Chapter 8
PHARMACOLOGICAL TREATMENT
OF BIPOLAR DISORDER
Joshua D. Rosenblat and Roger S. McIntyre
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Pharmacological interventions are the primary
modality of treatment for bipolar disorder (BD).
Numerous medications are currently approved in
the treatment of BD; however, medication selection
must be tailored to the specific patient and illness
phase. Careful medication selection and monitoring
is required to effectively treat BD, with numerous
patient and medication factors to consider when
selecting an optimal treatment plan. This chapter
provides an overview of currently available pharma-
cological treatments for BD, along with a discussion
of factors that should be considered when initiating
and continuing treatment. Additionally, the limita-
tions of current treatments are reviewed, with a brief
discussion of future treatments currently under
investigation.
EPIDEMIOLOGY AND PREVALENCE
BD is a severe and persistent mental illness associ-
ated with significant morbidity and mortality. In the
United States, the estimated lifetime prevalence of
BD is 4% (Blanco et al., 2017; Kessler et al., 2005).
Onset of illness is typically early in life, with initial
symptoms often experienced during adolescence
(Chengappa et al., 2003). The median age of onset
for BD is 25, which is substantially earlier compared
with major depressive disorder (MDD; median age
of onset is 32; Kessler et al., 2005). From the first
onset of initial mood symptoms, BD is character-
http://dx.doi.org/10.1037/0000133-008
APA Handbook of Psychopharmacology, S. M. Evans (Editor-in-Chief)
Copyright © 2019 by the American Psychological Association. All rights reserved.
ized by a relapsing and remitting course, typically
requiring lifelong pharmacological treatment.
Over the past several decades, numerous phar-
macological treatments for BD have been identified.
As with many treatments in psychiatry, the historical
identification and development of treatments for BD
primarily emerged through serendipitous discoveries.
For BD, essentially all treatments are medications
that were initially developed to treat a different
disorder that were subsequently repurposed to be
used in the treatment of BD. The exclusive use of
repurposed medications is somewhat unique to
BD compared with other major mental illnesses, as
numerous pharmacological treatments have been
developed specifically for other psychiatric disorders,
such as selective serotonin reuptake inhibitors (SSRIs)
for MDD or antipsychotics for schizophrenia. In
contrast, as noted, all BD treatments were initially
used for other indications. Lithium, anticonvulsants
(e.g., valproate, carbamazepine, lamotrigine),
and second-generation antipsychotics (SGAs) are
currently the primary treatments for BD; however,
lithium was first used in the treatment of gout
(Shorter, 2009), anticonvulsants for epilepsy, and
SGAs for schizophrenia.
The lack of de novo BD treatments speaks to some
of the complexity and difficulties of understanding
and treating BD. While decades of research have
revealed numerous potential contributing mecha-
nisms to the onset and progression of BD, the field
165
 Rosenblat and McIntyre
still lacks a unifying hypothesis to adequately explain
the pathoetiology of BD. The absence of clear hypoth-
eses has limited drug discovery, since BD treatment
advances have been forced to rely exclusively on seren-
dipity and repurposing of treatments initially designed
for other disorders rather than designing and testing
hypothesis-driven interventions.
The current chapter highlights evidence-based
pharmacological treatments of BD. The effective
use of pharmacological treatments may allow many
patients to achieve full remission of symptoms;
however, currently available treatments are still
associated with high rates of relapse, recurrence,
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treatment resistance, and poor tolerability. As such,
new treatments with improved efficacy and toler-
ability are still desperately needed. Further, the goal
of new treatments should move beyond remission of
symptoms and strive for disease-modifying effects
that may allow for full recovery and the experience
of wellness, rather than only the absence of
mood symptoms (Brown, McIntyre, Rosenblat, &
Hardeland, 2018).
DIAGNOSING BIPOLAR DISORDER
Similar to other psychiatric disorders, BD is a clinical
diagnosis based primarily on a thorough, complete
psychiatric assessment. In the Diagnostic and Statistical
Manual of Mental Disorders (5th edition; DSM–5),
Bipolar and Related Disorders has now been given its
own chapter between the Schizophrenia Spectrum
and Other Psychotic Disorders chapter and the
Depressive Disorders chapter in recognition that BD
is a distinct illness existing on the spectrum between
psychotic disorders and unipolar depressive disorders
(American Psychiatric Association, 2013). As in
the DSM–IV–TR, the diagnosis of BD is further
subcategorized into bipolar I disorder (BD-I) and
bipolar II disorder (BD-II). The diagnosis of BD-I
requires the history of at least one manic episode
with no requirement of previous major depressive
episodes (MDEs). For BD-II, a history of at least
one hypomanic episode and one MDE is required
(American Psychiatric Association, 2013).
When a patient presents with a current manic or
hypomanic episode, the diagnosis of BD is usually
clear; however, more commonly, patients will present
166
with a current MDE and an unclear history of poten-
tial previous manic or hypomanic episodes. The
assessor then has the difficult task of differentiating
bipolar from unipolar depression. The correct diag-
nosis of bipolar versus unipolar depression is of
critical importance, as it directly impacts treatment
selection along with predicted illness course (Forty
et al., 2008). Retrospective studies have shown that
patients with BD are frequently initially diagnosed
with MDD (i.e., unipolar depression), leading to
approximately 70% of BD patients being initially
misdiagnosed (Angst et al., 2011; Hirschfeld, Lewis,
& Vornik, 2003). Furthermore, one third of patients
do not receive the correct diagnosis of BD for more
than 10 years after initial symptom onset, leading
to a significant delay in the initiation of appro-
priate evidence-based pharmacological treatments
(Hirschfeld et al., 2003).
The misdiagnosis of BD as MDD frequently
leads to treatment with a first-line antidepressant
(as described in Chapter 7, this volume). Anti­
depressants pose the immediate risk of a manic
switch (i.e., causing a “switch” from an MDE to a
manic episode), which may have significant and
potentially irreversible medical, financial, social,
and occupational consequences (Wehr & Goodwin,
1987). Moreover, even in the absence of a manic
switch, the greater concern in the long term is
inadequate and inappropriate treatment, as initia-
tion of evidence-based treatment (e.g., mood stabi-
lizers) is delayed. With a missed diagnosis of BD,
patients may be trialed on several treatments for
MDD and be labelled as treatment refractory, when
in reality the lack of symptomatic improvement is
secondary to inappropriate treatment (e.g., receiving
antidepressants instead of mood stabilizers; Ghaemi,
Hsu, Soldani, & Goodwin, 2003).
A thorough evaluation of potential previous
hypomanic/manic episodes is paramount for an
accurate and timely diagnosis of BD. Delineating
an accurate timeline and the quality and severity
of manic symptoms through history obtained
directly from the patient along with collateral history
from people who might have witnessed previous
episodes is often helpful for clarifying the diagnosis.
Where the history of mania or hypomania is absent
or unclear, several clinical characteristics may help

