Curr Psychiatry Rep (2015) 17: 66

DOI 10.1007/s11920-015-0603-z

BIPOLAR DISORDERS (W CORYELL, SECTION EDITOR)

Management of Adverse Effects of Mood Stabilizers

Andrea Murru 1 & Dina Popovic 1 & Isabella Pacchiarotti 1 & Diego Hidalgo 1 &
Jordi León-Caballero 2 & Eduard Vieta 1,3

Published online: 19 June 2015

# Springer Science+Business Media New York 2015

Abstract Mood stabilizers such as lithium and anticonvul- of those can be transient or dose-related and can be managed
sants are still standard-of-care for the acute and long-term treat- by optimizing drug doses to the lowest effective dose. Some
ment of bipolar disorder (BD). This systematic review aimed to rare AEs can be serious and potentially lethal, and require
assess the prevalence of their adverse effects (AEs) and to abrupt discontinuation of medication. Integrated medical atten-
provide recommendations on their clinical management. We tion is warranted for complex somatic AEs. Functional reme-
performed a systematic research for studies reporting the prev- diation and psychoeducation may help to promote awareness
alence of AEs with lithium, valproate, lamotrigine, and carba- on BD and better medication management.
mazepine/oxcarbazepine. Management recommendations were
then developed. Mood stabilizers have different tolerability Keywords Bipolar disorder . Mood stabilizers . Adverse
profiles and are eventually associated to cognitive, dermatolog- effects . Management
ical, endocrine, gastrointestinal, immunological, metabolic,
nephrogenic, neurologic, sexual, and teratogenic AEs. Most
Introduction
This article is part of the Topical Collection on Bipolar Disorders
In the last 20 years, several drugs for the treatment of acute
* Eduard Vieta phases and for the prevention of relapses of bipolar disorder
EVIETA@CLINIC.UB.ES (BD) have been introduced [1]. Along with newer agents,
Andrea Murru Bclassical^ mood stabilizers are still considered among the
AMURRU@clinic.ub.es most effective drugs both in acute and in the long-term treat-
Dina Popovic ment of BD, either as monotherapy or combination therapy,
popovic.dina@gmail.com ranking as first- or second-line treatments in most internation-
Isabella Pacchiarotti al clinical guidelines [2, 3, 4••, 5, 6]. Specifically, lithium still
PACCHIAR@clinic.ub.es represents a cornerstone in the treatment of BD, and the long
Diego Hidalgo clinical experience associated with the use of this drug makes
DAHIDALG@CLINIC.UB.ES it a relatively safe tool to prevent recurrences of BD, especially
Jordi León-Caballero in patients with suicide risk [1, 7, 8]. Valproate is also con-
JLeon@parcdesalutmar.cat templated in all major clinical guidelines as first-line treatment
in acute manic or maintenance, despite concerns over long-
1
Bipolar Disorders Unit, Institute of Neuroscience, Hospital Clínic,
term efficacy and tolerability, with especial concern regarding
University of Barcelona, IDIBAPS, CIBERSAM, its use in women at childbearing age [9, 10]. Lamotrigine is an
Barcelona, Catalonia, Spain established treatment option in predominantly depressive bi-
2
Institut de Neuropsiquiatria i Addiccions, Parc de Salut Mar, polar patients, especially in combination therapy [11]. Carba-
CIBERSAM, Barcelona, Catalonia, Spain mazepine and oxcarbazepine have limited evidence of effec-
3
Bipolar Disorder Unit, Hospital Clínic, c/Villaroel 170, esc. 12 pl. 0, tiveness in the treatment of BD and are considered as second-
08036 Barcelona, Spain and third-line options [4••].
66 Page 2 of 10 Curr Psychiatry Rep (2015) 17: 66

BD is typically associated with more comorbid medical Table 1 Most frequent side effects of Bclassical^ mood stabilizers
conditions compared to the general population [12]. As a Li Anticonvulsants
chronic illness, BD normally requires long-term, potentially
lifetime pharmacotherapy and monitoring [13, 14]. CBZ/OXC DVP LAM
Treatment-related adverse effects (AEs) are important consid-
Cardiac
erations in the management of BD, as they may require mod-
Cognitive problems + + +
ification of treatment, additional medications and may compro-
Cognitive
mise patients’ general health, functioning, and quality of life,
Cognitive problems +/− + +
influencing their adherence to the prescribed treatment [15].
