Drug Profile
For reprint orders, please contact reprints@future-drugs.com
CONTENTS
Bipolar I disorder
Disruptive behavior
disorders
Autistic spectrum disorders
Use of divalproex sodium in
pediatric populations
Clinical efficacy
Expert opinion
Five-year view
Key issues
References
Affiliations
†
Author for correspondence
Stanford University, School of
Medicine, Department of
Psychiatry and Behavioral Sciences,
Division of Child Psychiatry and
Child Development,
401 Quarry Road, Stanford,
CA 94305 5719, USA
Tel.: +1 650 723 5420
Fax: +1 650 723 5531
mrana@stanford.edu
KEYWORDS:
adolescents, anticonvulsant,
bipolar disorder, children,
divalproex sodium, mood
stabilizer, valproic acid
www.future-drugs.com
Divalproex sodium in the
treatment of pediatric
psychiatric disorders
Manasi Rana†, Leena Khanzode, Niranjan Karnik, Kirti Saxena,
Kiki Chang and Hans Steiner
Divalproex sodium is an anticonvulsant that is used extensively in adults with indications for
epilepsy, acute mania and migraine prophylaxis. It has been used in children and
adolescents as a first-line agent for mania in bipolar disorder. Its efficacy as a mood
stabilizer has been established, and there have been studies outlining its efficacy as an
agent effective in the treatment of conduct disorder, disruptive behavior disorders,
aggression and explosive disorder. Longer-acting formulations are now available that
cause less gastrointestinal side effects and can also be taken once a day, thus potentially
increasing adherence, an important factor in this patient population. Future directions
would include developing a more potent valproic acid formulation with fewer side effects,
completing randomized controlled trials to establish the efficacy of divalproex sodium in
various other pediatric psychiatric disorders, establishing the relative efficacy of the
compound in head-to-head comparisons with other mood stabilizers, examining
systematically the value of the compound in multimodal pediatric psychiatric treatment
packages, and complete effectiveness trials that demonstrate the short- and long-term
effectiveness of the compound in the real world of clinicians. In this drug profile, divalproex
sodium and its uses in the pediatric population for psychiatric conditions are reviewed.
Expert Rev. Neurotherapeutics 5(2), 165–176 (2005)
Psychiatric diagnoses requiring mood stabili- in treating children with mental retardation
zation are numerous. Among the most com- and other mood symptoms with divalproex
mon are bipolar spectrum disorders. Accord- sodium. It has additionally been studied in
ing to the Diagnostic and Statistical Manual youths with conduct disorders (CD) and
of Mental Disorders (DSM) – IV – Text behavioral problems.
Revision (TR), there are four types of bipolar
spectrum disorders. These diagnoses are char- Bipolar I disorder
acterized by several varying mood states. Bipolar I disorder is characterized by one or
First, mania and hypomania are characterized more manic or mixed episodes, usually accom-
by some type of elevation of behavior, expan- panied by one or more major depressive epi-
sive or irritable mood. Second, depression, sodes. Bipolar II disorder is characterized by a
dysthymia or unspecified depression all refer major depressive episode with at least one
to states of dysphoric mood characterized by hypomanic episode. Bipolar disorder (BD) not
anhedonia, loss of function and negative feel- otherwise specified is a term associated with
ings. Finally, mixed states refer to conditions disorders with bipolar features that do not
in which both manic and depressive elements otherwise meet criteria for any specific BD.
are simultaneously present. Similar to adult BD typically develops in late adolescence or
populations, pediatric bipolar spectrum dis- early adulthood. However, some individuals
orders have been effectively treated with have their first symptoms during childhood, or
divalproex. There has also been some success can develop them much later in life. The
10.1586/14737175.5.2.165 © 2005 Future Drugs Ltd ISSN 1473-7175 165
Rana, Khanzode, Karnik, Saxena, Chang & Steiner
illness has been increasingly and better recognized during child-
hood and adolescence as a better understanding of the patho-
genesis and early manifestations of this disorder has emerged. It
has been found that many, if not most, adults when examined
retrospectively and biographically had symptoms of BD during
their early childhood. These studies have been critiqued due to
concerns that some portion of these findings could be due to
artifacts of retrospective assessment.
Historically, these early onset bipolar patients were diagnosed
as having attention deficit hyperactivity disorder, mood lability
or irritability. With earlier and more accurate diagnosis, as well
as an increased knowledge base of the risks for, precursors of
and prodromes of the illness, children can often be treated
closer to or even before their first manic episode.
The National Institute of Mental Health estimates that 1%
or 2.3 million adult Americans suffer from BD. Epidemiologic
studies have found that the lifetime prevalence of bipolar I is
between 0.7 and 1.6%, and for bipolar II is between 0.5 and
2% [1,2]. The mean age at onset ranges from 18 years in the
USA to 27 years in Puerto Rico [2].
The prevalence of BDs in older adolescents is approximately
1% as measured by Levinsohn and colleagues [3]. An additional
5.7% of this sample reported having experienced a distinct
period of abnormal or irritable mood even though they never
met criteria for mania or depression.
Ideally, medications for treating BD should serve as anti-
manic agents during manic episodes and as antidepressants dur-
ing depressive episodes, in order to maintain a euthymic state.
The aim would be to also prevent switching between manic and
depressive states, prevent relapse and maintain a euthymic state.
Identifying BD in the pediatric population is challenging since
patients may present with varied symptoms of mania, hypoma-
nia and depression. Children and adolescents in this regard are
unlikely to resemble adult bipolar patients in their presenta-
tion. Other challenges include variable patient response to
treatment, patient adherence to treatment regimens, side effects
of medications and high rates of psychiatric comorbidities.
Research is ongoing to determine treatments that reduce fre-
quency, intensity and duration of acute episodes, delay recur-
rence of symptoms, minimize cycling and maintain euthymia
with minimal side effects.
Disruptive behavior disorders
Mood stabilizers can potentially help in the treatment of dis-
ruptive behavior disorders. The disruptive behavior disorders
listed in DSM-IV-TR (oppositional defiant disorder [ODD]
and CD) have no standard psychopharmacologic treatment.
Although there has been a steady accumulation of data, the
psychopharmacology of maladaptive aggression is still in its
developing stages [5,6].
Since children and adolescents with these disorders are at a high
risk for delinquency, addiction, incarceration and a poorer quality
of life, it is important to find effective treatments for this popula-
tion. This most definitely should include psychopharmacologic
interventions, which have been traditionally neglected.
166
CD is defined by the DSM-IV-TR as a disorder characterized
by a repetitive and persistent pattern of behavior in which the
basic rights of others or major age appropriate societal norms or
rules are violated. This would include aggression to people and
animals, destruction of property, deceitfulness or theft and seri-
ous violations of rules. CD is further subtyped according to age
of onset (before or after 10 years of age) and severity (mild,
moderate or severe).
Prevalence in the general population is estimated to be
between 1.5 and 3.4% of children and adolescents, the ratio of
boys to girls with CD being 5:1 [4]. Attention deficit hyperac-
tivity disorder is the most common comorbid condition that
repeatedly overlaps with CD. Mood, anxiety disorders and
post-traumatic stress disorder are frequently found in children
with CD.
Treatment for CD has consisted of various interventions at
the behavioral level. Multiple studies show both parenting skills
training and training for the child, aimed at improving peer
relationships, academic skills and compliance with demands
from authority figures, are effective treatment modalities for
CD. In all cases, psychopharmacologic treatment alone is
insufficient to treat CD [4].
