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3 The Basic Principles andPrecautions ofDrug Therapy
341
3.4.2 Several Problems inDrug Therapy forWomen
withEpilepsy During Different Life Periods
3.4.2.1 ASMs andReproductive Endocrine Disorders
Key evidence indicates that women with epilepsy are more prone to reproductive
endocrine dysfunction than are ordinary women. Patients can present with menstrual disorders, polycystic ovaries, sexual dysfunction, infertility, premature menopause, etc. Reproductive endocrine disorders can also increase the frequency of
seizures and the risk of comorbidities such as female cancers, migraine, and mental
illness. Therefore, reducing the occurrence of reproductive endocrine disorders in
the treatment management of women with epilepsy is critical [60, 61]. The mechanism of reproductive endocrine disorders may be related to epilepsy itself (such as
the type and frequency of seizures) and ASM exposure [62, 63]. Here, we focus on
the effects of ASMs on the reproductive endocrine system.
ASMs can be divided into liver enzyme-inducing and non-enzyme-inducing
antiepileptic drugs, as shown in Table 3.1, with signicant differences in their
effects on female reproductive hormone levels. Enzyme-inducing antiepileptic
drugs (EIASMs), such as phenobarbital, phenytoin sodium, and carbamazepine, can
alter liver metabolism and reduce reproductive hormone concentrations. They also
induce the production of sex hormone-binding globulin (SHBG), which further
reduces plasma free estradiol concentrations, leading to menstrual disorders [59].
The non-EIASM sodium VPA is thought to have a direct effect on the production of
follicular steroids in the ovaries. VPA can increase testosterone secretion and reduce
Table 3.1 EIASMs and
non-EIASMs
EIASMs Non-EIASMs
Carbamazepine Acetazolamide
Eslicarbazepine acetate Clobazam
Oxcarbazepine Clonazepam
Phenobarbital Ethosuximide
Phenytoin Gabapentin
Primidone Lacosamide
Runamide Levetiracetam
Topiramate Piracetam
Perampanel Pregabalin
Sodium valproate
Stiripentol
Tiagabine
Vigabatrin
Zonisamide
EIASMs enzyme-inducing antiepileptic drugs, non-EIASMs
non-enzyme-inducing antiepileptic drugs
342
Q. Wang et al.
estradiol secretion, and the testosterone/estrogen ratio increases. This effect leads to
an androgen-dominated microenvironment in the ovaries, which may lead to polycystic changes in the ovaries and menstrual disorders [64].
The most common reproductive endocrine disorder among women with epilepsy
is polycystic ovary syndrome (PCOS). Among all antiseizure drugs, VPA is most
closely associated with the development of PCOS.In 1993, Isojarvi et al. [65]
reported that the incidence of polycystic ovaries and/or hyperandrogenemia was
extremely high in epileptic patients treated with VPA alone or in combination and
that the age at initial VPA exposure was also an important factor. The risk of PCOS
appears to be particularly high when VPA treatment is initiated in childhood or
adolescence.
Other reproductive endocrine disorders include infertility, sexual dysfunction,
and premature menopause. Infertility is considered to be related to seizures and the
effects of ASMs on reproductive hormones. Although most women with epilepsy
have a normal sex life, there have been reports of sexual dysfunction in this population, including decreased libido and inadequate orgasm satisfaction. The types of
ASMs used may be related to sexual dysfunction [66], but more studies have shown
that the etiology of sexual dysfunction in women with epilepsy is multifactorial,
including physiological and psychological factors, and that epilepsy-related depression is also an important factor in sexual dysfunction in women with epilepsy [67].
Premature menopause may occur in women with epilepsy, especially when the frequency of seizures is high and multiple EIASMs are used throughout their lifetime [68].
In summary, to reduce the occurrence of reproductive endocrine disorders in
women with epilepsy, a reasonable selection of ASMs is essential. Adolescents and
women of reproductive age should avoid the use of VPA.If they cannot avoid it,
they should try to use the smallest effective dose. Even in women in late childhood
(more than 10years old), it is necessary to consider the adverse effects of VPA on
the endocrine system and carefully choose the drug. In addition, choosing nonEIASMs can reduce the risk of reproductive endocrine disorders.
