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272 The APA Publishing Textbook of Mood Disorders, Second Edition
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Lithium
Pharmacokinetics
Lithium negligibly binds to plasma protein and is eliminated almost exclusively via
kidney. Of importance, age-related changes require careful consideration in the el
derly. Elimination may be substantially increased or decreased by certain medications,
such as certain diuretics and nonsteroidal anti-inflammatory drugs. Oral lithium is ab
sorbed completely within 8 hours, and peak plasma levels are reached between 1 and
3 hours after ingestion. Absorption is not affected by the presence of food. Limited
data suggest that brain/serum lithium concentration ratios vary widely and may pos
itively correlate with age, weakly to moderately correlate with serum levels in the
therapeutic range, and only significantly correlate with daily dosing for longer than 6
months. Higher brain/serum ratios were reported with single daily doses of lithium
at bedtime than with twice-daily dosing.
Lithium in Acute Mania
The efficacy of lithium in the treatment of acute mania is supported by numerous
DBPCTs. Lithium and valproic acid/divalproex are also commonly used for combina
tion or adjunctive therapy with other medications for acute mania or bipolar depression. With a few exceptions, overall evidence supports that lithium monotherapy is as
effective as other antimanic agents (Gao et al. 2015a), and combining lithium with an
anticonvulsant mood stabilizer or an atypical antipsychotic is more effective than
lithium alone. However, it has not been shown to be superior to placebo or divalproex
in reducing manic symptoms in children and adolescents. In contrast, lithium ap
peared to be significantly less effective in reducing manic symptoms compared with
risperidone (Duffy et al. 2018). A recent randomized, double-blind study of lithium
versus divalproex in elderly patients with manic symptoms supported its use in the
elderly with bipolar disorder. Both lithium and divalproex reduced manic symptoms
significantly, but lithium was more effective than divalproex in patients with a Young
Mania Rating Scale score greater than 30 points (Young et al. 2017).
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Lithium in Acute Bipolar Depression
Early studies of lithium in bipolar depression were confounded by study designs and
small sample sizes. In a bipolar depression study with quetiapine, lithium monotherapy was not significantly superior to placebo in reducing depressive symptoms regardless of lithium levels, but quetiapine monotherapy was (Gao et al. 2015a); however,
lithium plus adjunctive personalized treatment was as effective as quetiapine plus
adjunctive personalized treatment for bipolar depression (Nierenberg et al. 2016).
Lithium reduced depression and anxiety symptoms as well as quetiapine did in patients with bipolar depression and different comorbidities (Gao et al. 2018). Lithium
or divalproex plus lurasidone was indicated for bipolar depression. Although lithium
and lamotrigine alone were not effective in reducing depressive symptoms, the two
used in combination were significantly superior to lithium monotherapy. Lithium
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plus modafinil was also more efficacious in patients who had not responded to lithium monotherapy, but the results of adding armodafinil or antidepressant(s) to lithium or other mood stabilizers were inconsistent (Gao et al. 2015b). In some studies of
bipolar II depression, lithium appeared significantly less effective than antidepres
sants for acute and long-term treatments (McElroy and Israel 2019).
Lithium in Maintenance Treatment of Bipolar Disorder
The efficacy of lithium monotherapy or adjunctive therapy was evaluated with modern
study designs and DSM nomenclature during the development of divalproex, lamo
trigine, olanzapine, and quetiapine for maintenance treatment of bipolar disorder (Gao
et al. 2016). The overall impression was that lithium was as effective as other FDAapproved agents in preventing any mood relapse and more effective in preventing
manic than depressive relapse. Lithium, along with quetiapine and lamotrigine, was
the only medication superior to placebo in preventing depressive relapse, although
lithium’s magnitude was less than that of the other two medications (Gao et al. 2016).
However, in a population-based study, lithium was more effective than valproic acid,
olanzapine, and quetiapine (Hayes et al. 2016a), and in another study, lithium ap
peared to be superior to carbamazepine in preventing mood relapses (Peselow et al.
