Bipolar Disorder in Adults: The Right Clinical Information, Right Where It's Needed

Bipolar disorder
in adults
The right clinical information, right where it's needed
Last updated: Sep 13, 2018

Table of Contents
Summary 3
Basics 4
Definition 4
Epidemiology 4
Etiology 4
Pathophysiology 5
Classification 5
Prevention 7
Screening 7
Secondary prevention 8
Diagnosis 9
Case history 9
Step-by-step diagnostic approach 10
Risk factors 12
History & examination factors 14
Diagnostic tests 15
Differential diagnosis 18
Diagnostic criteria 21
Treatment 24
Step-by-step treatment approach 24
Treatment details overview 30
Treatment options 33
Emerging 70
Follow up 71
Recommendations 71
Complications 72
Prognosis 75
Guidelines 76
Treatment guidelines 76
Online resources 78
Evidence scores 79
References 80
Disclaimer 94
Summary
◊ A recurrent and sometimes chronic mental illness marked by alternating periods of abnormal mood
elevation and depression associated with a change or impairment in functioning.
◊ The long-term course of illness is characterized by a predominance of depression, although a history

of at least one manic, hypomanic, or mixed episode is required to make the diagnosis of a bipolar
disorder.
◊ Diagnosis is based on interviews with the patient and family, using diagnostic criteria for bipolar
disorder.
◊ Misdiagnosis of bipolar disorder is common, with unipolar major depressive disorder the most
frequent diagnostic error made.
◊ The management of acute mania requires the use of mood stabilizers or atypical antipsychotics,
as monotherapy or in combination. There are fewer approved treatment options for acute bipolar
depression; traditional antidepressants are not indicated.
◊ Bipolar disorder requires individualizing a long-term management plan that includes maintenance
medication(s), adjunctive psychosocial therapies, and careful monitoring for any treatment-emergent
complications.
Bipolar disorder in adults Basics
Definition
Bipolar disorder, previously termed manic depression, is a psychiatric diagnosis characterized by abnormally
elevated or irritable mood episode(s) accompanied by disruptive symptoms of distractibility, indiscretions,
BASICS
grandiosity, flight of ideas, hyperactivity, decreased need for sleep, and talkativeness.[1] Manic episodes
include a clustering of these symptoms over at least a period of 1 week, and are more disruptive than
hypomania (milder symptoms, >4 days' duration). It is marked by alternating mood elevation (mania or
hypomania) and depression.
Epidemiology
Bipolar disorder is the sixth leading cause of disability in the developed world among those between the ages
of 19 and 45 years. The total lifetime cost of illness in the US is estimated at $202 billion.[4] [5] [6] This cost
estimate is for bipolar disorder type I alone.
The lifetime prevalence of bipolar disorder type I in the US is estimated to be between 0.5% and 1.0%,
affecting men and women equally.[7] [8] [9] The lifetime prevalence of bipolar disorder type II in the US
is estimated to be between 0.5% and 1.1%, with women more likely than men to be affected.[8] [9] [10]
Between 1% and 4% of all patients attending a primary care setting meet the diagnostic criteria for bipolar
disorder according to one systematic review.[11] One US patient survey found that 69% of individuals with
bipolar disorder had been misdiagnosed, most frequently with unipolar depression.[12] Thirty-five percent
of the patients were symptomatic for >10 years before being accurately diagnosed, with women significantly
more likely than men to be misdiagnosed.[12]
Since 1990, studies have cited an average age at onset of between 19 and 31 years; there is a generally
accepted decline in risk after age 50 years.[13] Patients with bipolar disorder are symptomatic nearly half of
their lives, with depressive symptomatology predominating in their subjective experience.[14] Up to 50% of
all people with bipolar disorder have been estimated to make at least 1 suicide attempt in their lifetime, with
10% to 15% of untreated patients with bipolar disorder completing suicide.[13] The highest rates of suicidality
occur during the acutely depressed phase of bipolar disorder.[15] [16]
The lifetime prevalence of any substance misuse disorder among patients with bipolar I disorder is 61%, and
among those with bipolar II disorder is 48%; these rates are higher than those observed among patients with
schizophrenia (47%), obsessive-compulsive disorder (33%), and major depressive disorder (27%).[17]
Etiology
The exact etiology of bipolar disorder is unknown, although the risk for disease is thought to be influenced
by several genes.[18] Family and twin studies substantiate the importance of genetic factors influencing a
person's risk for bipolar disorder, with environmental stressors or triggers being likely to contribute to the
phenotypic expression of the underlying mood disorder.[19]
One large-scale genome-wide association study (GWAS) of bipolar disorder examined over 550,000
single-nucleotide polymorphisms (SNPs) using pooled DNA, with selected SNPs confirmed by individual
genotyping. Although no single SNP of large effect was discovered, several genes met prior criteria for
replication and carried individual association signals of moderate effect; sizes suggested that several
genes reproducibly influenced bipolar disease risk. The strongest association signals were detected at
CACNA1C, and at other genes encoding synaptic components, as well as immune and energy metabolism
4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 13, 2018.
BMJ Best Practice topics are regularly updated and the most recent version
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subject to our disclaimer. © BMJ Publishing Group Ltd 2018. All rights reserved.
components.[20] However, the CACNA1C SNP finding also overlaps with other psychiatric conditions
including schizophrenia, suggesting commonalities in the biologic pathways in both conditions. One meta-
analysis of GWAS studies investigated the biologic pathways that contribute to risk for bipolar disorder.[21]
It found involvement of biologic pathways that include hormonal regulation, calcium channels, second
BASICS
messenger systems, and glutamate signaling. These findings suggest that multiple genetic and cellular
mechanisms underlie predisposition to bipolar disorder.
Pathophysiology
Information about the putative neural substrates of bipolar disorder has emerged with advances in imaging
technology beyond computed tomography scanning, including magnetic resonance imaging (MRI), magnetic
resonance spectroscopy (MRS), positron emission tomography, and functional imaging (fMRI and fMRS).
Studies utilizing these techniques continue to provide growing insight into the pathophysiology of bipolar
disorder. Structural findings using MRI include increased rates of deep white matter hyperintensities, an
increased corpus callosum cross-sectional area, and smaller hippocampus and basal ganglia compared
with patients with major depressive disorder, as well as an increased lateral ventricle volume and increased
rates of subcortical gray matter hyperintensities compared with healthy controls.[22] Although several brain
regions have been implicated as abnormal using MRI in bipolar disorder, the prefrontal cortex is of particular
interest, and several studies have uncovered structural pathology in the prefrontal cortex among patients with
bipolar disorder.[23] Abnormalities include reduced cortical gray matter thickness in the frontal, temporal, and
parietal regions of both brain hemispheres.[24] [25]
Functional MRI studies of emotional processing in bipolar disorder support the existence of alterations
in patients' ability to identify and to generate emotionally salient information and experience on a
neurophysiologic basis.[26] The irregular patterns of prefrontal cortical processing and connectivity with
subcortical responses, compared with healthy individuals, may further explain the common difficulties
with the regulation of emotional expression (such as inappropriate or labile affect) and behavior (such as
impulsivity or sexually inappropriate behaviors) observed clinically among patients with bipolar disorder.[26]
MRS allows for the identification of neurochemical information within specific brain regions, and studies have
demonstrated alterations in N-acetylaspartate, choline, myoinositol, glutamate, and other critical substrates
involved in regulation of mood.[27]
Classification
Diagnostic and Statistical Manual of Mental Disorders (DSM-5) for
bipolar disorder[2]
• Bipolar disorder, type I
• At least 1 manic or mixed episode

• Bipolar disorder, type II
• Never had a full manic episode; at least 1 hypomanic episode and at least 1 major depressive
episode
• Substance/medication-induced bipolar and related disorder
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 13, 2018.
5
• Prominent and persistent disturbance of mood characterized by elevated, expansive, or

irritable mood with or without depressed mood which develops during substance intoxication or
withdrawal, and the substance/medication is capable of producing disturbance of mood
• Other specified bipolar and related disorder
BASICS
• Clinically significant impairment in social, occupational, or other important areas of functioning

caused by symptoms characteristic of bipolar and related disorder but symptoms are not severe
enough to meet full criteria for any of the above disorders
• Cyclothymia
• Chronic, fluctuating course of mood disturbance characterized by numerous periods of

hypomanic symptoms and numerous periods of depressive symptoms; the symptomatic periods
are of insufficient severity, pervasiveness, or duration to meet full criteria for a manic episode or
for a major depressive episode.
Bipolar disorder in adults Prevention
Screening
Bipolar disorder is a fairly prevalent mental disorder in the general population and is commonly encountered
in the primary care setting. It is a recurrent and sometimes chronic disorder involving episodes of mood
depression, elevation, or irritability. The most common presentation is with depression; as a unipolar
major depressive episode may be indistinguishable from a bipolar depressive episode, history-taking and
screening are essential in order to rule in or rule out bipolar disorder prior to the initiation of treatment for
major depressive disorder. Undiagnosed, untreated bipolar disorder is associated with greater morbidity,
elevation of suicide risk, higher utilization of medical services and costs, and more hospitalizations per year
of illness.[60] [61] [62]
Multiple methods may be used to screen for the potential presence of bipolar disorder. No screening
methodology can compare to a comprehensive current and past history by a clinician, augmented by
collateral sources of information such as medical records and family interview.[51] Asking about current
and past symptoms of mania/hypomania in line with Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) criteria, while taking into account the impact of the symptoms on a patient's life and the longitudinal
pattern of mood episodes over the lifetime course, allows for improved diagnostic detection beyond the use
of a simple screening instrument.[52]
Screening tools
PREVENTION
Depression screening options include the Primary Care Evaluation of Mental Disorders (PRIME-MD)
and Patient Health Questionnaire (PHQ-9) for adults.[53] [54] The US Preventive Services Task Force
recommends that primary care practices screening adults should have systems in place that ensure positive
screening results are followed by accurate diagnosis, effective treatment, and careful follow-up.[63] In
addition, all patients with depression should be screened for bipolar disorder prior to the prescription of
antidepressant therapy.
PRIME-MD
• A useful tool for identifying mental disorders in primary care practice and research.
PHQ-9
• Can be used as a diagnostic and disease management tool and has been validated for use in primary
care settings to screen for depression.[54]
• 9-item questionnaire that reflects the DSM-IV-TR criteria. It classifies current symptoms on a scale of 0
(no symptoms) to 4 (daily symptoms).
• This questionnaire is still being used in clinical practice, despite the release of DSM-5.
PHQ-2
• A briefer version, with only the 2 following screening questions, has been validated:[55]
• "Over the past 2 weeks have you felt down, depressed, hopeless?"
• "Over the past 2 weeks have you felt little interest or pleasure in doing things?"
• A positive response to either question warrants a thorough review of the DSM-IV-TR criteria or use of
an equivalent tool.
Mood Disorder Questionnaire (MDQ) [Mood Disorder Questionnaire (MDQ)]
• A screening instrument for bipolar disorder that has been validated in a variety of populations. This
self-assessment instrument includes 13 questions that ask about symptoms of mania/hypomania
based on DSM-IV-TR criteria. A score of 7 or more positive responses to the 13 questions, as well as
endorsing the clustering of the symptoms into an episode that caused at least moderate distress or
negative consequences, is a positive MDQ screen and has been correlated with a diagnosis of bipolar
disorder.[56]
7
Bipolar disorder in adults Prevention
Bipolarity Index [Bipolarity Index]
• This recently described system of evaluating for bipolar disorder risk takes into consideration a
dimensional approach, rather than a pure categoric diagnosis, by scoring 5 dimensions of bipolarity:
episode characteristics (mania or hypomania); age at onset; illness course; response to medications;
family history. Each dimension is scored up to a maximum of 20 points, for a maximum total score of
100. Most patients with bipolar I disorder score >60 points in total.[57]
Composite International Diagnostic Interview (CIDI) [World Health Organization World Mental Health
Composite International Diagnostic Interview (WHO WMH-CIDI)]
• The CIDI was developed by the World Health Organization and includes a diagnostic section that can
be used by trained lay interviewers for the assessment of mental disorders, including bipolar disorder.
Several short-form versions exist for both interview use and patient self-assessment, including both
paper-and-pencil and computer-driven formats.
Bipolar Spectrum Diagnostic Scale (BSDS) [Bipolar Spectrum Diagnostic Scale (BSDS)]
• Uses a 1-page story depicting typical mood swing experiences, while asking the patient to place a
check mark at the end of each sentence that agrees with their own experience.[64]
PREVENTION
Comprehensive structured interviews such as the Mini-International Neuropsychiatric Interview and the
Structured Clinical Interview for DSM can be employed should "research-level" diagnostic accuracy be
desired.[65] [66]
Secondary prevention
It is advisable to include trusted family or friends who can alert the patient and the clinician, should warning
signs of relapse emerge. The patient should work with their doctor to identify individual patterns of relapse
and recurrence (e.g., noting that a lack of sleep predates prior manic episodes, so that any future changes
in sleep are taken seriously in an effort to prevent full syndromal relapse). Patients should be encouraged
to speak openly about their experience of bipolar illness, feelings of stigma, and any adverse effects of
medications that may threaten adherence and sustained mood stability.
Bipolar disorder in adults Diagnosis
Case history
Case history #1
A 20-year-old man presents to the emergency room accompanied by his parents, owing to a change
in mental status and behavior, marked by uncharacteristic argumentativeness, eruptions of laughter,
excessive talking, and unusual thoughts. He is being treated for depression and insomnia, and has
recently been drinking more alcohol. For the past 2 weeks, he has missed college classes, while staying
up most nights until 4 or 5 a.m., writing feverishly into several notebooks. When asked, he reports that
he is writing 2 novels at the same time and also documenting his accomplishments in an autobiography.
He denies any illicit substance use while admitting to increasing alcohol consumption "like all the great
novelists do." Efforts by his family to understand his recent change in thinking and behavior have been
met with loud and rambling discourses, and he angrily accuses them of wanting him to stay "subjugated
by the tyranny of depression."
Case history #2
A 32-year-old nurse presents to her primary care provider complaining of frequent headaches, irritable
bowel, insomnia, and depressed mood. She currently takes no medication and has no history of
substance misuse or major medical problems beyond treatment for a single depressive episode when
she was a college freshman. Her physical exam, routine labs, and computed tomography of the brain
are all within normal limits. Her family history is notable for several ancestors who have been affected by
psychiatric illness, including depression, bipolar disorder, and schizophrenia. Her paternal grandfather
and a maternal aunt committed suicide. She has had 3 prior episodes of several weeks' duration
characterized by insubordinate behavior at work, irritability, high energy, and decreased need for sleep.
She regrets impulsive sexual and financial decisions that she took during these episodes, and has
recently filed for personal bankruptcy. For the past month her mood has been persistently low, and she
has had reductions in sleep, appetite, energy, and concentration, with some passive thoughts of suicide.
DIAGNOSIS
Other presentations
In addition to the common presentations of bipolar disorder in classic manic or depressed phases of
the illness, individuals may present with other variants or with complex comorbidities that can make
diagnosis challenging. Mixed episodes are marked by the coexistence of simultaneous symptoms of
depression and mania and may represent a more difficult-to-treat state. Rapid-cycling bipolar disorder is
characterized by 4 or more mood episodes in a 12-month period; it is more resistant to pharmacologic
treatment and may be worsened by traditional antidepressants. In some patients, severe psychotic
symptoms and thought disorder may mimic schizophrenia. Most patients with bipolar disorder have at
least 1 comorbid condition that may complicate diagnosis and treatment. The most common comorbidities
include alcohol or substance misuse disorders, anxiety disorders, attention-deficit disorder, personality
disorder, and common medical conditions such as obesity, diabetes, hypertension, migraine, and irritable
bowel syndrome.[3]
9
Step-by-step diagnostic approach