3.4.2.2 ASMs andContraception
Contraceptive counseling is an important part of managing the treatment of women
of childbearing age with epilepsy. Effective contraceptive measures can ensure a
planned pregnancy, reduce the occurrence of malformations, and improve the quality of life of patients. A two-way pharmacokinetic interaction between ASMs and
hormonal contraceptives can reduce the efcacy of either drug. Moreover, the combined use of hormonal contraceptives and ASMs may lead to unintended pregnancy,
increased seizures, and drug-related adverse reactions [69]. Many steroid hormonal
contraceptives and ASMs are metabolized by the liver P450 enzyme pathway.
Steroid hormones, especially the 3A4 isoenzyme, are substrates of the cytochrome
P450 enzyme system. EIASMs, including phenytoin sodium, phenobarbital, and
carbamazepine, increase the metabolism of steroid hormones, reduce the
3 The Basic Principles andPrecautions ofDrug Therapy
343
concentration of ethinyl estradiol and various synthetic progesterone contraceptive
drugs, reduce their efcacy, and increase the risk of unintended pregnancy [70]. The
new types of ASMs, felbamate, topiramate, and oxcarbazepine, are weak EIASMs
and may also have some effect on steroid hormonal contraceptives. In addition,
some ASMs can increase the production of SHBG, resulting in an increased ability
to bind to progesterone, ultimately reducing the free concentrations of hormonal
contraceptives [71]. Non-EIASMs such as ethosuximide, VPA, gabapentin,
lamotrigine, tiagabine, levetiracetam, zonisamide, pregabalin, and linamarin do not
activate the CYP3A4 isoenzyme system and therefore do not increase the risk of
contraceptive failure.
Thus, non-EIASMs are preferable for women with epilepsy who are using hormonal contraceptives. If EIASMs are used, it is recommended that the dose of contraceptives be increased appropriately. The use of nonhormonal contraceptive
measures, such as intrauterine devices, condoms, contraceptive sponges, diaphragms, and cervical caps, is also recommended. For older women who no longer
need to maintain fertility, sterilization surgery can also be used [69]. In addition,
some hormonal contraceptives also affect ASM metabolism. Lamotrigine is currently the most commonly used drug for women of reproductive age, and studies
have shown that in women with epilepsy, the use of contraceptives containing ethinylestradiol signicantly increases lamotrigine metabolism and reduces the serum
concentration by approximately 50% [72]. Therefore, it may be necessary to adjust
the dose of LTG and monitor its concentration.
3.4.2.3 ASMs andPregnancy
Pregnancy is the most critical and challenging period for women with epilepsy.
There may be some variation in seizure frequency throughout pregnancy, and seizure frequency tends to remain stable during pregnancy in most women with epilepsy, increasing in approximately one-third of patients and decreasing in some
women [73]. Owing to concerns about the adverse effects of ASMs on the fetus,
some women choose to reduce or stop drug therapy during pregnancy, which can
cause an increase in seizures, endangering the health of pregnant women and the
fetus. Epileptic seizures can increase pregnancy complications, such as premature
delivery, miscarriage, obstructed labor, vaginal bleeding, and placental abruption,
resulting in an increased risk of death. Epileptic seizures can also lead to intrauterine hypoxia, stillbirth, low birth weight, and an increase in the rate of neonatal
malformation. Epilepsy has the greatest impact on the fetus in the rst 3months of
pregnancy [74]. Therefore, it is crucial to establish a multidisciplinary cooperation
model led by epilepsy specialists and involving obstetricians, geneticists, and psychologists to provide guidance throughout conception, pregnancy, childbirth, and
lactation for female reproductive-aged epilepsy patients [75].
