodium for agitation in dementia. Am J Geriatr

Psychiatry 9:58–66, 2001 [PubMed]

Prevey ML, Delaney RC, Cramer JA, et al: Effect of valproate on cognitive functioning: comparison with carbamazepine. The

Department of Veteran Affairs Epilepsy Cooperative Study 264 Group. Arch Neurol 53:1008–1016, 1996 [PubMed]

Quiroz JA, Gray NA, Kato T, et al: Mitchondrially mediated plasticity in the pathophysiology and treatment of bipolar disorder.

Neuropsychopharmacology 33:2551–2565, 2008 [PubMed]

Rall TW, Schleifer LS: Drugs effective in the therapy of the epilepsies, in Goodman and Gilman’s The Pharmacological Basis of

Therapeutics, 7th Edition. Edited by Gilman AG, Goodman LS, Rall TW. New York, Macmillan, 1985, pp 446–472

Rasgon NL, Altshuler LL, Gudeman D, et al: Medication status and polycystic ovary syndrome in women with bipolar disorder: a

preliminary report. J Clin Psychiatry 61:173–178, 2000 [PubMed]

Rimmer E, Richens A: An update on sodium valproate. Pharmacotherapy 5:171–184, 1985 [PubMed]

Risinger RC, Risby ED, Risch SC: Safety and efficacy of divalproex sodium in elderly bipolar patients (letter). J Clin Psychiatry

55:215, 1994 [PubMed]

Sachs GS, Collins MA, Altshuler LL, et al: Divalproex sodium versus placebo for treatment of bipolar depression. Paper presented

at annual meeting of the American College of Neuropsychopharmacology, San Juan, PR, December 2001

Sachs G, Grossman F, Okamoto A, et al: Risperidone plus mood stabilizer versus placebo plus mood stabilizer for acute mania of

bipolar disorder: a double-blind comparison of efficacy and safety. Am J Psychiatry 159:1146–1154, 2002 [Full Text] [PubMed]

Salloum IM, Cornelius JR, Daley DC, et al: Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a

double-blind placebo-controlled study. Arch Gen Psychiatry 62:37–45, 2005 [PubMed]

Samren EB, Duijn CM, Koch S, et al: Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint

European prospective study of human teratogens associated with maternal epilepsy. Epilepsia 38:981–990, 1997 [PubMed]

Shaltiel G, Shamir A, Shapiro J, et al: Valproate decreases inositol biosynthesis. Biol Psychiatry 56:868–874, 2004 [PubMed]

Siafaka-Kapadai A, Patiris M, Bowden C, et al: Incorporation of [3H]-valproic acid into lipids in GT1–7 neurons. Biochem

Pharmacol 56:207–212, 1998 [PubMed]

Solomon DA, Ryan CE, Keitner GI, et al: A pilot study of lithium carbonate plus divalproex sodium for the continuation and

maintenance treatment of patients with bipolar I disorder. J Clin Psychiatry 58:95–99, 1997 [PubMed]

Sovner R: The use of valproate in the treatment of mentally retarded persons with typical and atypical bipolar disorders. J Clin

Psychiatry 50:40–43, 1989 [PubMed]

Sovner R, Davis JM: A potential drug interaction between fluoxetine and valproic acid (letter). J Clin Psychopharmacol 11:389,

1991 [PubMed]

Swann AC, Bowden CL, Morris D, et al: Depression during mania: treatment response to lithium or divalproex. Arch Gen

Psychiatry 54:37–42, 1997 [PubMed]

Swann AC, Bowden CL, Calabrese JR, et al: Differential effect of number of previous episodes of affective disorder on response to

lithium or divalproex in acute mania. Am J Psychiatry 156:1264–1266, 1999 [Full Text] [PubMed]

Swann AC, Bowden CL, Calabrese JR, et al: Mania: differential effects of previous depressive and manic episodes on response to

treatment. Acta Psychiatr Scand 101:444–451, 2000 [PubMed]

Swann AC, Bowden CL, Calabrese JR, et al: Pattern of response to divalproex, lithium, or placebo in four naturalistic subtypes of

mania. Neuropsychopharmacology 26:530–536, 2002 [PubMed]

Tariot PN, Erb R, Podgorski CA, et al: Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J

