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patients, adverse drug reactions in 18.3% of patients, and voluntary discontinuation
in 1.7% of patients.
Due to the teratogenic nature of VPA and its unsuitability for women of childbearing age, levetiracetam (LEV) is increasingly being utilized for these patient
groups. Marson etal. [145] conducted an open-label, randomized controlled trial
comparing the efcacy and cost-effectiveness of LEV and VPA as rst-line treatments for patients with generalized or unclassiable epilepsy. The study involved
520 participants aged 5years or older with at least two noninduced generalized or
unclassiable seizures. The results indicated that, compared with LEV, VPA exhibited superior 12-month remission rates. Adverse events were reported by 37% of
participants in the VPA group and 42% in the LEV group. The study concluded that
LEV did not demonstrate superior clinical effectiveness or cost-effectiveness compared to VPA.These ndings contribute to the ongoing discussion regarding the
advantages and disadvantages of avoiding VPA use for girls and women of childbearing potential.
Idiopathic generalized epilepsies (IGEs) are the most common group of syndromes in GGE.Kiiski etal. [171] conducted a retrospective study of patients with
IGE treated at Tampere University Hospital between January 1, 2009, and December
31, 2018. The results showed that VPA was more frequently used in males than in
females, while LTG and LEV were more commonly used in females than in males.
LTG and LEV were used particularly as monotherapies for female epilepsy patients
and as a signicant part of combination therapy for males. When used as monotherapy in adults, VPA alternatives were as effective as VPA, but VPA remained the
most commonly used ASM in the pediatric subgroup. Reducing VPA use in women
with epilepsy did not increase the risk of seizure recurrence, suggesting that VPA
alternatives could be considered rst-line ASMs for women with epilepsy. Patients
with juvenile absence epilepsy (JAE) were more likely to return to VPA therapy
than those with generalized tonic–clonic seizures (GTCS) subtype alone, with a
total of 7.4% of JAE patients switching to VPA therapy experiencing sustained
myoclonic seizures, compared with 20.4% of patients treated with alternative medications. The authors concluded that although VPA treatment is not preferred as a
rst choice for women of childbearing age, there are some patients who can only
use VPA for seizure control, especially those with myoclonic seizures and JAE, and
that VPA is a commonly used and effective medication for the treatment of juvenile
myoclonic epilepsy (JME). Two-thirds of patients with drug-resistant juvenile myoclonic epilepsy are seizure free, and the combination of valproate and lamotrigine is
the most effective dual therapy [172]. Overall, patients with IGE who use VPA or
other broad-spectrum ASMs as monotherapy have shown favorable clinical outcomes. A study by Kılıç etal. [173] supported the use of VPA as an effective medication for the treatment of JME, although LEV has gradually become the preferred
initial ASM in recent years. The study revealed that VPA was the most frequently
selected initial ASM (50.9%), followed by LEV (44.4%) and LTG (4.7%), and that
VPA was preferred for male children, while LEV was preferred for female children.
During the rst 5years of the study period (2010–2015, n=66, 64%), VPA was the
most frequently chosen initial ASM, whereas LEV was the most common initial
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ASM in the last 5years (n=83, 53.9%, p=0.005); the most common reasons for
discontinuation were the ineffectiveness of LEV and adverse reactions to VPA
(p=0.001). During the follow-up period, 237 (92.2%) patients were seizure-free for
at least 12months, and 159 (61.9%) achieved EEG remission, with seizure remission (dened as complete seizure control for at least 12months) occurring earlier
than EEG remission (p<0.001). The authors concluded that LEV has gradually
become the preferred initial ASM in the treatment of JME, but VPA seems to be
more effective in achieving seizure control than LEV.Moon et al. [174] utilized
quantitative EEG (qEEG) to examine alterations in background EEG activity in 17
children with juvenile myoclonic epilepsy (JME) undergoing treatment with
VPA.The ndings revealed that VPA led to a reduction in background EEG activity
in the frontal, parietal, occipital, and limbic lobes, particularly in regions exhibiting
low-frequency (δ-θ) background EEG activity. Signicant variations were observed
in the occipital, parietal, and limbic lobes at δ frequencies, as well as in the frontal,
occipital, and limbic lobes at θ frequencies. Notably, the most pronounced differences were noted at δ frequencies in the left occipital and cuneate lobes and at θ
frequencies in the left medial frontal gyrus. The authors’ conclusion highlighted
that this study showcased the anticonvulsant impact of VPA on the neural networks
associated with juvenile myoclonic epilepsy (JME). Zöllner etal. [175] conducted
a study comparing the impact of VPA and LEV on the EEG alpha peak frequency
(APF). Their ndings indicated a notable increase in the APF as the VPA dose
decreased within the VPA group (p=0.005, n=13), while no signicant changes
were observed in the LEV group (p=0.47, n=18). In the VPA group, the APF
demonstrated a negative correlation with the daily VPA dose (r=−0.74± 0.12,
p= 0.0039), in contrast to the LEV group, where no signicant correlation was
noted (r=−0.17±0.18, p=0.4072). The researchers concluded that VPA treatment
delayed the onset of APF, with this reduction in APF being linked to the daily
VPA dose.