The objective of the present overview is to provide a com- Dermatological
prehensive insight on AEs that accompany the use of classical Acne + +
mood stabilizers and to provide an up-to-date review of their Hair Loss + ++ +
clinical management. Psoriasis + +
Endocrinological
Hyperthyroidism +
Methods Hypothyroidism ++ + +
Hyperprolactinaemia − −
A systematic search was performed using MEDLINE/PubMed/ PCOS +
Index Medicus, Cochrane Library, considering a time period Gastrointestinal
ending on 20 March 2015. A cross-check between references Diarrhea + +
obtained was done. The systematic search was performed by Nausea + +
two independent researchers (AM and DP), each blind to the Pancreatitis +
other’s results. When doubts over the relevance of a paper Vomiting + +
arose, a third researcher (IP) helped reach a final decision. Hematological
The authors searched for meta-analyses as well as random- Aplastic anemia + +
ized controlled trials, open studies as follows. Leucopenia ++ +
Thrombocytopenia-coagulopathy +
– MEDLINE/Pubmed/Index Medicus: authors used the Hepatological
keywords (((Mood stabiliz* OR lithium OR valproate ↑ NH4+ +
OR lamotrigine OR carbamazepine OR oxcarbazepine)) ↑ Transaminases + ++
AND side effects) AND (management). Hepatitis +
– Cochrane Library: keywords were mood stabiliz* OR Immunological
lithium OR valproate OR lamotrigine OR carbamazepine SLE-like syndrome +
OR oxcarbazepine AND side effects AND management. Serious rash +
Metabolic
Systematic reviews on the topic were considered for further Metabolic syndrome +
cross-check between references. The procedures adhered to Weight gain + ++
the PRISMA statement [16]. Nephrogenic
Clinical management recommendations were designed and Hyponatremia + +/+
aimed at the AEs described in the review. Renal failure
Neurological
Sedation + + +
Results Tremor ++ +
Encephalopathy +
Prevalence of Adverse Effects with Classical Mood Sexual
Stabilizers (Table 1) Decreased libido + +
Decreased function + +
Infertility + +
Teratogenic + ++ ++ +
Carbamazepine and Oxcarbazepine
Li lithium, CBZ carbamazepine, DVP valproate, LAM lamotrigine, PCOS
Tolerability problems with carbamazepine (CBZ) are not in- polycystic ovary syndrome, SLE-like systemic lupus erythematosus, +
frequent, and the therapeutic index is relatively low. Most effect present, ++ strong effect, − protective effect
Curr Psychiatry Rep (2015) 17: 66
frequent AEs include ataxia, nausea, dizziness, drowsiness,
vomiting, blurred vision, and diplopia. Less frequent are con-
stipation, dry mouth, erectile dysfunction, hair loss, head-
aches, light sensitivity, polyuria, and tinnitus [17].
Severe and potentially life-threatening adverse events with
CBZ include allergic reactions (Steven-Johnson syndrome
and toxic epidermal necrolysis). These AEs have been linked
to specific HLA-antigenic expression (HLA-B1502), frequent
in Asian populations [18].
Severe hematological disorders are associated with CBZ
treatment, including rare but severe aplastic anemia, agranu-
locytosis, and pancytopenia [19]. Mild anemia is possible in
less than 5 % of patients on CBZ, persistent leukopenia in 2 %
of patients [19, 20]
Fatal aplastic anemia is a rare but dangerous event, with a
prevalence of 1 out of 50,000 patients [21]. CBZ-induced
thrombocytopenia is also described although rare, and devel-
oped shortly after treatment initiation: it is often asymptomat-
ic, but it can present also with skin rashes, fever, and arthralgia
[22].
CBZ may cause bradycardia or Stokes-Adams attacks so
that should be avoided in people with preexisting atrioventric-
ular conduction problems [22, 23].
