CLINICAL AND RESEARCH REPORTS
Adjunctive Valproic Acid in Management-Refractory
Hyperactive Delirium: A Case Series and Rationale
Yelizaveta Sher, M.D., Anne Catherine Miller, M.D., Sermsak Lolak, M.D., Andrea Ament, M.D., José R. Maldonado, M.D.
Patients with delirium may fail to respond to standard therapies. Sixteen patients with management-refractory hyperactive
delirium responded to adjunctive valproic acid, with complete resolution of hyperactive delirium in 13 cases. A rationale for
using valproic acid in such circumstances is discussed.
J Neuropsychiatry Clin Neurosci 2015; 00:1–6; doi: 10.1176/appi.neuropsych.14080190
Delirium is the most commonly encountered psychiatric di-
agnosis in the general hospital setting and significantly in-
creases patients’ hospital stay, morbidity, and mortality.1 It
causes considerable distress to patients and their families and
is associated with later cognitive decline. Delirium is mediated
by several mechanisms, including neuronal aging, inflamm-
ation, oxidative stress, and dysregulation in cellular signaling
and secondary messenger systems, all of which lead to neu-
rotransmitter imbalance. Deficiency in acetylcholine and me-
latonin, excessive dopaminergic and glutamatergic activity, and
alterations in g-aminobutyric acid (GABA), serotonin, and
histamine have all been implicated in its development.1
Although antipsychotics are often considered a first-line
pharmacological treatment, there may be multiple contra-
indications (e.g., akathisia, movement disorders, QTc pro-
longation).1 Valproic acid (VPA) is one potential alternative,
alone or as an adjunct, in the management of hyperactive
and mixed-type delirium. VPA is available intravenously
and orally, which allows for greater flexibility in adminis-
tration, especially in agitated, delirious patients in need of
rapid behavioral control.
VPA’s mode of action involves many of the neurotrans-
mitters involved in the development of delirium. VPA has
antiglutamatergic and N-methyl-D-aspartic acid (NMDA) re-
ceptor antagonistic activity.2,3 It potentiates GABA effects,
induces expression of melatonin receptor,4 and decreases do-
pamine in the striatum5 and basolateral complex of amygdala6
while increasing dopaminergic activity in the hippocampal
and prefrontal areas.7 In addition, VPA increases acetylcholine
efflux in rat hippocampus.7 Finally, VPA has anti-inflammatory
and antioxidant properties2; exerts transcriptional effects
through epigenetic modulation of gene expression,2 including
histone deacetylase inhibition; and has beneficial effects on
the kynurenine pathway.8
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Currently, the data on VPA’s efficacy in delirium are limited
to only two case series comprising a total of eight patients.9,10
In addition, there are limited data on VPA’s usefulness in the
management of agitation in patients with dementia,11 traumatic
brain injury (TBI),12 alcohol withdrawal, and corticosteroid-
induced mania.13 Finally, emerging data support the use of VPA
for neuroprotection in acute central nervous system injuries
because of its anti-inflammatory, antiapoptotic, and neurotrophic
effects.14
METHODS
We conducted a retrospective chart analysis of hyperactive
delirium patients treated by the psychosomatic medicine ser-
vice at our institution over a period of 13 months using VPA as
an adjunct in cases refractory to conventional antipsychotic-
based therapy. Identified patients were diagnosed with
delirium by a psychiatrist using DSM-IV-TR criteria.15 A
hyperactive motor subtype of delirium was identified accord-
ing to Liptzin criteria.16 Patients younger than 18 years of age
and those in active alcohol withdrawal at the time of the initial
consult were excluded. Electronic medical records were re-
viewed for patient demographics, clinical presentation, medi-
cations, and mental status examinations.
Serum aspartate aminotransferase levels, alanine amino-
transferase levels, hemoglobin levels, platelet counts, and
international normalized ratio values before and after initi-
ation of VPA were extracted. VPA levels were recorded if
available.