In a study by Ozyurek etal. [176], the impact of VPA treatment on cerebral blood
ow in children with idiopathic generalized epilepsy (IGE) was investigated. The
trial involved 33 children receiving VPA treatment and 34 age-matched controls.
Doppler and spectral measurements were conducted on various arteries, including
the common carotid artery (CCA), internal carotid artery (ICA), external carotid
artery (ECA), anterior cerebral artery (ACA), and middle cerebral artery (MCA), to
assess parameters such as the maximal ow velocity (VM), end-diastolic ow
velocity (EDV), resistance index (RI), pulsatility index (PI), and ow rate (FR). The
mean ages of the VPA and control groups were 9.33± 2.11 and 9.74 ±2years,
respectively, with a follow-up period of 17.7±3.2months during the VPA treatment
phase. No signicant differences in VM, EDV, RI, PI, or FR values obtained from
the bilateral ICA, ACA, or MCA were observed between the control and VPA
groups, suggesting that the dosage of VPA did not impact forebrain blood ow.
It is wellknown that visuospatial ability is the basis for good academic performance and daily functioning; Operto etal. [177] conducted a study to investigate
the impact of ASMs, including VPA monotherapy, on visuospatial memory in children. The trial involved 207 children and adolescents with epilepsy (mean age
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10.35±2.39years) and revealed that the mean immediate recall scores in the VPA
group signicantly worsened. Immediate recall scores were found to be correlated
with age, age at seizure, seizure duration, and executive function. This study highlights the importance of monitoring cognitive function in children receiving ASM
treatment.
Regarding ASM combinations, VPA has enzyme inhibitory properties and
requires caution when used with sodium channel blockers (SCBs), and its combination with topiramate (TPM) or zonisamide (ZNS) may lead to enhanced toxicity
[178]. Zhu etal. [179] conducted a review of randomized controlled clinical trials
on VPA combined with LEV for children with epilepsy. Their searches included the
Cochrane Library (January 1946 to May 2021), PubMed, Web of Science, Chinese
Journal Full Text Database (CNKI), WANGFANG DATA, and Sino Med. The
review included seven studies with 617 participants who met the data criteria. The
results showed that VPA combined with LEV for the treatment of epilepsy in children signicantly improved the overall treatment effect (RR = 1.24, 95% CI:
1.16–1.33, p=0.927) and reduced the incidence of adverse events (RR=0.54, 95%
CI: 0.37–0.79, p=0.602). Based on these ndings, the authors recommended VPA
in combination with LEV for the treatment of pediatric patients with epilepsy.
