psychotropic agents commonly used in BD is either not ideal or unknown. VPA

and CBZ are categorized as US Food and Drug Administration (FDA) category D

during pregnancy; the general consensus is that these medications are genuine

teratogens and should be avoided.

117 Among 1,558 exposures, lamotrigine, FDA

category C, had 35 major congenital malformations among first trimester

monotherapy exposures (2.2%, 95% CI = 1.6%–3.1%).

118

Typical and most atypical antipsychotics are classified as pregnancy category C,

suggesting that adverse morphologic outcomes are less common with these treatments

than with mood stabilizers. Clozapine and lurasidone are pregnancy category B. In a

comparison of AAPs of placental passage, olanzapine was associated with the

highest exposure (72% ratio of umbilical cord-to-maternal plasma concentrations),

followed by haloperidol (65%), risperidone (49%), and quetiapine (24%).

119

Olanzapine was also associated with the highest rates of low birth weight and

neonatal intensive care unit admissions.

A.J. and her physician should discuss her individual risks related to lithium

treatment. In addition to the risks of teratogenicity, they must consider the harm that

could result from the possible recurrence of episodes of mania or depression and the

risks inherent in discontinuing lithium or switching to another antimanic agent. Also,

A.J. should be actively involved in the decision-making process.

If A.J. and her physician decide that she is to remain on lithium, her serum levels

must be monitored closely during pregnancy and her dosage adjusted accordingly.

Lithium clearance increases during the third trimester by 30% to 50%, resulting in a

reduction in lithium levels and a need for dosage adjustment.

114 Approximately 16 to

18 weeks after conception, screening tests, high-resolution ultrasound, and fetal

echocardiography can be used to determine whether cardiac defects have

developed.

114

If possible, A.J.’s physician should consider decreasing the lithium

dose before delivery to minimize lithium levels in the newborn and to offset the

reduction in lithium excretion that occurs after delivery.

114

If A.J. and her physician decide that she is to discontinue lithium, they must be

prepared to deal with the risks of lithium discontinuation. Several cases of presumed

rebound mania have occurred after abrupt cessation of lithium therapy. If lithium is to

be discontinued in A.J., it should be gradually reduced over at least 4 weeks.

CASE 87-4, QUESTION 2: A.J. did not use lithium throughout her pregnancy. After delivery, A.J. and her

physician decide to restart lithium. How soon can lithium be reinitiated in A.J.?

Lithium can be restarted as soon as A.J.’s urine output is established and she is

fully hydrated. However, this decision also may be affected by whether or not A.J.

chooses to breastfeed her child because lithium passes into breast milk and is present

in concentrations up to 72% of that found in the maternal blood.

114 Risks to the

newborn include hypothyroidism, cyanosis, hypotonia, lethargy, and cardiac

dysrhythmias. Hydration status must be closely monitored because lithium toxicity

may develop during infantile illnesses. Thus, A.J. and her physician must discuss the

advantages of breastfeeding versus the risks of exposing the newborn to lithium or

withholding lithium during the postpartum period. A.J. should be informed that

approximately 40% to 70% of women with BD experience affective episodes after

delivery.

114–119

If A.J. chooses to breastfeed while taking lithium, she should consider using infant

formula when the child becomes ill because febrile illness, vomiting, and diarrhea

can increase the risk of lithium toxicity. She also should be instructed to contact her

pediatrician if the infant experiences diarrhea, vomiting, hypotonia, poor sucking,

muscle twitches, restlessness, or other unexplained changes in behavior.

Atypical Antipsychotics

CASE 87-5

QUESTION 1: D.W., a 34-year-old female singer and musician, recently experienced her fourth hospital

admission for a manic episode. Her past medical history includes psoriasis and asthma. A trial of lithium led to

worsening of her psoriasis and an unacceptable tremor, which interfered with her guitar playing. Use of

propranolol was not considered because of her asthma. She was subsequently switched to VPA monotherapy;

however, tremor has again become problematic. Furthermore, she is concerned about her appearance because

she has begun to experience weight gain and hair loss from the VPA. What other drugs are available for the

treatment of acute mania?