Bipolar disorder is marked by alternating mood elevation (mania or hypomania) and depression. Hypomania
is defined as elevated states without significant functional impairment. Bipolar I disorder is characterized
by the occurrence of 1 or more manic episodes or mixed episodes, and bipolar II disorder is characterized
by the occurrence of 1 or more hypomanic episodes.[2] Individuals with bipolar I or II disorder commonly
experience major depressive episodes.
Risk factors include: family history of bipolar disorder or suicide, onset of mood disorder prior to age 20,
poor or limited response to traditional antidepressants, highly recurrent mood episodes, comorbid anxiety or
substance misuse disorders, and a pattern of psychosocial instability.
In addition to the common presentations in classic manic or depressed phases of the illness, individuals
may present with other variants or with complex comorbidities that can make diagnosis challenging. Mixed
episodes are marked by the coexistence of simultaneous depression and mania symptoms, and may
represent a more difficult-to-treat state. Rapid-cycling bipolar disorder is characterized by 4 or more mood
episodes in a 12-month period, is more resistant to pharmacologic treatment, and may be worsened by
traditional antidepressants. In some patients, severe psychotic symptoms and thought disorder may mimic
schizophrenia.
Most patients have at least 1 comorbid condition that may complicate diagnosis and treatment. The most
common comorbidities include alcohol or substance misuse disorders, anxiety disorders, attention-deficit
disorder, and common medical conditions such as obesity, diabetes, hypertension, migraine, and irritable
bowel syndrome.[47] Comorbid personality disorders, particularly borderline and narcissistic, are also
identifiable in about 20% to 50% of patients with bipolar disorder.[48] [49] [50]
History
A comprehensive current and past history, augmented by collateral sources of information such as
medical records and family interviews, should be taken.[51] Questions about current and past symptoms
of mania/hypomania in line with Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria,
DIAGNOSIS
while taking into account the impact of the symptoms on a patient's life and the longitudinal pattern of
mood episodes over the lifetime course, allow for improved diagnostic detection.[52]
Depression is the initial and most common symptom complex reported by the majority of patients. When
evaluating a patient with a major depressive episode, it is important to establish whether a prior history of
mania or hypomania exists, or if there is a family history of mania.
DSM-5 criteria should be applied to all patients suspected of having bipolar disorder or who have a
positive screening test for mania/hypomania. Clinicians should inquire about the following symptoms,
which can be present to a significant degree during a manic or hypomanic episode in bipolar disorder:[2]
• Inflated self-esteem or grandiosity

• Decreased need for sleep
• More talkative than usual, or feeling pressure to keep talking
• Flight of ideas, or subjective experience that thoughts are racing
• Distractibility
• Increase in goal-directed activity or psychomotor agitation
• Excessive involvement in pleasurable activities that have a high potential for adverse
consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish
business investments).
Also according to DSM-5, mood symptoms contribute to impairment in, for example, social or
occupational functions. A key distinction is made here between manic and hypomanic episodes:[2]
• With manic episodes, marked impairment or hospitalization results

• With hypomanic episodes, DSM criteria do not require marked impairment to occur but do require
that the disturbance in mood and the change in functioning are observable by others.
The mood symptoms should not be related to substance misuse or a general medical condition (e.g.,
hyperthyroidism).[2] Manic-like or hypomanic-like episodes that are clearly caused by antidepressant
treatment (e.g., medication, electroconvulsive therapy, light therapy) or other prescribed medication
causing secondary mania (e.g., levodopa, corticosteroid) should not count towards a diagnosis of bipolar I
or II disorder.
Depression questionnaires
Options include the Primary Care Evaluation of Mental Disorders (PRIME-MD) and Patient Health
Questionnaire (PHQ-9) for adults.[53] [54] All patients with depression should be screened for bipolar
disorder prior to the prescription of antidepressant therapy.
• PRIME-MD
• A useful tool for identifying mental disorders in primary care practice and research.
• PHQ-9:
• A 9-item questionnaire that reflects the DSM-IV-TR criteria

• This questionnaire is still being used in clinical practice, despite the release of DSM-5
• It classifies current symptoms on a scale of 0 (no symptoms) to 4 (daily symptoms).
• PHQ-2
DIAGNOSIS
• A briefer version, with only the 2 following screening questions, has been validated:[55]
• "Over the past 2 weeks have you felt down, depressed, hopeless?"
• "Over the past 2 weeks have you felt little interest or pleasure in doing things?"
• A positive response to either question warrants a thorough review of the DSM-5 criteria, or
use of an equivalent tool.
Mania/hypomania questionnaires
Mood Disorder Questionnaire (MDQ) [Mood Disorder Questionnaire (MDQ)]
• The MDQ is a screening instrument for bipolar disorder that has been validated in a variety of
populations. This self-assessment instrument includes 13 questions that ask about symptoms of
mania/hypomania based on DSM-IV-TR criteria. A score of at least 7 positive responses to the 13
questions, as well as endorsing the clustering of the symptoms into an episode that caused at least
moderate distress or negative consequences, is a positive MDQ screen and has been correlated
with a diagnosis of bipolar disorder.[56]
11
Bipolarity Index [Bipolarity Index]
• This recently described system of evaluating for bipolar disorder risk takes into consideration
a dimensional approach, rather than a pure categoric diagnosis, by scoring 5 dimensions of
bipolarity: episode characteristics (mania or hypomania); age at onset; illness course; response to
medications; family history. Each dimension is scored up to a maximum of 20 points for a maximum
total score of 100. Most patients with bipolar I disorder score >60 points in total.[57]
Composite International Diagnostic Interview (CIDI) [World Health Organization World Mental Health
Composite International Diagnostic Interview (WHO WMH-CIDI)]
• The CIDI was developed by the World Health Organization and includes a diagnostic section
that can be used by trained lay interviewers for the assessment of mental health disorders,
including bipolar disorder. Several short-form versions exist for both interview use and patient self-
assessment, including paper-and-pencil and computer-driven formats.
Young Mania Rating Scale (YMRS) [Young Mania Rating Scale]
• A validated symptom scale with point-score ranges generally associated with degrees of severity.
Contains 11 items scored on the basis of subjective reporting of symptoms in the previous 48 hours
and clinical observations during the course of an interview.
• Commonly used to measure changes in manic symptoms in response to treatment.[58]
Exam
There are no definitive findings of bipolar disorder on physical exam, although it may be useful in
ruling out common conditions that can cause or aggravate mood disorders (e.g., hypothyroidism or
hyperthyroidism) and in looking for commonly comorbid illnesses (e.g., obesity, metabolic syndrome).
Investigations
DIAGNOSIS
Simple laboratory tests should be performed to exclude other causes of mood symptoms. Initial tests
include thyroid function tests, complete blood count, vitamin D, and toxicology screen. Serum glucose
and lipid profile should be ordered as part of an overall health evaluation, particularly given the common
co-occurrence of metabolic derangements among patients with bipolar disorder as well as complications
from medications used to stabilize mood.
For new-onset mania or atypical presentations, brain neuroimaging with magnetic resonance imaging
is recommended only to rule out an organic etiology, such as brain tumor or multiple sclerosis, although
some evidence points to whole brain and regional brain volume changes among groups of patients with
bipolar disorder.[59]
Risk factors
Strong
family history of bipolar disorder
• A family history has positive predictive value for an individual patient and has been described as the
most important external diagnostic validator in psychiatry.[28] [29]
• For a patient experiencing a major depressive episode, the presence of a positive family history
increases the likelihood that the depression is of the bipolar type or that a bipolar course will follow.[28]
[30] [31]
onset of mood disorder prior to age 20 years

• Studies since 1990 have cited an average age at onset of between 19 years and 31 years; there is a
generally accepted decline in risk after age 50 years.[32]
• The Stanley Center Bipolar Disorder Registry has reported the median age at onset of 17.5 years and
a mean age of 19.8 years.[33]
• Childhood or adolescent major depression is associated with increased risk for bipolar disorder in
young adulthood.[34]
stressful life events

• A comprehensive review, focusing on the psychosocial context of bipolar disorder, found that studies of
life events overall report that people with bipolar disorder experience increased stressful events prior to
first onset and recurrences of mood episodes.[35]
previous history of depression

• One US patient survey found that 69% of people with bipolar disorder had been misdiagnosed, most
frequently with unipolar depression.[36] Bipolar disorder is relatively common in primary care; between
1% and 4% of all patients attending a primary care setting meet the diagnostic criteria for bipolar
disorder according to one systematic review.[37]
lifetime history of a substance misuse disorder

• Among all serious mental health disorders, patients with bipolar disorder are known to have the
highest rates of comorbid alcohol and other substance misuse disorders.[38] [39] [40] It is unknown
DIAGNOSIS
from these studies whether this is a cause-and-effect relationship, but it is a noted comorbidity.
presence of an anxiety disorder

• In the US National Comorbidity Survey, >90% of patients with bipolar disorder met lifetime criteria for
an anxiety disorder.[38]
• Nearly one third of patients met current criteria for an anxiety disorder at time of entry into a large
multicenter study, with social anxiety disorder and generalized anxiety disorder the 2 most common
conditions (each 13.3%).[41] Whether this is a cause or an effect is unknown, but it is a noted
comorbidity.
Weak
obesity
• Between 19% and 49% of patients with bipolar disorder, with a mean of 31%, have comorbid
obesity.[42] In addition to the adverse medical consequences related to obesity, obese patients with
bipolar disorder are more susceptible to relapse/recurrence (especially depression) and are more
prone to suicide.[43] [44]
13
• Patients treated with antipsychotic drugs are more likely than matched population controls to develop
a central body-fat distribution pattern.[45] Emerging evidence suggests that some of these side effects
can be corrected with lifestyle modifications.[46]
cardiovascular disease
• Although a clear cause-and-effect relationship between bipolar disorder and multiple cardiovascular
disease factors has not been firmly established, compelling evidence exists to suggest linkages with
hypertension, type 2 diabetes mellitus, and dyslipidemias.[42]
History & examination factors

Key diagnostic factors
major depressive episode(s) (common)
• Patients with bipolar I or II disorder commonly experience major depressive episodes. The DSM-5
criteria for a major depressive episode are identical for unipolar major depressive disorder and bipolar
affective disorder. Criteria include characteristic depressed mood or anhedonia, changes in weight
and libido, loss of energy, difficulty concentrating,and over- or under-sleeping; psychomotor problems,
excessive guilt, and suicidal ideation are often present.[1]
episode(s) of manic or mixed episodes (common)

• According to DSM-5, bipolar I disorder is characterized by the occurrence of 1 or more manic episodes
or mixed episodes (coexistence of simultaneous depression and mania symptoms). Patients often
have also had 1 or more major depressive episodes.
episode(s) of hypomania (common)

• Bipolar II disorder is characterized by the occurrence of 1 or more hypomanic episodes. Patients often
have also had 1 or more major depressive episodes.[1]
inflated self-esteem or grandiosity (common)

DIAGNOSIS
• Can be present to a significant degree during a manic or hypomanic episode.[1]
decreased need for sleep (common)

• Decreased need for sleep (e.g., feeling rested after only 3 hours of sleep) can be present to a
significant degree during a manic or hypomanic episode.[1]
more talkative than usual, or feels pressure to keep talking (common)

flight of ideas, or subjective experience that thoughts are racing (common)

distractibility (common)
• Attention easily drawn to unimportant or irrelevant external stimuli.
increase in goal-directed activity or psychomotor agitation (common)
• Increased goal-directed activity (either socially, at work or school, or sexually) or psychomotor
agitation.
excessive involvement in pleasurable activities that have a high potential for

adverse consequences (common)
• Activities with adverse consequences may include engaging in unrestrained buying sprees, sexual
indiscretions, or foolish business investments.
functional impairment (common)

• Mood symptoms contribute to impairment (e.g., in social or occupational functions).
• A key distinction is made here between manic and hypomanic episodes: with manic episodes, marked
impairment or hospitalization results, whereas with hypomanic episodes DSM-5 criteria do not require
marked impairment to occur but do require that the disturbance in mood and the change in functioning
are observable by others.
no substance misuse (common)

• According to DSM-5 criteria, the mood symptoms should not be related to substance misuse.[1]
• Symptoms observed in manic, mixed, or hypomanic episodes may occur as part of an intoxication or
withdrawal phenomenon from a drug of misuse.
no underlying medical cause (common)

• Mood symptoms should not be due to a general medical condition (e.g., hyperthyroidism).[1]
not due to somatic antidepressant treatment or other prescribed medication

(common)
• Manic-like or hypomanic-like episodes that are clearly caused by antidepressant treatment (e.g.,
medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of bipolar I or
II disorder.[1]
DIAGNOSIS
• Some prescribed medication (e.g., levodopa, corticosteroids) can also produce mood disturbances.
These are not counted toward a diagnosis of bipolar disorder.
Diagnostic tests
1st test to order
Test Result
Primary Care Evaluation of Mental Disorders (PRIME-MD) positive result can be
used to screen for mental
• A validated tool for identifying mental disorders, including bipolar
health disorders in
depression, in primary care practice and research.[53]
primary care
15
Test Result
Patient Health Questionnaire (PHQ-9) positive result can
be used to screen for
• The PHQ-9 can be used as a diagnostic and disease management
tool and has been validated for use in primary care settings to screen depression
for depression.[54] The PHQ-9 is a 9-item questionnaire that reflects
the DSM-IV-TR criteria. It classifies current symptoms on a scale
of 0 (no symptoms) to 4 (daily symptoms). Repeating the PHQ-9
during treatment allows the clinician to objectively monitor response
to therapy.
• This questionnaire is still being used in clinical practice, despite the
release of DSM-5.
Mood Disorder Questionnaire (MDQ) positive result can be
used to screen for a
• The MDQ can be used as a diagnostic aid and has been validated
history of mania or
as a screening instrument for bipolar disorder in a variety of settings,
hypomania
including primary care.[56]
• This self-assessment instrument includes 13 questions that ask about
symptoms of mania/hypomania based on DSM-IV-TR criteria. A
score of 7 or more positive responses to the 13 questions, as well as
endorsing the clustering of the symptoms into an episode that caused
at least moderate distress or negative consequences, is a positive
MDQ screen and has been correlated with a diagnosis of bipolar
disorder. [Mood Disorder Questionnaire (MDQ)]
• This questionnaire is still being used in clinical practice, despite the
release of DSM-5.
Composite International Diagnostic Interview (CIDI) positive result can be
used to screen for a
• The CIDI was developed by the World Health Organization and
history of mania or
includes a diagnostic section that can be used by trained lay
interviewers for the assessment of mental disorders, including bipolar hypomania
disorder. Several short-form versions exist for both interview use
and patient self-assessment, including both paper-and-pencil and
computer-driven formats. [World Health Organization World Mental
Health Composite International Diagnostic Interview (WHO WMH-
CIDI)]
DIAGNOSIS
Bipolarity Index >60 points for bipolar I