2016). Lithium and divalproex were similar in preventing mood relapses in patients
with rapid-cycling bipolar disorder, but lithium plus divalproex was not significantly
different from lithium alone in patients with comorbid substance use disorder (Gao
et al. 2015a). In children and adolescents, data on lithium’s long-term use were lim
ited (Hafeman et al. 2020).
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Lithium in Pregnancy and the Peripartum
Overall, there is a moderate level of agreement among international practice guidelines on the potential teratogenic effects of lithium, valproic acid, and carbamazepine
(Graham et al. 2018). Valproic acid is not recommended during pregnancy, but no au
thoritative data support the discontinuation of lithium, lamotrigine, or carbamazepine
during pregnancy (Scrandis 2017). Exposure to lithium or anticonvulsants, including
valproic acid, lamotrigine, topiramate, and carbamazepine, in the first 20 weeks of
pregnancy was not associated with an increased risk for ischemic placenta disease
(Cohen et al. 2019). However, an increased risk for cardiac or major congenital malformations from uterine exposure to lithium was confirmed (Munk-Olsen et al. 2018;
Patorno et al. 2017). Although children from ages 1 to 15 years who had lithium exposure in utero had normal development (Poels et al. 2018b), current data on the long-
term effects of prenatal psychotropic exposure on child development are both limited
and of poor quality (Haskey and Galbally 2017).
Lithium use during pregnancy may have some benefits for mothers, including
mood stabilization and relapse prevention (Poels et al. 2018a), but it increases the risk
for major congenital malformations in their children. If a patient has to take lithium
during pregnancy, a minimal effective dosage should be attempted. Levels should be
monitored closely, and high-resolution ultrasound should be performed at week 20
(Poels et al. 2018a; Wesseloo et al. 2017b). Immediately restarting lithium after delivery is recommended for women who discontinue it during pregnancy. Because new-
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borns with lithium exposure are likely to have complications, specialized hospitals
with comprehensive care for mothers and newborns should be considered for deliv
ery whenever possible.
Lithium in Major Depressive Disorder
DBPCTs of lithium as an adjunctive therapy to antidepressants have been small, of
short duration, and mainly focused on tricyclic antidepressants. A network metaanalysis of 48 trials at different stages of treatment-resistant depression found that
lithium, quetiapine, aripiprazole, and thyroid hormone adjunctive therapy to antidepressant(s) were significantly more effective than placebo (Zhou et al. 2015), but a remission rate of 15.9% with lithium augmentation in patients with stage 2 treatmentresistant depression in a Sequenced Treatment Alternatives to Relieve Depression
(STAR*D) study (Nierenberg et al. 2006) suggests that the benefit with lithium aug
mentation is relatively small.
Lithium in Suicide Prevention
It has been reported that lithium possesses some degree of antisuicidal efficacy in
adults and in children and adolescents, based on observational studies and random
ized trials (Hafeman et al. 2020; Tondo and Baldessarini 2018). This antisuicidal effect
appeared not to be solely related to lithium’s mood-stabilizing properties, because
nonresponders also had fewer suicide attempts while taking lithium (Sarai et al.
2018). A prospective 8-year study found that rates of suicidal behavior were significantly reduced during treatment with lithium but not with valproic acid (Song et al.
2017). Overall evidence suggests that the antisuicidal effects of lithium are long term.
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Safety and Tolerability
In efficacy and effectiveness DBPCTs, lithium was relatively well tolerated, comparable with placebo or active comparators (Bai et al. 2019). Irreversible chronic kidney
disease, nephrogenic diabetes insipidus, and hyperparathyroidism may be avoided if
detected earlier. Patients taking atypical antipsychotics and lithium had significantly
higher rates of urinary concentrating deficiency than those taking lithium alone. Both
lithium and anticonvulsant mood stabilizers were associated with an increased risk
of chronic kidney disease, but the use of lithium was not associated with an increased
risk for end-stage renal disease (Kessing et al. 2015). No benefit was found for discontinuing lithium in patients with chronic kidney disease (Kessing et al. 2017).