AAPs can be selected as first-line choices for the treatment of acute mania.

Three recent systematic reviews and meta-analyses support the efficacy of AAPs

as a class.

120–122 Perlis et al.

120

reviewed data from 12 randomized, placebocontrolled, monotherapy studies and six adjunctive studies and found a collective

response rate of 53% for AAPs compared with 30% for placebo. There was no

difference in response between the individual AAPs. In adjunctive studies, the mean

odds ratio was 2.4 for a 50% improvement with the addition of an AAP to a mood

stabilizer (primarily lithium or VPA). Scherk et al.

121 conducted a meta-analysis of

24 randomized controlled trials and found superiority of AAPs for acute mania in

comparison with placebo and equal efficacy to lithium, VPA, and haloperidol. In this

analysis, the addition of an AAP to lithium, VPA, or CBZ was found to be more

effective in reducing manic symptoms and yield less treatment discontinuation than

lithium or the anticonvulsant alone. The results of a different meta-analysis

specifically designed to evaluate combination treatment of AAPs with lithium or an

anticonvulsant also found greater efficacy for the combined regimen.

122

In most

combination therapy studies, AAPs were limited to patients having no response or

only a partial response to lithium or an anticonvulsant. Thus, the utility of drug

combinations as initial therapy cannot be directly assessed.

In a more recent systematic review of 68 randomized controlled trials [eliminate

“to”] comparing the efficacy and acceptability of antimanic drugs either against

placebo or against one another in the treatment of acute mania was completed via a

multiple-treatment meta-analysis. Fourteen treatment options were analyzed

including: aripiprazole, asenapine, carbamazepine, valproic acid, gabapentin,

haloperidol, lamotrigine, lithium, olanzapine, paliperidone, quetiapine, risperidone,

topiramate, ziprasidone, and placebo. All of the antipsychotic drugs were found to be

significantly more effective than mood stabilizers in the treatment of acute mania,

with risperidone and olanzapine being ranked as superior for efficacy and

tolerability. Lamotrigine, topiramate, and gabapentin were not significantly better

than placebo in terms of efficacy and should not have a place in the treatment of acute

mania.

123

Additionally, a comparative analysis of 32 placebo-controlled trials demonstrated

that YMRS scores improved significantly more with second-generation

antipyschotics than mood stabilizers but the efficacy needs to be balanced against

anticipated common adverse effects.

124 A significant concern about the use of AAPs

is the risk of metabolic complications, including weight gain, glucose dysregulation,

and dyslipidemia (see also Chapter 85, Schizophrenia). Clozapine and olanzapine

have the highest risk for metabolic complications, quetiapine, iloperidone,

paliperidone, and risperidone are associated with an intermediate risk, and

ziprasidone, brexpiprazole, cariprazine, asenapine, lurasidone, and aripiprazole

appear to have the lowest risk.

48,125 Clozapine is also associated with significant

safety concerns, including agranulocytosis, seizures,

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sialorrhea, anticholinergic side effects, and orthostasis. Efficacy data with

clozapine are limited compared with the other AAPs, but clozapine appears to be

effective in treatment-resistant mania and in long-term mood stabilization.

126–128

Sedation is common with clozapine, olanzapine, asenapine, and quetiapine, and

this effect may be beneficial in the treatment of acute mania; however, sedation can

also lead to non-adherence with long-term use.

129 Aripiprazole and ziprasidone are

less sedating; thus, the adjunctive use of a benzodiazepine is often necessary in the

acute management of mania with these AAPs. Adjunctive benzodiazepines may also

benefit treatment of emergent akathisia, which occurs in 11% to 18% of patients

treated with aripiprazole.

130,131 Cariprazine has also been associated with treatment

emergent akathisia and extrapyramidal disorders (>10%).

132 Asenapine can cause

dysgeusia or oral hypoesthesia, although a black-cherry formulation can help with the

unpleasant taste.