• This recently described system of evaluating for bipolar disorder risk
takes into consideration a dimensional approach, rather than a pure
categoric diagnosis, by scoring 5 dimensions of bipolarity: episode
characteristics (mania or hypomania); age at onset; illness course;
response to medications; family history. Each dimension is scored up
to a maximum of 20 points, for a maximum total score of 100. Most
patients with bipolar I disorder score >60 points in total. [Bipolarity
Index] [57]
Young Mania Rating Scale (YMRS) scores presence and
• A validated symptom scale with point-score ranges that are generally severity of mania
symptoms
associated with degrees of severity. Contains 11 items that are
scored on the basis of subjective reporting of symptoms in the
previous 48 hours and clinical observations during the course of an
interview. Commonly used to measure changes in manic symptoms
in response to treatment. [Young Mania Rating Scale] [58]
CBC normal
• Should be performed to exclude other possible causes of mood
symptoms.
Test Result
thyroid function tests usually normal
• Hyperthyroidism may mimic manic or hypomanic states;
hypothyroidism can produce mental depression.
serum vitamin D normal
symptoms.
toxicology screen negative
symptoms.
• Symptoms observed in manic, mixed, or hypomanic episodes may
occur as part of an intoxication or withdrawal phenomenon from a
drug of misuse.
Other tests to consider
Test Result
fasting lipid profile abnormal if metabolic
syndrome present
• Often abnormal, as lipid derangements are commonly found in
patients with bipolar disorder.
• Test should be ordered as part of overall health evaluation,
particularly given common co-occurrence of metabolic derangements
among patients with bipolar disorder as well as complications from
medications used to stabilize mood.
fasting glucose may be elevated if
• Often abnormal, as type 2 diabetes commonly occurs among patients metabolic syndrome
present
with bipolar disorder.
• Test should be ordered as part of overall health evaluation,
particularly given common co-occurrence of metabolic derangements
among patients with bipolar disorder as well as complications from
DIAGNOSIS
medications used to stabilize mood.
MRI brain typically normal
• Some evidence points to whole brain and regional brain volume
changes among groups of patients with bipolar disorder.
• Test should not routinely be ordered except in the case of new onset
of mania or atypical presentations, to rule out an organic etiology,
such as brain tumor or multiple sclerosis.
17
Differential diagnosis
Condition Differentiating signs / Differentiating tests

symptoms
Mood disorder due to • May be clinically • Specific testing based
general medical condition indistinguishable; however, on suspected underlying
people often have atypical condition. May include CT
mood symptoms. head, MRI brain, and thyroid
• Symptoms and signs specific function testing.
for the underlying medical
condition (e.g., stroke,
thyroid disease, and multiple
sclerosis) may be present.
Substance-induced mood • May be clinically • Laboratory findings,

disorder indistinguishable. including blood alcohol level
• The mood disorder is and toxicology screens.
judged to be temporally
associated with exposure
to the causative substance.
Withdrawal states from some
substances can last for up to
4 weeks.
Major depressive disorder • Criteria include depressed • Clinical diagnosis using

mood most of the day, as DSM-5 criteria for major
self-reported or observed by depressive disorder.
others; diminished interest or
pleasure in all or almost all
activities; significant weight
loss when not dieting, weight
gain, or decrease or increase
in appetite; insomnia or
hypersomnia; psychomotor
DIAGNOSIS
agitation or retardation;
fatigue or loss of energy;
feelings of worthlessness or
excessive or inappropriate
guilt; diminished ability
to think or concentrate;
recurrent thoughts of death,
recurrent suicidal ideation
without a specific plan.[1]
• However, patients have
never had a manic,
hypomanic, or mixed
episode.

symptoms
Dysthymic disorder • A form of depression • Clinical diagnosis using
characterized by a chronic DSM-5 criteria for dysthymic
course (persistent for 2 years disorder.
or longer).
• Symptoms of dysthymic
disorder include 2 of the
following: poor appetite/
overeating, insomnia/
hypersomnia, low energy/
fatigue, low self-esteem,
poor concentration, feelings
of hopelessness.
• However, patients have
never had a manic,
hypomanic, or mixed
episode.
Cyclothymic disorder • Cyclothymic disorder is • Clinical diagnosis using

characterized by a minimum DSM-5 criteria.
duration of 2 years marked
by numerous periods of
hypomanic symptoms
that do not meet criteria
for a manic episode, and
numerous periods with
depressive symptoms that
do not meet criteria for a
major depressive episode.
During the 2-year period,
the person has not been
without mood symptoms for
>2 months at a time.
DIAGNOSIS
Psychotic disorders • Psychotic disorders • Clinical diagnosis using
such as schizophrenia, DSM-5 criteria.
schizoaffective disorder, and
delusional disorder are all
characterized by periods of
psychotic symptoms that
occur in the absence of
prominent mood symptoms.
19

symptoms
Personality disorders • A personality disorder is an • Clinical diagnosis using
enduring pattern of inner DSM-5 criteria.
experience and behavior
that deviates from cultural
expectations and is marked
by persistent disturbances
in cognition, affectivity,
interpersonal functioning,
and impulse control.
• The pattern is maladaptive,
inflexible, pervasive, stable,
and of long duration, in
contrast with the episodic
nature of bipolar disorder.
Obsessive-compulsive • Anxiety disorder • Clinical diagnosis using

disorder characterized by persistent DSM-5 criteria.
or repetitive thoughts
(obsessions) and/or
behaviors (compulsions)
experienced as unwanted,
excessive, and unpleasant
by the patient.
• The obsessions or
compulsions are recognized
by the person as excessive
or unreasonable at some
point during the course of
illness, and cause marked
distress, consume additional
time, or significantly interfere
with functioning.
DIAGNOSIS
ADHD • Symptoms of inattention, • Clinical diagnosis using

hyperactivity-impulsivity DSM-5 criteria.
must be present in 2 or
more settings (e.g., at
work and at home) with
clear evidence of clinically
significant impairment
in social, academic, or
occupational functioning.
• These ADHD symptoms
must not occur exclusively
during the course of a manic,
hypomanic, or depressive
episode, or any other mental
disorder.
• Problems with attention,
hyperactivity, and/or
impulsiveness noted to have
emerged before age 7 years
may persist into adulthood
and confound the diagnosis
of bipolar disorder.
Diagnostic criteria
Diagnostic and Statistical Manual of Mental Disorders (DSM-5)[2]
Bipolar I disorder:
• Characterized by the occurrence of 1 or more manic or mixed episodes (the manic episode may have
been preceded by and may be followed by hypomanic or major depressive episodes, but these are not
required for diagnosis)
• Distinct period of abnormally and persistently elevated, expansive, or irritable mood, and increased
goal-directed activity or energy lasting ≥1 week (any duration if hospitalized), present most of the day,
nearly every day
• During the mood disturbance and increased energy or activity, ≥3 (or 4 if irritable mood only) of the
following:

• Pressured speech
• Racing thoughts or flight of ideas
• Distractibility
• Increased activity
• Excess pleasurable or risky activity.
• Marked impairment not due to a substance or medical condition
• In addition, these symptoms:
• Do not meet criteria for a mixed episode

• Cause functional impairment, necessitate hospitalization, or there are psychotic features
• Are not related to substance misuse
• Are not due to a general medical condition
DIAGNOSIS
• Are not caused by somatic antidepressant therapy.
• Criteria for mixed episode:
• Criteria are met both for a manic episode and for a major depressive episode during at least a 1-
week period
• Causes functional impairment, necessitates hospitalization, or there are psychotic features
• Symptoms are not due to substance misuse, a general medical condition, or somatic
antidepressant therapy.
Bipolar II disorder:
• Never had a full manic episode; at least 1 hypomanic episode and at least 1 major depressive episode
• Distinct period of abnormally and persistently elevated, expansive, or irritable mood, and increased
goal-directed activity or energy lasting ≥4 but <7 days, and clearly different from usual nondepressed
mood, present most of the day, nearly every day
• During the hypomanic episode, ≥3 (or 4 if irritable mood only) of the following:
21

• Pressured speech
• Racing thoughts or flight of ideas
• Distractibility
• Increased activity
• Excess pleasurable or risky activity.
• Episode is unequivocal change in functioning, uncharacteristic of person, and observable by others
• Not severe enough to cause marked impairment, not due to substance or medical condition, and no
psychosis (if present, then this is mania by definition)
• During the major depressive episode, ≥5 of the following symptoms are present during the same 2-
week period, and represent a change from previous functioning. At least one of the symptoms is either
depressed mood or loss of interest or pleasure:
• Depressed mood most of the day, nearly every day

• Markedly diminished interest or pleasure, nearly every day
• Significant weight loss when not dieting or weight gain, or decrease or increase in appetite,
nearly every day
• Insomnia or hypersomnia, nearly every day
• Psychomotor agitation or retardation, nearly every day
• Fatigue or loss of energy, nearly every day
• Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional), nearly
every day
• Diminished ability to think or concentrate, or indecisiveness, nearly every day
• Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation with or without a
specific plan.
• In addition, these depressive symptoms:
• Cause functional impairment (e.g., social, occupational)

DIAGNOSIS
• Are not better explained by substance misuse, medication side effects, or other psychiatric or
somatic medical conditions.
Substance/medication-induced bipolar and related disorder
• Prominent and persistent disturbance of mood characterized by elevated, expansive, or irritable mood
with or without depressed mood which develops during substance intoxication or withdrawal, and the
substance/medication is capable of producing disturbance of mood.
Other specified bipolar and related disorder
• Formerly known as bipolar disorder not otherwise specified (NOS)
• Does not meet criteria for bipolar I disorder or bipolar II disorder

• Allows for diagnosis of a bipolar disorder with atypical presentations or when differentiation from a
substance-induced mood disorder or mood disorder due to general medical condition is not possible
• Criteria include:
• short duration mania (i.e., 2-3 days) and a major depressive episode
• major depressive episode and insufficient criteria hypomania
• hypomania without major depressive episode
• cyclothymia for less than 24 months.
Mania symptom severity

The Young Mania Rating Scale (YMRS) is a validated 11-item instrument used to assess the severity of
mania symptoms in patients with a diagnosis of bipolar disorder. [Young Mania Rating Scale] [58] It can be
used to track improvement in mania or hypomania with treatment.
DIAGNOSIS
23
Bipolar disorder in adults Treatment
Step-by-step treatment approach

Guidelines for management of bipolar disorder are complex because of the recurrent nature of the condition,
with episodes of differing mood polarity (depressed versus manic or hypomanic), as well as more complex
presentations of mixed states: rapid cycling, psychotic bipolar disorder, and treatment-refractory bipolar
disorder. The best treatment approach goes beyond the resolution of acute episodes and takes into account
the need to simultaneously design an individualized strategy that can prevent future episodes, or that results
in reduction of episode frequency and improvement in functioning and quality of life.[67] The fundamentals of
management include diagnosis, access to services, the safety of the patient and others, and enhanced care
efforts (therapeutic alliance, patient and family education, treatment adherence, management of functional
impairments).[68] [69]
Mild, moderate, or severe symptoms can occur. They will generally be represented by an individual clinician's
determination, based on the patient's presentation and the clinician's past experience. The clinician should
consider using both subjective and clinical questionnaire-based rating scales when assessing the severity
of symptoms. Clinically, "mild" generally means few symptoms and little functional disruption; "severe" is
used where more significant symptoms and functional disruption is seen, or where psychosis is also present;
"moderate" is everything in between.
If a validated symptom scale is used, such as the Young Mania Rating Scale (YMRS), there are point-score
ranges that are generally associated with degrees of severity. [Young Mania Rating Scale] [58]
Where possible, patients should participate in decision-making concerning the treatment plan. This may
improve adherence, and close collaboration with patients and their families can help with identifying periods
where the risk of relapse is high, allowing timely adjustments of treatment.[70]
The time taken to respond to treatment varies between patients and according to the nature of the acute
episode (e.g., whether manic versus depressive symptoms are present). As a general guide, response to
pharmacologic treatment for acute mania should be observed within 2 weeks, after which time patients
should be considered nonresponders to specific medication(s) at the specific dosage(s). For acute bipolar
depression and acutely mixed episodes, response to treatment may take longer than this, and improvements
may be more subtle.[71]
Acutely manic or hypomanic patients

