The diagnosis of a cyclothymic disorder is for a person who has experienced at

least 2 years of both hypomanic and dysthymic periods without ever fulfilling the

criteria for an episode of mania, hypomania, or major depression.

The DSM-5 also uses a series of descriptors called specifiers to further

characterize the course of illness and the most recent type of episode experienced by

the individual. Recent episodes are first classified as hypomanic, manic, or

depressed. A mixed specifier is diagnosed when a patient meets criteria for either

manic or hypomanic episode with at least 3 depressive symptoms being present

during the current or most recent episode of mania or hypomania or when a patient

meets criteria for depressive episode with at least 3 manic or hypomanic symptoms

being present during the current or most recent episode of depression.

12 They may be

described further in terms of severity (mild, moderate, severe), the presence of

psychotic features (in partial or full remission), with or without catatonic features, or

with peripartum onset. Other specifiers convey information regarding the pattern of

illness. For example, some individuals experience major depressive episodes at a

characteristic time of the year (usually the winter) or switch from depression to

mania during a particular season, “with seasonal pattern”. The rapid cycling

specifier applies to those who experience at least four mood episodes in the previous

12 months that meet criteria for manic, hypomanic, or major depressive episode.

12

Overview of Treatment

During the previous 15 to 20 years, several treatment guidelines have been

published. Recent treatment guidelines have been published by the Department of

Veterans Affairs (2010), the British Association for Psychopharmacology (2016),

Canadian Network for Mood and Anxiety Treatments (CANMAT), World Federation

of Societies of Biological Psychiatry (WFSBP), and the Harvard South Shore

Program (2010/14).

35,46–50 The reader is advised that published efficacy research is

categorized by bipolar type (I vs. II), mood episode (manic vs. mixed vs. depressed),

and treatment phase (acute vs. maintenance). As such, treatment guidelines may

reflect these specifiers, depending upon their date of publication. Additionally, there

is often an uneven amount of published evidence supporting treatment

recommendations in these clinical categories.

The reader is advised that when considering the published efficacy research and

guidelines for bipolar disorder, it is necessary to first consider acute versus chronic

treatment, and then manic versus depressed episode.

The goals of treatment across the phases of illness are numerous, including the

control of acute symptoms, achieving symptomatic remission, returning to a normal

level of functioning, prevention of relapses, and prevention of suicide.

11 Both the

acute treatment of manic and depressive episodes and the maintenance treatment for

prevention of future episodes require individualization of therapy. Treatment

decisions should take into account presenting symptoms, medication history, patient

preference, and comorbid medical or substance use conditions.

Initial treatment for acute hypomanic or manic episodes should be with one of the

well-established antimanic agents such as lithium, valproate (VPA), or one of

several atypical antipsychotics (AAP). During episodes of mania, short-term

adjunctive use of benzodiazepines is often useful to reduce agitation and promote

sleep.

11

In the case of severe manic symptoms or in those only partially responsive to

an adequate trial of monotherapy (generally 1–2 weeks), a two-drug combination of

lithium, valproate, or an AAP is recommended.

46 Carbamazepine (CBZ) and a typical

antipsychotic, alone or in combination with a preferred antimanic drug, are potential

alternatives. For treatment-resistant cases, electroconvulsive therapy (ECT),

clozapine, and a three-drug combination of lithium plus an anticonvulsant (CBZ or

VPA) plus an AAP are recommended. When drug combinations are used, the

individual agents should be from different medication classes. Lamotrigine is not

recommended for the treatment of acute mania.

In the case of acute mixed states, VPA or an AAP is preferred over lithium

because of its poor efficacy. If monotherapy with VPA or an AAP is ineffective or

undesirable, then a combination of the two is advised.

Medications for the treatment of bipolar depression ideally produce an acute

antidepressant response and prevent future depressive episodes, all while not

inducing mania or mood cycling. Long-term tolerability is critical because of the

chronic recurrent nature of depressive episodes in BD. First-line treatment options

vary based on the chosen guideline, but it includes choices of lithium, lamotrigine,

lurasidone, olanzapine or quetiapine monotherapy or lithium or valproic acid or

olanzapine with a selective serotonin reuptake inhibitor (SSRI), lithium plus valproic

acid, or lithium or valproic acid plus bupropion.

47–52 Subsequent treatment trials

again vary on guideline, but include different combinations of the above choices.