133 Ziprasidone may cause activation; however, this effect is

attenuated at doses of 120 mg/day or more.

134 Risperidone may overall be the best

tolerated of the AAPs, but this drug carries a higher risk for serum prolactin

elevation and extrapyramidal symptoms.

135

D.W.’s concern about her weight gain makes aripiprazole, cariprazine, asenapine,

or ziprasidone rational choices for her manic episode. In addition to symptom

response, D.W. should be monitored for characteristic antipsychotic side effects,

such as movement disorders, and metabolic complications. If D.W. fails to respond

to the initially selected AAP, a switch to a different AAP may prove beneficial given

the variability in individual response.

47 Table 87-6 provides dosing information for

AAPs approved for the treatment of acute mania.

CASE 87-5, QUESTION 2: What alternative agents are available for acute mania if lithium, VPA, or an

AAP fail?

Anticonvulsants

CBZ represents an alternative treatment for the management of acute mania when

lithium, VPA, and AAPs fail.

11,46,47

In 2005, the FDA-approved extended-release

CBZ for the treatment of acute manic and mixed episodes based on the results of two

double-blind, randomized, placebo-controlled trials.

136 A meta-analysis of four

randomized, controlled trials (n = 464 patients) found that maintenance treatment

with carbamazepine has similar efficacy as, and fewer discontinuations due to

adverse effects than, lithium.

137 Despite demonstrated efficacy, CBZ remains a less

than popular choice in BD due to significant tolerability and drug–drug interaction

risks. If elected for treatment, CBZ should be started at 100 to 200 mg twice daily.

The dose should be increased by 200 mg every 3 to 4 days until adequate serum

levels have been reached.

11 Although no correlation between CBZ serum levels and

response in BD has been established, serum levels greater than 12 mcg/mL are

associated with sedation and ataxia. The recommended target serum level for seizure

prophylaxis is 4 to 12 mcg/mL.

11 Average daily doses for maintenance therapy range

from 200 to 1,600 mg/day (see Chapter 60, Seizure Disorders).

Oxcarbazepine, a structural analog of CBZ, offers some advantages over CBZ,

including improved tolerability and fewer drug interactions; however, there is a

paucity of well-designed clinical trials in BD.

138 Cochrane reviews suggest that there

are insufficient trials of adequate methodological quality to recommend use for either

acute or maintenance treatment for bipolar disorder.

139,140

Other anticonvulsants studied in mania include lamotrigine, gabapentin,

topiramate, tiagabine, zonisamide, and levetiracetam. Initial open-label studies of

lamotrigine in mania were promising, but two unpublished trials were negative.

141

Currently, experts doubt that lamotrigine has any significant effect in acute mania.

Open trials and case reports suggested adjunctive treatment with gabapentin was

effective in manic, hypomanic, and depressive states of BD.

142–144 A more recent

controlled trial found no benefit of gabapentin.

145

In this double-blind, placebocontrolled trial, gabapentin was administered as an adjunctive treatment in patients

with bipolar I disorder whose current episode was manic, hypomanic, or mixed. At

12 weeks, gabapentin failed to show any significant benefit compared with placebo.

In fact, the placebo group did significantly better than the gabapentin-treated patients.

In four double-blind, placebo-controlled trials, topiramate did not separate from

placebo and was less effective than lithium in the treatment of acute mania.

146,147

Tiagabine, levetiracetam, and zonisamide have been studied in BD but lack adequate

safety or efficacy data to receive any formal evaluation.