Women of reproductive age should consult an epilepsy specialist and an obstetrician before preparing for pregnancy. It is generally recommended that women with
epilepsy of reproductive age plan pregnancy after a seizure-free period of at least
344
Q. Wang et al.
9months. If the patient has been seizure-free in the last 3–5years and her EEG is
normal, gradually reducing and stopping drug treatment can be considered, but the
patient should be fully informed of the possibility of epilepsy recurrence. However,
most patients need to continue taking ASMs throughout pregnancy, and the goal
during pregnancy is to balance the risk of seizures with the potential teratogenic
effects of ASMs [74]. The incidence of major congenital malformations (MCMs) in
women of reproductive age due to intrauterine exposure to ASMs is 4–9%, which is
2–3 times greater than that in the general population. MCMs mainly include cardiac
developmental malformations, neural tube defects, urogenital tract malformations,
skeletal malformations, cleft palate, etc. [76].
The teratogenicity of ASMs is related to the drug type, drug dose, and number of
drugs used in combination. In a recent prospective EURAP study comparing the
incidence of MCMs with monotherapy using eight ASMs, VPA (10.3%) was the
most common, followed by phenobarbital (6.5%), phenytoin (6.4%), carbamazepine (5.5%), and topiramate (3.9%). Oxcarbazepine (3.0%), lamotrigine (2.9%),
and levetiracetam (2.8%) showed high safety indices, and the incidence of MCMs
was comparable to that in pregnant women who did not take ASMs [13]. Generally,
the teratogenicity of rst-generation ASMs, especially VPA, was signicantly
greater than that of second-generation ASMs. Another EURAP cohort study showed
a 27% decrease in the incidence of MCMs at birth in the 2010–2013 cohort, with
reduced use of VPA and carbamazepine and increased use of lamotrigine and levetiracetam compared with the previous cohort from 2000 to 2005 [77]. The safety
data of third-generation novel ASMs, including eslicarbazepine, perampanel, and
lacosamide, during pregnancy are limited. In addition, the teratogenic risk of ASMs
is dose-dependent. When the total daily dose of VPA is less than 650mg, the incidence of MCMs decreases to 6.3%, and when the dose exceeds this level, the incidence of teratogenic risk increases signicantly. The total safe daily doses of
carbamazepine and lamotrigine are 700mg and 325mg, respectively. The overall
incidence of MCMs was signicantly greater in women using combination therapy
than in those using monotherapy, especially when VPA was included in the regimen.
It is also important to note that ASM exposure is not the only factor that increases
the risk of MCMs in women of reproductive age. The Australian Pregnancy
Antiepileptic Drugs Register study reported that maternal age >31years, family
history of abnormalities, preexisting maternal mental illness, and smoking were all
independently associated with a greater risk of MCMs [78].
In addition to the structural teratogenicity of ASMs, postnatal cognitive abnormalities associated with intrauterine exposure to ASMs should also be of concern.
The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study revealed
that 6-year-olds exposed to VPA in utero had lower full- scale IQ scores than did
those exposed to carbamazepine, lamotrigine, or phenytoin. In addition, this relationship with VPA was dose-dependent; the higher the dose was, the lower the cognitive score was [79]. A recent systematic review of 35 articles on neurocognitive
developmental outcomes in children exposed to novel ASMs was conducted. The
results showed that children exposed to lamotrigine and levetiracetam in utero had
3 The Basic Principles andPrecautions ofDrug Therapy
345
better cognitive outcomes, similar to those in the control group. Data on oxcarbazepine, gabapentin, and topiramate are limited and contradictory. No studies have
assessed cognitive outcomes in children exposed to eslicarbazepine, lacosamide,
perampanel, or zonisamide in utero, and more research is needed on the effects of
novel ASMs on the development of structural and cognitive abnormalities [80].
Treatment recommendations for pregnant women with epilepsy include choosing ASMs that are effective for the type of seizure the patient has and have the lowest risk of teratogenicity and cognitive impairment in offspring. Maintaining the
lowest effective dose of monotherapy during pregnancy preparation, replacing
highly teratogenic drugs, and avoiding multidrug combination therapy where possible can effectively optimize the health of offspring [81]. However, replacement or
dose reduction of ASMs should be performed before pregnancy, as changing medications during pregnancy may increase the risk of epilepsy recurrence. New ASMs
should be preferred during pregnancy preparation, and VPA use should be avoided
as much as possible. If the pregnancy is unplanned and the patient is using VPA and
seizures are well-controlled, replacing VPA during pregnancy is not recommended,
but a lower dose can be administered. If seizures are not well controlled, more
rapid-acting ASMs should be attempted. Low levels of folic acid are associated with
neural tube defects, abortion, and intrauterine fetal growth inhibition. Daily supplementation with small doses of folic acid plays an important role in preventing fetal
neural tube malformations and promoting the cognitive development of offspring.