CBZ may induce hypogonadism due to reduction of estra-
diol, progesterone, and testosterone, resulting in amenorrhea
or oligomenorrhea in women and sexual dysfunction and low-
er fertility in both sexes, but these effects are fully reversible
after drug discontinuation [24]. Rarely, CBZ may induce a
systemic lupus erythematosus (SLE)-like syndrome. Its onset
may be months or even years after CBZ treatment initiation,
and its symptoms are usually mild [25]. Oxcarbazepine
(OXC) and CBZ may be related to alterations in thyroxin
and free thyroxin serum levels, but normal TSH levels. These
abnormalities are not clinically significant [26].
CBZ is not associated with significant weight gain [27], but
the duration of CBZ monotherapy is significantly associated
with acceleration of atherosclerosis in patients with epilepsy
[28].
Cognitive AEs related to treatment with CBZ or OXC are
generally considered to be mild, mostly affecting psychomo-
tor speed, attention, and memory [29, 30].
Enzyme-inducing drugs like CBZ and OXC may reduce
reproductive hormone levels in women with epilepsy, thus
presenting with sexual AEs [31].
CBZ is teratogenic, with absolute rates of 2.9 % of congen-
ital malformations among offspring exposed to it in utero [32].
The estimated risk of neural tube defects, mostly spina bifida,
is 0.5–1 % [33]. Studies on poor cognitive outcomes in off-
spring of mothers treated with CBZ show contradictory re-
sults, but most suggest that major poor cognitive outcomes
should not be attributed to exposure to CBZ [34].
OXC has been infrequently used in bipolar patients as al-
ternative to CBZ [35]. However, also OXC has an interaction
Page 3 of 10 66
potential with other medications. Hyponatremia, defined as
sodium <135 mmol/l, is more common and severe in patients
taking OXC rather than CBZ, and it is more common when
concomitant medications as diuretics or selective serotonin
reuptake inhibitors are used [36].
Lamotrigine
Lamotrigine (LMT) is usually well tolerated in the long-term
treatment of BD [37] and represents a good option in patients
with depressive predominant polarity [38]. In a study analyz-
ing the safety and tolerability of lamotrigine in the treatment of
BD gathered from 12 placebo-controlled trials, the most com-
mon AEs reported by the lamotrigine groups were headache
(24.4 %), nausea (12.8 %), and any rash (8.2 %), similar to
those for patients receiving placebo. The incidence rate of
sedation is higher in LMT groups and not associated to dose
used [39].
The incidence of rash is a common AE of treatment with
LMT, reaching 10 % in patients treated with current manufac-
turer dosing recommendations [40]. It may range from urti-
caria, and erythema multiforme, to serious reactions, such as
hypersensitivity syndrome, Stevens-Johnson syndrome, and
toxic epidermal necrolysis [40]. Overall, the incidence of a
serious rash appears low with the recommended slow titration
scheme [4••, 40]. An analysis of placebo-controlled studies
with LMT demonstrated that the incidence of serious rashes,
including Stevens-Johnson syndrome, in clinical trials of BD
is approximately 0.08 % (0.8/1000) in adult patients on LMT
monotherapy and 0.13 % (1.3/1000) on adjunctive LMT treat-
ment [39].
LTG appears to have a safer neurocognitive profile on bi-
polar patients, compared with other anticonvulsants [41].
LTG shows a neutral metabolic profile and a substantial
lack of weight gain [27]. Its effects on atherosclerosis in pa-
tients with epilepsy are neutral [28].
In epileptic patients, LMT has specifically been associated
with improvement in sexual functioning [42].
Absolute rates of major congenital malformations have
been described in 1.9 % of offspring exposed to LMT in utero,
being the teratogenic risk with LMT suggested at doses ex-
ceeding 200 mg/day [32, 43]. Lamotrigine is associated with a
10–24-fold risk of oral cleft versus the general population
[44]. So far, most of the investigations available suggest that
fetal exposures to LMT are safer with regard to cognition
when compared with other antiepileptic drugs [34].
Lithium
The tolerability profile of lithium (Li) consists of AEs espe-
cially at high doses [45, 46]. Common acute AEs that are
usually transient and manageable with dose reduction include
gastrointestinal disturbances (nausea, dysgeusia, vomiting,
66 Page 4 of 10
loss of appetite, and diarrhea), fatigue, lethargy, polydipsia,
polyuria, and a fine resting peripheral tremor [47, 48]. These
AEs are more likely to occur when Li is initiated or increased
rapidly in plasma [49].