More-severely affected patients and/or those without insight into their illness may require urgent
psychiatric hospitalization to assure their safety and that of others. Therapy includes medication to
rapidly reduce manic symptoms while minimizing adverse effects, and the promotion of full remission and
recovery. If a manic or hypomanic patient is on antidepressants, these should be discontinued.
For an agitated patient with mania, initial management is to provide a tranquil environment with reduced
stimuli, and to attempt verbal de-escalation.[70] Intramuscular administration of medication may
subsequently be necessary. In some cases, patient cooperation may not be readily obtained and forced
or involuntary administration may be required (e.g., where the health and life of the patient or of others
may otherwise be at risk). Suggested first-line options include aripiprazole or olanzapine. Other agents
TREATMENT
that may be beneficial include ziprasidone, haloperidol, or lorazepam.
For hypomania or mild mania, monotherapy using lithium,[72] divalproex, carbamazepine,

or atypical antipsychotics approved to treat mania (e.g., risperidone, olanzapine, quetiapine,
aripiprazole,1[A]Evidence ziprasidone, asenapine,2[A]Evidence cariprazine, or paliperidone3[A]Evidence)
is recommended. The results of one meta-analysis suggest that olanzapine is more effective in patients
with more severe symptoms of mania at baseline, compared with those with less severe symptoms
initially.[78] In the US, standard practice is that valproate and its analogs are only prescribed for the
treatment of manic episodes associated with bipolar disorder during pregnancy if other alternative
medications are not acceptable or not effective. In 2018 the European Medicines Agency (EMA)
recommended that valproate and its analogs are contraindicated in bipolar disorder during pregnancy due
to the risk of congenital malformations and developmental problems in the infant/child.[79] In both Europe
and the US, valproate and its analogs must not be used in female patients of childbearing potential unless
there is a pregnancy prevention program in place and certain conditions are met.[79]
For moderate to severe mania, the same monotherapies may be attempted, although the more common
practice is the combination of a mood stabilizer, such as lithium, plus an atypical antipsychotic.[72] [80]
[81] [82] This will be a clinical decision, dependent on the severity of the patient's illness. Patients prefer
monotherapy, but most experts and clinical experience suggest a combination is more effective.[83] [84]
[85] [86]
For patients who do not respond, consideration of dose optimization and medication adherence is
recommended. However, alternative strategies may be necessary. These may include switching to
an alternative mood stabilizer, use of combination regimens, a benzodiazepine (e.g., clonazepam) as
adjunctive therapy, and use of a typical antipsychotic agent such as haloperidol or chlorpromazine. Depot
therapy may be considered in these patients.[87]
Manic patients who are more severely ill, catatonic, or not responding to several trials of medication
should be considered candidates for either clozapine treatment[88] or electroconvulsive therapy
(ECT).[89] Off-label treatments may also be considered for these patients; oxcarbazepine, tamoxifen,
tiagabine, gabapentin, lamotrigine, and verapamil have all been reported in many evidence-based
treatment guidelines. Evidence for brain stimulation techniques is expanding and in pharmacotherapy-
resistant patients, a trial of vagus nerve stimulation or transcranial magnetic stimulation may be given off-
label.[90]
Patients with an acutely mixed episode

Management of a mixed state is very similar to the approach used when treating an acutely manic patient.
Most treatment guidelines favor addressing the manic symptoms with tapering and discontinuing any
current antidepressant medications. Lithium is particularly suited to the treatment of mixed state bipolar
disorder.[72]
Acutely depressed patients

Less evidence exists, and fewer treatments are approved, for the treatment of acute bipolar depression,
and there is much debate about the use of traditional antidepressant medications for this specific
condition. There are very limited data from controlled studies to support their use in bipolar depression.
Furthermore, antidepressants may cause emergence of mania or rapid cycling, and they have not been
associated with any durable remission or recovery.[91] [92]
TREATMENT
First-line options include olanzapine/fluoxetine combination formulation, olanzapine,[93]

quetiapine,4[B]Evidence or lurasidone.[95] For patients not fully responding to such therapy, the use of
an additional agent is recommended. Agents include lithium,[72] lamotrigine, bupropion, aripiprazole,[96]
divalproex,5[B]Evidence and modafinil. Dual therapy with quetiapine and any selective serotonin-reuptake
inhibitor may also be considered, and there is evidence for the addition of lurasidone to either lithium or
25
divalproex for patients with bipolar I depression.[100] For patients refractory to combination therapy, the
use of additional agents may be beneficial. These include other atypical antipsychotics (e.g., aripiprazole,
risperidone, or ziprasidone), pramipexole, carbamazepine, riluzole, and omega-3-acid ethyl esters.[101]
Adjunctive armodafinil may also be used for bipolar depression.[102] Other drugs that have been used but
with lower-level evidence include topiramate, monoamine oxidase inhibitors, and tricyclic antidepressants.
The lack of efficacy of antidepressants in the acute treatment of bipolar depression may limit their clinical
utility.[103] For severely depressed patients, there is evidence suggesting that aripiprazole monotherapy
may provide some improvements in core depressive symptoms.[104]
The addition of psychosocial interventions for bipolar depression has been associated with higher
recovery rates at 1 year, as well as shorter times to recovery.[105] [106] Patients with bipolar depression
who received any 1 of 3 intensive psychotherapies (family-focused therapy, interpersonal social rhythm
therapy, cognitive behavioral therapy) reported better total functioning, relationship functioning, and life
satisfaction over a 9-month period of follow-up.[105] [106] The results of a small, 12-week, pilot study
suggests that interpersonal social rhythm therapy and quetiapine treatment are equally effective in the
acute treatment of patients with bipolar II depression.[107]
ECT should be considered for a bipolar depressive episode that has not responded to several adequate
medication trials, and can safely and effectively be used in these cases. ECT may also be indicated for
bipolar depression marked by acute suicidality/high risk of suicide; catatonic or psychotic features; rapidly
deteriorating physical condition brought on by the depression, such as anorexia; when the medication
risks outweigh ECT risks (older, medically frail, or pregnant patients); a prior history of good response to
ECT; or a patient preference.[108] [109]
Rapid-cycling patients
The treatment approach to a patient who is experiencing rapid cycling (4 or more mood episodes in a 1-
year period) requires deliberate planning and patience. Shifts in mood states may occur quite suddenly,
and treatment of the current individual episode may be counterproductive. For example, the addition of,
or increase in dose of, an antidepressant to a rapid-cycling patient who is depressed may precipitate a
switch to mania or acceleration of cycles.
When managing a rapid-cycling patient with bipolar disorder, it is essential to look for and remove any
factors that may destabilize mood. These include use of antidepressant and psychostimulant medications,
use of alcohol or illicit drugs, excessive caffeine intake, unnecessary hormonal treatments, and diet pills
or over-the-counter "remedies."
Pharmacotherapy should focus on the use of medications that can act as mood stabilizers. Generally
these are the antimanic therapies or agents approved for use in bipolar mania. Rapid-cycling bipolar
disorder is well known for its relative resistance to most monotherapies, generally requiring combinations
of mood stabilizers. However, starting with monotherapy may be advisable, then reassessing mood
control and cycle frequency after a 3- to 4-month period. Adding a second or third mood stabilizer may be
necessary.
Although rapid cycling was introduced as a potential variant or course specifier for bipolar disorder
TREATMENT
highlighting the failure of lithium prophylaxis in its treatment, lithium therapy should not be avoided in
such patients, given the noted benefits of lithium on the overall course of illness.[110] [111] In addition,
an argument can be made to include lithium as part of the pharmacotherapeutic treatment plan, or use
in combination with other psychotropic drugs such as atypical antipsychotics, in most patients with rapid
cycling.[72] [112] Lithium is safe, effective, and cost-effective; bipolar disorder requires lifelong treatment,
and lithium remains the definitive maintenance therapy.[72] Furthermore, bipolar disorder carries a high
risk for suicide, and lithium may confer some degree of protection.[72] [113] Lithium has an unknown yet
likely unique mechanism of action, making it an attractive option to complement other mood stabilizers
for rapid-cycling patients. The addition of lithium to address residual symptoms, particularly manic or
subsyndromal ones in rapid cycling, may aid in the efforts to stabilize mood and improve functioning.
Older patients
Although the prevalence is believed to decline in late life, older patients with new onset or persistence of
lifelong bipolar disorder present certain treatment challenges. Psychiatric and medical comorbidity are
generally observed among older people with bipolar disorder as frequently as, if not more so than, among
younger patients.
Onset of mania after age 60 years is more likely associated with a general medical condition (such as
stroke or other brain lesion) than with bipolar disorder.
Limited data exist on the treatment of older patients. However, the same medications with efficacy in
younger adults are often effective in the treatment of late-life bipolar disorder. It is recommended to
"start low and go slow" with the dosing, due to the increased potential of reduced renal clearance, drug
interactions, and pharmacokinetic issues (such as reduced protein binding) in an older patient.
Pregnant patients
Pregnancy is not protective against relapse for women with bipolar disorder, and the postpartum period
is considered a time of high risk for episodes of mood disturbance, particularly depressive and psychotic
episodes.[114] [115] The most effective management during pregnancy ideally starts prior to conception
as part of a planned pregnancy. This allows for the patient and her family to consult with the psychiatrist
and obstetrician and receive education on the heritability of bipolar disorder, and the risks (known and
unknown) of medication exposure during pregnancy versus risks of drug discontinuation, to avoid any
potential teratogenicity, and to establish a plan for intervention should recurrence occur during pregnancy
or in the postpartum period.
Reviews on the use of medication during pregnancy are available in literature, and include emerging data
on some of the most common mood stabilizers used in the treatment of bipolar disorder.[116] Common
recommendations for management during pregnancy include the following points.
• Avoidance of medication if possible, particularly during the first trimester, depending on the patient's
individual risk for recurrence.[117]
• When medications are required, the lowest effective doses of monotherapy should be
prescribed.[117] [118]
• In the US, standard practice is that valproate and its analogs are only prescribed for the
treatment of manic episodes associated with bipolar disorder during pregnancy if other alternative
medications are not acceptable or not effective. In 2018 the EMA recommended that valproate and
its analogs are contraindicated in bipolar disorder during pregnancy due to the risk of congenital
malformations and developmental problems in the infant/child.[79] In both Europe and the US,
TREATMENT
valproate and its analogs must not be used in female patients of childbearing potential unless there
is a pregnancy prevention program in place and certain conditions are met.[79]
• Anticonvulsant mood stabilizer use during pregnancy is associated with increased risk of fetal
malformations.[119]
27
• Lithium therapy during pregnancy increases the risk for Ebstein anomaly 20-fold according to
some studies, with particular risk conferred by lithium use during weeks 2 to 6 after conception.[72]
[120] However, some women on lithium and at high risk of a relapse may require ongoing therapy,
and in such cases careful monitoring of dose and serum lithium levels throughout pregnancy, at
delivery, and immediately postpartum is crucial given the significant volume of distribution changes
that take place. In this scenario, based on one cohort study of 113 pregnancies that looked at
lithium levels during gestation and in the postpartum period, the author of this topic recommends
checking lithium levels every 3-4 weeks during the first 34 weeks of pregnancy, then every week
until birth, then twice a week in the early postpartum period.[121] One large meta-analysis of
data from pregnant women exposed to lithium use found that their children had an increased
risk of congenital malformations attributable specifically to lithium use during the first trimester of
pregnancy.[122] However, the data from this study suggest that the absolute risk of malformations
is considered to be small. The treatment decision must weigh the benefits of treating or reducing
the risk of relapse of the mood disorder against the potential increased risks associated with lithium
use during pregnancy.
• For lurasidone, animal reproduction studies have failed to demonstrate a risk to the fetus and there
are no adequate and well-controlled studies in pregnant women.
• Specialty consultation with a psychiatrist, particularly one familiar and comfortable with managing
mood disorders during pregnancy, is recommended.
• In line with general principles of safe medical practice, clinicians should routinely ask all women of
child-bearing age and potential about their use of contraceptive methods, particularly prior to the
prescription of any psychotropic medication.
Duration of acute phase treatment

Advice on this is limited, and available treatment guidelines are primarily based on expert opinion given
the absence of evidence.[68] [71] For manic symptoms, acute phase treatment is recommended with
the same medication and at the same dosage for a minimum of 2 months after the achievement of the
full resolution of symptoms.[71] However, full recovery from mania may take longer, and treatment may
be continued for a period of 3 to 6 months to achieve mood stability.[68] For depressive symptoms,
continuation of treatment is recommended for 6 months following the full resolution of symptoms
according to one set of international consensus guidelines; after this period, treatment should either
be continued or gradually switched to the recommended maintenance treatment.[71] By contrast, the
British Association for Psychopharmacology recommends that prescribers consider tapering down and
ultimately discontinuing antidepressants from 3 months of recovery onwards. However, it advises that
longer treatment periods are required if patients relapse when treatment is withdrawn.[68]
Long-term preventive treatment

In general, treatment guidelines endorse initiation of maintenance therapy after a single manic episode
and suggest discussing maintenance options in collaboration with all patients stabilized after an acute
episode. Medications utilized to stabilize an acute episode may be continued as maintenance therapy for
most patients, remaining vigilant for relapse or recurrence as well as any treatment-emergent adverse
effects, particularly neurologic (extrapyramidal side effects, tardive dyskinesia) or metabolic (obesity,
TREATMENT
diabetes, dyslipidemias) effects, or toxicity (renal, hepatic, hematologic, thyroid).
Preventing early relapse after a single manic episode may be associated with a more benign course of
illness, and patients who have been stable on treatment for several years should be advised to remain on
maintenance indefinitely, as recurrence risk remains high.[68]
Monitoring and enhancing adherence should be a routine part of long-term bipolar disease management,
because nonadherence is commonly associated with recurrence.[123] Effective therapies that maximize
adherence share common characteristics: education, self-monitoring, recurrence prevention, managing
adverse effects, identifying and managing stressors, and addressing belief systems and attitudes to
illness.[124]
Pharmacologic treatment options for maintenance include lithium,[72] [125] [126] [127] olanzapine,
aripiprazole,6[B]Evidence lamotrigine, quetiapine (as an adjunct to lithium or divalproex, or as
monotherapy),[129] ziprasidone,[130] and asenapine.[131] Lithium has the strongest evidence for
prophylaxis in bipolar disorder compared with other agents, and remains the treatment of choice for long-
term maintenance therapy.[72] [126] One large Finnish nationwide cohort study found that maintenance
treatment with lithium was associated with the lowest risk of hospitalization due to a mental or somatic
disorder, and that, of the other treatments studied, long-acting injectable antipsychotics as a group were
associated with a 30% lower risk of rehospitalization compared with oral antipsychotics.[132] However,
the data in favor of individual long-acting injectable antipsychotics over their oral counterparts did not
reach statistical significance. Clinicians may consider long-acting injections as an alternative to oral
medication if nonconcordance resulting in frequent relapse is a concern, and/or if the patient would
prefer intramuscular administration.[87] [133] Before prescribing a long-acting injectable preparation, the
clinician must first ensure that the patient has been stabilized on (and had a good response to) the oral
preparation of the same medication.
Lithium,[72] olanzapine, and aripiprazole monotherapies are more effective in preventing mania than
depression. Lamotrigine is more effective in preventing depression than mania, but is also indicated as
preventive treatment for hypomania. One study has shown that, compared with lamotrigine alone, there
does not appear to be any significant difference in time to relapse with long-term use of aripiprazole plus
lamotrigine in stabilized patients with manic or mixed episodes.[134] For patients with both mania and
depression, lithium or divalproex in combination with quetiapine is protective. For patients stabilized with
quetiapine, there is evidence to suggest that continuation of quetiapine or switching to lithium is effective
in delaying recurrence of manic and depressive events compared with placebo.[129]
Second-line maintenance options, particularly as adjunctive agents, include aripiprazole,[135] divalproex