ODD is defined by negativistic, hostile and defiant behavior
lasting at least 6 months. Furthermore, the condition includes
losing one’s temper, arguing with adults and being spiteful or
vindictive. It differs from CD by its emphasis on minor beh-
avioral challenges to parents, and maintenance of these behav-
iors within the scope of the family unit. It is a diagnosis for chil-
dren that presents to the clinician with a pattern of behavior that
is troubling but that would not rise to the level where aggressive
or intense treatment would be required. In this regard, ODD
cannot lead to hospitalization purely for the treatment of this
condition. However, ODD is highly problematic, predicts pro-
gression to CD in 33% of ODD children, and requires early
intervention. Pharmacologic treatment for ODD is largely not
seen within the standard of practice, and psychotherapy and
family therapy remain the mainstays of treatment [5–7]. However,
it is becoming increasingly apparent that psychopharmacologic
treatment can be helpful in difficult and complex cases of ODD.
Currently, an open-label clinical trial in outpatients with ODD
is nearing completion [58], which may also demonstrate the value
of divalproex sodium in this population.
The DSM-IV-TR reserves disruptive behavior disorder not
otherwise specified for disorders characterized by conduct or
oppositional defined behaviors that do not meet the criteria for
CD or oppositional disorder.
Autistic spectrum disorders
Autistic spectrum disorders (ASD) are characterized by devi-
ant reciprocal social interaction, delayed and aberrant com-
munication skills and a restricted repertoire of activities and
interests. These disorders are believed to occur at a rate of five
cases per 10,000 children (0.05%). Other abnormalities
include seizures, electroencephalogram abnormalities, impul-
sivity, aggression and affective instability. Ideal agents for the
Expert Rev. Neurotherapeutics 5(2), (2005)

treatment of ASD would address social and communication
deficits, self-stimulating behaviors, and impulsive or aggres-
sive behaviors. As in CD, divalproex may have a role in help-
ing to address the symptoms of ASD which are resistant to
behavioral or psychotherapeutic interventions.
Use of divalproex sodium in pediatric populations
This drug profile has two specific aims: to review the broad
spectrum of activity of divalproex in the treatment of various
disorders in children and adolescents and to highlight potential
areas of research for the use of divalproex in this population.
Overview of the market & existing data regarding the
psychopharmacology of conditions potentially benefiting from
divalproex sodium
There have been three double-blind, placebo-controlled rand-
omized clinical trials [6,7,26], eight open-label clinical trials
[22–24,27,29–32] and three case series [25,28,68] highlighting the use
of divalproex in children and adolescents. There is open data
supporting the acute efficacy of divalproex in pediatric BD.
However, there have been no published placebo-controlled
studies of divalproex in children and adolescents with BD.
There have been three case series of adolescents with BD
treated with divalproex. The largest of these series studied
15 adolescents and young adults, aged 15–20 years old, over a
7-week period. At the end of the trial, most subjects showed
improvement. It has to be noted that all subjects required
additional medications for acute symptom management.
Research is ongoing to find appropriate medications for use
in children and adolescents that would target symptoms with-
out affecting normal development. This is a challenge as it is
difficult to devise and execute studies with various agents with-
out the appropriate adult data and safety profile to support
them [35].
Even though there are many medications that have been
approved for the adult population over recent years for different
psychiatric conditions, studies are currently ongoing to determine
their safety and efficacy in the pediatric population (TABLE 1).
The US Food and Drug Administration (FDA) approved
lithium for the treatment of manic episodes in BD in adults in
1970. Divalproex was FDA approved in 1995 for use in adults
with mania. Lamotrigine is the first FDA-approved therapy
since lithium for the maintenance treatment of adults with
bipolar I disorder. Additionally, the FDA has noted that find-
ings for lamotrigine were more robust in bipolar depression.
Olanzapine was FDA approved in 2000 as monotherapy or in
combination with lithium or valproate for the treatment of
bipolar mania and then was subsequently approved for mainte-
nance therapy. In December 2003, the olanzapine and fluoxet-
ine combination tablet was the first FDA medication approved
for the treatment of depressive episodes associated with BD.
Risperidone was FDA approved in December 2003 as mono-
therapy or in combination with lithium or valproate for the
short-term treatment of acute manic or mixed episodes associ-
ated with bipolar I disorder. Quetiapine, ziprasidone and
www.future-drugs.com
Divalproex sodium
aripiprazole all received indications for adult bipolar mania in
2004. Agents approved for use in adjunct with divalproex or
lithium include olanzapine, risperidone and quetiapine. In
adults, other agents with reported antimanic activity include
clozapine, benzodiazepines, calcium channel blockers and
thyroid hormone [101].
Lithium has been found to be effective in those with adoles-
cent-onset BD [29,36–40]. However, the overall response may be
less than that for adults, possibly because youths with mania
often have either mixed manic-depressive syndromes and/or a
predominance of psychotic symptoms, both of which are
generally more refractory to lithium treatment [5].
Anticonvulsants such as carbamazepine and divalproex have
been used in patients who do not respond to or are intolerant
of lithium. They are especially useful in rapid cycling and dys-
phoric mania. Atypical antipsychotics such as olanzapine, risp-
eridone, ziprasidone and quetiapine derive their usage from
studies performed in the adult population.
CD requires interventions at the family, school, peer group
and individual level with the patient. No medication has been
approved specifically for individuals diagnosed with CD. Most
experts feel that medications are particularly well suited for
acute aggression [41], and chronic treatment resistant aggression,
especially of the reactive/affective/defensive/impulsive type [56].
Antidepressants, lithium carbonate, carbamazepine and pro-
pranolol are currently used clinically for CD [4]. Studies of
treating youths with CD have been conducted using divalproex
with favorable outcomes [6,7]. Usually this is in addition to
other nonpharmacologic interventions, such as environmental
manipulation and a range of psychotherapies.
Medications have been used for symptoms that are a source of
impairment or distress to the individual with autistic disorder.
Aggression is a commonly occurring problem that has been tar-
geted by various medications including neuroleptics, selective sero-
tonin reuptake inhibitors, tricyclic antidepressants, lithium, mood
stabilizers (including divalproex) and anxiolytics [8,32,42–45].
Divalproex sodium comes in several formulations, including
instant-release and extended-release (ER) forms. Depakote® (the
instant-release form) was first approved in 1983 for the treatment
of epilepsy. In 1995 it received an indication for bipolar mania. It
does not currently have a maintenance indication, but is widely
used in psychiatry for this off-label purpose. Divalproex sodium
ER has been studied for the treatment of acute mania, it has only
been FDA approved for the prophylaxis of migraine headaches
and in the treatment of epilepsy at this time [69,70]. Divalproex is
contraindicated in patients with hepatic disease or significant
hepatic dysfunction in patients with known hypersensitivity to
the drug and in patients with known urea cycle disorders. This is
according to the US-approved labeling for all divalproex
sodium/Depakene® formulations. Use in children younger than
6 years or with clonazepam is not contraindicated in the USA.
Introduction to the compound
Valproic acid was originally synthesized in 1882 in the USA by
Burton and was used as an organic solvent. Meunier and
167
Rana, Khanzode, Karnik, Saxena, Chang & Steiner

Table 1. Ongoing studies to determine the safety and efficacy of drugs for the treatment of pediatric
psychiatric disorders.
Diagnosis Study Sample Treatment Duration Measures Findings Ref.