Dermatological AEs, mainly acne, are commonly present-
ed in 3.4–45 % of Li-treated patients, especially male, and
normally presenting in the first weeks of Li initiation [50].
Li-associated psoriasis has an estimated prevalence ranging
from 1.8 to 6 % of treated cases [51].
Mild cognitive symptoms with higher plasma levels of Li
are frequent. Tremor affects up to 65 % of patients treated with
Li and a severe tremor may be a sign of toxicity. Nausea,
diarrhea, or blurred vision may also be signs of toxicity [52].
Some effects are especially hard to bear for patients such is the
case of weight gain and the risk of cognitive side effects and
emotional blunting [53]. However, in a meta-analysis, treat-
ment with Li was associated with rather minor cognitive im-
pairment [54]. Moreover, the real impact of therapeutic blood
levels of Li on cognitive impairment has not yet been clarified
[55].
Long-term Li treatment affects kidney function [56], and
after many years of treatment, renal impairment may occur
[57]. Although glomerular filtration rate is impaired by Li
treatment, impairment is not clinically significant in most pa-
tients [58]. Li-induced renal toxicity mainly manifests as
nephrogenic diabetes insipidus due to inhibition of the sensi-
bility of the adenilcyclase to antidiuretic hormone, with pro-
gressive reduction in urinary concentrating ability that can
progress to chronic interstitial nephropathy and permanently
impaired renal function [58]. End-stage renal disease is a very
rare complication of long-term lithium treatment, affecting
1 % of patients who have taken Li for over 15 years [56],
and, in general, 0.53 % of patients taking Li compared to 0·
2 % in the general population [59]. Older Li users have 6-year
prevalence rates of chronic kidney disease, acute kidney inju-
ry, and nephrogenic diabetes insipidus of 13.9, 1.3, and 3.0 %,
respectively [60].
Thyroid function is frequently affected by treatment with
Li. The prevalence of hypothyroidism is estimated to be about
20 % [61, 62]. Up to 50 % of patients on Li may develop a
goiter [63]. Female subjects seem more susceptible to devel-
oping a thyroid dysfunction, as 22 % of them presented with
hypothyroidism, with no differences between patients receiv-
ing Li for 10–20 and those taking it for more than 20 years
were found [64].
Li may also have a significant impact on parathyroid func-
tion (leading to hyperparathyroidism) and calcium levels [58].
In a recent case-control study, PTH and ionized calcium levels
were significantly higher in Li-exposed patients, and the pro-
portions of subjects with hyperparathyroidism (8.6 %) and
hypercalcaemia (24.1 %) were significantly greater in Li-
exposed patients [65]. Li may constitute a safe option in BD
patients with high risk of hyperprolactinemia, considering that
Curr Psychiatry Rep (2015) 17: 66
it lowers serum prolactin levels, especially during long-term
treatment [66, 67].
Treatment with Li may induce weight gain. Clinically sig-
nificant weight gain (>7 %) was found more frequent in pa-
tients receiving Li than in those receiving placebo in a meta-
analysis on 14 trials [58]. Li at therapeutic serum levels is also
associated with both atrial and ventricular electrical instability,
but these changes should be seen as indicators of susceptibility
to cardiovascular AEs rather than clinically relevant abnor-
malities [68].
Approximately one third of the patients receiving Li expe-
rience sexual dysfunction, and this is associated with poor
medication adherence [69]. Clinical reports suggest that Li
may reduce sexual thoughts and desire, worsen erectile func-
tion, and reduce sexual satisfaction [70].
The teratogenic risk is relatively low in absolute terms [71,
72]. Potential heart dysplasias can nowadays be detected early
by routine sonography and be corrected in utero.
Discontinuing Li during pregnancy might not be justified
balancing risks and benefits [73].
Valproate
Frequent mild side effects include gastrointestinal AEs, neu-
rological symptoms such as tremor and sedation, and asymp-
tomatic increase of liver transaminases which are dose-
dependent and may be therefore attenuated with dose reduc-
tion [10].