(added to lithium),[136] carbamazepine, risperidone, ziprasidone, olanzapine/fluoxetine combination
formulation, paliperidone, oxcarbazepine, topiramate, gabapentin, phenytoin, omega-3-acid ethyl esters,
and antidepressants. Clozapine and ECT (monthly session) may also be considered.
Mounting evidence supports the efficacy of the following specific psychosocial interventions for
maintenance therapy of bipolar disorder in the Canadian Network for Mood and Anxiety Treatments
(CANMAT).[108]
• Education to recognize and manage early warning symptoms:
• Increased time to any mood recurrence, reduced hospitalization rates, improved

functioning.[137]
• Adjunctive cognitive therapy:
TREATMENT
• Reduced depression scores, lengthened time to depressive recurrence, improved

dysfunctional attitudes.[138]
• Family-focused therapy
29
• Interpersonal social rhythm therapy.
Another psychosocial intervention approach that is commonly used for bipolar disorder is
psychoeducation. Psychoeducation has been shown to reduce relapse rates, improve long-term treatment
adherence, and help improve overall social functioning in patients.[139]
Treatment details overview

Consult your local pharmaceutical database for comprehensive drug information including contraindications,
drug interactions, and alternative dosing. ( see Disclaimer )
Acute ( summary )
not rapid-cycling and nonpregnant:
acute mania, hypomania, or mixed
with agitation 1st intramuscular neuroleptic or

benzodia zepine
no agitation: mild severity 1st oral monotherapy: mood stabilizer or

atypical antipsychotic
adjunct clona zepam
2nd oral monotherapy: alternative mood

stabilizer or atypical antipsychotic
adjunct clona zepam
2nd oral combination therapy: mood stabilizer

+ atypical antipsychotic
2nd oral typical antipsychotic
3rd clozapine or electroconvulsive therapy

(ECT)
4th alternative pharmacotherapy or brain

stimulation techniques
no agitation: moderate to 1st oral mood stabilizer and/or atypical

severe severity antipsychotic
adjunct clona zepam
2nd alternative oral mood stabilizer and/or

adjunct clona zepam

TREATMENT
(ECT)
4th alternative pharmacotherapy

acute depression
Acute ( summary )
1st mood stabilizer and/or atypical
antipsychotic and/or antidepressant
plus psychosocial interventions
adjunct additional pharmacotherapy
2nd electroconvulsive therapy (ECT)
rapid-cycling and nonpregnant
1st oral mood stabilizer or atypical

antipsychotic monotherapy
plus removal of exacerbating factors
2nd combination therapy
pregnant
1st consult psychiatrist and obstetrician
Ongoing ( summary )
after stabilization of acute episode:
nonpregnant
with mania predominant 1st mood stabilizer or atypical antipsychotic

feature
plus psychosocial interventions and

monitoring
adjunct electroconvulsive therapy (ECT)
with depression 1st lamotrigine

predominant feature

monitoring
with both mania and 1st lithium or divalproex sodium and/or

depression quetiapine
TREATMENT

monitoring
31
Ongoing ( summary )

pregnant

TREATMENT
Treatment options
Acute
acute mania, hypomania, or mixed
with agitation 1st intramuscular neuroleptic or

benzodia zepine
Primary options
» aripiprazole: 9.75 to 15 mg intramuscularly

every 2 hours, maximum 30 mg/day
OR
» olanzapine: 2.5 to 10 mg intramuscularly

every 2-4 hours, maximum 30 mg/day
Secondary options
» ziprasidone: 10 mg intramuscularly every

2 hours, or 20 mg intramuscularly every 4
hours, maximum 40 mg/day
OR
» haloperidol lactate: 5 mg intramuscularly

every 30-60 minutes, maximum 20 mg/day
OR
» lorazepam: 1-2 mg intramuscularly every

30-60 minutes, maximum 8 mg/day
» Severely affected patients and/or those without

insight into their illness may require urgent
psychiatric hospitalization to assure their safety
and that of others. In the first instance, aim to
provide a tranquil environment with reduced
stimuli, and attempt verbal de-escalation.[70]
» For an agitated patient with mania,

intramuscular administration of medication
may be necessary. In some cases, patient
cooperation may not be readily obtained and
forced or involuntary administration may be
required (e.g., where the health and life of the
patient or others may otherwise be at risk).
TREATMENT
» Suggested first-line options include

aripiprazole or olanzapine. Other agents
that may be beneficial include ziprasidone,
haloperidol, or lorazepam.
33
Acute
no agitation: mild severity 1st oral monotherapy: mood stabilizer or
Primary options
» lithium: 600-900 mg/day orally (immediate-

release) initially given in 2-3 divided doses,
adjust dose according to response and serum
drug level, maximum 1800 mg/day
Serum trough level target: 0.6 to 1.2 mEq/L.
OR
» divalproex sodium: 20 mg/kg orally

(extended-release) once daily initially,
increase according to response and serum
drug level, maximum 60 mg/kg/day
Serum level target: 80-100 micrograms/mL
OR
» carbamazepine: 200-800 mg/day orally

(extended-release) initially given in 2 divided
doses
OR
» risperidone: 1 mg orally once daily initially,

increase according to response, maximum 6
mg/day
OR
» olanzapine: 5 mg orally once daily initially,

mg/day
OR
» quetiapine: 50 mg orally (immediate-

release) once daily initially, increase
according to response, maximum 800 mg/day
given in 2-3 divided doses
OR
» aripiprazole: 15 mg orally once daily initially,

mg/day
TREATMENT
OR
» ziprasidone: 40 mg orally twice daily

initially, increase according to response,
maximum 160 mg/day
Acute
OR
» cariprazine: 1.5 mg orally once daily initially,

increase gradually according to response,
maximum 6 mg/day
» Clinically, "mild" generally means few

symptoms and little functional disruption.
» For hypomania or mild mania, monotherapy

using lithium,[72] divalproex, carbamazepine,
or atypical antipsychotics approved to treat
mania (e.g., risperidone, olanzapine, quetiapine,
aripiprazole, ziprasidone, or cariprazine) is
recommended. The results of one meta-analysis
suggest that olanzapine is more effective in
patients with more severe symptoms of mania at
baseline, compared with those with less severe
symptoms initially.[78]
» Limited data exist on the treatment of older

patients with bipolar disorder. However, the
same medications with efficacy in younger adults
are often effective in the treatment of late-life
bipolar disorder. It is recommended to "start
low and go slow" with the dosing due to the
increased potential of reduced renal clearance,
drug interactions, and pharmacokinetic issues
(such as reduced protein binding) in an older
patient.
» If a manic or hypomanic patient is on

antidepressants, these should be discontinued.
For patients with an acutely mixed episode, most
treatment guidelines favor addressing the manic
symptoms with tapering and discontinuing any
current antidepressant medications. Lithium is
particularly suited to the treatment of mixed state
bipolar disorder.[72]
» The time taken to respond to treatment varies

between patients and according to the nature of
the acute episode (e.g., whether manic versus
depressive symptoms are present). As a general
guide, response to pharmacologic treatment for
acute mania should be observed within 2 weeks,
after which time patients should be considered
nonresponders to specific medication(s) at the
specific dosage(s). For acute bipolar depression
and acutely mixed episodes, response to
treatment may take longer than this, and
TREATMENT
improvements may be more subtle.[71]
» In the US, standard practice is that valproate

and its analogs are only prescribed for the
treatment of manic episodes associated with
bipolar disorder during pregnancy if other
35
Acute
alternative medications are not acceptable or
not effective. In 2018 the European Medicines
Agency recommended that valproate and its
analogs are contraindicated in bipolar disorder
during pregnancy due to the risk of congenital
malformations and developmental problems in
the infant/child.[79] In both Europe and the US,
valproate and its analogs must not be used in
female patients of childbearing potential unless
there is a pregnancy prevention program in place
and certain conditions are met.[79]
»
adjunct clona zepam
Primary options
» clonazepam: 1 mg/day orally initially give

in 2-3 divided doses, increase according to
response, maximum 6 mg/day
» For patients who do not respond to

monotherapy, a benzodiazepine such as
clonazepam can be added.
2nd oral monotherapy: alternative mood
stabilizer or atypical antipsychotic
Primary options

OR

OR

doses
OR
TREATMENT

mg/day
OR
Acute
mg/day
OR

OR

mg/day
OR

maximum 160 mg/day
OR

maximum 6 mg/day

monotherapy, consideration of dose optimization
and medication adherence is recommended.
However, switching to an alternative mood
stabilizer or atypical antipsychotic agent should
be tried if the original agent is ineffective.

patient.

TREATMENT

37
Acute

»
adjunct clona zepam
Primary options
» clonazepam: 1 mg/day orally initially given


monotherapy, a benzodiazepine such as
2nd oral combination therapy: mood stabilizer
+ atypical antipsychotic
Primary options

-or-
-or-
doses
TREATMENT
--AND--
mg/day
-or-
Acute
mg/day
-or-
-or-
mg/day
-or-
maximum 160 mg/day

monotherapy, a combination of a mood stabilizer
and an atypical antipsychotic should be
considered.

patient.


TREATMENT

39
Acute
»
Primary options
» haloperidol: 2 mg/day orally initially given

OR
» chlorpromazine: 30 mg/day orally initially

given in 1-4 divided doses, increase
according to response, maximum 1000 mg/
day

monotherapy, an alternative option is an oral
typical antipsychotic. Agents include haloperidol
or chlorpromazine.
(ECT)
Primary options
» clozapine: consult specialist for guidance

on dose
Restricted distribution in the US
» Patients with symptoms of mania who have not

responded to several trials of medications should
be considered candidates for either clozapine or
ECT.
» More severely affected patients and/or those

without insight into their illness may require
urgent psychiatric hospitalization to assure their
safety and that of others.
» ECT should be considered for a bipolar

depressive episode that has not responded to
several adequate medication trials, and can
safely and effectively be used in these cases.
» ECT may also be indicated for bipolar

depression marked by acute suicidality/high
risk of suicide; catatonic or psychotic features;
rapidly deteriorating physical condition brought
TREATMENT
on by the depression, such as anorexia; when

the medication risks outweigh ECT risks (older,
medically frail, or pregnant patients); a prior
history of good response to ECT; or a patient
preference.[108] [109]
Acute
4th alternative pharmacotherapy or brain
stimulation techniques
» Manic patients not responding to several trials

of medication may be considered candidates
for off-label treatments that appear in many
evidence-based treatment guidelines.
» Agents include oxcarbazepine, tamoxifen,

tiagabine, gabapentin, lamotrigine, and
verapamil. These are used for more
extraordinary cases.
» More-severely affected patients and/or those

» Evidence for brain stimulation techniques is

expanding and in pharmacotherapy-resistant
patients, a trial of vagus nerve stimulation or
transcranial magnetic stimulation may be given
off-label.[90]
no agitation: moderate to 1st oral mood stabilizer and/or atypical
severe severity antipsychotic
Primary options

-or-
-or-
doses
--AND/OR--
mg/day
-or-
mg/day
-or-
TREATMENT

-or-
41
Acute
mg/day
-or-
maximum 160 mg/day
-or-
» asenapine: 5-10 mg sublingually twice daily,
maximum 20 mg/day
-or-
» paliperidone: 3 mg orally once daily initially,
mg/day
-or-
maximum 6 mg/day
» Clinically, "mild" generally means few

symptoms and little functional disruption.
"Severe" is used where patients exhibit
significant symptoms and functional disruption
is seen, or where psychosis is also present;
"moderate" is everything in between. Severely
affected patients and/or those without insight
into their illness may require urgent psychiatric
hospitalization to assure their safety and that of
others.
» For moderate to severe mania, monotherapy

using a mood stabilizer or atypical
antipsychotic may be attempted. Agents
include lithium,[72] divalproex, carbamazepine,
or atypical antipsychotics approved to
treat mania (e.g., risperidone, olanzapine,
quetiapine, aripiprazole,1[A]Evidence
ziprasidone, asenapine,2[A]Evidence
paliperidone,3[A]Evidence or cariprazine).
» The more common practice is a combination

of a mood stabilizer, such as lithium, plus an
atypical antipsychotic.[72] [80] [81] [82] This
will be a clinical decision, dependent on the
severity of the patient's illness. Patients prefer
monotherapy, but most experts and clinical
experience suggest a combination is more
effective.[83] [84] [85] [86]
» If a patient with manic or hypomanic symptoms

is on antidepressants, these should be
discontinued. For patients with an acutely
TREATMENT
mixed episode, most treatment guidelines favor

addressing the manic symptoms with tapering
and discontinuing any current antidepressant
medications.
Acute
patient.


adjunct clona zepam
Primary options

» For patients who do not respond to therapy

with a mood stabilizer and/or an atypical
antipsychotic, a benzodiazepine such as
TREATMENT
2nd alternative oral mood stabilizer and/or

Primary options

43
Acute
-or-
-or-
doses
--AND/OR--
mg/day
-or-
mg/day
-or-
-or-
mg/day
-or-
maximum 160 mg/day
-or-
maximum 20 mg/day
-or-
mg/day
-or-
maximum 6 mg/day
» For patients who do not respond, consideration

of dose optimization and medication adherence
is recommended.
» Switching to a different combination of mood

TREATMENT
stabilizer and atypical antipsychotic should be

tried if the original combination was ineffective.
If monotherapy was used, a different mood
stabilizer or atypical antipsychotic should be
tried.
Acute
patient.


»
adjunct clona zepam
Primary options

» For patients who do not respond to therapy

with a mood stabilizer and/or an atypical
antipsychotic, a benzodiazepine such as
TREATMENT

Primary options
45
Acute
» haloperidol: 2 mg/day orally initially given
OR
» chlorpromazine: 30 mg/day orally initially

given in 1-4 divided doses, increase
day
» For patients who do not respond to oral mood

stabilizers and/or atypical antipsychotics, an
alternative option is an oral typical antipsychotic.
» Agents include haloperidol or chlorpromazine.