Psychiatry 155:54–61, 1998 [Full Text] [PubMed]

Tohen M, Baldessarini RJ, Zarate C et al: Blood dyscrasias with carbamazepine and valproate: a pharmacological study of 2,228Print: Chapter 36. Valproate

http://www.psychiatryonline.com/popup.aspx?aID=431827&print=yes…

14 of 14

10/05/2009 16:17

patients at risk. Am J Psychiatry 152:413–418, 1995 [Full Text] [PubMed]

Tohen M, Chengappa KNR, Suppes T, et al: Efficacy of olanzapine in combination with valproate or lithium in the treatment of

mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry 59:62–69, 2002 [PubMed]

Tohen M, Ketter TA, Zarate CA: Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of

remission: a 47 week study. Am J Psychiatry 160:1263–1271, 2003 [Full Text] [PubMed]

Tremolizzo L, Carboni G, Ruzicka WB, et al: An epigenetic mouse model for molecular and behavioral neuropathologies related to

schizophrenia vulnerability. Proc Natl Acad Sci U S A 99:17095–17100, 2002 [PubMed]

Tremolizzo L, Doueiri MS, Dong E, et al: Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by

methionine in mice. Biol Psychiatry 57:500–509, 2005 [PubMed]

Vasudev K, Goswami U, Kohli K: Carbamazepine and valproate monotherapy: feasibility, relative safety and efficacy, and

therapeutic drug monitoring in manic disorder. Psychopharmacology 150:15–23, 2000 [PubMed]

Wagner KD, Weller EB, Carlson GA, et al: An open-label trial of divalproex in children and adolescents with bipolar disorder. J Am

Acad Child Adolesc Psychiatry 41:1224–1230, 2002 [PubMed]

Wassef AA, Dott SG, Harris A, et al: Randomized, placebo-controlled pilot study of divalproex sodium in the treatment of acute

exacerbations of chronic schizophrenia. J Clin Psychopharmacol 20:357–361, 2000 [PubMed]

Wassef AA, Hafiz NG, Hampton D, et al: Divalproex sodium augmentation of haloperidol in hospitalized patients with

schizophrenia: clinical and economic implications. J Clin Psychopharmacol 21:21–26, 2001 [PubMed]

Wilder BJ: Pharmacokinetics of valproate and carbamazepine. J Clin Psychopharmacol 12 (suppl):64S–68S, 1992

Wilder BJ, Karas BJ, Penry JK, et al: Gastrointestinal tolerance of divalproex sodium. Neurology 33:808–811, 1983 [PubMed]

Willmore LJ, Triggs WJ, Pellock JM: Valproate toxicity: risk-screening strategies. J Child Neurol 6:3–6, 1991 [PubMed]

Wisner KL, Perel JM: Serum levels of valproate and carbamazepine in breastfeeding mother-infant pairs. J Clin Psychopharmacol

18:167–169, 1998 [PubMed]

Yatham LN: Efficacy of atypical antipsychotics in mood disorders. J Clin Psychopharmacol 23:S9–S14, 2003

Yatham LN: Atypical antipsychotics for bipolar disorder. Psychiatr Clin North Am 28:325–347, 2005 [PubMed]

Ylmaz E, Dosan Y, Gurgoze MK, et al: Serum lipid changes during anticonvulsant treatment in epileptic children. Acta Neurol Belg

101:217–220, 2001

Zajecka J, Weisler R: Divalproex sodium vs olanzapine for the treatment of mania in bipolar disorder. Presented at the 39th

Annual Meeting of the American College of Neuropsychopharmacology, San Juan, Puerto Rico, December 2000

Zajecka J, Weisler R, Sachs G, et al: A comparison of the efficacy, safety and tolerability of divalproex sodium and olanzapine in

the treatment of bipolar disorder. J Clin Psychiatry 63:1148–1155, 2002 [PubMed]

Zanarini MC, Gunderson JG, Frankenburg FR, et al: The Revised Diagnostic Interview for Borderlines: discriminating BPD from

other Axis II disorders. J Personal Disord 3:10–18, 1989

Zarate CA Jr, Tohen M, Narendran R, et al: The adverse effect profile and efficacy of divalproex sodium compared with valproic

acid: a pharmacoepidemiology study. J Clin Psychiatry 60:232–236, 2000

Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.