Hematological alterations such as thrombocytopenia and
leucopenia are the most frequent adverse effects, ranging in
prevalence between 5 and 60 % of patients in VPA treatment
[74]. Luckily, they are usually asymptomatic and fully revers-
ible after discontinuation of the drug. A dose-dependent
thrombocytopenia (platelet count <150,000/μl) is present in
about 20 % of VPA-treated patients, but it is symptomatic in a
minority of the cases (platelet count <50.000/μl) which can
present petechia, ecchymosis, excessive menstrual flow, hem-
orrhagic colitis, and hematemesis and generally with high
(80–150 μg/ml) VPA serum levels [75]. Less frequently and
especially at high doses (>100 μg/ml), VPA may induce co-
agulopathy, anemia, leucopenia, and hypofibrinogenemia, as-
sociated with a low incidence of bleeding symptoms [74].
Asymptomatic elevation of transaminases during treatment
with VPA is observed in about 40 % of cases. Hepatic
steatosis has been found to be present in 61 % patients treated
with VPA [76]. Hepatological complications leading to VPA
discontinuation are not frequent. Despite being not frequent or
dose-dependent, an idiosyncratic hepatic failure represents a
severe and potentially lethal AE. Potential risk factors are
represented by age under 3 years (an occurrence unlikely to
happen in the treatment of BD), an antiepileptic polytherapy,
and a developmental delay [77], and VPA can cause pancrea-
titis, usually mild but it can be fatal. It has been reported in
Curr Psychiatry Rep (2015) 17: 66
case reports and case series, mostly on patients affected with
epilepsy, but also with BD, and occurs in 40 % of cases within
the first 3 months of treatment, in 70 % of cases in the first
year [78, 79]. It is idiosyncratic and unpredictable, but identi-
fied risk factors are a young age and polypharmacy [80]. VPA-
induced hyperammonemia with subsequent encephalopathy
has been described in cohorts of patients affected by epilepsy.
Its onset is quick (less than a week) and reversible with abrupt
discontinuation of the drug. A combination of antiepileptic
medications represents a risk factor unlikely to happen in
samples of patients affected by BD. A genetic predisposition
has also been documented, so that its possible onset has to be
considered in VPA-based BD management [4••]. Symptoms
usually start within 3–4 days and reverse with abrupt discon-
tinuation of the drug [4••].
Weight gain is a frequent AE in long-term treatment, af-
fecting up to 50 % of people treated with VPA monotherapy
and can be significant (defined as >10 % gain from baseline
weight), thus influencing treatment acceptability [4••]. In a
retrospective study on almost 20,000 patients affected by ep-
ilepsy, VPA showed a proportion of people with a significant
weight gain (95 % CI) of 11.9 % (8.9 to 14.8 %) [27]. Body
weight increases occur as early as after 2–3 months of treat-
ment and may continue for months or years throughout treat-
ment [81]. A recent study on epileptic patients in long-term
treatment with VPA showed a relationship between long-term
VPA use and abdominal adiposity, which could have signifi-
cant health implications. Despite its limited sample size, the
long-term follow-up of more than 10 years adds valuable in-
formation due to the potentially lifelong use of this drug [82].
The duration of monotherapy VPA is significantly associated
with acceleration of atherosclerosis in patients with epilepsy
[28].
VPA use may increase androgen levels resulting in hirsut-
ism, acne, and alopecia in women in about 0.5–4 % of pa-
tients, but it is usually mild and transient [83]. Polycystic
ovary syndrome (PCOS) in VPA-treated female patients is
also an important issue. In a meta-analysis, the raw incidence
of PCOS in VPA-treated women with epilepsy is approxi-
mately 1.95-fold that in other antiepileptic-drugs-treated
women [84]. As for prolactin levels, the only available data
on VPA come from two controlled studies that used it as active
comparator in which no significant prolactin increase was
found [85, 86].
At high serum concentrations, VPA may induce a fine
tremor that is manageable with dose reductions. In the elderly,
it may induce Parkinsonism at low doses and after years of
treatment [87, 88]. VPA may induce mild cognitive adverse
effects related to treatment, mostly affecting psychomotor
speed, attention, and memory [29, 30].