The electronic medical records of the primary medical,
nursing, and consulting psychiatry teams were reviewed to
determine whether patients met DSM-IV-TR criteria for
delirium on a daily basis and to characterize the degree of
their agitation.
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VALPROIC ACID IN MANAGING DELIRIUM
The primary outcome was resolution of delirium; sec-
ondary outcomes included resolution of agitation associated
with delirium and VPA-related adverse effects.
The study protocol was approved by the Stanford Uni-
versity Institutional Review Board (IRB #25647).
RESULTS
Fifteen patients with 16 total episodes of hyperactive de-
lirium meeting DSM-IV-TR and Liptzin criteria for a hy-
peractive motor subtype were identified16 (see Table 1 for
brief descriptions of these cases). Fourteen patients were
male, and the average age was 51.8 years (SD 5 15.7, range 5
25–87). Most patients were treated in the intensive care unit
(ICU). Of note, one patient had dementia (patient #7), one
patient had newly acquired TBI (patient #9), four patients
were treated with high-dose corticosteroids (patient #1 for
immunosuppression after heart transplantation; patient #5
for intracranial swelling; patient #12 for immunosuppression
after lung transplantation; patient #13/14 for myasthenia
gravis), and one patient exhibited residual alcohol withdrawal
after being weaned off dexmedetomidine. Based on a chart
review, delirium started an average of 5.5 days prior to VPA
initiation (SD 5 4.6, range 5 1–17). The etiologies of delirium
included postoperative status, hypoxia, infection, acute renal
injury/uremia, intracranial pathology, opiate use, benzodiaz-
epine use, corticosteroid use, and, most frequently, a combi-
nation of these factors.
In most cases, prior to a psychiatric consult, the primary
team had tried multiple medications in an attempt to control
agitation associated with hyperactive delirium, including
various antipsychotic and benzodiazepine agents, opiates,
dexmedetomidine, and propofol. The primary teams also at-
tempted to address the etiology of each patient’s delirious state
(e.g., treatment for infections, reduction of offending medi-
cations, dialysis). One subject (patient #9) was treated solely
with VPA and received no antipsychotics because of a pro-
longed baseline QTc. All other subjects failed to adequately
respond to antipsychotics, at which point treatment with VPA
was initiated by the psychiatry consult team.
After initiation of VPA, complete resolution of delirium
according to DSM-IV-TR criteria was documented in 13 cases.
The average time from VPA initiation to delirium resolution
was 6.2 days (SD 5 8.0, range 5 1–30). Two patients resolved
within 1 day, four resolved within 2 days, two resolved within
3 days, one resolved within 4 days, and four resolved after
9 days or longer (9, 11, 11, and 30 days). Excluding the outlier of
30 days, the average number of days to delirium resolution was
4.2 days (SD 5 3.8). The median time to delirium resolution
was 3 days.
All study patients, including three patients whose delirium
did not resolve completely after VPA initiation, experienced
marked improvement in agitation and behavioral management
as reflected by documented mini-mental state evaluations; re-
ports of decreased impulsivity, restlessness, and aggression;
an ability to discontinue restrains; and a decreased need for
2 neuro.psychiatryonline.org
sedation. Three patients whose terminal delirium did not re-
solve despite decreased agitation and improved comfort were
transitioned to comfort care, transferred out of the ICU, and
eventually passed away because of their primary medical con-
dition. The average dose of standing VPA used on days 1 through
4, when most patients experienced delirium resolution, was
1133–1258 mg per 24 hours (SD 5 480–625), administered in
two to three divided daily doses.
Meropenem may decrease VPA serum level and efficacy
by up to 92%,17 and indeed, this was observed in three of our
patients. In these three cases, a dramatic normalization of
the VPA level and effectiveness was observed 24 hours after
discontinuation of meropenem.