VPA fortheTreatment ofSE
Generalized convulsive status epilepticus (GCSE) guidelines recommend stepwise
treatment with benzodiazepines followed by second-line ASM therapy, including
VPA.Sharshar etal. [180] conducted a multicenter, double-blinded, randomized
controlled trial to assess whether VPA, as a stepwise therapeutic strategy for complementary therapy, improves the prognosis of patients with GCSE. The trial
involved 244 adults with GCSE treated with ASM in the intensive care units of 16
French hospitals between 2013 and 2018. Patients received standard benzodiazepine therapy and second-line ASM therapy, with patients in the VPA group receiving an intravenous loading dose of 30mg/kg VPA followed by an infusion of 1mg/
kg/h over 12h, while those in the placebo group received the same 0.9% saline IV
injection and continuous infusion. The primary endpoint was the proportion of
patients discharged on Day 15, and the secondary outcomes were seizure control,
adverse events, and cognition on Day 90. The results showed no signicant differences between groups in patients discharged on Day 15, and there were no differences in secondary outcomes between groups. The authors concluded that VPA was
well-tolerated as a recommended regimen for GCSE in adults and did not increase
the proportion of patients discharged on Day 15. Liampas etal. [181] conducted a
meta-analysis of randomized controlled trials (RCTs) on the use of injectable VPA
in patients with status epilepticus (SE). Thirteen RCTs were retrieved, with ve
comparisons available, four of which involved two or more studies. The results
showed no signicant differences between VPA and phenytoin sodium in terms of
efcacy and tolerability, with phenobarbital being more often associated with multiple adverse effects than VPA.Diazepam was determined to be inferior to VPA in
terms of safety issues, including severe respiratory depression and severe
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hypotension. There were no differences in efcacy between the combination of
lorazepam (LZP) and VPA and the combination of LZP and LEV.Based on these
conclusions, VPA was determined to be a safe and effective option for the management of SE.Zhang etal. [182] conducted a search for randomized controlled trials
aiming to assess the preferred ASMs for pediatric convulsive status epilepticus
(SE). They found eight rst-line ASM studies involving 1686 pediatric participants
and eight second-line ASM studies involving 1711 pediatric participants. VPA was
identied as advantageous for preventing SE recurrence within 24h in these studies.
Jain etal. [95] conducted a routine and network meta-analysis of randomized controlled trials in patients (>1month old) with benzodiazepine-resistant status epilepticus. Their analysis included 17 studies, 16 of which were included in the network
meta- analysis. Phenobarbital was identied as having the greatest likelihood of
being the best intervention for stopping seizures within 60min, followed by highdose LEV and high-dose VPA.This indicates that phenobarbital may be particularly
effective in managing benzodiazepine-resistant status epilepticus.
The incidence of valproate-associated encephalopathy in patients with epilepsy
receiving long-term treatment ranges from 0.1% to 2.5%. Whereas valproateassociated encephalopathy is frequent and unpredictable in status epilepticus
patients, even in the absence of comorbid hyperammonemia, vigilance should be
maintained for associated clinical symptoms, and discontinuation of sodium valproate should be considered immediately in suspected patients [183].
VPA andWomen withEpilepsy
Issues related to female epilepsy have gained increasing attention in recent
years due to increasing scientic research into the multiphasic effects of hormones, seizures, and ASMs, as well as concerns about pregnancy-related fertility, seizure instability, and ASM-related teratogenicity. External hormonal
inuences, such as gender-afrming medications, hormone replacement therapy, and fertility therapies, can also affect female patients with epilepsy.
Although epilepsy itself is not associated with signicantly impaired fertility in
the absence of preexisting fertility problems, the use of high-dose VPA
(≥1500mg or higher total daily dose) during pregnancy is primarily associated
with signicant congenital malformations and developmental disorders, several
times more so than in the general population. Therefore, careful consideration
is needed to choose medication and dosage to mitigate these risks, as well as
taking steps such as a pregnancy prevention program (PPP) and the completion
of an Annual Risk Acknowledgment Form (ARAF) to reduce the use of VPA in
women of potential childbearing age [184, 185]. Eriksson etal. [185] collected
data from neurologists registered with the Association of British Neurologists
and epilepsy nurse specialists through the Epilepsy Nurses’ Association of
Great Britain to assess the level of awareness among women of childbearing age
taking VPA about the risks of taking VPA during pregnancy, the need for highly
effective contraception, and enrolling in the ARAF.The results showed that the
majority of women were informed of the risks of taking VPA during pregnancy
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and the need for highly effective contraception, but there were still individuals
whose data were not available. The authors concluded that further work is
needed to facilitate the identication of women taking VPA and to implement
signing up for the ARAF.For clinicians, careful emphasis needs to be placed on
informing women of the teratogenic risks of continuing to take VPA and the risk
of worsening seizure control if VPA is discontinued, which is particularly true
in women with focal epilepsy. It may be necessary to switch to a safer, equally
effective alternative to ASMs. Spoendlin etal. [186] conducted a retrospective
descriptive study using the health care claims database of the Swiss health
insurance Helsana (2014–2018) to assess VPA use in women of gestational and
childbearing age. They found that VPA use decreased from 28/10,000 women in
2014 to 21/10,000 women in 2018, and the rate of VPA exposure during pregnancy in Swiss women of childbearing age was comparable to that in Denmark
but lower than that in other European countries. Despite the decrease in exposure rates, VPA use in Swiss women of childbearing age appears to be greater
than the actual clinical need. A study by Atalar etal. [187] provided valuable
insights into the outcomes and predictors of decision-making regarding the discontinuation/switching or continuation of VPA therapy in women with epilepsy
(WWE). They followed 214 WWE for an average of 9.57±7.04years, 142 of
whom had used VPA during their childbearing years, and 72 were still using
VPA.The main reasons for remaining on VPA were a high risk of seizure recurrence (63.9%), cognitive impairment (27.8%), and no desire for pregnancy
(8.3%). In the group that successfully discontinued VPA, 47.1% of patients
maintained seizure remission, with 38.8% experiencing relapse during followup. The incidence of side effects associated with the new drugs LEV and LTG
was 36.6%.