Rates of congenital malformations among offspring ex-
posed to VPA monotherapy in utero range from 6 to 11 %
[89]. The risk of major malformations is higher for offspring
Page 5 of 10 66
exposed to VPA compared to CBZ or LMT [90]. Apart from
immediate fetal risk, exposure to valproate during pregnancy
may have long-term effects on the offspring. The
Neurodevelopmental Effects of Antiepileptic Drugs (NEAD)
study showing that children exposed to VPA products while
their mothers were pregnant had decreased IQs at age 6 com-
pared to children exposed to other antiepileptic drugs [91••].
Fetal valproate exposure showed dose-dependent associations
with reduced cognitive abilities across a range of domains.
The difference in average IQ between the children who had
been exposed to VPA and the children who had been exposed
to other antiepileptic drugs varied between 8 and 11 points,
depending on the drug to which VPA was compared.
Management of Adverse Effects
General Considerations on the Management of Adverse
Effects
Patients’ attitudes and fears toward medications may compro-
mise their adherence to treatment more frequently than the ac-
tual incidence of adverse effects [92]. An early psychoeducative
intervention on euthymic patients may modulate patients’ atti-
tudes and beliefs toward medication. Psychoeducation pro-
grams include information on AEs of commonly used medica-
tions and may improve patient’ adherence to treatment and
global illness outcome [93].
Even when a structured intervention is not available, clini-
cians should encourage patients to report AEs [94].
Many AEs (e.g., nausea, diarrhea, vomiting) can be man-
aged by optimizing drug doses to the lowest possible effective
dose.
Complex somatic AEs should be managed in
multispecialistic team.
Specific Management Considerations
Cognitive Side Effects
Cognitive impairment can be distressing for patients and may
hamper their compliance to treatment. Patients affected by
euthymic BD present with impaired functioning across a
range of cognitive domains, independently of pharmacologi-
cal treatment [95]. Nonetheless, the assessment of cognitive
impairment is often neglected in clinical practice. An assess-
ment of cognitive impairment should be routinely implement-
ed with the aid of quick tools such as the COBRA scale [96].
For patients with significant cognitive impairment, a func-
tional remediation program as adjunctive treatment is warrant-
ed [97••]. There may be relevant differences as regards to the
cognitive tolerability of antibipolar drugs [98].
66 Page 6 of 10
Dermatological
Acne For mild to moderate acne treatment, topical salicylic
acid, oral antibiotics, hormonal antiandrogens for female pa-
tients and oral isotretinoin, as well as other combination treat-
ments [99].
Alopecia Hair regrowth usually occurs without discontinuing
treatment, and discontinuation of the drug causing it (e.g.,
DVP, LMT, or CBZ) results in reversal of changes over time
[83].
Steven-Johnson Syndrome or Toxic Epidermal Necrolysis A
prescreening of the involved HLA alleles has already been put
to practical use as a biomarker to avoid the life-threatening
adverse drug reactions [100].
Psoriasis Topical steroids, keratolytics, vitamin D analogues,
oral retinoids, combined psoralen and ultraviolet A therapy,
and methotrexate. In case of a treatment-resistant psoriasis, Li
discontinuation may be considered and the patient may be
switched to another mood stabilizer [51].
Endocrinological
Hyperprolactinemia It is often asymptomatic. Clinical con-
sequences of hyperprolactinemia may occur early after initi-
ating treatment and adversely affect medication adherence,
but also after a long time, with the development of severe
associated medical conditions. Some of the drugs approved
for the treatment of BD have shown protective or no signifi-
cant effects on prolactin serum levels, such as Li and VPA
[101].
Parathyroid Given the underestimated prevalence of para-
thyroid alterations in Li-treated patients, calcium (and eventu-
ally PTH) should be added to routine lab tests [65].
Polycystic Ovary Syndrome It is important that clinicians
consider the association of PCOS in women treated with
VPA, as is associated with metabolic disorders (such as obesity,
glucose intolerance, hyperinsulinaemia, and dyslipidaemia)
and endometrial carcinoma in the long term [26]. PCOS should
be monitored in women with VPA monotheraphy/polytherapy
[84]. A careful multispecialist approach is required for evalu-
ating the risks and benefits of this treatment in the presence
PCOS and related conditions [102].