(ECT)
Primary options

on dose

responded to several trials of medications should
be considered candidates for either clozapine or
ECT.


depressive episode that has not resopnded to

4th alternative pharmacotherapy
TREATMENT

responded to several trials of medication may be
considered candidates for off-label treatments
that appear in many evidence-based treatment
guidelines.
Acute
» Agents include oxcarbazepine, tamoxifen,
tiagabine, gabapentin, lamotrigine, and
verapamil.

safety and that of others.[90]
acute depression
1st mood stabilizer and/or atypical

antipsychotic and/or antidepressant
Primary options
» olanzapine/fluoxetine: 6 mg/25 mg orally

once daily initially, increase according to
response, maximum 12 mg/50 mg once daily
OR

mg/day
OR

day given in 2-3 divided doses; 300 mg orally
(extended-release) once daily, increase
OR
» lurasidone: 20 mg orally once daily initially,

increase according to response, maximum
120 mg/day
OR

maximum 6 mg/day
OR

TREATMENT

mg/day
Secondary options
47
Acute
-or-
--AND--
-or-
» lamotrigine: dose depends on any
concomitant drugs; consult specialist for
guidance on dose
-or-
» bupropion hydrochloride: 150 mg orally
(sustained-release) once daily initially,
450 mg/day given in 2 divided doses
-or-
mg/day
-or-
-or-
» modafinil: 100 mg orally once daily initially,
400 mg/day
OR

--AND--
» citalopram: 20 mg orally once daily initially,
mg/day
-or-
» escitalopram: 10 mg orally once daily
TREATMENT

maximum 20 mg/day
-or-
» fluoxetine: 20 mg orally once daily initially,
mg/day
Acute
-or-
» fluvoxamine: 50 mg orally once daily
maximum 300 mg/day
-or-
» paroxetine: 20 mg orally once daily initially,
mg/day
-or-
» sertraline: 50 mg orally once daily initially,
200 mg/day
Tertiary options

120 mg/day
--AND--
-or-
» Few treatments are approved for the treatment

of acute bipolar depression, and there is
much debate about the use of traditional
antidepressant medication for this specific
condition. There are very limited data from
controlled studies to support their use in bipolar
depression. Furthermore, antidepressants may
cause emergence of mania or rapid cycling, and
they have not been associated with any durable
remission or recovery.[92] [91]
» First-line options include olanzapine/

fluoxetine combination formulation, olanzapine
monotherapy,[93] quetiapine,4[B]Evidence
lurasidone, or cariprazine.[95] For severely
depressed patients, there is evidence suggesting
that aripiprazole monotherapy may provide
some improvements in core depressive
symptoms.[104]
TREATMENT
» For patients not fully responding to such

therapy, the use of an additional agent is
recommended. Agents include lithium,[72]
lamotrigine, bupropion, aripiprazole,[96]
divalproex,5[B]Evidence and modafinil. Dual
therapy with quetiapine and any selective
49
Acute
serotonin-reuptake inhibitor may also be
considered, and there is evidence for the
addition of lurasidone to either lithium
or divalproex for patients with bipolar I
depression.[100]
» The lack of efficacy of antidepressants in the

acute treatment of bipolar depression may limit
their clinical utility.[103]


» The addition of psychosocial interventions for

bipolar depression has been associated with
higher recovery rates at 1 year as well as shorter
times to recovery.[105] [106]
» Patients with bipolar depression who received

any 1 of 3 intensive psychotherapies (family-
focused therapy, interpersonal social rhythm
therapy, cognitive behavioral therapy) reported
better total functioning, relationship functioning,
and life satisfaction over a 9-month period of
TREATMENT
follow-up.[105] [106] The results of a small, 12-

week, pilot study suggests that interpersonal
social rhythm therapy and quetiapine treatment
are equally effective in the acute treatment of
patients with bipolar II depression.[107]
Acute
Primary options

mg/day
OR

mg/day
OR
» ziprasidone: 40 mg orally once daily initially,

120 mg/day
OR
» pramipexole: 1 mg/day orally initially given

in 3 divided doses, increase according to
OR

doses
OR
» riluzole: consult specialist for guidance on

dose
OR
» omega-3-acid ethyl esters: consult

specialist for guidance on dose
OR
» armodafinil: 150 mg orally once daily in the

morning
» For patients refractory to combination therapy,

the use of additional agents may be beneficial.
TREATMENT
These include other atypical antipsychotics

(e.g., aripiprazole, risperidone, or ziprasidone),
pramipexole, carbamazepine, riluzole, and
omega-3-acid ethyl esters.[101] Adjunctive
armodafinil may also be used for bipolar
depression.[102]
51
Acute
» Other drugs that have been used but with
lower-level evidence include topiramate,
monoamine oxidase inhibitors, and tricyclic
antidepressants.
2nd electroconvulsive therapy (ECT)


» The addition of psychosocial interventions for

bipolar depression has been associated with
higher recovery rates at 1 year as well as shorter
times to recovery.[105] [106]
» Patients with bipolar depression who received

any 1 of 3 intensive psychotherapies (family-
focused therapy, interpersonal social rhythm
therapy, cognitive behavioral therapy) reported
better total functioning, relationship functioning,
and life satisfaction over a 9-month period of
follow-up.[105] [106]
rapid-cycling and nonpregnant
1st oral mood stabilizer or atypical

antipsychotic monotherapy
Primary options

OR

TREATMENT

Serum level target: 80-100 micrograms/mL.
OR
Acute
doses
OR

mg/day
OR

mg/day
OR

OR

mg/day
OR

maximum 160 mg/day
OR

maximum 6 mg/day
» Patients experiencing rapid cycling (4 or more

mood episodes in a 1-year period) require
deliberate treatment planning and patience.
Shifts in mood states may occur quite suddenly,
and treatment of the current individual episode
may be counterproductive. For example,
the addition of, or increase in dose of, an
antidepressant to the rapid-cycling patient who is
TREATMENT
depressed may precipitate a switch to mania or

acceleration of cycles.
» Pharmacotherapy should focus on the use of

medications that can act as mood stabilizers.
Generally these are the antimanic therapies
53
Acute
or agents approved for use in bipolar mania.
Although rapid cycling was introduced as a
potential variant or course specifier for bipolar
disorder highlighting the failure of lithium
prophylaxis in its treatment, lithium therapy
should not be avoided in such patients, given the
noted benefits of lithium on the overall course of
illness.[72] [110] [111] [112]
» Rapid-cycling bipolar disorder is well known

for its relative resistance to most monotherapies,
generally requiring combinations of mood
stabilizers. However, starting with monotherapy
may be advisable, then reassessing mood
control and cycle frequency after a 3- to 4-month
period. Adding a second or third mood stabilizer
may be necessary.

» It is essential to look for and remove any

factors that may destabilize mood. These include
use of antidepressant and psychostimulant
medication, use of alcohol or illicit drugs,
excessive caffeine intake, unnecessary
hormonal treatments, and diet pills or over-the-
counter "remedies."
2nd combination therapy
Primary options

guidance on dose
--AND--
TREATMENT

--AND--
Acute
» clonazepam: 1 mg/day orally initially give
-or-
mg/day
-or-
mg/day
-or-
-or-
mg/day
-or-
maximum 160 mg/day
» Rapid-cycling bipolar disorder is well known

for its relative resistance to most monotherapies,
generally requiring combinations of mood
stabilizers. However, starting with monotherapy
may be advisable, then reassessing mood
control and cycle frequency after a 3- to 4-month
period. Adding a second or third mood stabilizer
may be necessary.
» It is essential to look for and remove any

factors that may destabilize mood. These include
use of antidepressant and psychostimulant
medication, use of alcohol or illicit drugs,
excessive caffeine intake, unnecessary
hormonal treatments, and diet pills or over-the-
counter "remedies."
pregnant
» Specialty consultation with a psychiatrist,

particularly one familiar and comfortable with
managing mood disorders during pregnancy, is
recommended.
TREATMENT
» Reviews on the use of medication during

pregnancy are available in literature and include
emerging data on some of the most common
mood stabilizers used in the treatment of bipolar
disorder.[116]
55
Acute
» Common recommendations for management
of bipolar disorder during pregnancy include
avoidance of medication if possible, particularly
during the first trimester, depending on the
patient's individual risk for recurrence, and
when medications are required, that the lowest
effective doses of monotherapy should be
prescribed.[117] [118]

malformations and developmental problems
in the infant/child.[79] In both Europe and
the US, valproate and its analogs must not
be used in female patients of childbearing
potential unless there is a pregnancy prevention
program in place and certain conditions are
met.[79] Lithium therapy during pregnancy
increases the risk for Ebstein anomaly 20-fold
according to some studies, with particular risk
conferred by lithium use during weeks 2 to 6
after conception.[72] [120] However, some
women on lithium and at high risk of a relapse
may require ongoing therapy, and in such cases
careful monitoring of dose and serum lithium
levels throughout pregnancy, at delivery, and
immediately postpartum is crucial given the
significant volume of distribution changes that
take place. In this scenario, based on one
cohort study of 113 pregnancies that looked
at lithium levels during gestation and in the
postpartum period, the author of this topic
recommends checking lithium levels every 3-4
weeks during the first 34 weeks of pregnancy,
then every week until birth, then twice a week
in the early postpartum period.[121] One
large meta-analysis of data from pregnant
women exposed to lithium use found that their
children had an increased risk of congenital
malformations attributable specifically to lithium
use during the first trimester of pregnancy.[122]
However, the data from this study suggest that
the absolute risk of malformations is considered
to be small. The treatment decision must weigh
TREATMENT
the benefits of treating or reducing the risk

of relapse of the mood disorder against the
potential increased risks associated with lithium
use during pregnancy.
Acute
» For lurasidone, animal reproduction studies
have failed to demonstrate a risk to the fetus
and there are no adequate and well-controlled
studies in pregnant women.
» Electroconvulsive therapy (ECT) may also be

indicated for bipolar depression if the medication
risks outweigh ECT risks.
Ongoing
nonpregnant
with mania predominant 1st mood stabilizer or atypical antipsychotic

feature
Primary options

OR

mg/day
OR

30 mg/day; 300-400 mg intramuscularly once
monthly
Intramuscular administration: oral aripiprazole
(or another oral antipsychotic) should
be continued for 14 days after the first
intramuscular dose in order to maintain
adequate therapeutic serum levels during the
initiation of intramuscular therapy.
OR

guidance on dose
TREATMENT
OR

maximum 160 mg/day
57
Ongoing
OR

maximum 20 mg/day
OR

mg/day; or 25-50 mg intramuscularly every 2
weeks
Intramuscular administration: oral risperidone
be continued for 3 weeks after the first
» If mania is the more predominant feature,

lithium,[72] [126] olanzapine, aripiprazole,
6[B]Evidence ziprasidone,[130] risperidone,
or asenapine[131] monotherapy can be used.
Lamotrigine is also indicated as preventive
treatment for hypomania. Lithium has the
strongest evidence for prophylaxis in bipolar
disorder compared with other agents, and
remains the treatment of choice for long-term
maintenance therapy.[72] [126] There does not
appear to be any significant difference in time
to relapse with long-term use of aripiprazole
plus lamotrigine, compared with lamotrigine
alone, in stabilized patients with manic or mixed
episodes.[134]
» Long-acting injectable antipsychotics as

a group appear to be a safe and effective
alternative for patients in whom lithium is
not suitable, according to one large Finnish
nationwide cohort study.[132] However, the
data in favor of individual long-acting injectable
antipsychotics over their oral counterparts did
not reach statistical significance. Clinicians
may consider long-acting injections as an
alternative to oral medication if nonconcordance
resulting in frequent relapse is a concern, and/
or if the patient would prefer intramuscular
administration.[87] [133] Before prescribing a
long-acting injectable preparation, the clinician
must first ensure that the patient has been
stabilized on (and had a good response to) the
oral preparation of the same medication.
TREATMENT
» Treatment guidelines endorse initiation of

maintenance therapy after a single manic
episode and suggest discussing maintenance
options in collaboration with all patients
stabilized after an acute episode. Preventing
Ongoing
early relapse after a single manic episode may
be associated with a more benign course of
illness, and patients who have been stable on
treatment for several years should be advised
to remain on maintenance indefinitely, as
recurrence risk remains high.[68]
» Medications utilized to stabilize an acute

episode may be continued as maintenance
therapy for most patients, remaining vigilant for
relapse or recurrence as well as any treatment-
emergent adverse effects, particularly neurologic
(extrapyramidal side effects, tardive dyskinesia)
or metabolic (obesity, diabetes, dyslipidemias)
effects, or toxicity (renal, hepatic, hematologic,
thyroid).
monitoring
» Monitoring and enhancing adherence should

be a routine part of long-term bipolar disease
management, because nonadherence is
commonly associated with recurrence.[123]
Education, self-monitoring, recurrence
prevention, managing adverse effects, identifying
and managing stressors, and addressing belief
systems and attitudes to illness are all helpful to
enhance adherence.[124]
» Mounting evidence supports the efficacy

of specific psychosocial interventions for
maintenance therapy of bipolar disorder as
advocated in Canadian Network for Mood
and Anxiety Treatments (CANMAT).[108]
These include education to recognize and
manage early warning symptoms, adjunctive
cognitive therapy, family-focused therapy, and
interpersonal social rhythm therapy.
» Another psychosocial intervention approach

that is commonly used for bipolar disorder is
psychoeducation. Psychoeducation has been
shown to reduce relapse rates, improve long-
term treatment adherence, and help improve
overall social functioning in patients.[139]
Primary options

TREATMENT

Serum level target: 80-100 micrograms/mL.
OR
59
Ongoing
doses
OR

maximum 160 mg/day
OR

mg/day
OR
» oxcarbazepine: consult specialist for

guidance on dose
OR
» topiramate: consult specialist for guidance

on dose
OR
» gabapentin: consult specialist for guidance

on dose
OR
» phenytoin: consult specialist for guidance

on dose
OR

OR

on dose
» Additional pharmacotherapy can be used.

TREATMENT
» Patients who have been stable on treatment

for several years should be advised to remain
on maintenance indefinitely, as recurrence risk
remains high.[68]
Ongoing
thyroid).



with depression 1st lamotrigine
predominant feature
Primary options

guidance on dose
» If depression is the more predominant feature,

lamotrigine, which is more effective in preventing
TREATMENT
depression, is used.

episode and suggest discussing maintenance
61
Ongoing
stabilized after an acute episode.[140]
Preventing early relapse after a single manic
episode may be associated with a more benign
course of illness, and patients who have been
stable on treatment for several years should be
advised to remain on maintenance indefinitely,
as recurrence risk remains high.[68]

thyroid).
monitoring



Primary options

TREATMENT

OR
Ongoing

doses
OR

weeks
OR

maximum 160 mg/day
OR

OR

mg/day
OR

mg/day
OR

120 mg/day
OR
TREATMENT

guidance on dose
OR
63
Ongoing

on dose
OR

on dose
OR

on dose
OR

OR

on dose

remains high.[68]

thyroid).
» Antidepressants can also be considered, but

caution must be applied, as there is the risk of
induction of mania, or cycling, or suicide.

TREATMENT

Ongoing


with both mania and 1st lithium or divalproex sodium and/or
depression quetiapine
Primary options

-or-
--AND/OR--
» For patients with both mania and depression,

lithium or divalproex in combination with
quetiapine is protective. For patients stabilized
with quetiapine, there is evidence to suggest that
continuation of quetiapine or switching to lithium
is effective in delaying recurrence of manic and
depressive events compared with placebo.[129]
TREATMENT

episode, and suggest discussing maintenance
stabilized after an acute episode. Preventing
early relapse after a single manic episode may
65
Ongoing
be associated with a more benign course of
illness, and patients who have been stable on
treatment for several years should be advised
to remain on maintenance indefinitely, as
recurrence risk remains high.[68]

thyroid).