The rate of discontinuation failure was signicantly lower in focal epilepsy
patients (13.9%) than in generalized epilepsy patients (86.1%). In patients with generalized epilepsy, all three types of seizures were associated with discontinuation
failure, as well as the presence of ASM resistance. Women with focal epilepsy,
although more likely to be ASM resistant and have sustained seizures, did not typically experience worsening of their condition after discontinuation of VPA, making
it unnecessary to expose them to teratogenic risk. In generalized epilepsy, certain
predictive factors, such as known ASM resistance and the presence of three seizure
types, should be considered before attempting to discontinue VPA.
SE during pregnancy is a critical medical emergency for both mothers and
fetuses. The management of SE during pregnancy is complex due to pregnancyrelated pharmacokinetic changes and fetal risks associated with ASM and anesthetic drugs. Although there is no standardized treatment regimen for pregnant
patients with SE, benzodiazepines are typically the drug of choice. LEV and phenytoin are considered the most appropriate second-line medications. VPA should
only be used when other ASMs have failed and should be avoided during the rst
trimester of pregnancy to minimize teratogenic risks. This underscores the importance of careful management and consideration of ASM use in pregnant women
with epilepsy [188].
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VPA andBreastfeeding
Some studies have shown that breastfed infants have higher IQs and better verbal skills at age 6 than nonbreastfed infants. Breast milk has previously been
found to contain very low levels of VPA, and infant serum levels of VPA range
from undetectable to very low; moreover, breastfeeding during VPA monotherapy does not appear to adversely affect infant growth or development. A safety
scoring system study showed that VPA can be used during breastfeeding, and
there have been no reports of denite adverse effects of VPA use in breastfed
infants. However, it is theoretically possible for breastfed infants to develop
VPA-induced hepatotoxicity, so infants should be monitored for jaundice and
other signs of liver damage during maternal VPA therapy. Suspected cases of
thrombocytopenia have also been reported, so infants should be monitored for
unusual bruising or bleeding.
VPA Use inEpilepsy Comorbidities withSomatic Disorders
Epilepsy is a chronic disease, and comorbidity with somatic disorders is common.
In recent years, there has been increasing interest in and research on epilepsy
comorbidities.
Patients with epilepsy who have preexisting cardiac arrhythmias are at increased
risk of sudden death, and appropriate ASM therapy should be administered to manage comorbidities of cardiovascular disorders. However, the concomitant use of
antiarrhythmic agents and ASM therapy can cause potential drug–drug interactions
due to their similar mechanisms of action. Studies have shown that interactions
between antiarrhythmic drugs and ASMs are most likely to occur when the drug
components block sodium channels and have membrane-stabilizing properties.