CD 71 ± 23 vs. n = 58; age mean ± SD Randomized clinical 7 weeks CGI-S, CGI-I, Significant findings [6]
13.8 ± 5.1 15.9 ± 1.1 year; trial DVPX low vs. high WAI for CGI-S (p = 0.02),
range: 14–18 dose CGI-I (p = 0.0008)
and for self-restraint
and impulse control
in the WAI
ODD/CD Mean VPA n =20; age mean ± SD Double-blind, placebo- 12 weeks total Modified Overt DVPX significantly [7]
concentration 13.8 ± 2.4 years; controlled crossover 6 weeks of Aggression Scale, better than placebo:
82 ± range: 10–18 years design of DVPX placebo vs. DVPX anger–hostility 8 of 10 responded to
19 mcg/ml then crossover to subscale of the DVPX and 0 of 10
6 weeks of DVPX SCL-90 responded to
or placebo placebo
ODD/CD/ Mean VPA n =10; age range: Open-label trial DVPX 5 weeks Ratings of mood Mood lability, [22]
ADHD/MJ concentration 15–18 years lability and number of outbursts
75 mcg/ml outbursts based and GAF were
(45–113) on Modified significantly
Overt Aggression affected
Scale, GAF
Bipolar Mean VPA n = 24; age mean ± SD Open-label trial DVPX 12 weeks CGI-I, YMRS, Significant [23]
Offspring concentration 11.3 ± 3.9 years; HAM-D improvement of
with mood or 79 ± range: 6–18 years scores in CGI-I,
behavioral 26.8 mcg/ml YMRS (p < 0.0001),
disorders and and HAM-D
at least mild (p = 0.0002)
affective
symptoms
Bipolar I/II Mean VPA n = 90; age mean ± SD Open-label Li + DVPX 11.3 weeks YMRS, CDRS-R, Significant [24]
concentration 10.9 ± 3.4 years; for 4 weeks, then length CGAS improvement in all
80 ± 26 range: 5–17 years randomized into of time was up scores (p < 0.0001)
mcg/mol either Li or DVPX to 20 weeks at end of week 8 and
monotherapy at end of study
Bipolar I/II/ Mean VPA n = 15; age mean ± SD Retrospective chart Mean duration CGI-I Eight out of 15 [25]
NOS concentration 13.3 ± 4.0 years; review ± SD 1.4 ± (53%) responded
79 ± range: 4–18 years 1.5 years, range:
23 mcg/ml 2 weeks –
5.5 years
Bipolar I n = 30; Randomized clinical 6 weeks YMRS DVPX + quetiapine [26]
age range: trial >DVPX + placebo,
12–18 years DVPX followed by p = 0.03
6 weeks of quetiapine
vs. placebo
Bipolar Mean VPA n = 40; Open-label DVPX 2–8 weeks MRS, BPRS, 61% showed >50% [27]
disorder concentration age range: 7–19 years CGI-S, HAM-D improvement in MRS
83 ± 25 scores with DVPX
mcg/ml
Bipolar n=9 Case series [28]
disorder
Bipolar I and Mean VPA n = 42; Open-label 6 weeks CGI-I, MRS Response rates were [29]
II disorder concentration mean age 11.4 years Lithium, DVPX, CBZ 53% for DVPX, 38%
83 ± 23 for Li and 38%
mcg/ml for CBZ

168 Expert Rev. Neurotherapeutics 5(2), (2005)

 Divalproex sodium

Table 1. Ongoing studies to determine the safety and efficacy of drugs for the treatment of pediatric
psychiatric disorders. (cont.)
Diagnosis Study Sample Treatment Duration Measures Findings Ref.
Bipolar Mean VPA n =15; Open-label 7 weeks MMRS, BPRS, 13 out of 15 showed [30]
affective concentration mean age: 17.3 years; DVPX CGI improvement on
disorder- 93 ± 26 range: 12–20 years MMRS and CGI
manic subtype mcg/ml scores
Bipolar with Mean VPA n =11; Open-label 6–26 days YMRS, HAM-D, 9 out of 11 had a [31]
manic subtype concentration age 12–17 years Treated with DVPX after HAM-A moderate
74 mcg/ml failure with Li and/or therapeutic response
(38–94) antipsychotics when DVPX was
added to their
concurrent
antipsychotic
medication. SS
received
concurrent Li
Bipolar Mean VPA n = 44; Open-label Treated with CGI-I Li and DVPX more [68]
disorder concentration mean age ± SD retrospective study DVPX, CBZ or Li efficacious than CBZ
years range DVPX, CBZ, Li
Autistic Mean VPA n =14; Open-label Treated with CGI-I 10 out of 14 [32]
spectrum concentration mean age ± SD retrospective study DVPX for 10.7 ± improved with DVPX,
75.8 ± 12.6 17.93 ± 10.24 years; DVPX 12.3 months; with improvement in
mcg/ml range: 5–40 years range: 0.5–43 core symptoms of
months autism, impulsivity
and aggression
ADHD: Attention deficit hyperactivity disorder; BPRS: Brief Psychiatric Rating Scale; CBZ: Carbamazepine; CD: Conduct disorder; CDRS: Children’s Depression Rating Scale;
CGAS: Children's Global Assessment Scale; CGI-I: Clinical Global Impressions – Improvement scale; CGI-S: Clinical Global Impressions – Severity scale; DVPX: Divalproex;
GAF: Global Assessment of Function scale; HAM-A: Hamilton rating Scale for Anxiety; HAM-D: Hamilton Rating Scale for Depression; Li: Lithium; MRS: Mania Rating Scale;
NOS: Not otherwise specified; ODD: Oppositional defiant disorder; SCL: Symptom checklist; SD: Standard deviation; SS: Subjects; VPA: Valproic acid;
WAI: Weinberger Adjustment Inventory; YMRS: Young Mania Rating Scale.

colleagues discovered its anticonvulsant properties in 1963 in
France and it was used clinically in Europe in the 1960s and
was FDA approved in the USA as an anticonvulsant in 1983 [9].
In 1966 it was reported to have mood-stabilizing properties by
Lambert and colleagues.
Until it was approved for use in treating mania in 1995, it
was indicated exclusively in the treatment of epilepsy. This
new indication for the treatment of mania was a breakthrough
because divalproex was the first new medication approved to
treat the symptoms of mania in 25 years. It has since been
FDA approved as a first-line agent for the treatment of
bipolar mania.
Valproic acid is rapidly absorbed after oral administration.
Peak serum levels occur approximately 1–4 h after a single
oral dose for Depakene. Time to maximum concentration
(Tmax) for Divalproex sodium is 3–5 h which increases to
4–8 h with food. Divalproex sodium ER is slower to be
absorbed and Tmax is 4–17 h [PACKAGE INSERT]. The serum
half-life of valproate is typically in the range of 9–16 h. A
slight delay in absorption occurs when the drug is adminis-
tered with meals but this does not affect the total absorp-
tion. Valproate is rapidly distributed throughout the body
and the drug is strongly bound (90%) to plasma protein –
especially albumin. It is primarily metabolized in the liver to
the glucuronide conjugate. Elimination of valproate and its
metabolites occurs principally in the urine (a small part is
unmetabolized), with minor amounts in the feces and
expired air.
Chemistry
Valproic acid and divalproex sodium are branched chain fatty
acid derivatives of carboxylic acid. Divalproex is constituted of
a 1:1 formulation of valproic acid and sodium valproate. Both
valproic acid and divalproex sodium dissociate to the valproate
ion in the gastrointestinal tract prior to absorption and it is the
valproate ion which provides the pharmacologic effect and is
what is measured in the body.
Pharmacodynamics
The exact mechanism by which valproate exhibits its effects is
unknown. The antiepileptic and psychiatric effects of valproate
have been contributed to its potentiation of γ-aminobutyric
acid (GABA) function in the CNS. Valproate potentially inhib-
its the catabolism of GABA, increases its release, decreases its
turn over, increases GABA type B receptor density and proba-
bly also enhances the neuronal responsiveness to GABA. These
effects of valproate on GABA potentiation have been impli-
cated in reducing the manic states in BD. There have been a

www.future-drugs.com 169
Rana, Khanzode, Karnik, Saxena, Chang & Steiner
number of animal studies that have shown a link between low
GABA levels in the CNS and symptoms of mania such as
decreased sleep, irritabilty and aggression [10–12]. Other effects
of valproate that may contribute to its mood stabilizing effect
are altered serotonin function, decreased N-methyl-D-aspartate-
mediated currents, decreased dopamine turnover and decreased
aspartate release [13–19]. There is some data suggesting that as
with lithium, valproate inhibits protein kinase C [47]. It may
promote neuroprotective proteins and inhibit apoptotic
proteins through other second-messenger systems [48].