Regarding adverse effects, two patients developed throm-
bocytopenia, one of whom experienced gastrointestinal
bleeding (patient #12). Of note, the same patient experi-
enced gastrointestinal bleeding 10 days after discontinuation
of VPA; therefore, the correlation between VPA and gastro-
intestinal bleeding remains unclear. There were no statistical
differences between the averages for aspartate aminotrans-
ferase, alanine aminotransferase, hemoglobin, platelets, and
international normalized ratio prior to VPA and following
VPA initiation. There were no other adverse effects attributed
to VPA.
DISCUSSION
This case series adds to the limited data available and sug-
gests potential benefits of VPA in the treatment of refractory
hyperactive delirium. More importantly, the adverse effects
were minimal, and overall the agent was well tolerated. Of
note, almost one-half of the patients had dementia, TBI, pres-
ence of corticosteroids, or residual alcohol withdrawal, con-
ditions in which VPA has been shown to be beneficial.11–13
As an open-label, nonrandomized case series, our study
has some limitations, including the lack of a control group;
the heterogeneity of the study group; the concomitant use of
multiple pharmacological agents; the retrospective nature of
data collection; and the lack of validated scales to measure
delirium severity. However, the patients in this study rep-
resented some of the sickest patients seen by the psycho-
somatic medicine service at our institution. All had failed
multiple pharmacological interventions prior to VPA ini-
tiation. Arguably, the use of polypharmacy prior to VPA
initiation, including benzodiazepines and opiates, could
have contributed to the severity of delirium. However, in-
troduction of VPA allowed patients to taper off their use of
these sedative medications, all of which have themselves
been associated with the worsening of delirium. It is also
possible that in some cases VPA addressed withdrawal from
benzodiazepines, which made weaning off these and other
GABA-ergic agents (such as propofol) challenging before
the introduction of VPA. As a result, all patients experi-
enced some degree of improvement in behavior and cog-
nition, with 13 patients experiencing complete resolution of
delirium.
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 TABLE 1. Case Descriptions
Number of Days Until
Number of Psychotropic Psychotropic Delirium Resolutionb
Patient Presenting Medical Delirium Days Medications Used Medications (Other Significant
Number Age/Sex Condition Location Delirium Etiology Prior to VPA Prior to VPA Used with VPA Outcomes)

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1 42/F Status post heart ICU Postoperative delirium, 1 CLN, DEX, FEN, HAL 2 (Extubated in 2 days)
transplantation, on hypoxia,a hypokalemia,a MIDAZ, OLZ, PROP,
corticosteroids, unable to steroids, opiates, SER
extubate due to agitation benzodiazepines
on postoperative day 3
2 47/M Status post ventricular ICU Postoperative delirium, 11 CLN, DEX, HYDRM, ARIP, doxepine 3
assistive device hypoxia,a infection,a PROP
placement, agitation, benzodiazepines, opiates
elevated QTc
3 53/M Status post aortic dissection, ICU Postoperative delirium, acute 3 DEX, FEN, PROP CLO, HAL 3 (Extubated in 3 days)
agitation kidney injury, infection,a
methamphetamine
withdrawal, opiates
4 46/F Cardiomyopathy with CCU Acute kidney injury ,a 3 HAL, LOR HAL 2 (Underwent successful
ongoing anxiety, delirium, benzodiazepines, opiates VAD implantation)
agitation
5 25/M Pontine hemorrhage, Floor Intracranial pathology, 5 HAL, LOR, SER OLZ 2
ongoing agitation, infection,a steroids,a
insomnia after surgery, benzodiazepines
akathisia on HAL
6 49/M Severe ischemic ICU Cardiogenic shock,a 17 DEX, DIAZ, FEN, LOR, GAB, HAL, 11 (Mental status