Women with epilepsy taking ASMs need to supplement more folic acid than the
general population, especially when ASMs that antagonize folic acid metabolism,
such as VPA, phenobarbital, phenytoin, and carbamazepine, are used together.
Supplementation with 5 mg of folic acid daily is recommended from 3 months
before pregnancy until delivery [82].
Physiological changes in pregnant women during pregnancy can affect the pharmacokinetics of various drugs. These changes include changes in kidney and liver
function and changes in serum ALB levels. The glomerular ltration rate increases
by 40–50% during pregnancy, which leads to an increase in antiepileptic drugs
cleared by the kidneys and a decrease in serum drug concentration. Liver changes
occur involving the cytochrome P450 enzyme system and glucosylation, and some
cytochrome P450 enzymes (CYP3A4, CYP2D6, and CYP2C9) can increase the
metabolism of antiepileptic drugs, with drug concentrations decreasing to varying
degrees [83]. During pregnancy, the blood concentrations of levetiracetam, topiramate, and oxcarbazepine can be reduced by 30–50%, and the blood concentration
of lamotrigine can be reduced by up to 70% [84, 85]. Therefore, detecting ASM
blood concentrations before pregnancy and establishing a reference baseline value
for drug dosage adjustment during pregnancy are recommended. Monthly monitoring of the ASM concentration is required during pregnancy, and an appropriate
increase in the ASM dose may be required during pregnancy to maintain efcacy
and prevent the recurrence of epilepsy. Drug metabolism gradually normalizes after
delivery, and the risk of excessive maternal blood drug concentration increases. The
blood drug concentration should be assessed 10–14days after delivery, and the drug
346
Q. Wang et al.
dosage should be appropriately reduced by referring to the prepregnancy drug concentration. When mothers use EIASMs (carbamazepine, oxcarbazepine, phenytoin
sodium, and topiramate) during pregnancy, the risk of neonatal bleeding increases,
and intramuscular injection of vitamin K is recommended at birth [86].
3.4.2.4 ASMs andBreastfeeding
The safety of breastfeeding is important for female patients taking ASMs.
Breastfeeding provides infants with nutrients needed for growth and development,
reduces the risk of infectious diseases, and improves the parent–child relationship
[87]. Most ASMs can be secreted into milk, and the concentration of ASMs in milk
depends on the plasma protein binding rate of the ASMs; the concentration of ASMs
in milk is generally lower than that in plasma. Therefore, the concentration of ASMs
encountered by infants from breast milk is very low; thus, breastfeeding is generally
safe for women exposed to ASMs [88].
Assessing the risks of breastfeeding is complex and requires a comprehensive
evaluation of multiple aspects. Several parameters are used to calculate an infant’s
exposure to ASMs during breastfeeding, such as the ASM milk/plasma ratio (M/P),
which is the ratio between the concentration of drugs in breast milk and maternal
plasma; an M/P ratio greater than 1 indicates a high concentration of drugs in breast
milk. However, the M/P ratio does not reect the actual exposure level of children;
therefore, its clinical value is limited [89]. The relative infant dose (RID) is the most
important measure for evaluating the risk of breastfeeding, and any drug with an
RID of less than 10% of the maternal dose is considered safe. Assuming that the
mother weighs 70kg, the RID is calculated by dividing the dose received by the
baby through the milk (mg/kg/day) by the dose in the mother’s body (mg/kg/day).
The RID values of phenobarbital, ethosuximide, topiramate, and zonisamide exceed
10%, which may not be safe and need to be reduced during breastfeeding [90].