Pharmacokinetics & metabolism
All valproate preparations are rapidly and completely absorbed
after oral administration (the exception would be divalproex
sodium ER which is absorbed over 18–24 h). Approximately
90% of the drug is bound to plasma proteins. The relationship
between dose and total valproate concentration is nonlinear; con-
centration does not increase proportionally with the dose, but
rather increases to a lesser extent due to saturable plasma protein
binding. Plasma protein binding of valproate decreases as the
total concentration increases. Therefore, higher doses may not
produce equivalent higher serum valproate concentrations.
However, the kinetics of unbound valproate are linear.
The unbound or free portion of the drug in the blood crosses
readily into the cerebrospinal fluid by passive diffusion and can
cause therapeutic as well as toxic effects. Generally, 90% of the
drug is protein bound at the therapeutic level of 75–80 µm/ml.
Valproate is metabolized almost entirely by the liver. Approxi-
mately 30–50% is metabolized by conversion to a glucuronide
conjugate, 40% by mitochondrial β-oxidation, 10–20% by
microsomal cytochrome P450 enzymes in the liver and the
remaining 3–5% is excreted unchanged in the urine [50]. Several
valproate metabolites such as 2-propyl-2-pentenoic acids have
potent anticonvulsant properties. The clearance of valproate is
affected by age – it is increased by 50% in children and reduced in
adults. One of the other factors that affects its clearance is coad-
ministration of another drug such as carbamazepine, phenobarbi-
tal or rifampicin, which are also metabolized by P450 enzymes.
Some of these medications also affect valproate’s half-life, which
normally ranges between 9 and 16 h [20].
Caution should be noted in specific patient populations in
which albumin may be decreased, such as the elderly, those
with renal and hepatic failure or malnourished patients. The
elimination half-life of lamotrigine increases in the presence of
divalproex and so the pre-existing dose of lamotrigine should be
reduced by 50% when divalproex is added. Divalproex sodium
ER is given in doses 8–20% higher than the total daily dose of
divalproex sodium for equivalency.
Preparations
The different preparations available are valproic acid capsules and
syrup, divalproex sodium-coated particles in capsules, enteric-
coated divalproex sodium delayed-release tablets, divalproex
sodium ER tablets and sodium valproate intravenous formulation.
Valproic acid rectal suppositories are not available in the USA.
170
The immediate, delayed and ER oral preparations differ in
the rate of absorption and in the time to reach a peak level.
However, the bioavailability is close to 100% for oral
preparations and is approximately 80–90% for the ER
tablets [69,70]. When divalproex sodium ER is given in doses
8–20% higher than the total daily dose of divalproex sodium,
the two formulations are equivalent. Once a day dosing of the
ER formulation may be more acceptable to children and ado-
lescents, and may increase compliance. Although divalproex
sodium ER is promising, it has not yet been studied in children
and adolescents with psychiatric disorders.
Loading & blood level
Based on adult studies, the therapeutic range for mania is
50–125 mcg/ml. There is some loading data from studies in
adults demonstrating that levels over 50 µg/ml were achieved by
day 3 for loading doses of 30 mg/kg/day [71]. An optimum range
for manic adults and adolescents may be 75–120 mcg/ml [52]. In
children and adolescents who are outpatients, dosing may be ini-
tiated at 125–250 mg QHS (at bed time), and increased by
125–250 mg every 3–4 days to achieve desired serum levels. In
the pediatric population, a dose range of 15 to 20 mg/kg/day of
valproate has been studied and used. This can be given in two to
three divided doses. One can give a loading dose of
15 mg/kg/day. By doing this, a serum level of 50–120 mcg/ml by
day 5 can be reached. This may not be scientifically accurate if
the dose is being prescribed to a child who is younger than
10 years old. Children aged 10 years or younger clear valproate
50% faster than patients over the age of 10 years.
The maintenance dose of divalproex in the pediatric popula-
tion ranges from 375 to 2000 mg/day. However, there is no
clinical data in children.
With all formulations (except divalproex sodium ER), the
steady state can be achieved as early as 3.5 days
(5 x 16 h = 80 h) after dose initiation or change. For divalproex
sodium ER with a half-life of 9–16 h, steady state is achieved in
5 days [49]. One should therefore check the blood level between
3 and 5 days.
Adverse effects of divalproex sodium
In children and adolescents, the most common adverse effects
reported with the use of divalproex are nausea, sedation,
tremor, dizziness and weight gain [61]. Hair loss and thrombo-
cytopenia may occur, but less frequently. Hepatotoxicity has
been mostly reported in children aged less than 2 years taking
other anticonvulsants concurrently. Although rare, this could
be fatal and is also stated in the black box warning on the prod-
uct label [62]. Another uncommon side effect, which may
become life threatening, is pancreatitis. Abdominal pain, nau-
sea, vomiting and/or anorexia may be symptoms of pancreatitis
which require prompt medical evaluation.
Divalproex has a 1–2% risk of neural tube defects in babies
born to mothers who are taking the drug during their preg-
nancy. It is thought that this may be secondary to reduction of
serum folate levels [60]. There has been a report of a higher
Expert Rev. Neurotherapeutics 5(2), (2005)

incidence of polycystic ovaries (PCO) in epileptic women tak-
ing divalproex compared with women taking other
antiepileptics [63]. Hence, there is some concern about the
possibility of polycystic ovary syndrome (PCOS) when treating
adolescent females. As PCO occur in 17–22% of the female
population, the presence of PCO is not necessarily pathologic.
Additionally, up to 25% of women with PCO diagnosed by
ultrasound have no endocrine or menstrual difficulties [64].
Bauer and colleagues found no increased incidence of PCOS in
women with epilepsy taking divalproex compared with other
antiepileptics [65]. Similarly, Rasgon and colleagues found no
increased incidence of PCOS in women with BD taking dival-
proex compared with lithium. In women with BD, menstrual
irregularities were also found to have preceded treatment with
mood stabilizers [66]. Currently, it is not clear that there is a true
association between PCOS and divalproex therapy, even
though it appears that women with seizure disorders, and
possibly BD may have higher incidences of PCO.
Clinical efficacy
Bipolar disorder
An open-label clinical trial performed by Papatheodorou and col-
leagues involved 15 subjects who were treated with divalproex for
7 weeks [30]. An improvement in Modified Mania Rating Scale,
the principal outcome measure was observed in 13 subjects (eight
with marked, four with moderate and one with some improve-
ment). Furthermore, improvements in Global Assessment Scale,
Clinical Global Impressions scale and the Brief Psychiatric Rat-
ing Scale were observed. The mean dose of divalproex was
1423.08 mg/day with a range of 750 to 2000 mg/day.
West and colleagues conducted an open-label trial of val-
proate in the treatment of adolescent mania [31]. A total of
11 patients, aged 12–17 years with a diagnosis of BD were
treated with divalproex prospectively after having failed lith-
ium and/or antipsychotics. All patients received antipsy-
chotics and five patients received lithium to which dival-
proex was added. Nine out of the 11 patients had a
moderate response after addition of divalproex with a dose
range of 500 to 2000 mg/day.
Chang and colleagues studied 24 children aged 6–18 years
with at least one biologic parent with BD [23]. Participants were
diagnosed with either major depressive disorder or dysthymic
disorder or cyclothymic disorder or attention deficit hyperactiv-
ity disorder and all had at least moderate affective symptoms
(28-item Hamilton Rating Scale for Depression or Young
Mania Rating Scale score >12). After a 2-week washout period,
subjects were treated with divalproex for 12 weeks, titrated to
achieve serum levels of 50–120 µg/ml. A total of 78% were
considered responders by primary outcome criteria (very much
improved or much improved on the Clinical Global
Impressions – Improvement scale).