predict an increased likelihood of a diagnosis of BD
(Forty et al., 2008). Using these clinical characteris-
tics, the International Society for Bipolar Disorders
(ISBD) has created a probabilistic model to help predict
the risk of BD based on several factors that increase
the probability of a diagnosis of bipolar depression,
including hypersomnia, hyperphagia, recurrence
(i.e., greater than five MDEs), psychotic symptoms,
and a family history of BD, as summarized in Table 8.1
(Mitchell, Goodwin, Johnson, & Hirschfeld, 2008).
In addition to a thorough psychiatric assessment,
as previously described, the use of several screening
and diagnostic tools may aid in the recognition
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of BD. Validated screening and assessment tools
are summarized in Table 8.2. The Mood Disorder
Questionnaire (MDQ) is often preferred for clinical
use given its validity and brevity. The MDQ is a five
minute clinically validated screening tool that is
publicly available and has been shown to increase
detection rates for both BD-I and BD-II (Hirschfeld
et al., 2000). If an assessor lacks confidence or
experience in diagnosing BD, a positive MDQ screen
would indicate that a referral to a mood disorder
TABLE 8.1
Proposed Probabilistic Approach to the Diagnosis of Bipolar I Depression in a Person Experiencing
a Major Depressive Episode With No Clear Prior Episodes of Mania
The greater likelihood of the diagnosis of bipolar I
depression should be considered if >4 of the
following features are presenta
Symptomatology and mental state signs
■ Hypersomnia and/or increased daytime napping
■ Hyperphagia and/or increased weight
■ Other “atypical” depressive symptoms such as “leaden paralysis”
■ Psychomotor retardation
■ Psychotic features and/or pathological guilt
■ Lability of mood/manic symptoms
Course of illness
■ 
Early onset of first depression (<25 years)a
■ 
Multiple prior episodes of depression (>4 episodes)a
Family History
■ 
Positive family history of bipolar disorder
Note. From “Diagnostic Guidelines for Bipolar Depression: A Probabilistic Approach,” by P. B. Mitchell, G. M.
Goodwin, G. F. Johnson, and R. M. Hirschfeld, 2008, Bipolar Disorders, 10, p. 150. Copyright 2008 by Wiley.
Reprinted with permission.
aConfirmation of the specific numbers to be used requires further study and consideration.
Pharmacological Treatment of Bipolar Disorder
specialist is recommended to increase the likelihood
of an accurate diagnosis and initiation of appropriate
treatment.
EVIDENCE-BASED PHARMACOLOGICAL
TREATMENTS OF BIPOLAR DISORDER
Pharmacological therapies are the primary form of
treatment in BD, with lifelong pharmacotherapy
usually indicated due to the high risk of relapse and
recurrence when treatment is discontinued (McIntyre,
2015; Yatham et al., 2013). Pharmacological treat-
ment of BD is unique compared with most other
psychiatric disorders, as efficacy and U.S. Food and
Drug Administration (FDA) approval is specific to
illness phase. As such, BD treatments are specifically
approved for the acute treatment of bipolar depres-
sive, manic, or mixed episodes, or for maintenance
treatment, as shown in Table 8.3. Of note, many
treatments are still commonly and appropriately used
during other phases (i.e., prescribed “off-label”) in the
absence of FDA approval (e.g., lithium or lamotrigine
for treatment of bipolar depression).
The greater likelihood of the diagnosis of unipolar
depression should be considered if >3 of the
following features are presenta
■ Initial insomnia
■ Appetite and/or weight loss
■ Normal or increased activity levels
■ Somatic complaints
■  Later onset of first depression (>25 years)a
■  Long duration of current episode (>6 months)a
■  Negative family history of bipolar disorder
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 Rosenblat and McIntyre