Like VPA, mexiletine is an antiarrhythmic drug that blocks sodium channels and
has membrane-stabilizing properties. When mexiletine is combined with VPA,
mexiletine can attenuate the antiepileptic seizure effect of VPA, as shown in studies
conducted using the MES test in mice [189]. It is important to note that VPA also
affects coagulation and platelet counts, and antiplatelet agents associated with the
treatment of heart disease, in which salicylic acid increases the free dispersion of
VPA, can potentially interact with VPA.European guidelines do not recommend the
use of VPA in patients taking oral anticoagulants (DOACs). A prospective multicenter cohort study showed that patients with nonvalvular AF treated with both
DOACs and ASMs, including VPA, had a relatively high incidence of thromboembolic events [190]. However, intravenous application of VPA is a safe and effective
therapeutic option for the treatment of SE patients with epilepsy comorbid with
cardiovascular or respiratory diseases.
For SE treatment, VPA is contraindicated in patients with liver disease due to its
potential hepatotoxicity. Similarly, in chronic antiepileptic therapy, VPA is not recommended for patients with hepatic insufciency and should be avoided if possible.
VPA is mainly eliminated by the liver and is therefore recommended for renal injury
and hemodialysis.
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Patients with poststroke comorbid epilepsy are more susceptible to ASM-induced
adverse effects, and elevated lipoprotein levels and weight gain, which are associated with an increased risk of cerebrovascular disease, have been found in VPAtreated patients; therefore, VPA is generally less recommended for stroke patients.
Despite these drawbacks, intravenous injections of VPA remain a better choice for
use in acute situations. Patients with multiple sclerosis appear to be at three times
greater risk of seizures than the general population, and seizures may be a symptom
of this disease that does not affect motor or cognitive function. Low doses of VPA
may be the drug of choice.
When using VPA in patients with brain tumors, drug interactions with chemotherapeutic agents should be considered, as some agents can reduce VPA levels and
lead to poor seizure control. For example, methotrexate can reduce VPA levels and
lead to seizure recurrence [191]. VPA can reduce the metabolism of cisplatin, etoposide, and teniposide drugs, leading to toxic drug aggregation effects. However,
VPA still shows good efcacy and tolerability in the treatment of epilepsy in patients
with brain tumors, and IV injections are still a good choice for patients with brain
tumors in cases of SE.
In infectious diseases, ASMs and anti-infectives often need to be used in combination, and clinically signicant interactions between them may lead to adverse drug
reactions or treatment failure. The European Medicines Agency (EMA), in its drug
safety report, suggests that concomitant use of carbapenems and VPA should be
avoided and that interactions between the two cannot be monitored by determining
VPA plasma concentrations or by adjusting the dose, but if they are already used in
combination, it is recommended that other ASMs be added and that VPA concentrations be continuously monitored. A recent retrospective study showed that the interaction between VPA and carbapenems results in lower plasma concentrations of VPA
and possibly liver injury. The study involved data from 141 patients in the Department
of Neurosurgery, Baiqiu’en Hospital, Shanxi, China, from January 2018 to December
2019. The results showed that the serum concentration of VPA in the VPA+meropenem group was signicantly lower than that in the VPA monotherapy group. The difference in the incidence of liver injury between the VPA monotherapy group, the
VPA+meropenem group, and the VPA+imipenem group was statistically signicant, and the liver injury rate in the VPA+meropenem group was greater than that in
the VPA+imipenem and VPA monotherapy groups. Although there was no signicant difference in the rate of hepatic injury between the VPA+imipenem group and
the VPA monotherapy group, the ALT value in the VPA+imipenem group was signicantly greater than that before. These ndings suggest that the interaction between
VPA and carbapenems can result in lower plasma concentrations of VPA and possibly
liver injury. Clinicians should be aware of this potential interaction and closely monitor VPA concentrations and liver function when using carbapenems in combination
with VPA.Different carbapenems used in combination with VPA may have different
effects on blood concentrations and liver function, so careful consideration is needed
when using these drugs together [192]. Clinicians should be aware of this potential
interaction and closely monitor VPA concentrations and liver function when using
carbapenems in combination with VPA.Chen etal. [193] assessed the risk factors for
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117
seizures or SE resulting from the combination of VPA and carbapenem antibiotics in
adult patients in the ICU.The results showed that 104 out of 162 patients (64.2%)
experienced seizures and 45 (27.8%) experienced SE.The risk factors for seizures
were age, initial antiepileptic regimen, and serum concentration of VPA after concomitant administration of carbapenems, while the independent risk factor for SE was
the combined VPA serum concentration after application of carbapenems. The concomitant administration of imipenem/cilastatin did not signicantly reduce VPA
blood concentrations compared with meropenem or ertapenem. Patients with concomitant seizures or SE had a signicantly increased length of stay and days of ventilation after concomitant carbapenems in the ICU. The authors concluded that
carbapenem antibiotics reduced VPA blood levels and increased the risk of seizures
and SE, thereby prolonging ICU hospitalization. Furthermore, there have been case
reports of the use of meropenem to lower blood levels of VPA to treat acute VPA poisoning [194]. In another study by Yang etal. [195], LC–MS/MS was used to determine the interactions of VPA and its six metabolites in human serum with carbapenems
in patients with epilepsy. The method was found to be simple, rapid, accurate, and
precise for routine clinical analysis of VPA and its metabolites in human serum.