Kowatch and colleagues conducted an open-label trial to
develop effect sizes for divalproex, lithium and car-
bamazepine for the treatment of bipolar I or II disorder [29].
The 42 subjects with a mean age of 11.4 years were
www.future-drugs.com
Divalproex sodium
randomly assigned to 6 weeks of open treatment with these
three agents. Clinical Global Impressions – Severity scale and
Young Mania Rating Scale were used to evaluate improve-
ment. The response rates were 53% for divalproex, 38% for
lithium and 38% for carbamazepine.
An open-label trial on 40 subjects (age range: 7 to
19 years) consisted of initial stabilization of BD; manic;
hypomanic; or mixed episode with divalproex (serum level:
45–125 µm/ml). Lorazepam, clonazepam or haloperidol were
used as adjuncts. Moreover, lithium was added if patients did
not meet response criteria. Subjects were then randomized to
either divalproex or placebo. Those taking lithium were tapered
off, 61% of the patients showed a 50% improvement in Mania
Rating Scale, and there were significant reductions in the Brief
Psychiatric Rating Scale, Clinical Global Impressions – Severity
scale, and Hamilton Rating Scale for Depression. [27]
A clinical trial performed by Henry and colleagues showed
that children and adolescents with BD responded to divalproex
over 18 months of open treatment [25]. Responders were
defined as those showing moderate-to-marked response on the
Clinical Global Impression – Improvement scale, and 53%
patients responded to divalproex treatment for mixed episode,
disruptive behavior, pure mania or depression. Approximately
40% discontinued divalproex, mostly due to side effects.
Manuel Mota-Castillo reported nine case series of juvenile
mania, six of which started in the preschool years [28]. These
patients were treated successfully with divalproex.
Findling conducted an open-label study to examine the effec-
tiveness of the combination of divalproex and lithium therapy
with youths diagnosed with BD [24]. A total of 90 patients
(66 males and 24 females), aged 5–17 years meeting DSM-IV
criteria for BD I or II, were treated prospectively for up to
20 weeks with divalproex and lithium. Assessments included
the Young Mania Rating Scale, Children’s Depression Rating
Scale – Revised) and the Children’s Global Assessment Scale.
Significant improvement (p < 0.0001) in all outcome measures
was observed by week 8 as well as at the end of study.
Delbello and colleagues published a study on the efficacy of
divalproex and quetiapine in the treatment of adolescent
mania [26], 30 manic or mixed bipolar I adolescents of an age
range between 12 and 18 years were randomly assigned to
6 weeks of combination therapy with quetiapine and dival-
proex, or divalproex and placebo. The study showed that
quetiapine in combination with divalproex sodium was more
effective for the treatment of adolescent bipolar mania than
divalproex sodium with placebo.
Disruptive spectrum disorders
There is some evidence to support the use of divalproex in the
treatment of CD and ODD. Steiner and colleagues con-
ducted a randomized clinical trial using divalproex, low versus
high dose, for the treatment of incarcerated male youths in a
California Youth Authority campus [6]. Intent-to-treat analy-
ses showed significant associations between assignment to the
high-dose condition and ratings on the Clinical Global
171
Rana, Khanzode, Karnik, Saxena, Chang & Steiner
Impressions – Severity of Illness (p = 0.02) and Clinical Glo-
bal Impressions – Improvement (p = 0.0008). Self-reported
weekly impulse control was significantly better in the high-
dose condition (p < 0.05), and association between improve-
ment in self-restraint and treatment condition was of
borderline statistical significance (p < 0.06).
An open-label trial of divalproex completed in 1997 by
Donovan showed that it may be helpful in teenagers who have
explosive tempers and severe mood swings [22].
In another double-blind, placebo-controlled study, Dono-
van and colleagues investigated the role of divalproex in the
treatment of disruptive behavior disorders (CD and
ODD) [7], 20 outpatient children and adolescents (ages
10–18 years) with a disruptive behavior disorder received
6 weeks of divalproex treatment and 6 weeks of placebo by ran-
dom assignment. At the end of Phase I, eight out of ten subjects
had responded to divalproex; zero of ten had responded to pla-
cebo. Of the 15 subjects who completed both phases, 12 had a
superior response to divalproex. Subjects taking divalproex did
significantly better overall than those taking placebo.
Autistic spectrum disorders
There is limited data on the use of divalproex in autistic disor-
ders. A retrospective pilot study conducted by Hollander and
colleagues involved 14 subjects with a diagnosis of a pervasive
developmental disorder and concurrent affective instability,
impulsivity and aggression [32]. This included ten children and
adolescents, and four adults. They were treated with divalproex
for a mean duration of 10.7 months. Ten out of the 14 subjects
showed improvement on the Clinical Global Impressions –
Improvement scale with improvement in the core symptoms of
autism, impulsivity and aggression.
Expert opinion
The use of psychopharmacologic medications in pediatric
populations has come under review from a number of direc-
tions. The public, FDA and other government agencies have
undertaken studies to better understand the data on the effi-
cacy of medications and potential risks posed in using them.
Divalproex has not been central to these discussions, but it
seems prudent to consider the uses and potential misuses of
this medication.
We believe that divalproex shows good promise in the
treatment of pediatric BD and CD. In addition, it is useful
as an adjunctive agent in other psychiatric conditions when
behavioral manifestations such as aggression, irritability or
impulsivity are present. Furthermore, many of these symp-
toms may herald the onset of BD, and children of families
with strong histories of BD who present with early signs of
mania or depression should be considered for treatment with
divalproex. We use divalproex in the pediatric population
based on empirical evidence from studies in adults, children
and adolescents. For example, we use divalproex for treating
all forms of mania in children, alone or in combination with
other mood stabilizers or atypical antipsychotics. Divalproex
172
may be particularly beneficial for treating mixed states and
rapid-cycling subtypes of BD. Often, children and adoles-
cents do not meet DSM-IV-TR criteria for a certain diagno-
sis, but still have symptoms of that diagnosis that are impair-
ing to their social and occupational functioning, warranting
treatment. In this regard, our clinical experience has found
divalproex to be effective in treating target symptoms of irri-
tability, aggression and impulsivity. Studies conducted by
Donovan [7] and Steiner [6] in children with CD have demon-
strated that divalproex may have utility in decreasing impul-
sive-reactive aggression, irrespective of diagnosis. One signif-
icant challenge for the developmentally aware practitioner is
the fact that children’s behavior and mood are often context
dependent. Thus we do not expect that monotherapy is
going to be sufficient in most cases, embedded in a psycho-
social nexus, which drives symptoms, compliance and in
some cases pathogenesis. Nevertheless, it is vitally important
for the treating clinician to keep in mind that medications
alone are not a panacea, and that the use of medications
across different illnesses shows the best outcomes when med-
ications are used in concert with behavioral and family
therapy as part of a multimodal treatment approach.
Five-year view
The authors anticipate positive results from additional rand-
omized controlled studies to emerge within the next 5 years.
For example, placebo-controlled studies will be completed in
children and adolescents with BD as well as youths with ODD.
Due to the potential neuroprotective effects of DVPX, a partic-
ularly interesting expected development is further investigation
into the possibility of using divalproex to prevent the
development of certain disorders such as BD.
Intensive research in the development of a second-generation
valproic acid has been ongoing in an attempt to find a more
potent valproic acid with fewer adverse effects. Amide deriva-
tives of valproic acid have been tested in vivo and are in clinical
trials in patients with epilepsy [33]. We would encourage clinical
trials with these new compounds in patients with BD, if these
compounds were found to be safe and efficacious, particularly
in youths. There is widespread use and availability of divalproex
in the USA, but this may not be the case globally. Additionally,
generic formulations of Depakene are available in the USA.