TABLE 8.2

Screening and Diagnostic Tools to Aid in the Recognition of Bipolar Disorder

Tool
Mood Disorder Questionnaire (Hirschfeld et al., 2000)
Hypomania Checklist (HCL-32; Altinbas et al., 2014)
Bipolar Depression Rating Scale (Galvão et al., 2013)
Mini International Neuropsychiatric Interview (Hergueta & Weiller, 2013)
Clinically Useful Depression Outcome Scale with DSM–5 Mixed
(Zimmerman, Chelminski, Young, Dalrymple, & Martinez, 2014)
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Description
Clinically validated self-report screening tool for bipolar I disorder
and bipolar II disorder
Patient self-report that screens for lifetime hypomanic symptoms
Clinician-administered assessment of current symptoms
Patient self-report assessing current manic symptoms
Patient self-report assessing current manic symptoms as part
of mixed features

FDA approval based on illness phase (e.g., rather
than approving treatments for all phases of BD) occurs
because of the substantial differences in efficacy
depending on illness phase. For example, numerous
agents have been shown to be efficacious in the acute
treatment of manic episodes (Yildiz, Nikodem, Vieta,
Correll, & Baldessarini, 2015); however, consider-
ably fewer agents have demonstrated efficacy in
the acute treatment of bipolar depression (Selle,
Schalkwijk, Vázquez, & Baldessarini, 2014). With
these differences in efficacy depending on illness
phase, the treatment of BD is often considered the
most complex, with numerous factors and caveats to
consider when selecting and optimizing treatment.

TABLE 8.3

FDA-Approved Treatments for Bipolar Disorder

Drug (generic name) Common trade names Depression Mania Mixed Maintenance
Lithium Eskalith , Lithobid
® ®
X X
Anticonvulsants
Valproate Depakote , Epival ® ® X X
Carbamazepine Tegretol , Carbatrol
® ® X X
Lamotrigine Lamictal ®
X
Antipsychotics/neuroleptics
Quetiapine a Seroquel ® X X X
Lurasidone Latuda ®
X
Aripiprazole a Abilify
® X X X
Risperidonea Risperdal® X X
Ziprasidone Geodon®, Zeldox® X X
Cariprazine Vraylar ® X X
Olanzapine a
Zyprexa ®
X X X
Olanzapine/fluoxetine Symbyax ® X
combination (OFC)
Asenapinea Saphris®, Sycrest® X X
Chlorpromazinea Largactil®, Thorazine® X

Note. Listed approval is for adults (age 18–65), unless otherwise specified (aalso approved for adolescents
age 13–17). Approval information obtained from http://www.fda.gov, as of October 2017.

168
 Pharmacological Treatment of Bipolar Disorder

The complexity of treatment is further increased as Principles of Pharmacological Treatment

medications that may help to alleviate one pole of
symptoms may simultaneously exacerbate symp-
toms of the opposite mood pole, thus increasing the
risk of relapse or recurrence of the opposite mood
state. For example, SSRIs and stimulants may
sometimes be beneficial in the acute treatment of
bipolar depression, however, they carry significant
risk of causing a manic switch. Similarly, many effec-
tive treatments of mania may lead to depressive symp-
toms, such as hypersomnia and low energy secondary
to the sedating effects of many antimanic agents.
Several other factors contribute to the complexity
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Numerous factors must be considered when selecting
pharmacological treatments for BD. The following
section reviews these considerations, along with
general principles required to effectively and safely
treat patients with BD. Both phase-specific efficacy
and tolerability must be considered in selecting
a treatment. Understanding unique patient and
medication factors is also important to find the best
treatment for each individual patient.
Considerations for phase-specific efficacy.  In
medication selection, several factors must be con-
sidered, as summarized in Exhibit 8.1. Central to

of treating BD, such as high rates of psychiatric and
medical comorbidity and the poor tolerability of
many BD treatments.
While the treatment of BD is often challenging,
an organized and structured approach may allow
for effective treatment to alleviate current symp-
toms and decrease the risk of relapse and recur-
rence. Towards this end, in this section we will
summarize the following: (a) basic principles
of BD treatment, (b) descriptions of commonly
prescribed mood stabilizers, and (c) an approach
to treatment of specific illness phases (i.e., acute
treatment of mania and depression and mainte-
nance treatment).
medication selection is consideration of expected
efficacy and tolerability. Current symptomatology
often largely dictates treatment selection. As shown
in Tables 8.4 and 8.5, different mood stabilizers have
variable efficacy in the treatment and prevention of
major depressive and manic episodes. As such, in an
acute mood episode, specifically selecting a mood
stabilizer with demonstrated efficacy in that specific
mood state is required.
The use of monotherapy (i.e., use of only one
medication) should be prioritized when possible to
minimize the risk of additional side effects, drug–
drug interactions, and increasing costs. However, the
use of combination therapies is often required due

EXHIBIT 8.1

Key Consideration and Principles in the selection of Pharmacological Treatment for Bipolar Disorder

■ Prior to prescribing treatment, a thorough psychiatric assessment is required.

■ A medical evaluation with relevant baseline bloodwork is usually indicated.
■ Once a diagnosis of bipolar disorder has been confirmed, treatment with a mood stabilizer (e.g., lithium, anticonvulsants, or anti­
psychotics) is indicated, regardless of phase of illness.
■ The informed consent discussion should include evaluation of phase-specific efficacy, along with short- and long-term side effect profiles.