Müller etal. [196] investigated the differences between VPA intravenous therapy for
SE in diabetic and nondiabetic patients. The study revealed that the tolerability of
VPA therapy was comparable in both groups and that diabetes, as a relevant comorbidity, may portend a post-SE potential increased risk of adverse outcomes in diabetic
patients presenting with SE.
Approximately 25% of patients with intellectual disability (PwID) have comorbid
epilepsy, and up to two-thirds of these patients are resistant to treatment. Epigenetic
pathways are also thought to be associated with altered cognitive function. VPA has
been reported to inhibit the expression of aminorhodamine 2,3 dioxygenase (IDO), the
tryptophan pathway that regulates tryptophan metabolism. However, the complex epigenetic cascade of VPA-induced responses implies long- term benecial and deleterious
effects on intraneuronal homeostasis and plasticity. BSN-mutant mice are commonly
used as a model for long-term synaptic plasticity decits in the hippocampus, leading to
hippocampal learning decits. VPA treatment reversed the physiological long-term
potentiation effect but did not reverse the morphological alterations in dendritic spines
or the impairment of nonspatial hippocampal memory. Although VPA inhibited neurogenesis in an animal model of SE, thereby preventing cognitive decline, it failed to
improve cognitive performance in rats in the Morris water maze swim test.
Prospective studies in humans have consistently demonstrated that VPA is associated with an increased risk of cognitive impairment and in utero malformations in
young children. Dose-dependent negative effects of VPA were found in children of
mothers receiving VPA monotherapy. The children performed a number of cognitive tests, including those related to IQ, verbal and nonverbal abilities, memory, and
executive function. However, Snoeijen-Schouwenaars et al. [197] conducted an
exploratory, retrospective study of patients with intellectual disabilities in England
and the Netherlands and found that the most commonly prescribed medication in
both centers was still VPA.This is the rst observational study to reveal the unique
characteristics of epilepsy management in this complex population.
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Kessing etal. [198] studied 154 patients with bipolar disorder and comorbid
epilepsy and 8381 patients with bipolar disorder without comorbid epilepsy identied in Denmark between 1995 and 2017. The authors concluded that patients with
bipolar disorder with comorbid epilepsy should be prioritized for treatment with
VPA and LTG. They also emphasized the need for close clinical monitoring and
psychological support for patients with bipolar disorder and comorbid epilepsy, as
well as further long-term studies on the effects of interventions.
VPA Use inOther Diseases
Mental Illness
The drug insert included in VPA packaging notes that valproic acid (VPA) can
effectively manage manic episodes in bipolar disorder patients and exerts a stabilizing inuence on mood [199]. Hsieh etal. [200] used data from the National
Health Insurance Research Database (NHIRD) in Taiwan to conduct a correlation
analysis to study the effect of long-term use of VPA on the mortality of patients
with bipolar disorder and found that the long-term use of VPA reduces the mortality of patients with BD risk, especially in the male population and the 65-yearsor-older population. Xie et al. [201] conducted a study involving 30
Sprague–Dawley (SD) rats to explore the effects of VPA on hippocampal magnetic resonance imaging (MRI) images, neurocognition, and activity of the JAK1/
STAT3 pathway in depressed rats. Their results demonstrated the efcacy of VPA
in enhancing hippocampal volumetric features, memory, and neurocognitive function in a model of depression.