The magnitude of risk from lithium-related reduction in glomerular filtration rate
(GFR), chronic kidney disease, or end-stage renal disease has yet to be determined,
although overall evidence suggests that the risk is small (Azab et al. 2015). Factors associated with a decline in GFR, in order of decreasing importance, were longer lithium
treatment, lower lithium dosages, higher serum lithium levels, older age, and medical
comorbidity, especially cardiovascular comorbidity (Aiff et al. 2019; Tondo et al. 2017).
Lithium dosing more than once a day, lithium levels greater than or equal to 0.6 mEq/
L, and use of first-generation antipsychotics were independently associated with an
increased risk of renal dysfunction.
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Clinical Applications
Lithium is recommended as a first-line medication for mania, bipolar depression, and
maintenance treatment of bipolar disorder (Yatham et al. 2018). Patients with a mania-depression interval sequence, family history of bipolar disorder, shorter prelith
ium illness duration, later age at onset, and absence of rapid cycling or psychosis may
respond better to lithium (Hui et al. 2019). For mania, lithium carbonate 300 mg three
or four times daily, with a target blood level of 0.8–1.2 mEq/L, is reasonable; clinicians
should obtain a trough plasma level on days 4 or 5 in healthy adults and watch for
any signs of toxicity. For milder mania or hypomania, 300 mg twice a day and a lower
target blood level (0.6–0.8 mEq/L) may sufficiently stabilize mood. For bipolar de
pression, lithium can be started at 300 mg/day for 3 days, and then raised to a dosage
of 600 mg/day, with target lithium levels ranging from 0.6 mEq/L to 1.2 mEq/L, de
pending on the maintenance goal. For maintenance, a higher therapeutic level is more
effective in preventing manic relapse, although lower levels of 0.6–0.8 mEq/L may be
adequate for preventing depressive relapses. For the elderly, serum levels of 0.4–0.8
mEq/L for patients ages 60–79 years and 0.4–0.7 mmol/L for patients ages 80 years
and older were recommended (Shulman et al. 2019). Therapeutic levels at 0.4–0.6
mEq/L may be acceptable for good responders with poor lithium tolerance (Nolen et
al. 2019). However, subtherapeutic dosages of lithium (300–600 mg/day) had mini
mal benefits for improving acute depressive or manic symptoms (Nierenberg et al.
2013). No therapeutic levels have been established for MDD, although therapeutic
levels for bipolar disorder were often used in previous studies. Because lithium appeared to have better tolerability in manic patients than in depressed patients (Gao et
al. 2008), adjustment of the lithium dosage and titration speed may be necessary
based on the phase of illness.
Tremor, headache, constipation, nausea, vomiting, upset stomach, sedation, fatigue, and dizziness are common acute side effects of lithium. Weight gain, thirst, and
polyuria are also observed with long-term use. Gastrointestinal disturbances and
tremor can be mitigated by slower dosing strategies. These adverse effects typically
subside within 1–2 weeks. Worsening of any of these adverse effects or the emergence
of bradycardia, syncope, confusion, or ataxic gait should prompt a check of the pa
tient’s lithium level to rule out lithium toxicity. The possibility of drug interactions
must always be considered, particularly with thiazide diuretics, angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, and other psychotropics. In addition, lithium caused small but significant impairment in immediate verbal
learning and memory and creativity, as well as psychomotor performance, in patients
receiving long-term treatment (Wingo et al. 2009). An increased risk for cataract with
long-term lithium use was reported in a population-based study from Taiwan (Chu
et al. 2018). Lithium does not appear to affect bone density.
General medical history, physical examination, complete blood count, comprehensive metabolic panel, thyroid function tests, and pregnancy tests for women of childbearing age are recommended before starting lithium. Routine electrocardiographic
monitoring is not necessary, but for high-risk patients older than 60 years or patients
with ischemic heart disease, hypertension, hyperlipidemia, diabetes, cigarette smoking, or a family history of cardiovascular disease, a baseline electrocardiogram and
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subsequent testing every 6–12 months may be necessary (Mehta and Vannozzi 2017).