■ Considerations of medication costs and drug coverage should be part of the informed consent discussion.
■ Selection of medications with both demonstrated efficacy in the current phase of illness and favorable tolerability/safety profiles
should be prioritized.
■ Monotherapy should be used if possible; however, combination therapy may be required when severe symptoms, psychotic features,
or treatment resistance is evident.
■ Use of metabolically neutral (e.g., no weight gain) treatments should be prioritized.
■ Sedating treatments should be dosed once daily at night time, if possible.
■ The potential for drug–drug interactions should be considered.
■ Simplicity of use (e.g., once daily oral dosing) should be considered.
■ Patient preference should be elicited in the medication selection process.
■ Lifelong pharmacological treatment is usually required, with few exceptions.
■ Use of adjunctive psychosocial interventions should be considered; however, they should only be used in combination with adequate
pharmacological treatment.

169
 Rosenblat and McIntyre

TABLE 8.4

Overview of Efficacy and Tolerability of Lithium and Anticonvulsants (Based on Evidence and Expert
Consensus)

Efficacy in mania Efficacy in depression

Relapse Relapse
Drug Acute prevention Acute prevention Notable safety/tolerability concerns*
Lithium +++ +++ ++ ++ Renal, thyroid, metabolic
Divalproex +++ ++ + +/− Bone marrow suppression, metabolic, PCOS, teratogenicity
Carbamazepine ++ ++ + + Blood marrow suppression, sedation, teratogenicity
Oxcarbazepine + + +/− +/− Sedation
Lamotrigine +/− +/− ++ ++ Risk of severe rash
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Topiramate − − + + Cognitive dysfunction

Gabapentin − − − − Sedation

Note. For efficacy during specified illness phase: +++ = highly efficacious, ++ = moderately efficacious, + = mildly
efficacious, +/− = minimal or unclear efficacy, − = evidence for lack of efficacy. PCOS = polycystic ovarian syndrome.
*Not a complete list of side effects, only highlighting key concerns. “Metabolic” refers generally to all metabolic
effects (e.g., weight gain, dyslipidemia, insulin resistance).

TABLE 8.5

Overview of Efficacy and Tolerability of Antipsychotic Efficacy (Including Only Select Agents
Commonly Used in North America)

Efficacy in mania Efficacy in depression

Relapse Relapse
Drug Acute prevention Acute prevention Notable safety/tolerability concerns*

First-generation antipsychotics
Haloperidol** +++ ++ + +/− Parkinsonism
Chlorpromazine ++ + +/− +/− Parkinsonism, sedation
Second-generation antipsychotics
Quetiapine +++ +++ +++ +++ Sedation, metabolic
Olanzapine +++ +++ + + Sedation, metabolic
Clozapine ++ ++ + + Sedation, metabolic, myocarditis,
agranulocytosis, seizures
Risperidone** +++ +++ + + Parkinsonism
Paliperidone**a +++ +++ + + Parkinsonism
Lurasidone + + +++ ++ Akathisia
Asenapine ++ ++ +/− + Sedation
Ziprasidone ++ + − +/− Akathisia, QTc prolongation
Partial dopamine agonists
Aripiprazole** ++ + +/− + Akathisia
Cariprazine ++ + + +/− Akathisia
Brexpiprazole +/− +/− +/− +/− Akathisia

Note. For efficacy during specified illness phase: +++ = highly efficacious, ++ = moderately efficacious, + = mildly
efficacious, +/− = minimal or unclear efficacy, − = evidence for lack of efficacy. QTc = corrected QT interval.
*Not a complete list of side effects, only highlighting key concerns. “Metabolic” refers generally to all metabolic
effects (e.g., weight gain, dyslipidemia, insulin resistance). **Also available as long-acting depot injection.
aSuggested efficacy for paliperidone largely extrapolated from risperidone data.