Lithium and valproate have recently been demonstrated to
robustly increase the expression of the cytoprotective protein
bcl-2 in the CNS. Valproate’s effects on bcl-2 and glycogen syn-
thase kinase 3β suggest that this mood stabilizer may also
possess neuroprotective/neurotrophic properties [48].
The extracellular signal-regulated kinase (ERK) pathway is
used by neurotrophic factors to regulate neurogenesis, neurite
outgrowth and neuronal survival. Hao and colleagues demon-
strated that valproate activates the ERK pathway and induces
ERK pathway-mediated neurotrophic actions [67]. This cascade
of events provides a potential mechanism whereby mood stabi-
lizers alleviate cerebral morphometric deficits associated with
manic depressive illness.
Expert Rev. Neurotherapeutics 5(2), (2005)
 Divalproex sodium

Key issues

Bipolar disorder
• The lifetime prevalence of bipolar I disorder is 0.7–1.6%, bipolar II 0.5–2% and bipolar spectrum 3–6.5%.
• The mean age at onset ranges from 18 to 27 years.
• Bipolar patients frequently present with attention deficit hyperactivity disorder symptoms during childhood.
• Lithium has been found to be effective in those with adolescent-onset bipolar disorder.
• Overall response to lithium in children may be less than that for adults.
• Carbamazepine and divalproex sodium have been used in patients who do not respond to or are intolerant of lithium and they are
useful in rapid cycling and dysphoric mania.
• Valproate has been reported to be beneficial in the depressive phases of bipolar II disorder. Studies are underway to establish
lamotrigine as a maintenance agent and for the treatment of bipolar depression.
Disruptive behavior disorders
• The disruptive behavior disorders listed in the Diagnostic and Statistical Manual of Mental Disorders – IV include oppositional defiant
disorder and conduct disorder (CD).
• These patients are at a high risk for delinquency, addiction, incarceration and a poorer quality of life.
• The prevalence in the general population is estimated to be between 1.5 and 3.4% of children and adolescents, the ratio of boys to
girls with CD being 5:1.
• Attention deficit hyperactivity disorder is the most common comorbid condition that repeatedly overlaps with CD.
• Psychopharmacologic treatment alone is insufficient to treat CD.
• Antidepressants, lithium carbonate, carbamazepine and propranolol are currently used clinically for CD.
• Divalproex has been used with good results in children with oppositional defiant disorder and CD.
Autistic spectrum disorders
• The incidence is of five cases per 10,000 children (0.05%)
• Impulsivity, aggression and affective instability often co-occur.
• Aggression has been targeted by various medications including neuroleptics, selective serotonin reuptake inhibitors, tricyclic
antidepressants, lithium and mood stabilizers, and anxiolytics.
• Divalproex has been used effectively in reducing impulsivity and aggression.
Formulations and properties of divalproex
• Valproic acid capsules and syrup (Depakene®), divalproex sprinkles (Depakote sprinkles), divalproex delayed-release tablets
(Depakote®), divalproex sodium extended-release tablets (Depakote ER), intravenous sodium valproate (Depacon®).
• Valproic acid rectal suppositories and the amide of valproic acid are not available in the USA but were approved for treating bipolar
disorder in 1995 in the USA.
• Valproic acid and divalproex dissociate in the gastrointestinal tract to the valproate ion prior to systemic absorption. The valproate ion
provides the pharmacologic effect and is what is measured in the body.
• Peak serum levels occur approximately 1–4 h after a single oral dose (this is for Depakene, not Depakote or Depakote
extended release).
• The serum half-life of valproate is typically in the range of 9 to 16 h.
• Valproate is strongly bound (90%) to plasma protein, especially albumin.
• The unbound portion of valproate has linear kinetics.
• The therapeutic range for trough serum valproate concentrations for the treatment of mania is 50–125 µm/ml.
• The free portion the drug in the blood crosses readily into the cerebrospinal fluid by passive diffusion. It is primarily metabolized in the
liver to the glucuronide conjugate. Elimination occurs principally in the urine.
• Clearance of valproate is affected by age, it is increased by 50% in children less then 10 years of age.
• Caution should be noted when using with drugs metabolized by the C450 enzyme.
• The dose of lamotrigine should be reduced by 50% when divalproex is added.
• Although the exact mechanism of action of valproate is unknown, it is thought to increase γ-amino butyric acid by decreasing the
production of the excitatory amino acid aspartate and by inhibiting neurons by increasing potassium conductance and blocking
sodium channels.
• Through γ-amino butyric acid potentiation, valproate reduces the manic states in bipolar disorder.
• Divalproex extended release may improve compliance, reduce peak-related side effects and valproate serum concentration monitoring
is the same for all formulations – it is a trough level. Improved tolerability has been studied (see text regarding evaluation of extended
release for bipolar disorder) with the idea that dose-related adverse events may be less due to the lower peak levels for extended
release versus divalproex sodium.

www.future-drugs.com 173
Rana, Khanzode, Karnik, Saxena, Chang & Steiner

References 11 Loscher W. Valproate: a reappraisal of its offspring with mood and behavioral
Papers of special note have been highlighted as: pharmacodynamic properties and disorders and at least mild affective
• of interest mechanisms of action. Progress Neurobiol. symptoms. J. Clin. Psychiatry 64(8),
58, 31–42 (1999). 936–942 (2003).
•• of considerable interest
12 Maes M, Calabrese JR. Mechanisms of 24 Findling RL, McNamara NK,Gracious BL
1 Weissman MM, Bland RC, Canino GJ
action of valproate in affective disorders. In: et al. Combination lithium and divalproex
et al. Cross-national epidemiology of major
Anticonvulsants in Mood Disorders. Marcel sodium in pediatric bipolarity. J. Am. Acad.
depression and bipolar disorder. JAMA 276,
Dekker, Inc., NY, USA, 93–110 (1994). Child Adolesc. Psychiatry 42(8),
293–299 (1996).
13 Whitton PS, Fowler LJ. The effect of 895–901(2003).
2 Weissman MM, Bruce ML, Leaf PJ, Floric
valproic acid on 5-hydroxytryptamine and 25 Henry CA, Zamvil LS, Lam C et al. Long
LP, Holzor C III. Affective disorders. In:
5-hydroxyindoleacetic acid concentration term outcome with divalproex in children
Psychiatric Disorders in America: The
in hippocampal dialysates in vivo. Eur. J. and adolescents with bipolar disorder. J.
Epidemiological Catchment Area Study.
Pharmacol. 200, 167–169 (1991). Child Adolesc. Psychopharmacol.13(4),
Robins LN, Reiger DA (Eds). The Free
14 Biggs CS, Pearce BR, Fowler LJ, Whitton 523–529 (2003).
Press, NY, USA, 53–80 (1991).
PS. Regional effects of sodium valproate on 26 Delbello MP, Schweirs ML, Rosenberg HL
3 Lewinsohn PM, Klein DN, Seeley JR.
extracellular concentrations of 5- et al. A double blind randomized, placebo-
Bipolar disorders in a community sample of
hydroxytryptamine, dopamine, and their controlled study of quetiapine as adjunctive
older adolescents: Prevalence,
metabolites in the rat brain – an in vivo treatment of adolescent mania. J. Am. Acad.
phenomenology, comorbidity, and course.
microdialysis study. J. Neurochem. 59, Child Adolesc. Psychiatry 41(10),
J. Am. Acad. Child Adolesc. Psychiatry 34(4),
1702–1728 (1992). 1216–1233 (2002).
454–463(1995).
15 Biggs CS, Pearce BR, Fowler LJ, Whitton 27 Wagner KD, Weller EB, Carlson GA et al.
4 Steiner H, Dunne J, Ayres W et al. Practice
PS. The effect of sodium valproate on An open label trial of divalproex in children
parameters for the assessment and
extracellular GABA and other amino acids and adolescents with bipolar disorder. J.
treatment of children and adolescents with
in the rat ventral hippocampus – an in vivo Am. Acad. Child. Adolesc. Psychiatry 41(10),
conduct disorder. J. Am. Acad. Child
microdialysis study. Brain Res. 594, 1224–1231 (2002).