According to a work by Hale etal. [91], Drugs and Breast Milk, drugs are classied
into ve categories of lactation risk, ranging from “safest” to “contraindication”
(L1–L5). According to this classication, most ASMs fall into three main risk categories during breastfeeding: “L2—safe,” “L3—moderately safe,” and “L4—possibly dangerous” (see Table3.2). Breastfeeding in epileptic patients taking ASMs is
generally encouraged because the benets of infant breastfeeding outweigh the
risks of moderate drug exposure.
To further guarantee the safety of breastfeeding, measures should be taken to
reduce the risk of side effects in infants. For example, phenobarbital has a long halflife, a high plasma protein binding rate, accumulation in milk, and sedative side
effects; therefore, infants should be carefully monitored during breastfeeding. In
particular, monitoring plasma drug concentrations is recommended for premature
infants or infants with lethargy, sucking difculties, or poor weight gain. If signicant side effects occur, breastfeeding should be restricted or switched to mixed/
articial feeding [92]. In addition, for drugs with short half-lives, breastfeeding can
3 The Basic Principles andPrecautions ofDrug Therapy
347
Table 3.2
Clinical parameters and main pharmacokinetic characteristics of each ASM and
assessment of their lactation risk
d
T½
(hours) M/P
Hale
e
2012
f
ASMs
Oral Bioavailabilityb
PB
a
(%) RID
(%)
c
(%)
Clonazepam 50-86 100 2.8 18–50 0.33 L3
Carbamazepine 74 100 3.8–5.9 18–54 0.69 L2
Diazepam 99 100 7.1 43 0.2–2.7 L3
Ethosuximide NA 100 31.4–71.5 30–60 0.94 L4
Phenytoin 89 70–100 0.6–7.7 6–24 0.18–0.45 L2
Phenobarbital 51 80–100 24 20–133 0.4–0.6 L3
Valproate 94 100 1.4–1.7 14 0.42 L3
Primidone 25 90 8.4–8.6 5–18 0.72 L3
Topiramate 15 75 24.5 18–24 0.86–1.1 L3
Lamotrigine 55 98 9.2 29 0.057–1.47 L3
Gabapentin <3 50–60 1.3–6.6 5–7 0.7–1.3 L2
Vigabatrin NA 50 1.5–2.7 7 <1 L3
Tiagabine 96 90 NA 7–9 NA L3
Zonisamide 40 NA 28.9–36.8 63 0.93 L4
Levetiracetam <10 100 3.4–7.8 6–8 0.76–1.55 L3
Pregabalin NA 90 NA 6 NA L3
Oxcarbazepine 40
a
PB: maternal plasma protein binding expressed as a percentage
b
Oral bioavailability: intestinal absorption after oral administration expressed as a percentage of
the administered dose
c
RID relative infant dose
d
T ½: half-life of the drug
e
M/P: milk-to-plasma ratio of a drug concentration
f
Hale lactation risk categories: L1: drugs with the highest level of safety, L2: safe, L3: moderately
100 1.5–1.7 9 0.5 L3
safe; L4: possibly dangerous, L5: contraindicated
be performed before the next dose, when the concentration of drugs in the milk is
lower; this can reduce the exposure of the baby [92]. During pregnancy, some
ASMs, such as lamotrigine, need to be increased to maintain the effective drug concentration and quickly adjusted after delivery to avoid excessive drug concentrations in the mother’s body and breastmilk [92]. Safe breastfeeding techniques are
important, and mothers can be advised to breastfeed in a supine position, preferably
in the presence of others, to protect the baby from trauma in the event of a seizure [92].
Present study risk categories: The moderately safe category has a less documented safety prole due to limited clinical experience and a lack of studies.
Moderately safe ASMs can be used, but the lowest dose of the drug should be chosen, the nursing infant should be clinically monitored, and when possible, his or her
plasma level should be checked.
The data were drawn from references [1, 41], except where otherwise specied.
NA: indicates that no data are available.