Table 87-6

Atypical Antipsychotic Dosing in Acute Mania

Atypical Antipsychotic Initial Dose Titration Effective Dose Range

Aripiprazole 15 mg/day Not required 15–30 mg/day

Asenapine 10 mg twice daily 5 mg twice daily 5–10 mg twice daily

Cariprazine 1.5 mg/day Increase to 3 mg on day 2,

then increase as needed in

1.5 or 3 mg increments

3–6 mg/day

Olanzapine 10–15 mg/day 5 mg/day 5–20 mg/day

Quetiapine 50 mg twice daily 50 mg twice daily 200–400 mg twice daily

Quetiapine XR 300 mg/day 300 mg/day 400–800 mg/day

Risperidone 2–3 mg/day 1 mg/day 1–6 mg/day

Ziprasidone 40 mg twice daily 20–40 mg twice daily 40–80 mg twice daily

Source: Abilify (aripiprazole) [package insert]. Tokyo, Japan: Otsuka Pharmaceutical; February 2012; Saphris

(asenapine) [package insert]. Whitehouse Station, NJ: Merck & Company; Vraylar (cariprazine) [package insert].

Parsippany, NJ: Allergan; April 2015; March 2015; Zyprexa (olanzapine) [package insert]. Indianapolis, IN: Eli

Lilly and Company; December 2014; Seroquel (quetiapine) [package insert]. Wilmington, DE: Astra Zeneca

Pharmaceuticals; October 2013; Seroquel Extended Release (quetiapine fumarate) [package insert]. Wilmington,

DE: Astra Zeneca Pharmaceuticals; October 2013; Risperdal (risperidone) [package insert]. Titusville, NJ:

Janssen, LP; April 2014; Geodon (ziprasidone) [package insert]. New York, NY: Pfizer; December 2014.

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COMBINATION TREATMENT

Despite the array of treatments available for the management of acute mania, large

numbers of patients fail to respond to monotherapy, and combination therapy is

becoming a first-line treatment option.

148 Potentially useful combinations include

lithium plus AAPs, VPA plus AAPs, and lithium plus VPA.

35,46 A combination to be

avoided is CBZ and clozapine owing to the increased risk of hematologic adverse

effects. Also combinations of CBZ with either olanzapine or with risperidone result

in more side effects and decreased efficacy; therefore, these combinations are not

recommended.

47

BENZODIAZEPINES AND ANTIPSYCHOTICS FOR ACUTE AGITATION

CASE 87-6

QUESTION 1: M.B. is a 39-year-old man hospitalized for an acute manic episode, but is refusing all

medications, reporting “I will be robbed of my superpowers.” He is found pacing around the inpatient unit

shouting orders for his release. When asked to return to his room by the clinical staff, he becomes agitated,

picks up a chair, and begins swinging it wildly at anyone who approaches him. In the past, M.B. experienced a

documented acute dystonic reaction to haloperidol. M.B. has a medical history of diabetes mellitus and

hypertension. What is an appropriate pharmacologic intervention for M.B.?

Benzodiazepines and antipsychotics are useful in treating agitation, irritability, and

hyperactivity associated with acute manic episodes. Oral formulations are preferred

and are favored by patients in psychiatric emergencies.

149 Oral dose delivery can be

facilitated with liquid concentrates and orally disintegrating tablets. Patients refusing

oral medications may require intramuscular (IM) injections.

150 Traditionally, the

combination of IM haloperidol and IM lorazepam has been used. Currently,

ziprasidone, aripiprazole, and olanzapine are available in rapid-acting IM dosage

forms. IM ziprasidone at doses of 10 and 20 mg is effective in psychotic

agitation.

151,152

IM aripiprazole at doses of 9.75 or 15 mg and IM olanzapine 10 mg

are effective for manic or mixed-state agitation.

153,154 Repeat doses of IM

ziprasidone, aripiprazole, and olanzapine can be administered 2 to 4 hours after the

first dose, if needed. The concurrent use of a benzodiazepine with an antipsychotic is

generally safe and potentially more effective than either agent alone. In the case of IM

olanzapine, concurrent benzodiazepines should not be used because the combination

may cause excessive sedation and cardiorespiratory depression.

155,156

Lorazepam is the preferred benzodiazepine for acute manic agitation. Advantages

of lorazepam include availability as both an IM and oral formulation (tablet and

concentrate), lack of active metabolites, and safety in hepatic and renal impairment.

The Expert Consensus Guideline recommends dosing lorazepam at 1 to 3 mg orally

or 0.5 to 3 mg IM, with repeat doses at least 60 minutes apart. The maximal dose

should not exceed 10 to 12 mg in the first 24 hours.