Adolesc. Psychiatry 36(Suppl. 10),
138–142 (1992). •• The findings of this study provide
S122–S139 (1997).
16 Baf MHM, Subhash MN, Lakshmana KM, preliminary support for the efficacy and
5 McClellan J, Werry J, Ayres W. AACAP effectiveness of divalproex in the
Rao BSSR. Sodium valproate induced
Official Action. Practice parameters for the treatment of pediatric bipolar disorder.
alterations in monoamine levels in different
assessment and treatment of children and
regions of the rat brain. Neurochem. Int. 24, 28 Mota-Castillo M, Torruella A, Engels B
adolescents with bipolar disorder. J. Am.
67–72 (1994). et al. Valproate in very young children: an
Acad. Child Adolesc. Psychiatry 36(1),
17 Takebayashi M, Motohashi N, Saito H, open case series with a brief follow up. J.
138–157 (1997).
Kagaya A, Yamawaki S. Effect of acute Affect. Dis. 67, 193–197 (2001).
6 Steiner H. Divalproex sodium for the
treatment with sodium valproate on 29 Kowatch RA, Suppes T, Carmody TJ et al.
treatment of conduct disorder: a
catecholamine and serotonin synthesis in Effect size of lithium, divalproex sodium
randomized controlled clinical trial. J. Clin.
mouse cerebral cortex. Neuropsychobiology and carbamazepine in children and
Psychiatry 64(10), 1183–1191(2003).
32, 124–127 (1995). adolescents with bipolar disorder. J. Am.
•• One of the few controlled
18 Kempf E, Mack G, Schleef C, Mandel P. Acad. Child. Adolesc. Psychiatry 39(6),
psychopharmacologic studies of conduct
Effect of valproic acid on brain serotonin 713–720 (2000).
disorder highlighting a possible role for
divalproex in the treatment of this disease. metabolism in isolated and grouped rats. 30 Papatheodorou G, Kutcher SP, Katic M
Pharmacol. Biochem. Behav. 17, 49–52 et al. The efficacy and safety of divalproex
7 Donovan SJ, Stewart JW, Nunes EV et al.
(1982). sodium in the treatment of acute mania in
Divalproex treatment for youth with
19 Loscher W, Honack D. Valproate and its adolescents and young adults: an open label
explosive temper and mood lability: a
major metabolite e-2-en-valproate induce trial. J. Clin. Psychopharmacol. 15(2),
double-blind, placebo-controlled crossover
different effects on behavior and brain 110–116 (1995).
design. Am. J. Psychiatry 157(5), 818–820
(2000). monoamine metabolism in rats. Eur. J. 31 West SA, Keck PE, McElroy SL et al. Open
Pharmacol. 299, 61–67 (1996). trial of valproate in the treatment of
8 Volkmar F, Cook EH Jr, Pomeroy J et al.
20 SuanL, McElroy MD, Harrison G, Pope adolescent mania. J. Child Adolescent
Practice parameter for the assessment and
MD Jr, Keck PE Jr. Valproate. In: Kaplan Psychopharmacol. 4(4), 263–267 (1994).
treatment of children, adolescents, and
adults with autism and other pervasive and Sadock’s Comprehensive Textbook of 32 Hollander E, Dolgoff-Kaspar R, Cartwright
developmental disorders. J. Am. Acad. Child Psychiatry Volume Two. 2289–2290 (2000). C et al. An open trial of divalproex sodium
Adolesc. Psychiatry 38(12), S32–S54 (1999). 21 Kutcher S. Child and Adolescent in autism spectrum disorder. J. Clin.
Psychopharmacology. WB Saunders Psychiatry 62(7), 530–534 (2001).
9 Meunier G, Caraz G, Meunier Y, Eymard P,
Aimard M. Properietes Company, PA, USA, 211–212 (1997). 33 Isoherranen N, Yemen B, Bialer M. New
pharmacodynamiques de l’acide n- 22 Donovan SJ. Divalproex treatment of CNS-active drugs which are second-
dipropylacetique. Therapie 18, 435–438 disruptive adolescents: a report of 10 cases. generation valproic acid: can they lead to
(1963). J. Clin. Psychiatry 58(1), 12–15 (1997). the development of a magic bullet? Curr.
Opin. Neurol. 16, 203–211(2003).
10 Tunnicliff G. Actions of sodium valproate 23 Chang KD, Dienes K, Blasey C, Adleman
on the central nervous system. J. Physiol. N, Ketter T, Steiner H. Divalproex 34 Chang KD, Steiner H, Ketter TA. A
Pharmacol. 50(3), 347–365 (1999). monotherapy in the treatment of bipolar psychiatric phenomenology of child and

174 Expert Rev. Neurotherapeutics 5(2), (2005)


adolescent bipolar offspring. J. Am. Acad.
Child Adolesc. Psychiatry 39(4), 453–460
(2000).
35 Chang K. Pediatric psychopharmacology:
an overview. In: Hand Book of Mental
Health Interventions in Children and
Adolescents. Steiner H (Ed.). Jossey-Bass,
CA, USA, 247–255 (2004).
36 Geller B, Cooper TB, Thomas B et al.
Double- blind and placebo-controlled
study of lithium for adolescent bipolar
disorders with secondary substance
dependency. J. Am. Acad. Child. Adolesc.
Psychiatry 37(2), 171–178 (1998).
37 DeLong, RG, Aldershof A. Long-term
experience with lithium treatment in
childhood: correlation with clinical
diagnosis. J. Am. Acad. Child Adolesc.
Psychiatry 26(3), 389–394(1987).
38 Hassanyeh F, Davison K. Bipolar affective
psychosis with onset before age 16 years. Br.
J. Psychiatry 137, 530–539 (1980).
39 Strober M, Morrell W, Burroughs J. A
family study of bipolar I disorder in
adolescence: early onset of symptoms
linked to increased familial loading and
lithium resistance. J. Affect. Dis. Special Issue
15(3) 255–268 (1988).
40 Varanka TM, Weller RA, Weller EB,
Fristad MA. Lithium treatment of manic
episodes with psychotic features in
prepubertal children. Am. J. Psychiatry
145(12) 1557–1559 (1988).
41 Connor DF, Glatt SJ, Lopez ID.
Psychopharmacology and aggression. I: a
meta-analysis of stimulant effects on
overt/covert aggression-related behaviors in
ADHD. J. Am. Acad. Child Adolesc.
Psychiatry 41(3), 253–261 (2002).
42 Di Martino A, Tuchman RF. Antiepileptic
drugs: affective use in autism spectrum
disorders. Pediatr. Neurol. 25(3), 199–207
(2001).
43 Gagliano A, Germano E, Pustorino G et al.
Risperidone treatment of children with
autistic disorder: effectiveness, tolerability,
and pharmacokinetic implications. J. Child
Adolesc. Psychopharmacol. 14(1), 39–47
(2004).
44 Akhondzadeh S, Erfani S, Mohammadi
MR. Cyproheptadine in the treatment of
autistic disorder: a double-blind placebo-
controlled trial. J. Clin. Pharm. Ther. 29(2),
145–150 (2004).
45 Hollander E, Phillips AT, Yeh CC. Targeted
treatments for symptom domains in child
and adolescent autism. Lancet 362(9385),
732–734 (2003).
46 Davanzo PA, McCracken JT. Mood
stabilizers in the treatment of juvenile
www.future-drugs.com
bipolar disorder: advances and
controversies. Child. Adoles. Psych. Clin. N.
Am. 9(1) 159–182 (2000).