348
Q. Wang et al.
3.4.2.5 ASMs andWomen withEpilepsy andComorbidities
The prevalence of comorbidities is signicantly greater in women with epilepsy
than in the general population. These comorbidities include nervous system, psychobehavioral, and systemic disease comorbidities. An observational study that
analyzed data from eight commercial health plans showed that women with epilepsy had more comorbidities than men did. In terms of prevalence, the top 10
comorbidities in women were mental illness (16%), hypertension (12%), asthma
(11%), hyperlipidemia (11%), headache (7%), diabetes (6%), urinary tract infection
(5%), hypothyroidism (5%), anemia (5%), and migraine (4%) [93]. Various comorbidities may cause further functional impairment in women with epilepsy, and early
screening for common comorbidities is needed. In treatment, it is necessary to fully
consider the interaction between epilepsy and comorbidities, the potential side
effects of ASMs on comorbidities, and the interaction between ASMs and other
therapeutic drugs. For example, EIASMs affect the metabolism of many other
shared drugs, and comprehensive consideration of these interactions will greatly
help to improve the overall health of female epilepsy patients [94]. Table3.3 shows
the recommended ASMs for women with epilepsy and comorbidities.
Women with epilepsy have a greater risk of anxiety, depression, and other psychiatric disorders. When using ASMs, it is necessary to pay attention to their positive and negative effects on psychiatric symptoms and to consider the interactions
between ASMs and antipsychotics. Many ASMs have positive or negative effects on
patient emotions. Among the commonly used ASMs, VPA has a mood stabilizing
effect and is also used to treat depression and bipolar disorder. Lamotrigine improved
depressive symptoms in patients with epilepsy as an additive therapy in a randomized, double-blind study; carbamazepine and oxcarbazepine use did not increase the
risk of suicide or depression. The third-generation ASM lacosamide has a positive
effect on depression. Some ASMs can aggravate or cause depression, and phenobarbital, cyclohexene acid, zonisamide, topiramate, and levetiracetam have adverse
effects on mood [94]. For patients with epilepsy and depression, it is recommended
to use mood-stabilizing drugs, such as VPA, lamotrigine, and lacosamide, while
avoiding or reducing the use of ASMs that may aggravate depressive mood, depending on the type of seizure. VPA, gabapentin, etc., have anticonvulsant and antianxiety effects because they can effectively control the symptoms of epilepsy. Therefore,
such drugs are recommended for treating epilepsy in patients with anxiety.
Benzodiazepines such as clonazepam and alprazolam are suitable for short-term use
against anxiety symptoms. In addition, attention should be given to the interactions
between ASMs and psychiatric drugs. ASMs with enzyme-inducing effects promote
the clearance of antidepressants, resulting in reduced efcacy, whereas VPA
increases the concentration of these drugs and can lead to poisoning. Tricyclic antidepressants and some selective serotonin reuptake inhibitors, such as uoxetine,
paroxetine, and uvoxamine, also inhibit the metabolism of ASMs, leading to toxicity symptoms. Other antidepressants, such as citalopram, escitalopram, sertraline,
3 The Basic Principles andPrecautions ofDrug Therapy
349
Table 3.3
Recommendations for the use of ASMs in WWE and other cormobidities
Most recommended ASMs Less recommended ASMs
Heart disease
Lung disease
Hepatic impairment
Renal impairment
Porphyria
Liver transplantation
Kidney
transplantation
Bone marrow
transplantation
Hypothyroidism
Osteoporosis
Obesity
HIV
Mental disability
Cognitive
impairment
Stroke
Brain tumor
LEV, LTG, TPM, VPA,
ZNS.GBP
LEV, LTG, OXC, PGB,
TPM, VPA, ZNS.GPB
LEV, OXC, PGB,