170

to the high rates of relapse and treatment resistance
with monotherapies. Combination therapies should
be considered within the context of severe symptoms,
treatment resistance, and/or psychotic features. For
example, with a severe manic episode with psychotic
features, the use of dual therapy with an antipsychotic
plus a conventional mood stabilizer (e.g., lithium or
anticonvulsant) is usually indicated. Clinical trials
have focused on combining SGAs with lithium or
divalproex, and as such are the most evidence-based
and commonly used combinations (Parker, Graham,
& Tavella, 2017). Table 8.6 summarizes specific
common and efficacious combinations used for the
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acute treatment of mania and depression along with
combinations used for maintenance therapy.
Considerations for tolerability and safety.  The
importance of considering tolerability and safety
has been increasingly emphasized by both patients
TABLE 8.6
Common Effective Combinations Used During
Specific Illness Phases of Bipolar Disorder
Illness phase Combinations
Mania Lithium + antipsychotic (quetiapine,
risperidone, olanzapine, aripiprazole,
asenapine)
Divalproex + antipsychotic (quetiapine,
risperidone, olanzapine, aripiprazole,
asenapine)
Lithium + divalproex
Depression Lurasidone + lithium
Lurasidone + divalproex
Olanzapine + fluoxetine* (available in
combination pill)
Quetiapine + SSRI* (except paroxetine)
Lithium + lamotrigine
Lithium + antidepressant* (bupropion or
SSRIs, except paroxetine)
Euthymia Lithium + antipsychotic (quetiapine,
(maintenance) risperidone, olanzapine, aripiprazole,
ziprasidone, lurasidone)
Divalproex +antipsychotic (quetiapine,
risperidone, olanzapine, aripiprazole,
ziprasidone, lurasidone)
Lithium + lamotrigine
Note. *Avoid use of antidepressant with mixed features
or history of rapid cycling or propensity for manic/
hypomanic episodes.
Pharmacological Treatment of Bipolar Disorder
and clinicians (McIntyre, 2015). In the short
term, poor tolerability may lead to early treatment
discontinuation and a potential rupture in the
therapeutic alliance with the treatment provider.
Further, for patients who continue poorly toler-
ated treatment, given that treatment is usually
lifelong, the significant side effects of many BD
treatments may lead to significant long-term medi-
cal sequelae. Most notably, several treatments are
associated with significant metabolic side effects,
leading to features of metabolic syndrome, such
as significant weight gain, dyslipidemia, insulin
resistance, and resultant cardiovascular disease
(Solmi et al., 2017). As such, treatment guidelines
now emphasize the importance of prioritizing
metabolically neutral agents (Parker et al., 2017).
Figure 8.1 illustrates the relative metabolic effects
of various mood stabilizers. If metabolic changes
are observed, switching to a more metabolically
neutral agent should be considered in conjunction
with evaluating the risk of relapse with a switch in
treatment (Kemp, 2014).
Common and problematic side effects also
include excessive sedation and risk of extra­
pyramidal symptoms (EPS). Table 8.7 summarizes
the variable effects of various mood stabilizing
treatments on wakefulness. Notably, individual
patients may have different reactions and report
experiencing sedative effects with any mood stabi-
lizing agent. As such, a thorough inquiry of poten-
tial side effects, especially the impact on sleep and
wakefulness, should be assessed for every patient
individually and treatment timing tailored accord-
ingly (e.g., sedating medications taken at night).
For antipsychotics, EPS is another common side
effect with variable prevalence (e.g., common
with risperidone, rare with quetiapine) and quality
(e.g., parkinsonism with risperidone, akathisia
with aripiprazole) depending on agent. Relative
rates and characteristics of EPS are further
reviewed in Chapter 10, this volume.
Taken together, as summarized in Exhibit 8.1,
several factors should be considered when selecting
a treatment for BD. Current symptom profile, severity
of symptoms, history of response (including personal
and family history of response), treatment resistance,
and side effect profiles should be considered.
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 Rosenblat and McIntyre

Least metabolic side effects Greatest metabolic side effects

Aripiprazole
Lurasidone
Cariprazine Carbamazepine Lithium Quetiapine
Clozapine
Ziprasidone Oxcarbazepine Risperidone Valproate
Olanzapine
Lamotrigine Haloperidol Paliperidone Chlorpromazine
Asenapine
Brexpiprazole
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FIGURE 8.1.   Relative metabolic effects of mood stabilizing treatments.

Summary of Select Mood Stabilizing antidepressants. Notably, the mechanism of action

Agents: Mechanisms of Action, leading to mood stabilizing effects remains largely
Efficacy, and Tolerability unknown for several of these medications.
As previously described, there is no “anti-BD”
Lithium.   Lithium is known as the “classic mood
medication, but rather, various classes of medi­
stabilizer” and has been routinely used in the treat-
cations that have been repurposed to target BD
ment of BD for more than 50 years (Shorter, 2009).
symptoms, with variable efficacy depending on
As one of the oldest treatments for BD, lithium
illness phase. The following section summarizes
remains a key treatment option during all phases of
the mechanism of action, efficacy and tolerability
illness. The definitive mechanism of action remains
of lithium, anticonvulsants, antipsychotics and
unclear; however, several plausible hypotheses have
emerged. The most studied targets of lithium are
TABLE 8.7 signal transduction sites beyond neurotransmitter
receptors. Lithium has been shown to inhibit mes-
Sedating Effects of Mood Stabilizing Agents senger enzymes, such as inositol monophosphate,
glycogen synthase kinase 3 (GSK-3), and protein
Sedating Sleep-wake neutral Wake-promoting kinase C (PKC), along with modulating G proteins
Clozapine Lamotrigine Aripiprazole (Jope, 1999). The net effect of these molecular
Olanzapine Risperidone Cariprazine changes is the alteration of neuronal signaling
Quetiapine Paliperidone Brexpiprazole cascades to promote neuroprotection and neuro-
Asenapine Ziprasidone
Chlorpromazine Lurasidone
plasticity, which may facilitate the mood stabilizing
Valproate Haloperidol effects of lithium (Malhi, Tanious, Das, Coulston,
Lithium & Berk, 2013). An additional hypothesis that has
Carbamazepine emerged is that the immunomodulatory effects of
Oxcarbazepine
lithium may play a significant role (Horrobin &