Thyroid Regular monitoring of serum TSH and FT4 in all
patients receiving Li is recommended at intervals of 3–
4 months for women over the age of 45, and every 6–
12 months for all others [62]. Patients already receiving treat-
ment for hypothyroidism prior to starting lithium therapy,
Curr Psychiatry Rep (2015) 17: 66
serum TSH and FT4 should checked after 4–8 weeks of Li
treatment initiation [103]. Substitution treatment is often indi-
cated [104].
Gastrointestinal
Hyperammonemia Symptoms generally reverse with abrupt
discontinuation of valproate [4••].
Liver Function Clinician should monitor the liver function
before prescribing high doses of an antiepileptic drug or be-
fore combining different antiepileptic drugs. Elder popula-
tions appear to be at increased risk of presenting with liver
AEs [10].
Nausea, diarrhea, and vomiting are common and generally
mild adverse symptoms related to Li treatment. Dose adjust-
ment of Li may improve them, but they can also be symptoms
of Li intoxication, so that dosing Li in serum has to be con-
sidered [53].
Pancreatitis Mild pancreatitis can be reversed with discon-
tinuation of VPA.
Hematological
Starting CBZ Treatment Before CBZ initiation, a complete
blood cell count should be performed and followed for the
first 12 weeks of treatments in patients with a low or near
the lower normal limits WBC count. CBZ should only be
discontinued if the WBC count falls below 3000/mm3, when
the neutrophil count is below 1000/mm3, or when infection
occurs with any degree of leucopenia [105]. Folic acid can
reduce the development of some blood cell abnormalities
linked to CBZ in children at doses of 1 mg/day irrespective
of the patient’s weight, but no optimal dose has been sug-
gested in adults [106].
Thrombocytopenia In patients on VPA treatment, close
monitoring of full blood count is required in women, particu-
larly at serum levels above 80 mg/mL. This may be particu-
larly important in older patients, for whom VPA dose reduc-
tion may be warranted [107].
Immunologic
Serious Rash Most commonly the immediate discontinua-
tion of the drug resolves the condition [108].
Systemic Erythematosus Lupus-Like Syndrome This con-
dition, induced by treatment with CBZ, is fully reversible after
CBZ discontinuation [25].
Curr Psychiatry Rep (2015) 17: 66
Metabolic
Cardiovascular Risk Great efforts to manage cardiovascular
risk factors are needed. Treating psychiatrists should collabo-
rate with primary care physicians to facilitate appropriate car-
diovascular risk management and treatment for their patients.
Nonetheless, the severity of illness (e.g., partial insight,
subdepressive symptoms) may complicate the management
of cardiovascular risks. Therefore, specialized models of care
that seamlessly integrate medical treatment with psychiatric
care have been invoked [109].
Metabolic Syndrome and Weight Gain A constant moni-
toring of weight, BMI, and blood pressure for patients taking
valproate is recommendable [82]. Anyway, given the early
age at which cardiovascular diseases manifest among people
with BD, a systematic screening for and treating cardiovascu-
lar risk factors in this population should be performed
irrespectively of the treatment used [110]. For BD patients
with comorbid obesity, first-line treatments should be ap-
proved medications with a neutral or negative profile on
weight change. Unluckily, many effective treatment options
are associated with weight gain. Behavioral weight manage-
ment strategies should be implemented with these patients
[111].
Neurologic
Hyperammonemic Encephalopathy In case of VPA-
induced hyperammonemic encephalopathy, there is consensus
on the need for withdrawal of the drug, and several approaches
have been successfully used, namely supplementation with car-
nitine, lactulose, or neomycin and protein restriction [112].
Ammonia levels greater than 400 μmol/L or significant clinical
symptoms secondary to hyperammonemia require rapidly re-
ducing blood ammonia levels with hemodialysis [113].
Tremor Beta-adrenergic blockers (e.g., propranolol) and vita-
min B6 are effective in reducing tremor [114]. As selective
serotonin reuptake inhibitors may worsen the tremor and pres-
ent with unclear benefits in most BD patients, their possible
switch to other options should be carefully assessed [4••, 115••].
Renal
Close monitoring of the glomerular filtration rate is essential
part of Li safety measures [116]. Older patients should be
closely monitored and other concomitant risk factors for kid-
ney impairment identified [60].