Creatinine, calcium, and thyroid-stimulating hormone (TSH) should be measured ev
ery 2–3 months for the first 6 months and then every 6–12 months thereafter (Gao et
al. 2015a; Shine et al. 2015). For patients with an emerging lack of energy or worsening
depression, TSH levels should be checked. For patients with GFR levels lower than
60, creatinine levels should be checked more frequently. Excessive fluid intake and
frequent urination need 24-hour urine volume and osmolality testing and urinalysis.
Anticonvulsant Mood Stabilizers
Pharmacokinetics
Bioavailability of divalproex is close to 100%, and that of the extended-release form is
close to 90%. Peak plasma concentrations are achieved within 3–5 hours, although the
extended-release form may take up to 17 hours. Half-life is about 12–16 hours, and
steady states are usually achieved within 3–4 days. Valproic acid/divalproex is metabolized almost entirely by the liver cytochrome P450 (CYP) 2D6 system. Coadministration with microsomal enzyme–inducing drugs, such as carbamazepine, will decrease
plasma levels of valproic acid. Toxicity can occur when divalproex is given along with
other highly protein-bound drugs. Valproic acid/divalproex inhibits lamotrigine metabolism by 50% when it is coadministered.
Oral lamotrigine is rapidly absorbed, with negligible first-pass metabolism. Peak
concentrations are reached in approximately 2–4 hours, and its half-life is approxi
mately 25 hours. Lamotrigine is approximately 55% protein bound. At steady-state
concentrations, lamotrigine levels are linear within a dosage range of 100–700 mg/
day; renal insufficiency and hepatic disease reduce its clearance. The rate of clearance
increases during each trimester of pregnancy, reaching a peak of baseline clearance by
gestational week 32. The dosage of lamotrigine should immediately be decreased by
20%–25% after delivery for women whose dosage was increased during pregnancy
(Kemp et al. 2017).
Carbamazepine is 80% bioavailable, nearly 80% protein bound, and primarily metabolized via the CYP3A4 system. Half-life is between 35 and 40 hours, but this falls to
12–17 hours with repeated dosing. Oxcarbazepine is a keto analogue of carbamaz
epine and is 67% protein bound. Oxcarbazepine is a pro-drug for 10-monohydroxy derivative (MHD), which is 38% protein bound and has less hepatic microsomal enzyme
induction and autoinduction. Overall, more than 96% of oxcarbazepine is excreted by
the kidneys. The half-life of MHD is 8–10 hours, and peak serum concentrations are
reached in 4–6 hours; half-life does not change appreciably with repeated dosing. The
relationship between oxcarbazepine dosage and plasma concentration appears linear
within 300–2,700 mg/day.
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Anticonvulsant Mood Stabilizers in Acute Mania
Divalproex sodium was the first anticonvulsant approved for treatment of bipolar
mania by the FDA (Gao et al. 2015a). Its antimanic effect was further verified during
the development of olanzapine. Like lithium, valproic acid/divalproex was com-
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monly used as an adjunctive therapy with atypical antipsychotics or other medications for mania. Valproic acid monotherapy was not found to be significantly superior
to placebo in children ages 10–17 years or in adolescents with manic or mixed symp
toms, but it was superior to placebo in children ages 3–7 years (Kowatch et al. 2015).
Valproic acid appeared to be less effective than antipsychotics in children and adoles
cents with mania.
Two large well-designed DBPCTs of carbamazepine monotherapy in acute mania
confirmed its efficacy in reducing manic symptoms from early small sample studies
(Gao et al. 2015a). A Cochrane review found the quality of studies of oxcarbazepine
in bipolar disorder to be poor. Oxcarbazepine was not significantly superior to pla
cebo in reducing manic symptoms in children and adolescents with bipolar disorder.