172

Lieb, 1981). Replicated evidence has demonstrated
a clear role of immune dysfunction in the patho-
physiology of BD (Rosenblat & McIntyre, 2017a).
As such, the immunomodulatory effect of lithium
has been suggested to be another potential mech-
anism of action facilitating lithium’s mood stabi-
lizing effects.
Regardless of the mechanism of action, replicated
evidence has demonstrated a robust antimanic effect
with lithium (Storosum et al., 2007). Lithium has
also been shown to have antidepressant effects
(in BD and MDD) and to be highly efficacious in the
prevention of future manic episodes, and, to a lesser
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extent, depressive episodes (Young & Newham,
2006). Further, lithium has been shown to have
a mood-independent (in BD and other disorders)
antisuicide effect and continues to be one of the
only medications proven to decrease suicide rates
(Cipriani, Hawton, Stockton, & Geddes, 2013).
Lithium may be effectively used as a monotherapy
during any illness phase or in combination with most
antipsychotics, valproate, or lamotrigine.
Despite the ample evidence of numerous benefits
of prescribing lithium in BD, the use of lithium
has significantly decreased in the United States as
the use of SGAs has become more popular in the
treatment of BD (Pillarella, Higashi, Alexander, &
Conti, 2012). This change in prescribing patterns
is likely partly related to the perceived simplicity in
prescribing SGAs versus the anticipated complexity of
prescribing lithium. Indeed, there is added complexity
in prescribing lithium as serum levels of the drug,
along with thyroid and renal function, must be moni-
tored regularly (Ng et al., 2009). The rare but poten-
tially lethal risk of lithium toxicity may also discourage
prescribers from using lithium (McKnight et al., 2012).
However, with adequate monitoring, side effects
and toxicity (as summarized in Exhibit 8.2) may
be detected early and treated appropriately, making
lithium a safe and often well tolerated treatment
option. Of note, SGAs also require regular moni-
toring and carry significant risk for metabolic
effects (Ng et al., 2009). As such, lithium use should
not be avoided simply based on perceived complexity
of prescribing and monitoring compared with SGAs.
Rather, lithium should be more frequently considered
in the treatment of BD.
Pharmacological Treatment of Bipolar Disorder
EXHIBIT 8.2
LITHIVM Mnemonic for Side Effects and Signs
of Lithium Toxicity
Leukocytosis/Lethargy
Insipidus (nephrogenic diabetes insipidus)
Tremor/Teratogenicity (Ebstein’s anomaly)
Hypothyroidism/Hyperparathyroidism
Increased weight
Vomiting
Metallic taste/Myocardial (ECG changes)
Note. ECG = electrocardiogram.
Anticonvulsants.   Along with lithium, anti­
convulsants are also considered conventional mood
stabilizers. Anticonvulsants were initially repurposed
for the treatment of mania given the theoretical
parallels between seizures and manic episodes. The
phenomenon of kindling has been proposed in both
epilepsy and BD, as seizures and mood episodes
respectively have a kindling effect in that every epi-
sode or seizure leads to neurobiological changes
that increase the risk of future occurrences (Berk
et al., 2017). Additionally, both mania and seizures
are associated with inappropriately overactive neural
circuits (i.e., imbalance between activating glutamate
signaling and inhibitory gamma-aminobutyric acid
[GABA] signaling). Valproate and carbamazepine
were among the first anticonvulsants assessed for
the acute treatment of mania and both proved to
be efficacious antimanic treatments (Yildiz et al.,
2015). A potential class effect was initially assumed,
leading to clinical trials assessing the antimanic
effects of numerous other anticonvulsants (e.g.,
pregabalin, gabapentin, levetiracetam, topiramate,
oxcarbazepine). These yielded mostly disappointing
results, with valproate and carbamazepine being the
only anticonvulsants to demonstrate a consistent anti-
manic effect (Grunze, 2010). Given this variability in
efficacy, the anticonvulsant effect in itself is unlikely
to be the only or primary mechanism of action for
the antimanic effects of valproate and carbamazepine.
Similar to lithium, the mechanism of action remains
unclear, with several unproven hypotheses.
Divalproex (the long-acting formulation of
valproate recommended for BD) is the most commonly
173
 Rosenblat and McIntyre
used anticonvulsant in BD. Proposed mechanisms
of action include inhibiting neuronal sodium chan-
nels, increasing the action of GABA, and modulating
downstream signaling cascades (i.e., similar to lithi-
um’s effect on second messenger systems; Williams,
Cheng, Mudge, & Harwood, 2002). Divalproex has
robust evidence for use in the acute treatment of
mania, in which it may be used as a monotherapy or
in combination with an SGA or lithium (Yildiz et al.,
2015). Divalproex also has evidence to support use
during maintenance therapy; however, divalproex
has a greater effect in preventing future manic episodes
with less of an effect in preventing depressive episodes
Copyright American Psychological Association. Not for further distribution.
(Vieta et al., 2011). Notably, divalproex has minimal
efficacy in the acute treatment of bipolar depression.
Similar to lithium, the use of divalproex has decreased
as the use of SGAs has become more popular.
Divalproex also requires monitoring of serum
levels, blood counts, and liver function, and for
metabolic side effects (Figure 8.2; Ng et al.,
2009). From a safety and tolerability perspective,
the greatest concerns with divalproex are the risk
for polycystic ovarian syndrome (PCOS), weight
gain, and teratogenicity (i.e., risk of fetal neural
tube defects if taken during pregnancy). The
recommended and most well tolerated formulation
of valproate is the long-acting formulation, dival-
proex, which should be used preferentially instead
of other formulations (e.g., valproic acid) when
possible (Yatham et al., 2013).
Carbamazepine was the first anticonvulsant
shown to have an antimanic effect; however, it is
currently used less frequently compared with dival-
proex, given differences in efficacy and tolerability.
Similar to divalproex, efficacy has primarily been
established for the acute treatment of mania along
with prevention of future manic episodes, and to
a lesser extent, prevention of depressive episodes
(Vieta et al., 2011). Significant safety concerns
for carbamazepine include risk of bone marrow
suppression leading to hematological complica-
tions, hepatic dysfunction, and risk of severe rash
(i.e., Stevens–Johnson syndrome). Of note, the
dosing of carbamazepine may also be challenging
as it autoinduces CYP450 3A4, the primary enzyme
responsible for its own metabolism. As such, serum
levels may decrease even if the dose is unchanged.
174
Regular monitoring of serum levels is thus required,
as shown in Figure 8.5.
The mechanism of action of carbamazepine
also remains unclear; the mechanism is likely
related to modulating sodium channels, but in
a different manner compared with divalproex
(Williams et al., 2002). Oxcarbazepine and eslicar-
bazepine likely have similar mechanisms of action
with less safety concerns; however, the efficacy
of these alternative mood stabilizers has yet to
be adequately demonstrated in BD (Popova,
Leighton, Bernabarre, Bernardo, & Vieta, 2007).
Lamotrigine is another commonly prescribed anti-
convulsant in BD; however, in contrast to other anti-
convulsants, lamotrigine is primarily prescribed for
the treatment and prevention of depressive episodes,
with limited benefit in the treatment and prevention
of manic episodes (Amann, Born, Crespo, Pomarol-
Clotet, & McKenna, 2011). Lamotrigine is generally
well tolerated with minimal propensity for metabolic
effects. The main side effect of concern is the risk of
a severe drug rash (e.g., Stevens–Johnson syndrome).
To minimize the risk of developing this severe rash,
a slow titration (e.g., 6 weeks to reach a therapeutic
dose) with regular monitoring for rashes is required.
With this necessary slow titration, lamotrigine requires
weeks to months before showing antidepressant
effects (Amann et al., 2011). The delayed effect is also
one of the reasons lamotrigine is only FDA approved
for maintenance treatment, although it is commonly
and appropriately prescribed for bipolar depressive
episodes with adequate patient counseling about the
delayed antidepressant effects. For patients with a
propensity to have recurrent manic or hypomanic
episodes, mixed features, or rapid cycling, lamotrigine
should be combined with a treatment with good
efficacy in the prevention of manic episodes, such as
lithium or an SGA. The combination of lamotrigine
with divalproex should be avoided, as there is a signif-
icant drug–drug interaction that increases the risk of
a severe rash as lamotrigine levels are increased. As
such, lamotrigine dosages should be decreased by half
during the titration (e.g., starting with 12.5 mg instead
of 25 mg) if coprescribing divalproex.
Antipsychotics.   Soon after the effects of anti-
psychotics were discovered for the treatment of
schizophrenia, antipsychotics were utilized in the
 Pharmacological Treatment of Bipolar Disorder