»
monitoring


TREATMENT

Ongoing
Primary options

30 mg/day; 300-400 mg intramuscularly once
monthly
Intramuscular administration: oral aripiprazole
be continued for 14 days after the first
OR

doses
OR

weeks
OR

maximum 160 mg/day
OR

TREATMENT
OR
67
Ongoing
mg/day
OR

mg/day
OR

guidance on dose
OR

on dose
OR

on dose
OR

on dose
OR

OR

on dose

remains high.[68]

TREATMENT

Ongoing
thyroid).
» Antidepressants can also be considered, but

caution must be applied, as there is the risk of
induction of mania or cycling or suicide.


pregnant
» Specialty consultation with a psychiatrist,

particularly one familiar and comfortable with
managing mood disorders during pregnancy, is
recommended.
» Pregnancy is not protective against relapse for

women with bipolar disorder, and the postpartum
period is considered to be a time of high risk
for episodes of mood disturbance, particularly
depressive and psychotic episodes.[114] [115]
» The most effective management of bipolar

disorder during pregnancy ideally starts prior
to conception as part of a planned pregnancy.
This allows for the patient and her family to
consult with the psychiatrist and obstetrician and
receive education on the heritability of bipolar
disorder, the risks (known and unknown) of
medication exposure during pregnancy versus
risks of drug discontinuation, to avoid any
potential teratogenicity, and to establish a plan
for intervention should recurrence occur during
pregnancy or in the postpartum period.
TREATMENT
» Electroconvulsive therapy (ECT) may also be

indicated for bipolar depression if the medication
risks outweigh ECT risks.
69
Emerging
Armodafinil
Armodafinil is a psychostimulant that is approved to treat narcolepsy. It has also demonstrated efficacy as an
adjunctive treatment in the treatment of bipolar depression; however, further studies are required before this
becomes an accepted treatment.[102]
Ketamine
A single administration of a subanesthetic dose of ketamine, a widely used anesthetic agent, improves
depression symptoms in patients with treatment resistant depression.[141] Ketamine has also been shown
to reduce suicidal thoughts and depression in patients with bipolar disorder.[142] This treatment is still
considered experimental,[143] and ongoing research is required to clarify the efficacy, safety, and tolerability
of repeated ketamine administration in the treatment of bipolar depression. Repeated use of ketamine in
other patient groups has been linked to urologic and liver toxicity, cognitive deficits, and dependency.[144]
Transcranial direct current stimulation (tDCS)

A novel treatment utilizing low levels of direct electric current to stimulate the brain, delivered using
electrodes on the head, tDCS shows promise within the treatment of unipolar major depression. One
randomized controlled trial (RCT) of 59 adults with bipolar disorder who were experiencing a major
depressive episode (already receiving a stable pharmacologic regimen) found tDCS to be effective compared
with sham tDCS. Within the study, this treatment appeared safe and well tolerated.[145] Larger multi-site
RCTs are now required to further examine the efficacy and safety of tDCS in bipolar disorder.
TREATMENT
Bipolar disorder in adults Follow up
Recommendations
Monitoring
FOLLOW UP
Bipolar disorder requires lifelong treatment and management. Patients experiencing acute episodes
should be monitored frequently until symptomatic improvement has persistently taken place. Severe
depression, the presence of serious suicidal thinking, or mania should prompt consideration of psychiatric
hospitalization for protection of the patient and others and to allow for daily monitoring and treatment
planning. Patients discharged from hospital should be seen weekly, because the immediate postdischarge
period may be associated with greater risk for nonadherence with treatment, relapse, and suicide.
In addition to patient self-report of symptoms, collateral information from family and the use of objective
rating scales of mood can enhance the monitoring of patient progress with treatment. The Patient Health
Questionnaire for adults (PHQ-9) may be used to assess response to treatment of depressive symptoms
(this questionnaire is still being used in clinical practice, despite the release of DSM-5), while the Young
Mania Rating Scale (YMRS) is commonly used to measure changes in manic symptoms in response to
treatment. [Young Mania Rating Scale] [171]
Patient instructions
Patients with bipolar disorder attempting to recover from an acute episode should avoid situations or
stressors known to trigger strong, negative emotions, based on their own individual past experience.
Unhealthy relationships, poor living conditions, or stressful jobs may easily overwhelm their fragile state
of recovery. Similarly, alcohol and all illicit drugs should be discontinued. Reaching out to supportive
friends and family members helps avoid isolation and create an extended early detection system for
relapses. Remembering to take medications as prescribed is critical; some patients need reminders
or pill-boxes to organize and structure their efforts at adherence. Protection of a healthy sleep routine
and schedule, eating properly, and moderate exercise should become routines of daily living. [National
Institute of Mental Health: bipolar disorder] Joining and participating in community organizations, and
patient advocacy groups such as the National Alliance for Mental Illness or the Depression Bipolar
Support Alliance, can foster recovery for the patient and their family. [Depression and Bipolar Support
Alliance]
For female patients of childbearing potential, valproate treatment should not be started unless alternative
treatments are not suitable; females of childbearing potential must follow a pregnancy prevention program
while on treatment with valproate medications. An example of one such program was launched in 2018 by
the European Medicines Agency, for use across EU countries, and includes the following:[79] [European
Medicines Agency: valproate medicines pregnancy prevention programme materials]
• an evaluation of a patient’s potential for becoming pregnant;
• pregnancy tests before starting and during treatment as needed;
• counseling about the risks of valproate treatment and the need for effective contraception
throughout treatment;
• a review of ongoing treatment by a specialist at least annually; and
• a risk acknowledgment form that patients and prescribers will go through at each such annual
review to confirm that appropriate advice has been given and understood.
71
Complications
Complications Timeframe Likelihood

FOLLOW UP
divalproex-induced hyperammonemic encephalopathy short term low
Hyperammonemic encephalopathy has been reported following initiation of divalproex therapy in patients
with urea cycle disorders. Prior to the initiation of divalproex, evaluation for urea cycle disorders should
be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma,
encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy,
unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical
vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a
family history of urea cycle disorders or a family history of unexplained infant deaths (particularly males);
4) those with other signs or symptoms of urea cycle disorders.[166]
lamotrigine-induced rash short term low
The rate of lamotrigine-induced rash of benign variety among patients with mood disorders has been
reported to be 8.3%, compared with 6.4% with placebo treatment.[169] Serious rash rate was 0.1% among
lamotrigine-treated patients across all controlled and open-label trials. Rash risk is likely to be related to
starting dose and rate of titration, so prevention of rash is best accomplished by following established
dosing guidelines for a slow, gradual up-titration. Early discontinuation of lamotrigine if serious rash is
suspected may prevent progression to Stevens-Johnson syndrome. Patients with a history of serious rash
should not be rechallenged with lamotrigine.[170]
cognitive dysfunction long term medium
The incidence of cognitive dysfunction among patients with bipolar disorder is not known, and is
complicated by state and trait variables. For example, impaired concentration or distractibility is common
during a state of active mood disturbance. However, studies have demonstrated several deficits in
neuropsychological function among patients with bipolar disorder during well periods, suggesting trait
abnormalities. Deficits in attention, executive function, and emotional processing have all been reported to
persist during euthymic states in bipolar disorder.[157] Neuropsychological testing may aid in the detection
of this complication, although prevention and treatment strategies remain to be established.
treatment-related weight gain/obesity long term medium
Weight gain is an unfortunate common adverse effect with the majority of medications used to treat
bipolar disorder. The incidence of this complication varies based on individual patient factors, specific
medication, and duration of treatment. Among the agents approved to treat bipolar disorder, only
lamotrigine, carbamazepine, aripiprazole, and ziprasidone are associated with a low risk for weight
gain. It has been found that 54% of patients with bipolar disorder are overweight, and 31% meet criteria
for obesity.[42] Medications are likely to contribute to this complication. Careful monitoring of weight at
baseline and throughout medication management is necessary. Healthy eating and exercise habits should
be encouraged.
lithium nephrotoxicity long term medium
Lithium-induced nephrogenic diabetes insipidus is a frequent complication, with 30% to 80% of patients
having some degree of difficulty concentrating the urine. Polyuria, nocturia, and thirst are symptomatic.
Diabetes insipidus is caused by inhibition of vasopressin-stimulated adenylate cyclase and reduced
density of vasopressin receptors in the collecting tubules. Using the lowest effective dose of lithium may
reduce the risk of developing diabetes insipidus.[164]
Chronic lithium nephropathy and nephrotic syndrome are rare complications of lithium therapy.[164]

lithium-induced hypothyroidism long term medium
FOLLOW UP
The prevalence of hypothyroidism in lithium-treated patients is in the range of 6% to 39.6%. The etiology
of lithium-induced hypothyroidism is thought to be related to an autoimmune process, or by direct action
of lithium on hormone secretion leading to goiter. Prevention through routine monitoring of thyroid function
tests every 6 to 12 months is recommended.[165]
atypical antipsychotic therapy-related metabolic long term low

syndrome
The incidence of metabolic syndrome in bipolar disorder is 30%.[42] Atypical antipsychotics have been
associated with weight gain, induction of type 2 diabetes, and dyslipidemias. The risk seems greatest
with olanzapine and clozapine, intermediate with quetiapine and risperidone, and low for aripiprazole and
ziprasidone (consensus statement). Prevention of this complication is best achieved by a combination of
choosing lower-risk agents first and careful monitoring of fasting blood glucose, weight, blood pressure,
abdominal circumference, and fasting lipids before and during treatment with any atypical antipsychotic.
The etiology for atypical antipsychotic-induced metabolic derangements is unknown.
suicide variable high
Severe, untreated bipolar disorder is associated with a 15% lifetime risk for suicide. Suicide risk is higher
earlier in the course of the illness, with recent estimates at around 25%.[154] The etiology of suicide is
unknown, although it is likely that a confluence of variables including social factors, psychological traits,
neurobiologic influences, and genetics merge to convert suicidal thoughts into action. Many risk factors
for suicide have been reported, but their common denominator may simply be human suffering.[155]
Suicide is preventable. Clinicians should be familiar with completion of a suicide risk assessment and
development of an intervention plan.[155] Acute intervention should start immediately.[150] Long-term
treatment with lithium is effective in preventing suicide and attempted suicide in patients with unipolar
and bipolar depression.[113] [150] [156] Other factors that may contribute to a good outcome for suicidal
patients include the establishment of a multidisciplinary treatment team, family involvement, social support,
and a safe and secure environment.[150]
disability variable high
Adults with bipolar disorder are 40% less likely to be gainfully employed and are 7 times more likely to
miss work.[158] [159] During periods of mania or severe depression, individuals with bipolar disorder may
clearly be unable to perform the activities of daily living, particularly if hospitalization becomes necessary.
Another contributing factor is that, despite the availability of effective treatments, the majority of patients
with bipolar disorder do not receive adequate care. Early detection and aggressive treatment may reduce
disability.
lithium intoxication variable medium
Signs and symptoms of lithium intoxication usually emerge at blood levels >1.5 mEq/L, although toxicity
may be observed at much lower concentrations in some patients. Intentional overdose, drug interactions,
recent increase in dose, a decrease in renal excretion, and recent medical illness, especially if marked
by excessive fluid loss, are all potential causes of lithium intoxication. The signs and symptoms of this
complication include neurologic (fine tremor, gait abnormality, hyperreflexia), gastrointestinal (nausea,
vomiting, diarrhea), and cardiovascular (bradycardia, T-wave changes, conduction blocks). With increasing
levels of lithium intoxication (2.5-3.5 mEq/L), slurring of speech, myoclonus, and a coarsening of the
tremor may occur. Lithium blood levels >3.5 mEq/L are life-threatening, as renal failure, stupor, seizures,
and cardiovascular collapse are likely.[162]
neurologic adverse effects of lithium variable medium
73

Neurotoxic effects of lithium per case reports include extrapyramidal side effects, cognitive dysfunction,
peripheral neuropathy, nystagmus, and pseudotumor cerebri. Pre-existing cerebral abnormalities,
FOLLOW UP
advanced age, and concomitant use of antipsychotics and tricyclic antidepressants may increase the risk
for this complication. Lithium initiation and chronic administration commonly cause a fine tremor of the
upper extremities that is a postural and/or action tremor of high frequency; approximately 20% prevalence
for lithium-induced tremor has been reported. Using the lowest effective dose of lithium may reduce or
eliminate the tremor. In some cases, low doses of propranolol can be used to treat the tremor.[163]
antipsychotic therapy-related sudden cardiac death variable low
Current users of both typical and atypical antipsychotic medications had dose-related increased risk
for sudden cardiac death.[160] The potential for adverse cardiovascular effects during antipsychotic
treatment has been recognized for many decades, although the absolute risk and mechanism of action are
unknown.[161]
atypical antipsychotic therapy-related extrapyramidal variable low

side effects (EPS)/tardive dyskinesia
At recommended therapeutic doses for the management of bipolar disorder, atypical antipsychotics are
associated with a very low risk for acute EPS phenomena such as dystonic reactions and akathisia.
Risperidone may have a greater risk for causing EPS and hyperprolactinemia than the other atypical
antipsychotics; aripiprazole is associated with akathisia. Although as a class of medications the atypicals
carry a much lower risk for EPS than the typical antipsychotics, case reports exist for all of the atypicals
linked to EPS and to tardive dyskinesia. Awareness of this potential neurologic adverse effect, early
detection, and removal of the offending agent is the best preventive strategy.
divalproex-induced hepatotoxicity variable low
Hepatic failure resulting in fatalities has occurred as a rare complication of divalproex therapy, usually
during the first 6 months of treatment. Serious or fatal hepatotoxicity may be heralded by malaise,
weakness, lethargy, facial edema, anorexia, and vomiting. Patients should be monitored closely for
appearance of these symptoms. Liver function tests should be performed prior to therapy and at frequent
intervals thereafter, especially during the first 6 months.[166]
divalproex-induced pancreatitis variable low
Life-threatening pancreatitis has been reported as a complication of divalproex therapy. Some of the cases
have been hemorrhagic, with rapid progression from initial symptoms to death. Onset of cases has been
variable, with some occurring shortly after initiation of divalproex, and others after several years of use. In
clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416 patients, representing
1044 patient-years of experience. The emergence of abdominal pain, nausea, vomiting, and/or anorexia
should prompt medical evaluation.[166]
blood dyscrasias due to carbama zepine variable low
Aplastic anemia and agranulocytosis have been reported as rare complications of carbamazepine therapy.
The risk of their occurrence is 5 to 8 times greater than that observed in the general population. Transient
or persistent decreased platelet or white blood cell counts have also been observed. Blood cell count
monitoring is recommended before and during treatment, increasing the frequency of monitoring should
any downward trend in white blood cells or platelets emerge.[167] [168]
Prognosis
FOLLOW UP
Bipolar disorder most often begins during late adolescence to young adulthood, with pooled data from recent
studies reporting average onset at around age 22.[32]
Likelihood of recurrence is almost certain, as the vast majority of patients have more than 1 lifetime episode.
Although considerable variability exists regarding relapses across individuals with bipolar disorder, it is
generally believed and supported by the evidence that, over time, episodes become more frequent and that
the euthymic intervals become shorter in between episodes. Subsyndromal symptoms may be chronic for
some patients with bipolar disorder.
Manic episodes typically have an abrupt onset, developing over a few days, while depressive episodes
usually develop more gradually. With treatment, episodes of mania, depression, or mixed states last
approximately 3 months.[151] Relapses that occur shortly after remission is achieved are typically a return to
the most recent pole (depressive or manic) of illness. However, during longer-term follow-up, in 85% of cases
the next episode is of the opposite polarity.[32] Life events or triggers are commonly linked as precipitants of
episodes, although this effect is more prominent in earlier than in later phases of bipolar disorder.[32]
The overall long-term outcome for bipolar disorder based on prospective cohort natural history studies is not
particularly good. Although treatments typically are effective at reducing symptoms, and episodes usually
remit, only a minority of patients are substantially well over long-term follow-up. Over an average of about 13
years of follow-up, the main outcome of treated bipolar I disorder was reported to be chronic subsyndromal
depression; patients were symptomatic despite treatment 47% of the time, with the majority of symptomatic
time spent experiencing depressive rather than manic or mixed symptoms.[152] Among bipolar II patients,
54% of their time was symptomatic, again with the depressive burden heavily outweighing the hypomanic
burden.[153]
Mortality is higher among patients with bipolar disorder when compared with the general population. The
standardized mortality ratio for bipolar disorder due to cardiovascular disease is reported to range between
1.2 and 3.0, while the standardized mortality ratio for suicide is between 14.0 and 23.4.[32]
75
Bipolar disorder in adults Guidelines
Treatment guidelines
International
Canadian Network for Mood and Anxiety Treatments (CANMAT) and