Anticonvulsant Mood Stabilizers in Acute Bipolar
Depression
A meta-analysis of divalproex in bipolar depression found that the efficacy for response was comparable with FDA-approved medications for bipolar depression
(Gao et al. 2015a). Lamotrigine monotherapy was not superior to placebo in acute bi
polar depression in most studies, but a meta-analysis of all DBPCTs found it to be superior to placebo for treatment response, and patients with higher baseline depression
severity had more benefits (Gao et al. 2015a). Lamotrigine was similar in response and
remission rates to olanzapine-fluoxetine combination, the first approved medication
for bipolar depression, in bipolar I patients with an index episode of depression (Gao
et al. 2015b). Lamotrigine adjunctive therapy with lithium and valproic acid in rapidcycling bipolar disorder, with or without a current substance use disorder, was not
significantly superior to placebo. There is limited evidence of lamotrigine use in pe
diatric and geriatric patients with bipolar disorder. Valproic acid and lamotrigine
may have potential benefit for comorbid substance use disorder in patients with bi
polar disorder (Coles et al. 2019).
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Anticonvulsant Mood Stabilizers in Maintenance
Treatment of Bipolar Disorder
Valproic acid/divalproex is commonly used as a maintenance therapy for bipolar disorder, although it was not approved by the FDA for this indication (Gao et al. 2015a,
2016). In contrast, lamotrigine was the second medication approved by the FDA for
maintenance treatment of bipolar disorder. Both lamotrigine and lithium were shown
to exhibit efficacy in protecting against an emerging mood episode compared with
placebo in two 18-month DBPCTs (Gao et al. 2016). However, lamotrigine plus divalproex did not have significant advantage over lamotrigine alone in the maintenance
treatment of patients with an index episode of bipolar depression (Bowden et al. 2012).
Similarly, lamotrigine or divalproex adjunctive to aripiprazole in patients with an
index manic or mixed episode was not significantly different from lamotrigine or divalproex alone (Gao et al. 2016). In contrast, quetiapine plus lamotrigine was more effective than quetiapine alone in reducing depressive symptoms in bipolar patients
with an index episode of depression (Geddes et al. 2016). For carbamazepine, mono-
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therapy produced variable results (Gao et al. 2015a), but there was stronger evidence
supporting its use in combination with other mood stabilizers for maintenance, par
ticularly with lithium.
Anticonvulsant Mood Stabilizers in Pregnancy
and Peripartum
Data from epilepsy studies have determined that early gestational exposure to valproic
acid is associated with the highest risk (≈10%) of major congenital malformations
among anticonvulsants, in a dose-dependent fashion (Andrade 2018). Valproic acid
exposure is also significantly associated with cognitive developmental delay, autism,
and psychomotor delay (Veroniki et al. 2017b), as well as low IQ (Bromley et al. 2014).
Carbamazepine is consistently associated with a higher risk of major congenital mal
formations relative to unexposed control groups and certain other anticonvulsants.
Oxcarbazepine monotherapy is associated with an increased risk for autism, and car
bamazepine polytherapy is associated with psychomotor delay (Bromley et al. 2014).
However, at conventional dosages, lamotrigine, levetiracetam, and oxcarbazepine,
and possibly zonisamide and gabapentin, are associated with absolute major congenital malformation risks similar to those in the general population (Andrade 2018; Veroniki et al. 2017a). Nevertheless, a significantly increased risk for autism associated
with exposure to lamotrigine monotherapy or lamotrigine plus valproic acid has been
reported (Veroniki et al. 2017b).
Although lamotrigine and lithium did not exhibit significant differences in mood
relapses or in the prevention of severe postpartum episodes (Wesseloo et al. 2017a),
the choice of a drug during pregnancy is complicated and should depend on safety
and efficacy. Data for lamotrigine appear to be more favorable than for other anticonvulsant mood stabilizers and lithium, but its long-term effect on development remains
uncertain. Even if lamotrigine is indicated during pregnancy, a minimal effective dos
age should be maintained, although no dose-dependent effect was observed with lamotrigine for major congenital malformations and IQ (Andrade 2018).