TPM.GBP
BZD, CBZ, ESM, PHT,
TGB, VPA
LEV, OXC, PGB.GBP
LEV, PGB, TPM.GBP
BZD, LTG, VPA
LEV, LTG, TPM.GBP
BZD, LEV, LTG, PGB,
ZNS.GBP
BZD, LEV, LTG, PGB,
ZNS.GBP
TPM, ZNS
LEV, PGB, TPM.GBP
LEV, LTG, OXC,
VPA.GBP
LEV, LTG, PGB.GBP
LEV, LTG.GBP
LEV, VPA.GBPa. PGBa,
ZNS*
a
Useful as an add-on therapy
ASMs to be
avoided
a
a
CBZ, OXC, PGB, PHT
CBZ, PHT
BZD, CBZ, ESM, PB, PHT,
a
PRM, ZNS
GBP, LEV, LTG, OXC, PB,
PGB, PRM, TPM, ZNS
BZD
CBZ, PB, PHT, PRM
a
ASMs with renal excretion
a
–
OXC, TPM, VPA
a
VPA
a
a
a
a
CBZ, CLB
BZD, LTG, OXC, VPA, ZNS
PGB, ZNS
CBZ, OXC, VPA, ZNS
CBZ, OXC, PHT, TPM,
a
VPA
CBZ, LTG, OXC, PHT,
TPM
a
–
BZD, PB,
PRM
LTG, VPA
–
CBZ, LTG,
PB, PHT,
PRM,
TGB, TPM,
VPA, ZNS
VPA
–
CBZ, OXC,
PB, PRM,
VPA
CBZ, PB,
PHT, PRM
CBZ, PB,
PHT, PRM
GBP, PGB,
VPA
CBZ, PB,
PHT, PRM
BZD, CBZ,
PB, PHT,
PRM, TPM
BZD, PB,
PHT, PRM,
TPM
BZD, PB,
PRM
PB, PRM
trazodone, and venlafaxine, have less effect on the pharmacokinetics of ASMs and
can be used as a rst choice. Most antipsychotics interfere with the liver metabolism
of ASMs to varying degrees, and there is a risk of eclampsia. Patients with epilepsy
should avoid clozapine and chlorpromazine, whereas olanzapine, quetiapine, and
risperidone are relatively safe (Table3.4).
The risk of pathological fracture is signicantly increased in women with epilepsy who have osteoporosis, especially menopausal and postmenopausal women.
The adverse effects of ASMs, especially EIASMs, on bone metabolism are the main
causes of bone diseases. Phenobarbital, carbamazepine, and phenytoin sodium
(EIASMs) can reduce active vitamin D levels, resulting in reduced calcium absorption and secondary hyperparathyroidism. Non-EIASM VPA can also cause
350
Q. Wang et al.
Table 3.4
Optimization of treatment in patients with epilepsy with psychiatric comorbidities
Antiseizure
medications Psychiatric drugs
Recommended To be
Depression CBZ, GBP, LTG,
OXC, PGB, VPA
Anxiety BZD, GBP, PGB,
VPA
Psychosis LTG, OXC, VPA ESM, LEV,
avoided
PB, PHT,
PRM, TGB,
TPM, PER
LEV, PER BZD SSRIs –
TPM
Recommended To be avoided
Citalopram
Escitalopram
sertraline trazodone
Venlafaxine
Olanzapine
quetiapine
risperidone
Amoxapine
Maprotiline bupropion
Chlorpromazine
clozapine
osteoporosis through other mechanisms. Data on the bone-specic effects of other
novel ASMs are limited, but changes in bone metabolism have also been reported in
patients treated with oxcarbazepine, gabapentin, and levetiracetam [95]. Therefore,
the bone mineral densities of women who take ASMs for a long time should be
regularly monitored, and adequate amounts of calcium and vitamin D should be
administered prophylactically.
3.4.3 Principles ofIndividualization intheLong-Term
Management ofTreatment inWomen withEpilepsy
Due to physiological and social factors, women with epilepsy face more difculties and challenges than men. In formulating drug treatments for these women, the
fact that recurrent seizures and long-term ASM treatment may affect female
patients should be considered, and their long-term management needs to be
strengthened. In long-term management, considering the different physiological
characteristics and needs of each life period and providing individualized drug
therapy are crucial. For adolescent female patients, the impact of ASM treatment
on sex hormones should be considered, the occurrence of menstrual disorders and
PCOS should be avoided, and the impact of ASMs on appearance and weight
should be considered. For women of childbearing age, reasonable contraception,
reducing the teratogenicity of ASMs, and breastfeeding are the main considerations. Menopausal/elderly epilepsy patients face more comorbidity/comedication
problems. The effects of ASMs on comorbidities and drug interactions should be
considered, and attention should be given to osteoporosis and mental health issues
in menopausal women.