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.
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.
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
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.
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
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
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
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 Presentation and Diagnosis
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
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
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.
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
7 Working long hours with reduced sleep may have served as a
predisposing factor for the development of a manic episode.
Selected Drugs Reported to Induce Mania
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
TCA, tricyclic antidepressant.
A variety of medications and clinical states can induce or precipitate manic
53–74 The drugs that most commonly precipitate mania affect
monoamine neurotransmitters, such as antidepressants and stimulants.
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
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
54 Despite this risk, up to 50% of patients with BD are
treated with antidepressants of which only half are receiving a concurrent mood
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%,
77 A meta-analysis found a higher “switch” to mania rate for TCAs
78 A controlled trial with bupropion,
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
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.
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
82 Any patient presenting with an acute manic episode should have a review
of medications completed to determine the risk of continuing antidepressant
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.
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.
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
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.
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
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
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
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.
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
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