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Anticonvulsant Mood Stabilizers in Major Depressive
Disorder
Some evidence suggests that adjunctive valproic acid, as well as carbamazepine and
lamotrigine, had beneficial effects for MDD. An RCT in treatment-resistant depression
found that valproic acid augmentation to paroxetine was as effective as risperidone,
buspirone, trazodone, or thyroid hormone augmentation, with the highest remission
rate of 48.7% (Fang et al. 2011). For lamotrigine, three large DBPCTs in non-treatmentresistant depression did not find a significant difference from placebo. Similarly, lamotrigine adjunctive therapy to antidepressants in MDD also did not significantly
differ from placebo (Solmi et al. 2016). A network meta-analysis did not find a signif
icant difference between lamotrigine and placebo adjunctive therapy to antidepressants in MDD (Zhou et al. 2015). However, a more recent meta-analysis including all
studies of lamotrigine in mood disorders found that, as a whole, lamotrigine was significantly superior to placebo in reducing depressive symptoms, but the results in
subgroups were less robust (Solmi et al. 2016).
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Anticonvulsant Mood Stabilizers in Suicide Prevention
Although the warning for suicidality from anticonvulsants was issued by the FDA in
2008 after the agency conducted a meta-analysis of 199 RCTs involving 11 anticonvul
sants, a number of studies and reviews in patients with bipolar disorder found that
anticonvulsants did not have an increased risk for self-harm, suicide attempt, or com
pleted suicide compared with placebo or lithium (Chen et al. 2019; Hayes et al. 2016b;
Song et al. 2017). Anticonvulsant mood stabilizers can even reduce patients’ risk for
suicide attempt compared with that for patients who did not receive any psychotro
pic medication, although the antisuicidal effect from anticonvulsant mood stabilizers
might be weaker than that from lithium (Hafeman et al. 2020; Tondo and Baldessarini
2018).
Safety and Tolerability
Overall, valproic acid/divalproex, lamotrigine, carbamazepine, and oxcarbazepine
were well tolerated in acute and maintenance treatment of bipolar disorder (Bai et al.
2019). Diarrhea, somnolence, nausea, vomiting, dizziness, dyspepsia, abdominal pain,
headache, and increased appetite are common side effects of divalproex. Ataxia, vomiting, dry mouth, dyspepsia, constipation, dizziness, and somnolence are common
side effects of carbamazepine. Dizziness, dry mouth, headache, and somnolence are
reported with lamotrigine use. Adverse effects during initial therapy with divalproex,
lamotrigine, or carbamazepine are usually mild, transient, and easily managed, but
rare, serious, and life-threatening adverse effects can potentially occur, including
agranulocytosis, aplastic anemia, and hyponatremia with carbamazepine; pancreatitis
and hyperammonemia with valproic acid/divalproex; and hepatic failure with val
proic acid/divalproex and carbamazepine.
Rashes with carbamazepine and lamotrigine are a major concern that can affect
their use. In a recent systematic review of lamotrigine in 122 RCTs, 8.6% of patients
with bipolar disorder developed skin reactions, and only 0.02% developed StevensJohnson syndrome or toxic epidermal necrolysis (Bloom and Amber 2017). However,
risk of rash with lamotrigine was increased in children younger than 12 years with
coadministration of valproic acid, or by exceeding the recommended initial dosage or
rate of dosage escalation. Therefore, to minimize the risk of life-threatening rash, care
ful attention should be given to the starting dosage, the rate of titration, and the coadministration of other drugs, such as valproic acid, that can prolong the elimination
of lamotrigine. Hepatic failure from valproic acid in children younger than 12 years
was also reported.