47 Manji HK, Moore GJ, Chen G. Lithium
up-regulates the cytoprotective protein bcl-
2 in the CNS in vivo: a role for
neurotrophic and neuroprotective effects in
manic depressive illness. J. Clin. Psych.
61(Suppl. 9), 82–96 (2000).
48 Manji HK, Moore GJ, Chen G. Clinical
and preclinical evidence for the
neurotrophic effects of mood stabilizers:
implications for the pathophysiology and
treatment of manic-depressive
illness. Biological Psych. 48(8), 740–754
(2000).
49 Dutta S, Zhang Y, Selness DS et al.
Comparison of the bioavailability of
unequal doses of divalproex sodium
extended-release formulation relative to the
delayed-release formulation in healthy
volunteers. Epilepsy Res. 49(1), 1–10
(2002).
50 Cloyd J C, Fischer JH, Kriel RL et al.
Valproic acid pharmacokinetics in children.
IV. Effects of age and antiepileptic drugs on
protein binding and intrinsic clearance.
Clin. Pharmacol. Ther. 53(1), 22–29
(1993).
51 Good CR, Feaster CS, Krecko VF.
Tolerability of oral loading of divalproex
sodium in child psychiatry inpatients. J.
Child Adolesc. Psychopharmacol. 11(1),
53–57 (2001).
52 Chang KD, Ketter TA. Special issues in the
treatment of paediatric bipolar disorder.
Expert Opin. Pharmacother. 2(4), 613–622
(2001).
53 Lish J D, Gyulai LR, Susan M. A family
history study of rapid-cycling bipolar
disorder. Psych. Res. 48(1), 37–46 (1993).
54 Perlis RH, Smoller JW, Fava M. The
prevalence and clinical correlates of anger
attacks during depressive episodes in
bipolar disorder. J. Affec. Dis. 79(1–3),
291–295 (2004).
55 Chang K, Steiner H, Dienes K. Bipolar
offspring: a window into bipolar disorder
evolution. Bio. Psychiatry 53(11), 945–951
(2003).
•• Highlights the importance of studying
bipolar offspring in an attempt to
understand early prodromal forms of
bipolar disorder. This may in turn lead to
early identification and subsequent
attenuation or prevention of
bipolar disorder.
56 Steiner H, Saxena K, Chang K.
Psychopharmacologic strategies for the
treatment of aggression in juveniles. CNS
Spectr. 8(4), 298–308 (2003).
Divalproex sodium
57 Steiner H, Remsing L. AACAP workgroup
on quality issues. Practice parameters for
the assessment and treatment of children
and adolescents with oppositional defiant
disorder. J. Am. Acad. Child Adolesc. Psych.
(2004) (In Press).
58 Saxena K, Khanzode L, Robin-Durkin A,
Delizonna L, Steiner H. Divaproex sodium
in adolescent outpatient disruptive behavior
disorders: an open label trial. American
Psychchiatric Association Annual Conference,
GA, USA (2005).
59 Wang PW, Ketter TA. Pharmacokinetics of
mood stabilizers and new anticonvulsants.
Psychopharmacol. Bull. 36(1), 44–66
(2002).
60 Samren EB, van 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 teratogenesis
associated with maternal epilepsy. Epilepsia
38(9), 981–990 (1997).
61 McDougle CJ, Stern AE, Bangs ME.
Bipolar disorder in children and
adolescents, Part II: valproate and other
newer treatments. Int. Drug Therapy
Newsletter 36(1), 1–8 (2001).
62 Bryant AE III, Dreifuss FE. Valproic
acid hepatic fatalities. III. US experience
since 1986. Neurology 46(2), 465–459
(1996).
63 Isojarvi JI, Laatikainen TJ, Pakarinen
AJ, Juntunen KT, Myllyla VV. Polycystic
ovaries and hyperandrogenism in
women taking valproate for epilepsy. N.
Engl. J. Med. 329(19), 1383–1388
(1993).
64 Ernst CL, Goldberg JF. The reproductive
safety profile of mood stabilizers, atypical
antipsychotics, and broad-spectrum
psychotropics. J. Clin. Psychiatry 63(Suppl.
4), 42–55 (2002).
65 Bauer J, Jarre A, Klingmuller D, Elger CE.
Polycystic ovary syndrome in patients with
focal epilepsy: a study in 93 women.
Epilepsy Res. 41(2), 163–167 (2000).
66 Rasgon NL, Altshuler LL, Gudeman D.
Medication status and polycystic ovary
syndrome in women with bipolar disorder:
a preliminary report. J. Clin. Psychiatry
61(3), 173–178 (2000).
67 Hao Y, Creson T, Zhang L et al. Mood
stabilizer valproate promotes ERK
pathway-dependent cortical neuronal
growth and neurogenesis. J. Neurosci.
24(29), 6590–6509 (2004).
68 Davanzo P, Gunderson B, Belin T et al.
Mood stabilizers in hospitalized children
with bipolar disorder: a retrospective
175
Rana, Khanzode, Karnik, Saxena, Chang & Steiner
review. Psych. Clin. Neurosci. 57(5),
504–510 (2003).
69 Centorrino F, Kelleher JP, Berry JM et al.
Pilot comparison of extended-release and
standard preparations of divalproex sodium
in patients with bipolar and schizoaffective
disorders. Am. J. Psychiatry 160(7),
1348–1350 (2003).
70 Horne 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(2), 176–181(2003).
71 Hirschfeld RM, Allen MH, McEvoy JP
et al. Safety and tolerability of oral loading
divalproex sodium in acutely manic bipolar
patients. J. Clin. Psychiatry 60(12),
815–818 (1999).
Website
101 Practices guideline for the treatment of
patients with bipolar disorder
www.psych.org/psych_pract/treatg/pg/
bipolar_revisebook_index.cfm
(Accessed February 2005)
176
Affiliations
• Manasi Rana, MD
Psychiatry Resident, Stanford University, School
of Medicine, Department of Psychiatry and
Behavioral Sciences, Division of Child Psychiatry
and Child Development, 401 Quarry Road,
Stanford, CA 94305 5719, USA
Tel.: +1 650 723 5420
Fax: +1 650 723 5531
mrana@stanford.edu
• Leena Khanzode, MD
Psychiatry Resident, Stanford University, School
of Medicine, Department of Psychiatry and
Behavioral Sciences, Division of Child Psychiatry
and Child Development, 401 Quarry Road,
Stanford, CA 94305 5719, USA
Tel.: +1 650 723 5420
Fax: +1 650 723 5531
• Niranjan Karnik, MD, PhD
Psychiatry Resident, Stanford University, School
of Medicine, Department of Psychiatry and
Behavioral Sciences, Division of Child Psychiatry
and Child Development, 401 Quarry Road,
Stanford, CA 94305 5719, USA
Tel.: +1 650 723 2423
Fax: +1 650 723 5531
• Kirti Saxena, MD
Research Fellow, Stanford University, School of
Medicine, Department of Psychiatry and
Behavioral Sciences, Division of Child Psychiatry
and Child Development, 401 Quarry Road,
Stanford, CA 94305 5719, USA
Tel.: +1 650 723 5420
Fax: +1 650 723 5531
• Kiki Chang, MD
Assistant Professor, Stanford University, School of
Medicine, Department of Psychiatry and
Behavioral Sciences, Division of Child Psychiatry
and Child Development, 401 Quarry Road,
Stanford, CA 94305 5719, USA
Tel.: +1 650 723 5420
Fax: +1 650 723 5531
• Hans Steiner, MD
Professor of Psychiatry, Stanford University,
School of Medicine, Department of Psychiatry
and Behavioral Sciences, Division of Child
Psychiatry and Child Development, 401 Quarry
Road, Stanford, CA 94305 5719, USA
Tel.: +1 650 723 5420
Fax: +1 650 723 5531
Expert Rev. Neurotherapeutics 5(2), (2005)