Additional options include adjunctive modafinil or other antidepressants. Third-line

treatment includes carbamazepine, ECT, or lithium plus pramipexole or a monoamine

oxidase inhibitor (MAOI) or a tricyclic antidepressant (TCA). Readers are referred

to individual guidelines for complete details.

Maintenance treatment of BD should include continuing the acute-phase treatment

while periodically simplifying and moving toward monotherapy with lithium, VPA,

or lamotrigine if possible. Many AAPs are effective in maintenance treatment of BD;

however, they must be used cautiously because of the long-term risk of metabolic and

neurologic complications.

48 Olanzapine, quetiapine, aripiprazole, and long-acting

injectable risperidone are effective. Regardless of the regimen selected, medication

adherence is critical to long-term recovery. Patients and caregivers must be actively

engaged in discussing causes of non-adherence, including ambivalence, adverse

effects, lack of insight, and a strong desire to achieve the euphoria and energy of

manic episodes.

11 Patients should also be advised to maintain regular patterns of

daily activities, a consistent sleep–wake cycle, meals, exercise routines, and other

schedules to promote stability.

CLINICAL ASSESSMENT

Clinical Presentation and Diagnosis

CASE 87-1

QUESTION 1: T.R. is a 25-year-old man, accompanied to the clinic by his wife, A.R. She called the clinic

before bringing him in and reported much of the following information. T.R. states that he was doing well until

about 3 weeks ago, when he returned home from a crab fishing trip where he works for the winter months.

Given the stress of the job, he borrowed some “nerve pills” from his fellow co-worker. Since then, T.R. has

been acting increasingly “wild.” He has been staying up later at night and often bursts into the bedroom at 2 or

3 AM and loudly awakens A.R. Sometimes, he presents her with expensive gifts, which they cannot afford. He

often jumps on the bed and starts singing her love songs in a loud voice. A.R. notes that T.R. then almost

always demands sex, after which he sleeps for 2 to 3 hours and then loudly gets up and leaves the house.

During the last several weeks, he was noted to be driving his car recklessly and well beyond the speed limit.

The police have

p. 1837

p. 1838

pulled him over several times and given him multiple tickets for not only speeding, but for running red lights

and passing on the double yellow lines. Last week, when his boss called to express concern about his behavior,

T.R. said he was quitting his job. He wrote an rambling, disorganized resignation note, which was at least 10

pages long, called an overnight air delivery service to send the note to his employer (who is located only 3 miles

from his home), and then left the house before the driver arrived to pick it up. T.R. returned several hours later

with a brand new car and wearing an expensive new suit, red cowboy boots, and a bright green hat with a large

feather. He told A.R. that he had a new job, which was going to make him a millionaire. Last night, she found a

large sum of money in his pants pocket when emptying the clothes hamper. He did not come home at all, but he

called her at 4 AM to tell her to pack for Dallas, where he was going to become the new head coach of the

professional football team.

On arriving at the clinic, T.R. insists, “I don’t need no doc. I am

supercalifragilistic!” He then bursts into song. He is dressed flamboyantly but needs

a shave and shower. He gives the examiner (a stranger) a bear hug and has trouble

sitting still, listening, or allowing others to talk. His speech is pressured and loud; he

often fails to complete sentences or communicate entire ideas, and he is rhyming and

punning. His mood obviously is elevated, but he becomes increasingly irritable

throughout the examination. He is oriented to person and place, but thinks it is

tomorrow. Intelligence seems average. When asked to interpret a proverb, T.R.

becomes angry and throws a chair across the room. How is T.R.’s presentation

consistent with the diagnosis of a manic episode?

The hallmark of a manic episode is changes in mood, behavior, cognition, and

perception (Table 87-1).

24 T.R. demonstrates an elevated mood. He is exuberant and

notes how great he feels. Nevertheless, manic patients often demonstrate lability in

their mood, and they may become irritable and easily frustrated, especially when

challenged. In this case, T.R. becomes irritable and resentful when questioned by the

examiner. His quick displays of anger further demonstrate the volatility of his mood.

T.R. displays behavior and speech typical of acute mania. He has a reduced need

for sleep, behaves recklessly, and is overactive. His speech is pressured, loud, and

full of rhymes and puns, and he sings to express his emotions and skips from topic to

topic reflecting a flight of ideas. Behavior often is characterized as being excessive.

T.R. dresses flamboyantly, hugs his examiner, writes an unnecessarily lengthy letter

of resignation, seeks an overnight courier service for local delivery, and presents his

wife with lavish gifts.