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Clinical Applications
Divalproex and lamotrigine were recommended as a first-line medication for acute
mania and bipolar I depression, respectively. Both medications were also recommended as first-line medications for the maintenance treatment of bipolar disorder
(Yatham et al. 2018). Before initiating valproic acid/divalproex, a general medical history with special attention to the hepatic or hematological system, a comprehensive
metabolic panel, a complete blood count, and a pregnancy test in women of childbearing age should be obtained. For acute mania, divalproex oral loading with a dos-
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age of 20–30 mg/kg/day is suggested over standard gradual titration schedules
because of its faster antimanic effect. Divalproex 250 mg three times a day or 500 mg
twice a day is recommended for patients with less severe mania or for elderly pa
tients. Reduced dosage, slower titration, and use of a slow-release divalproex formulation may lessen some acute side effects.
No pretreatment laboratory monitoring is required before initiating lamotrigine, although a routine physical examination, basic baseline chemistries, and pregnancy tests
are advisable. Any rash that cannot readily be explained by a known cause (e.g., con
tact dermatitis) should lead to immediate discontinuation of lamotrigine, and patients
should notify their treating physician(s) prior to resuming therapy. In unclear or diffi
cult cases, dermatological consultation should be obtained before restarting or rechallenging with lamotrigine. Rechallenging can be initiated in those who have non-lifethreatening rashes after a careful risk and benefit assessment with a slower titration
schedule. Flu-like symptoms, unexplained widespread skin pain, red or purple skin
rashes, or blisters or mucous on the skin need emergency attention. To reduce the risk
for severe rashes, standard titration schedules showed be followed. The presence of an
enzyme-inducing drug, such as carbamazepine, requires doubling of the lamotrigine
dosage, whereas coadministration of lamotrigine with valproic acid/divalproex requires a 50% reduction in the lamotrigine dosage. Coadministration of lamotrigine
with estrogen-containing oral contraceptives may require an increase in the lamotri
gine dose.
As with valproic acid/divalproex, a general medical history and physical examination, comprehensive metabolic panel, complete blood count, and pregnancy test in
women of childbearing age should be performed before starting carbamazepine/ox
carbazepine. More frequent monitoring is indicated in elderly patients or any patient
taking carbamazepine/oxcarbazepine who develops fever, easy bruising or bleeding,
weakness, or infection. No clear target serum levels of carbamazepine for acute mania
have been established, although a range of 6–12 μg/mL is recommended. Immediaterelease carbamazepine therapy may be started at dosages of 200–600 mg/day, with
incremental increases of 200 mg/day every 2–5 days up to 1,000 mg/day, followed by
careful monitoring of blood levels, side effects, and clinical efficacy. The beaded ex
tended-release form may be started at 400 mg/day and increased as tolerated up to
1,600 mg/day. Many factors can affect carbamazepine blood levels, including autoinduction metabolism and significant drug-to-drug interactions.
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Conclusion
Lithium has a spectrum of efficacy and effectiveness in the acute and maintenance
treatment of bipolar disorder. Valproic acid/divalproex and carbamazepine have also
been shown to exhibit efficacy in acute mania, and lamotrigine in maintenance treat
ment of bipolar disorder. Overall, combinations of lithium with valproic acid/divalproex, carbamazepine, or atypical antipsychotics for mania and combinations of
lithium and lamotrigine for bipolar depression are more effective than monotherapies.
It is reasonable to use lithium or an anticonvulsant mood stabilizer(s) as adjunctive or
combination therapy with other medications in patients with bipolar disorder or
MDD who fail to respond to standard monotherapy treatments. Lithium and anticon-
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vulsant mood stabilizers have different short- and long-term side effects. Regular
monitoring may reduce the risk for lithium-related end-stage renal disease, valproic
acid–related hepatitis, and other potential life-threatening side effects. To minimize
the risk of serious life-threatening rash with lamotrigine, the recommended titration
schedule should strictly be adhered to. Because most patients with a mood disorder,
especially bipolar disorder, need long-term if not lifelong medication treatment, the
long-term safety and side-effect burden should be seriously considered from the be
ginning.
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