Level 1A Established efficacy:

Mild to moderate severity and/or not requiring hospitalization
Optimize mood stabilizer (lithium*, divalproex*, or carbamazepine*) if already
prescribed. Check blood levels if appropriate.
Lithium* monotherapy
Monotherapy with aripiprazole, asenapine, divalproex*, quetiapine, risperidone,
ziprasidone, or cariprazine.
Severe and/or requiring hospitalization
Lithium* or divalproex* + aripiprazole, asenapine, quetiapine, or risperidone
Electroconvulsive therapy (ECT) is recommended if medical emergency/patient welfare
at risk and pharmacotherapy is insufficient.

Level 1B Established efficacy, but with safety concerns**:

Mild to moderate severity and/or not requiring hospitalization
Monotherapy with either haloperidol or olanzapine
Copyright American Psychological Association. Not for further distribution.

Severe and/or requiring hospitalization

Lithium* or divalproex* + either haloperidol or olanzapine

Level 2 If Levels 1A and 1B are ineffective and/or not well tolerated:

Combination treatment with lithium* + divalproex*
Combination with lithium* and/or divalproex* + second generation
antipsychotic (SGA) other than clozapine
Carbamazepine* monotherapy

Level 3 If Levels 1 and 2 are ineffective and/or not well tolerated:

Electroconvulsive therapy (ECT)
Clozapine + lithium* or divalproex*
Lithium* + carbamazepine*
Divalproex* + carbamazepine*

Level 4 If Levels 1–3 are ineffective and/or not well tolerated:

A three-drug combination of Level 1, 2, and 3. Drugs
may include first generation antipsychotic (FGA) or
second generation antipsychotic (SGA) but NOT TWO
antipsychotic medications.
Example: lithium* + (divalproex* or carbamazepine*) +
antipsychotic

Notes:
*Caution should be used when prescribing lithium, lamotrigine, divalproex or carbamazepine to
women of reproductive age due to increased risks to the fetus with use during pregnancy, including
neural tube and other major birth defects. Please see Florida Best Practice Recommendations for
Women of Reproductive Age with Serious Mental Illness and Comorbid Substance Use Disorders
and online guideline on the Pharmacological Treatment of Mood Disorders During Pregnancy.
**Side-effect concerns with these agents include weight gain, metabolic syndrome, and
extrapyramidal symptoms (EPS). Side-effects warrant vigilance and close monitoring on the part of
the clinicians.
Data for use of paliperidone to treat bipolar mania are mixed. Paliperidone >6 mg has some data
supporting efficacy.
Benzodiazepines may be used as an adjunct treatment for acute treatment of bipolar mania.