International Society for Bipolar Disorders (ISBD) collaborative update of
CANMAT guidelines for the management of patients with bipolar disorder:
update 2013 23237061 Yatham LN, Kennedy SH, Parikh SV, et al. Canadian
Network for Mood and Anxiety Treatments (CANMAT) and International
Society for Bipolar Disorders (ISBD) collaborative update of CANMAT
guidelines for the management of patients with bipolar disorder: update
2013. Bipolar Disord. 2013 Feb;15(1):1-44.
Published by: Canadian Network for Mood and Anxiety Treatments; Last published: 2013
International Society for Bipolar Disorders
The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force
GUIDELINES
recommendations for the management of patients with mood disorders and

comorbid substance use disorders 22303521 Beaulieu S, Saury S, Sareen
J, et al. The Canadian Network for Mood and Anxiety Treatments (CANMAT)
task force recommendations for the management of patients with mood
disorders and comorbid substance use disorders. Ann Clin Psychiatry. 2012
Feb;24(1):38-55.
Published by: Canadian Network for Mood and Anxiety Treatments Last published: 2012
The World Federation of Societies of Biological Psychiatry (WFSBP)

guidelines for the biological treatment of bipolar disorders: acute and
long-term treatment of mixed states in bipolar disorder 29098925 Grunze
H, Vieta E, Goodwin GM, et al. The World Federation of Societies of
Biological Psychiatry (WFSBP) guidelines for the biological treatment
of bipolar disorders: acute and long-term treatment of mixed states
in bipolar disorder. World J Biol Psychiatry. 2018 Feb;19(1):2-58.
ht tp://www.wfsbp.org/fileadmin/user_upload/Treatment_Guidelines/
The_World_Federation_of_Societies_of_Biological_Psychiatry_WFSBP_Guidelines_for_t
Published by: World Federation of Societies of Biological Psychiatry Last published: 2018
The International College of Neuro-Psychopharmacology (CINP) treatment

guidelines for bipolar disorder in adults (CINP-BD-2017), Part 3: the
clinical guidelines 27941079 Fountoulakis KN, Grunze H, Vieta E, et al. The
International College of Neuro-Psychopharmacology (CINP) treatment
guidelines for bipolar disorder in adults (CINP-BD-2017), Part 3: the clinical
guidelines. Int J Neuropsychopharmacol. 2017 Feb 1;20(2):180-95. ht tps://
www.ncbi.nlm.nih.gov/pmc/articles/PMC5408976/
Published by: The International College of Neuro-Psychopharmacology Last published: 2017
Bipolar disorder in adults Guidelines
International

guidelines for the biological treatment of bipolar disorders: update 2012
on the long-term treatment of bipolar disorder 23480132 Grunze H, Vieta
E, Goodwin GM, et al. The World Federation of Societies of Biological
Psychiatry (WFSBP) guidelines for the biological treatment of bipolar
disorders: update 2012 on the long-term treatment of bipolar disorder. World
J Biol Psychiatry. 2013 Apr;14(3):154-219. ht tp://www.wfsbp.org/fileadmin/
user_upload/Treatment_Guidelines/Grunze_et_al_2013.pdf

on the treatment of acute bipolar depression 20148751 Grunze H, Vieta E,
Goodwin GM, et al. The World Federation of Societies of Biological Psychiatry
GUIDELINES
(WFSBP) guidelines for the biological treatment of bipolar disorders: update
2010 on the treatment of acute bipolar depression. World J Biol Psychiatry.
2010 Mar;11(2):81-109. ht tp://www.wfsbp.org/fileadmin/user_upload/
Treatment_Guidelines/Guidelines_Acute_Bipolar_Depression_2010.pdf

on the treatment of acute mania 19347775 Grunze H, Vieta E, Goodwin GM,
et al. The World Federation of Societies of Biological Psychiatry (WFSBP)
on the treatment of acute mania. World J Biol Psychiatry. 2009;10(2):85-116.
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Evidence-based guidelines for treating bipolar disorder 26979387 Goodwin

GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating
bipolar disorder: revised third edition recommendations from the
British Association for Psychopharmacology. J Psychopharmacol. 2016
Jun;30(6):495-553. ht tp://www.bap.org.uk/pdfs/BAP_Guidelines-Bipolar.pdf
Published by: British Association for Psychopharmacology Last published: 2016
The European Psychiatric Association (EPA) guidance on suicide treatment

and prevention 22137775 Wasserman D, Rihmer Z, Rujescu D, et al. The
European Psychiatric Association (EPA) guidance on suicide treatment and
prevention. Eur Psychiatry. 2012 Feb;27(2):129-41. ht tp://www.europsy.net/wp-
content/uploads/2013/11/wasserman.pdf
Published by: European Psychiatric Association Last published: 2012
77
Bipolar disorder in adults Online resources
Online resources
1. Mood Disorder Questionnaire (MDQ) (external link)
2. Bipolarity Index (external link)
3. World Health Organization World Mental Health Composite International Diagnostic Interview (WHO
WMH-CIDI) (external link)
4. Young Mania Rating Scale (external link)
5. Bipolar Spectrum Diagnostic Scale (BSDS) (external link)
6. National Institute of Mental Health: bipolar disorder (external link)
7. Depression and Bipolar Support Alliance (external link)
8. European Medicines Agency: valproate medicines pregnancy prevention programme materials

(external link)
ONLINE RESOURCES
Bipolar disorder in adults Evidence scores
Evidence scores
1. Reduction in symptoms of mania: there is good-quality evidence that aripiprazole improves symptoms
of acute mania within 2 days compared with placebo. Improvement continues over 3 weeks and is
sustained over 12 weeks. The magnitude of improvement to week 12 is similar with aripiprazole and
lithium.[73]
Evidence level A: Systematic reviews (SRs) or randomized controlled trials (RCTs) of >200
participants.
2. Reduction in symptoms of mania: there is good-quality evidence that asenapine is efficacious and well
tolerated in patients experiencing manic symptoms compared with placebo.[74] [75] [76]
participants.
3. Reduction in symptoms of mania: there is good-quality evidence that paliperidone is efficacious and
tolerable in the treatment of acute mania.[77]
participants.
4. Reduction in symptoms of depression: there is medium-quality evidence that quetiapine immediate

release and quetiapine extended release[94] reduces the symptoms of depression after 8 weeks
compared with placebo.
Evidence level B: Randomized controlled trials (RCTs) of <200 participants, methodologically
flawed RCTs of >200 participants, methodologically flawed systematic reviews (SRs) or good quality
observational (cohort) studies.
5. Reduction in symptoms of depression: there is medium-quality evidence that divalproex sodium is

efficacious in the acute treatment of depressive symptoms compared with placebo.[97] [98] [99]
6. Reduction in symptoms of mania: there is medium-quality evidence that aripiprazole is efficacious and
well tolerated in the maintenance treatment of bipolar disorder.[128]
EVIDENCE SCORES
79
Bipolar disorder in adults References
Key articles
• McIntyre RS, Nguyen HT, Soczynska JK, et al. Medical and substance-related comorbidity in
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Lancet. 2010 Jan 30;375(9712):385-95. Abstract
• Muzina DJ. What physicians can do to prevent suicide. Cleve Clin J Med. 2004 Mar;71(3):242-50.
Abstract
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// Authors:
Sudhakar Selvaraj, MBBS DPhil MRCPsych

Assistant Professor of Psychiatry
University of Texas Health Science Center, Houston, TX
DISCLOSURES: SS has received intravenous citalopram for research from Lundbeck UK and participated
as a speaker organized by Global Medical Education. SS has third-party indirect share in the form of
convertible note in Flow MedTech, Inc (a medical device start-up company).
// Acknowledgements:
Dr Sudhakar Selvaraj would like to gratefully acknowledge Dr Prashant Gajwani and Dr David J. Muzina,
previous contributors to this topic. PG has served on the speakers' bureau for Merck and Sunovion. DJM is
an author of a number of references cited in this topic. DJM has previously received honoraria for research
support from Repligen Co. He has also previously received honoraria as a speaker and/or advisor from
AstraZeneca, Pfizer, BMS, Wyeth, Sepracor, and GSK. DJM is a full-time employee of Medco.
// Peer Reviewers:
Roger McIntyre, MD
Head
Mood Disorders Psychopharmacology Unit, University Health Network, Associate Professor of Psychiatry
and Pharmacology, University of Toronto, Ontario, Canada
DISCLOSURES: RM has received research funds from Stanley Medical Research Institute and National
Alliance for Research on Schizophrenia and Depression (NARSAD). RM is on the advisory boards for
AstraZeneca, Bristol-Myers Squibb, France Foundation, GlaxoSmithKline Janssen-Ortho, Solvay/Wyeth,
Eli Lilly, Organon, Lundbeck, Biovail, Pfizer, Shire, and Schering-Plough. RM is on the speakers' bureau for
Janssen-Ortho, AstraZeneca, Eli Lilly, Lundbeck, Biovail, and Wyeth. RM has received research grants from
Eli Lilly, Janssen-Ortho, and Shire.
Jan Scot t, MBBS

Professor of Psychological Medicine
University of Newcastle, Honorary Professor, Psychological Treatments Research, Institute of Psychiatry,
London, University Department of Psychiatry, Royal Victoria Infirmary, Newcastle upon Tyne, UK
DISCLOSURES: JS has received remuneration for attending advisory boards for AstraZeneca, BSM-
Otsuka, Eli Lilly, GSK, and Sanofi-Aventis.

Bipolar Disorder in Adults: The Right Clinical Information, Right Where It's Needed

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Bipolar Disorder in Adults: The Right Clinical Information, Right Where It's Needed

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Bipolar disorder

The right clinical information, right where it's needed

Last updated: Sep 13, 2018

◊ The long-term course of illness is characterized by a predominance of depression, although a history

• At least 1 manic or mixed episode

• Prominent and persistent disturbance of mood characterized by elevated, expansive, or

• Clinically significant impairment in social, occupational, or other important areas of functioning

• Chronic, fluctuating course of mood disturbance characterized by numerous periods of

Step-by-step diagnostic approach

• Inflated self-esteem or grandiosity

• With manic episodes, marked impairment or hospitalization results

• A 9-item questionnaire that reflects the DSM-IV-TR criteria

onset of mood disorder prior to age 20 years

stressful life events

previous history of depression

lifetime history of a substance misuse disorder

presence of an anxiety disorder

History & examination factors

episode(s) of manic or mixed episodes (common)

episode(s) of hypomania (common)

inflated self-esteem or grandiosity (common)

• Can be present to a significant degree during a manic or hypomanic episode.[1]

decreased need for sleep (common)

more talkative than usual, or feels pressure to keep talking (common)

flight of ideas, or subjective experience that thoughts are racing (common)

increase in goal-directed activity or psychomotor agitation (common)

excessive involvement in pleasurable activities that have a high potential for

functional impairment (common)

no substance misuse (common)

no underlying medical cause (common)

not due to somatic antidepressant treatment or other prescribed medication

Bipolarity Index >60 points for bipolar I

Other tests to consider

Condition Differentiating signs / Differentiating tests

Substance-induced mood • May be clinically • Laboratory findings,

Major depressive disorder • Criteria include depressed • Clinical diagnosis using

Condition Differentiating signs / Differentiating tests

Cyclothymic disorder • Cyclothymic disorder is • Clinical diagnosis using

Condition Differentiating signs / Differentiating tests

Obsessive-compulsive • Anxiety disorder • Clinical diagnosis using

ADHD • Symptoms of inattention, • Clinical diagnosis using

• Inflated self-esteem or grandiosity

• Do not meet criteria for a mixed episode

• Inflated self-esteem or grandiosity

• Depressed mood most of the day, nearly every day

• Cause functional impairment (e.g., social, occupational)

Substance/medication-induced bipolar and related disorder

• Formerly known as bipolar disorder not otherwise specified (NOS)

• Does not meet criteria for bipolar I disorder or bipolar II disorder

Mania symptom severity

Step-by-step treatment approach

Acutely manic or hypomanic patients

that may be beneficial include ziprasidone, haloperidol, or lorazepam.

For hypomania or mild mania, monotherapy using lithium,[72] divalproex, carbamazepine,

Patients with an acutely mixed episode

Acutely depressed patients

First-line options include olanzapine/fluoxetine combination formulation, olanzapine,[93]

Duration of acute phase treatment

Long-term preventive treatment

diabetes, dyslipidemias) effects, or toxicity (renal, hepatic, hematologic, thyroid).

Second-line maintenance options, particularly as adjunctive agents, include aripiprazole,[135] divalproex

• Education to recognize and manage early warning symptoms:

• Increased time to any mood recurrence, reduced hospitalization rates, improved