157 The primary concern regarding

the use of benzodiazepines for agitated mania is sedation. The risk of abuse and

addiction is minimal with short-term inpatient use.

M.B. is uncooperative and an immediate danger to others, thus warranting IM

therapy. Because of M.B.’s history of acute dystonia to haloperidol, an IM AAP

(such as olanzapine, ziprasidone, or aripiprazole) should be used. The combination

of ziprasidone 10 mg IM and lorazepam 2 mg IM is an appropriate intervention. IM

administration of aripiprazole and lorazepam may also be used. As M.B. becomes

calmer and more receptive to treatment, he can be transitioned to oral therapy.

TREATMENT OF ACUTE BIPOLAR DEPRESSION

CASE 87-7

QUESTION 1: H.C., a 31-year-old woman, was hospitalized for treatment of an acute manic episode 3

months ago. She was discharged on VPA 1,750 mg/day with a favorable response. Starting about 2 weeks ago,

her parents become concerned because H.C. started spending most of the day in bed. When out of bed, H.C.

sits on the couch without moving for hours. She only nibbles at the food her parents offer her. She has no other

signs or symptoms of physical illness and has not taken any additional medications, alcohol, or drugs of abuse to

her parents’ knowledge. They report that H.C. was diagnosed with diabetes mellitus type 2 last year. Her

serum glucose has been controlled by diet. On further questioning, H.C.’s parents report that she has been

intermittently tearful and expressed remorse for her behavior when she was manic. They also recall her as

saying “I am as low as I can go, and I just want to die.” Hence, they suspect she is suicidal. H.C.’s parents

report that she is taking VPA as prescribed and that the last time she experienced this level of depression, the

addition of lithium to VPA did not seem to help. Her VPA level on discharge was 84 mcg/mL. What change in

H.C.’s treatment should be instituted at this time?

Bipolar depression is both recurrent and chronic, accounting for three-quarters of

the time spent ill in BD.

158 Depression is often difficult to treat and puts patients at

significant risk for suicide, which occurs at a rate 15 times greater than that of the

general population.

159

In bipolar depression, complete remission of symptoms is the primary goal of

treatment. The ideal regimen should target acute depressive symptoms, decrease

suicide risk, and prevent future mood episodes (both manic and depressive). These

goals should be achieved without precipitating mania (switching) or mood cycling.

Because simply addressing the acute depressive symptoms is often shortsighted in an

illness with recurrent depressive episodes, the ability to prevent future depressive

episodes and the long-term tolerability are important considerations.

160

A logical first step in the management of bipolar depression is to verify adherence

and optimize the dose of the current mood stabilizer.

35 For H.C., she is already on a

therapeutic level of VPA; thus, no change in dose is needed.

Lithium

Lithium remains a first-line treatment for bipolar depression.

47,48 The CANMAT

guidelines recommend a level of 0.8 mEq/L or more for optimal response.

49 The

benefit of lithium was demonstrated in seven of eight placebo-controlled crossover

studies with a mean response rate of 76%.

161 Lithium may also be effective for

preventing depressive episodes. A 6-year follow-up study of patients maintained on

lithium found a reduction in the annual rate of depressive episodes by 46% and the

time spent ill by 53%.

162 A meta-analysis of 1- or 2-year-long studies found a 22%

relative risk reduction for a depressive relapse compared with placebo (risk ratio,

0.78; 95% CI = 0.60–1.01).

163 The difference from placebo was not statistically

significant.

156 Beyond antidepressant effects in BD, lithium also has the vital benefit

of reducing the risk of suicide, deliberate self-harm, and all-cause mortality.

164,165

Lamotrigine

Lamotrigine is recommended as a first-line treatment for bipolar depression by both

the World Federation of Societies of Biological

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Psychiatry (WFSBP) and CANMAT guidelines; however, more recent data from five

double-blind, placebo-controlled trials have brought this recommendation into

question.