Delusions are often present in acute mania and are grandiose or religious in nature

and deal with inflated abilities, self-importance, wealth, or special missions in life.

T.R. makes unrealistic comments about his money-making schemes, his singing

ability, and his position as the coach of a professional football team.

Patients with acute mania are often disorganized and do not complete tasks. They

tend to skip from idea to idea and scheme to scheme. In this case, T.R. neglects his

hygiene and neglects sending out his resignation letter.

Precipitating Factors

CASE 87-1, QUESTION 2: What factors make T.R. vulnerable to the occurrence of a manic episode at this

time?

T.R. is at the age at which his disorder would likely first manifest itself. In

addition, manic episodes are often precipitated by psychosocial and recurring life

stressors.

7 Working long hours with reduced sleep may have served as a

predisposing factor for the development of a manic episode.

Table 87-2

Selected Drugs Reported to Induce Mania

53–74

Anticonvulsants Gabapentin, lamotrigine, topiramate

Antidepressants Monoamine oxidase inhibitors, TCAs, SSRIs, SNRIs, bupropion, nefazodone,

trazodone, mirtazapine, vortioxetine

Antimicrobials Clarithromycin, ofloxacin, cotrimoxazole, erythromycin, isoniazid,

metronidazole, zidovudine, efavirenz

Antiparkinsonian drugs Levodopa, amantadine, bromocriptine

Anxiolytics/hypnotics Buspirone, alprazolam, triazolam

Atypical antipsychotics Aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone

CNS stimulants Caffeine, cocaine, methylphenidate, amphetamine

Drugs of abuse Marijuana, PCP, LSD

Endocrine Corticosteroids, thyroid supplements, androgens

Herbals Saint-John’s-wort, SAMe, ma-huang, omega-3 fatty acids, tryptophan

Sympathomimetics Ephedrine, phenylpropanolamine, pseudoephedrine, phenylephrine

Miscellaneous Cimetidine, tramadol, sibutramine

CNS, central nervous system; LSD, lysergic acid diethylamide; PCP, phencyclidine; SAMe, S-adenosyl-Lmethionine; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor;

TCA, tricyclic antidepressant.

A variety of medications and clinical states can induce or precipitate manic

episodes (Table 87-2).

53–74 The drugs that most commonly precipitate mania affect

monoamine neurotransmitters, such as antidepressants and stimulants.

53

Corticosteroids, anabolic steroids, isoniazid, levodopa, caffeine, and over-thecounter stimulants can induce or aggravate mania.

CASE 87-1, QUESTION 3: If the “nerve pills” borrowed by T.R. were antidepressants, could they have

contributed to the development of his manic episode?

Antidepressants are commonly prescribed for patients with bipolar depression

(35%–40%).

47 Their use is controversial though with criticisms that they lack

efficacy or that they destabilize mood and can cause a switch to mania. All of the

major classes of antidepressants including monoamine oxidase inhibitors, tricyclic

antidepressants (TCAs), SSRIs, and SNRIs have been associated with precipitating

mania in patients with BD.

54 Despite this risk, up to 50% of patients with BD are

treated with antidepressants of which only half are receiving a concurrent mood

stabilizer.

75 There are numerous case reports of mania or hypomania with

antidepressant treatment, but few controlled studies, making it difficult to make

comparisons across antidepressant classes.

76 See Case 87-7 for complete details of

the use of antidepressants in bipolar depression.

A comparison of the monoamine oxidase inhibitor, tranylcypromine, and the TCA,

imipramine, found a similar rate of treatment emergent mania (21% and 25%,

respectively).

77 A meta-analysis found a higher “switch” to mania rate for TCAs

(11%) than for SSRIs (4%).

78 A controlled trial with bupropion,

p. 1838

p. 1839

sertraline, and venlafaxine (all in combination with a mood stabilizer) found an

overall switch rate of 19% during acute treatment and 37% during the continuation

phase of the study with no difference among agents.

79 Antidepressants may also cause

cycle acceleration, which effectively decreases the time between mood episodes.

The risk for cycle acceleration may be heightened for patients who experience manic

or hypomanic symptoms on antidepressants despite receiving antimanic treatment

concurrently.

80 Other recent literature has suggested that adjunctive antidepressants to

mood stabilizers versus placebo are not associated with an increased efficacy or

with increased risks of treatment emergent affective switches.