cardiomyopathy, on hyponatremia,a infection,a MIDAZ, PROP guanfacine improved significantly
inotropes benzodiazepines in 3 days)
7 87/M Stroke, dementia, Floor Intracranial pathology, 8 HAL, QUE, RIS Ramelteon 2
rhabdomyolysis, elevated rhabdomyolysis, acute
QTc kidney injurya
8 27/M Pancreatitis, sepsis, agitation ICU Pancreatitis,a infection,a 3 DEX, HAL, HYDRM, CLO, GAB, HAL 1 (Mental status clear in 2
acute kidney injury,a MIDAZ, PROP days, discharged home
alcohol withdrawal, in 5 days)
opiates, benzodiazepines
9 46/M TBI, pneumonia, impulsivity, Floor Intracranial pathology, 9 DEX, morphine, PROP None 4 (Discharged to
elevated QTc infection,a opiatesa rehabilitation clinic in 5
days)
10 58/M Aortic dissection, stroke, ICU Intracranial pathology, 3 DEX, HAL, HYDRM CLO, HAL 1 (Transferred out of ICU
seizure, agitation, postoperative delirium, in 2 days)
combative attitude seizurea
11 46/M Intracranial hemorrhage, ICU → Intracranial pathology, 6 CLO, DEX, FEN, HAL, CLO, HAL 30 (Stabilized; discharged
status post evacuation, floor postoperative delirium, LOR, PROP home in 2 months)
septic, agitation, elevated methamphetamine
QTc on HAL withdrawal,
benzodiazepines
continued

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SHER ET AL.

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TABLE 1, continued
Number of Days Until
Number of Psychotropic Psychotropic Delirium Resolutionb
Patient Presenting Medical Delirium Days Medications Used Medications (Other Significant
Number Age/Sex Condition Location Delirium Etiology Prior to VPA Prior to VPA Used with VPA Outcomes)
12 47/M Status post lung ICU Postoperative delirium, 7 CLN, DEX, HYDRM, HAL 11 (Mental status
transplantation; on hypoxia, infection,a OLZ, PROP improved within a few
corticosteroids, drips, steroids, benzodiazepines, days; gastrointestinal
MER, OLZ, and opiates bleed on and off VPA)
benzodiazepines;

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consulted postoperative
day 2
13 66/M Myasthenia gravis, septic ICU Infection, septic shock,a 5 DEX, HAL, PROP HAL, MRZ 9 (MER discontinued on
VALPROIC ACID IN MANAGING DELIRIUM

shock, on MER, intubated, hypotension,a hypoxia,a day 5 of coadministration

agitation acute kidney injury,a with VPA; VPA level
hyperkalemia,a steroids became therapeutic and
delirium improved within
4 days)
14 66/M Patient re-hospitalized shortly ICU Infection,a uremia 2 MRZ, RIS HAL → QUE; NR (agitation improved
after discharge; Myasthenia MRZ but remained delirious;
gravis, pneumonia, sepsis, able to transfer out of
renal failure, on MER ICU and transferred to
comfort care)
15 51/M Diabetic ketoacidosis, acute ICU Diabetic ketoacidosis, 2 DEX, HAL CLO, HAL NR (agitation improved
renal failure, sepsis infection,a uremia, but remained delirious;
acidosis,a AKI, transitioned to comfort
hyponatremiaa care)
16 73/M Osler-Weber Rendu ICU Hypoxia,a hypotensiona 3 ARIP, DEX, HYDRM, ARP, MRZ NR (agitation improved
syndrome, AICD, massive MIRT but remained delirious;
epistaxis extubated, transitioned
to comfort care)
AICD: Automatic implantable cardioverter defibrillator; ARIP: aripiprazole; CCU: cardiac care unit; CLN: clonazepam; CLO: clonidine; DEX: dexmedotomidine; DIAZ: diazepam; F: female; FEN: fentanyl; GAB:
gabapentin; HAL: haloperidol; HYDRM: hydromorphone; ICU: intensive care unit; LOR: lorazepam; M: male; MER: meropenem; MIDAZ: midazolam; MRZ: mirtazapine; NR, no resolution; OLZ: olanzapine; PROP:
propofol; QUE: quietapine; RIS: risperidone; SER: sertraline; TBI: traumatic brain injury; VPA: valproic acid.
a
Delirium etiology that was addressed/treated by the primary team.
b
Delirium was defined according to DSM-IV-TR criteria based on daily evaluations by the psychosomatic medicine service at our institution.