If polyuria-polydipsia syndrome happens, lithium serum
levels should be maintained lower than 0.8 mEq/L with rein-
tegration of liquids. If it is severe, diuretics as tiazides or
amiloride may be added (indomethacin in resistant cases)
Page 7 of 10 66
[117]. Real-time lithium levels can be obtained with a special
point-of-care device which may help to close-monitor those
patients that need extra caution [118].
Sexual
General Considerations Scientific literature on the sexual
side effects of antiepileptic drugs is biased by the fact that
most of the studies are conducted on samples of patients af-
fected by epilepsy, a condition that already per se may affect
sexual function [31]. Lamotrigine seems to have a neutral
impact as per sexual adverse events [31].
Erectile Dysfunction A recent 6-week, double-blind ran-
domized clinical trial in men affected by bipolar disorder
and with Li-related erectile dysfunction concluded that ad-
junctive treatment with aspirin 240 mg/day may improve this
sexual AE [119]. Symptomatic treatment with PDE5 inhibi-
tors (sildenafil, tadalafil, vardenafil) seems the only option
based on clinical experience.
Teratogenic
General Considerations Overall, children exposed to antiep-
ileptic polytherapy prenatally appear to have worse cognitive
and behavioral outcomes compared with children exposed to
monotherapy, and with the unexposed. There is an increased
risk of neurodevelopmental deficits when polytherapy in-
volves the use of valproate versus other agents [34]. In a recent
study, a suboptimal evidence of teratogenic risk counseling at
antiepileptic drug initiation was found, involving 40 % of
individuals prescribed carbamazepine and 22 % of valproate
[120]. Thus, given the high rates of unplanned pregnancies, a
detailed appraisal of the risks and benefits associated with
anticonvulsant medication is fundamental and strongly rec-
ommended. Combinations of antiepileptic mood stabilizers
and treatment with valproate should be avoided in women of
child-bearing age, and pregnancy should be always planned so
that appropriate solutions (i.e., dose reduction or switch to
another medication) can be found. During Li treatment, the
risk of congenital malformations seems uncertain, so that the
balance of risks should be carefully considered before Li is
withdrawn during pregnancy [58].
Conclusions
Patients should be encouraged to report AEs. Close monitor-
ing with lab tests and more frequent visits may be crucial to a
correct management of complex AEs. When necessary, an
integrated multispecialistic case management is warranted.
Early psychoeducational interventions are essential to im-
prove treatment outcomes, as well as a thoughtful attention
66 Page 8 of 10
to the patients’ opinions and a careful management of their
global health. Drug levels frequent monitoring may help to
find the fine balance between effectiveness and tolerability
for those side effects that may be dose-related, especially in
the case of lithium.
Compliance with Ethics Guidelines
Conflict of Interest Jordi León-Caballero declares no conflict of
interest.
Andrea Murru has received honorarium payments from Adamed,
AstraZeneca, Bristol-Myers-Squibbs, Janssen, Lundbeck, and Otsuka.
Dina Popovic has received payment for manuscript preparation from
Ferrer and payment for development of educational presentations from
Bristol-Myers Squibb, Merck, Sharp, and Dohme, Janssen-Cilag, and
Ferrer. Dr. Popovic’s work is supported by a Sara Borrell post-doctoral
grant CD13/0149, provided by Carlos III Institute, Spanish Ministry of
Science and Innovation.
Isabella Pacchiarotti has received honorarium payments from
Adamed, Janssen-Cilag, and Lundbeck.
Diego Hidalgo has received honorarium payments from Ferrer,
Lundbeck, and Jansen-Cilag.
Eduard Vieta has received consultance fees from Adamed, Almirall,
AstraZeneca, Bial, Bristol-Myers Squibb, Elan, Eli Lilly, Ferrer, Forest
Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen-Cilag,
Jazz, Lundbeck, MSD, Novartis, Organon, Otsuka, Pfizer Inc, Pierre-
Fabre, Roche, Sanofi-Aventis, Servier, Solvay, Takeda, Teva, UBC, and
Wyeth. Dr. Vieta has also received grants from the Spanish Ministry of
Health, the Spanish Ministry of Science and Education, the Spanish Min-
istry of Economy and Competiveness, the Stanley Medical Research
Institute and the 7th Framework Program of the European Union.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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