81

In the case of T.R.,

an antidepressant may have precipitated the manic episode or shortened his cycle,

moving him into an episode of mania from a preexisting state of depression or

euthymia.

82 Any patient presenting with an acute manic episode should have a review

of medications completed to determine the risk of continuing antidepressant

medications.

35

Current guidelines state that the dual-action monoamine reuptake inhibitors carry a

greater risk of precipitating a switch to mania than single action drugs. Additionally,

they state that antidepressant medications medications appear unlikely to induce

mania when used in combination with a drug for mania.

47

TREATMENT OF ACUTE MANIA

CASE 87-1, QUESTION 4: Why does T.R. require treatment?

Manic episodes have a number of severe complications. Left untreated, severe

mania can result in confusion, fever, exhaustion, and even death. The impairment in

judgment, the excesses, and the risk-taking that occur during manic episodes may be

devastating. Detriments to relationships, careers, and finances and physical harm or

loss of life may occur. Manic individuals may engage in illegal activities or behave

in a manner that result in a violation of the law. T.R. drives recklessly; may have lost

his job; spends excessive amounts of money on gifts, clothing, and automobiles; and

plans to participate in a variety of money-making schemes. He has acquired a great

deal of cash suddenly, perhaps from withdrawing all of his family’s savings or from

some type of illegal enterprise. Manic patients may engage in risky sexual

encounters, leading to infection with sexually transmitted diseases including human

immunodeficiency virus. Alcohol and substance abuse are common and may

exacerbate or even precipitate mood episodes. Irritability, such as that demonstrated

by T.R., can lead to episodes of violence, resulting in potential harm to the patient or

to others. The goals of treatment are to reduce the severity and duration of the current

mood episode as well as to prevent recurrence of future episodes.

Valproate (Divalproex Sodium, Valproic Acid)

CASE 87-1, QUESTION 5: What is the appropriate treatment for T.R.’s acute manic episode?

Depending on the type and severity of mania, first-line treatment involves selecting

from lithium, VPA, AAPs, or a combination of these agents.

46–50

If psychosis is

present, an AAP would be an appropriate choice either as monotherapy or in

combination with a mood stabilizer. VPA is an ideal choice for T.R. considering the

rapid onset, tolerability, and the established efficacy of this agent for preventing

future mood episodes.

83–85

DOSING AND MONITORING

CASE 87-1, QUESTION 6: VPA was chosen for the management of T.R.’s mania. How should VPA be

initiated, and what baseline tests are necessary? How will T.R.’s response to therapy be monitored?

The initial dose of VPA for T.R. should be 250 mg 3 times per day.

11 The dosage

should then be increased by 250 to 500 mg every 2 to 3 days to obtain steady-state

serum VPA levels between 50 and 125 mcg/mL or a maximum dosage of 60

mg/kg/day.

86 An alternative strategy is to use an oral loading dose regimen of 20 to

30 mg/kg/day given on a 3 times a day schedule during an acute episode of mania.

This approach has been used during inpatient management and may result in a more

rapid onset of effect.

87 VPA levels of 50 mcg/mL are the minimum threshold with

higher concentrations offering greater benefit. In fact, those exceeding a serum

concentration of 84 mcg/mL by the third day of treatment may have greater early

symptom improvement.

88 A pooled analysis demonstrated a linear relationship

between serum concentration and efficacy with the greatest improvement found in

patients with VPA levels in excess of 94 mcg/mL.

89 VPA levels greater than 125

mcg/mL are more often associated with side effects and should be avoided.

83

Before VPA is initiated, baseline laboratory tests, including a complete blood

count (CBC) with differential and platelets, and liver function tests should be

measured. T.R.’s baseline weight and neurologic status should be recorded. In

premenopausal women who have not undergone surgical sterilization, a baseline

pregnancy test is warranted since VPA is a known teratogen. Attention should be

given to any medications that might be administered concurrently. Interactions with

aspirin, lorazepam, phenytoin, phenobarbital, lamotrigine, rifampin, warfarin,

felbamate, and CBZ are cited frequently (also see Chapter 60, Seizure Disorders).

VPA should decrease the severity and duration of T.R.’s current manic episode,

decrease the frequency of subsequent episodes, and increase his time spent in a

euthymic state. Once treatment has started, T.R. should be monitored for response of

his initial target symptoms, including grandiosity, decreased need for sleep,

pressured speech, distractibility, and impulsivity. Initial symptom improvement with

VPA can be expected in approximately 5 days.

89