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There are important considerations for the use of VPA.
Patients should be selected carefully and monitored for
possible adverse effects. VPA significantly increases the risk
of neural tube defects and neuropsychiatric deficits in the
fetus and thus should not be used in pregnant patients.
Thrombocytopenia, macrocytic anemia, and leucopenia
have all been described in patients using VPA.3 Thus, we
recommend daily monitoring of blood cell counts, especially
platelets, in critically ill patients on VPA. The hypothetical
risk of bleeding can be increased further in patients on war-
farin, as VPA raises warfarin levels via CYP2C9 and CYP2C19
inhibition and protein binding displacement.18
VPA-associated pancreatitis is thought to be a rare idio-
syncratic reaction to VPA use,3 thus administering physicians
should monitor for this possibility. Patients might present
with acute abdomen, nausea and vomiting, elevated white
blood cell count, fever, and an increase in the base deficit.
These symptoms should prompt urgent measurement of
lipase and amylase and, if indicated, discontinuation of
VPA.
The use of VPA may be associated with minor elevation of
liver transaminase enzymes and lactate dehydrogenase, usually
in the first months of treatment in a dose-dependent fashion.
On the other hand, serious VPA-induced hepatotoxicity, which
may lead to fulminant hepatic failure, has been reported in
1 out of 20,000 patients.3 This risk may be lower, however, in
patients treated with VPA for delirium, as VPA’s use in delirium
is usually short-lived. Similarly, VPA-induced hyperammonemic
encephalopathy (VHE) is rare,19 although asymptomatic ele-
vations of ammonia may be more common. VHE is mediated
by the effects of VPA on the urea cycle and impaired excretion
of ammonia.19 Patients with urea cycle disorders, mitochon-
drial disorders, and carnitine deficiencies are at higher risk.
Thus, it is important to check ammonia levels and consider
VHE in any patient whose mental status worsens while on
VPA or who appears to be transitioning from a hyperactive to
a hypoactive state. If there is concern for VHE, VPA should
be stopped and supplementation with L-carnitine should be
strongly considered. Of importance, the risk of encephalopa-
thy might be greater in patients who are taking a combination
of VPA and other psychotropic medications (e.g., lamotrigine,
zotepine, quetiapine), highlighting the need to monitor drug-
drug interactions.
CONCLUSIONS
We observed a significant improvement in symptoms of
hyperactive delirium with the adjunct use of VPA in patients
with failed or contraindicated conventional treatment. We
suggest that with proper monitoring of carefully selected
patients, VPA can be a promising adjunct for treatment of
hyperactive delirium, given its actions on multiple pathways
implicated in the pathophysiology of delerium. Of course,
randomized control trials are needed to determine the true
efficacy and side effects of VPA for the treatment of delirium
in this critically ill population.
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SHER ET AL.
AUTHOR AND ARTICLE INFORMATION
From the Stanford University School of Medicine, Stanford, CA (YS, AA,
JRM); and the George Washington University, Washington, DC (ACM, SL).
Send correspondence to Dr. Sher; e-mail: ysher@stanford.edu.
Previously presented at the American Delirium Society, Third Annual
Meeting June 4, 2013, Indianapolis, IN; the Academy of Psychosomatic
Medicine, 60th Annual Meeting, November 15, 2013, Tucson, AZ; and
the American Psychiatric Association, 167th Annual Meeting, May 5,
2014, New York, NY.
The authors report no financial relationships with commercial interests.
Received Aug. 14, 2014; revision received Dec. 17, 2014; accepted Dec.
30, 2014.
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