In addition, VPA has been increasingly used to treat delirium. Cuartas etal. [202]
systematically reviewed 21 abstracts spanning 1946 to January 12, 2021, and
included 10 studies (252 patients) evaluating the efcacy of VPA for the treatment
of delirium. Notably, patients showed improvement in delirium symptoms within
1–3days, with a mean starting dose of 733mg/day and a mean follow-up dose of
1061 mg/day. Common side effects included hyperammonemia (12–19%) and
thrombocytopenia (9–13%), with no reported VPA-related deaths.
Although intravenous (IV) VPA is not ofcially recommended for psychiatric
disorders, the literature suggests its potential efcacy. Olivola etal. [203] systematically reviewed studies on intravenous VPA for agitation treatment and concluded
that it effectively reduces agitation in psychiatric patients and is generally safer than
other antipsychotics or ASMs. However, the evidence is limited due to the reliance
on open-label studies or case series reports.
Migraine Prevention
The use of ASMs, including VPA, in the treatment of migraines has been supported
by evidence from numerous randomized controlled studies [148]. VPA, an FDAapproved drug, may work in migraine prevention and treatment by blocking neurogenic inammatory responses and responses to trigeminal vascular system
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activation. Its mechanism of action involves effects on voltage-gated sodium channels, γ-aminobutyric acid receptors, glutamate-mediated neurotransmission, and
calcium channels. By modulating the central nervous system pain mechanism and
inhibiting nociceptive modulation loops, VPA can help prevent migraine attacks.
When used alone, VPA has shown a migraine headache relief rate of 68–73%, with
the ability to reduce accompanying symptoms and cause fewer adverse reactions. It
can be effective within 1–4h of oral intake due to its high bioavailability.
Ischemic Stroke
The ndings we have highlighted regarding valproic acid (VPA) in a rodent model
of ischemic stroke are signicant in demonstrating the potential neuroprotective
effects of VPA in this context. Despite the typical caution in using VPA for stroke
patients due to its association with lipid metabolism and weight gain, the results
from an MCAO model suggest promising therapeutic implications for VPA in ischemic stroke patients. In tan MCAO model, VPA has been shown to inhibit histone
deacetylase (HDAC), leading to the suppression of NF-κB and metalloproteinase-9
activation. This inhibition plays a crucial role in reducing postischemic cerebral
blood barrier disruption and cerebral edema, which are important factors in the
pathophysiology of ischemic stroke. Additionally, VPA has been demonstrated to
reduce infarct size and improve clinical decit symptoms by upregulating the
expression of heat shock proteins, particularly of heat shock protein-70, while
inhibiting caspase-3 expression and activation. These mechanisms collectively contribute to the neuroprotective effects of VPA in ischemic stroke. Moreover, evidence
from invitro studies on ischemic injury further supports the neuroprotective potential of VPA.Specically, in an invitro model of oxygen and glucose deprivation,
VPA treatment has shown protective effects against ischemic injury. These ndings
suggest that VPA may have a signicant impact on mitigating neuronal damage and
promoting cell survival under ischemic conditions [150]. VPA has been found to
exhibit neuroprotective effects against ischemic stroke, as demonstrated by Gao
etal. [204] in a rat model of cerebral ischemia–reperfusion injury. After 4weeks of
VPA treatment, the volume of brain atrophy was signicantly reduced, and behavioral decits improved. In vitro studies also showed that VPA treatment protected
against OGD/Re-induced astrocyte death and reduced the expression of GFAP, neurocalcitonin, and phosphatidylinositol. These ndings suggest that VPA exerts neuroprotective effects and inhibits glial scarring during recovery from ischemic stroke
by inhibiting HDAC activity and inducing expression of heat shock protein-70.1B.
Atherosclerosis is a recognized risk factor for ischemic stroke, and abnormal
vascular smooth muscle cell (VSMC) proliferation is a key factor in the development of vascular diseases, including atherosclerosis. Research has shown that VPA
stimulates the phosphorylation of the Thr389 locus in VSMCs by inhibiting specic
protein phosphatase 2A (PP2A) and modulating platelet-derived growth factor
(PDGF) levels (p-p70S6K-Thr(389)). This mechanism reduces VSMC proliferation, suggesting that VPA may be useful for the treatment and prevention of atherosclerosis and in-stent restenosis [205]. These ndings provide additional support for
the potential positive effect of VPA in the context of ischemic stroke.