FIGURE 8.2.   Algorithm for treatment of mania and hypomania based on Florida
Medicaid guidelines. From “2017–2018 Florida Best Practice Psychotherapeutic
Medication Guidelines for Adults,” by R. S. McIntyre, 2018, pp. 16–17 (http://www.
medicaidmentalhealth.org/_assets/file/Guidelines/2018-Psychotherapeutic%20
Medication%20Guidelines%20for%20Adults%20with%20References.pdf). Copyright
2018 by the USF Medicaid Drug Therapy Management Program for Behavioral Health.
Reprinted with permission.

175
 Rosenblat and McIntyre
acute treatment of mania, particularly when
psychotic features were present. Early on, anti­
psychotics were found to be helpful in the acute
treatment of mania with quick effects, as mono­
therapy or in combination with a conventional
mood stabilizer (e.g., lithium or anticonvulsant).
As with schizophrenia, currently the use of SGAs is
predominant, with first-generation antipsychotics
infrequently prescribed given the risk of tardive
dyskinesia with long-term use. Details about mecha-
nism of action and side effect profiles are further
discussed in Chapter 10, this volume.
For the acute treatment of mania, it is likely that all
Copyright American Psychological Association. Not for further distribution.
antipsychotics have an effect; as shown in Table 8.3,
almost all are FDA indicated for the acute treatment
of manic and mixed episodes. A comparative network
meta-analysis comparing the antimanic effects of
all treatments found the following order of efficacy
of antimanic antipsychotics (from most efficacious
to least, with all antipsychotics being more effective
compared with placebo): haloperidol, risperidone,
olanzapine, aripiprazole, quetiapine, asenapine,
and ziprasidone (Yildiz et al., 2015). Given that
all antipsychotics appear to be effective antimanic
treatments, focusing on short- and long-term
tolerability is a key factor in deciding treatment
selection.
For the acute treatment of bipolar depression,
only lurasidone, quetiapine, and olanzapine–
fluoxetine combination pill (OFC) are FDA approved
with evidence for efficacy. Of these three SGAs,
lurasidone may be preferentially selected given that
quetiapine and OFC have significant metabolic
effects and sedation. Quetiapine is the only agent
with evidence for efficacy in the acute treatment of
BD-II depression. It is possible that other SGAs may
be effective (for both BD-I or BD-II depression),
but bipolar depression is very understudied, with
evidence limited to these three agents.
For maintenance treatment, it is likely that all
antipsychotics have an effect for relapse prevention
of mania and, to a lesser extent, depression; however,
only quetiapine, aripiprazole, and olanzapine
are FDA-approved maintenance treatments. If an
antipsychotic is being used as a monotherapy for
maintenance, it will likely need to be continued;
however, if it is being used adjunctively with a
176
conventional mood stabilizer, a careful assessment
of why the antipsychotic was initiated is required.
When used adjunctively, given the potential long-
term effects of antipsychotic use, discontinuation
of the antipsychotic a year after the most recent
mood episode should be considered. However,
if the patient’s condition is brittle, with a known
history of treatment resistance and frequent relapses,
continuing the combination therapy indefinitely may
be indicated due to the elevated risk of destabiliza-
tion when discontinuing the antipsychotic.
Antidepressants.   The use of antidepressants in BD
continues to be controversial. Antidepressants may
trigger or worsen manic symptoms (Altshuler et al.,
1995). As such, during an acute manic or hypomanic
episode or when mixed features are present, all
antidepressants should be discontinued (McIntyre,
2015). Further, in patients with a history of anti­
depressant treatment-emergent manic switches,
antidepressants should be avoided. Similarly, if a
patient has rapid cycling or a propensity for manic
or hypomanic episodes, antidepressants should be
avoided.
The use of antidepressants should be limited
to the acute treatment of bipolar depression, with
a greater role likely in BD-II compared with BD-I
(Altshuler et al., 2017; Yatham et al., 2013). When
using antidepressants in BD, two specific concerns
arise: (a) the risk of a potential manic switch (Viktorin
et al., 2014) and (b) the risk of inefficacy (Ostacher,
Tandon, & Suppes, 2016). Most prescribers are more
hypervigilant about the first risk (i.e., causing a manic
episode, a manic switch), but the risk of inefficacy
is of greater long-term concern, especially with
anti­depressant monotherapy. Mood stabilizers have
greater effect for the acute treatment of bipolar
depression as well as for relapse prevention. As
such, if a patient is being treated instead with anti­
depressant monotherapy, they are not receiving the
most evidence-based treatment, thus potentially
delaying remission and recovery (Pacchiarotti et al.,
2013). Taken together, antidepressants should not be
used first line, but they may have a role for augmenting
mood stabilizers when an inadequate response is
found with evidence-based mood stabilizer treatments.
Indeed, while their use remains controversial, repli-
cated evidence has shown antidepressant effects of

adjunctive antidepressants in the acute treatment of
bipolar depression (Liu et al., 2017).
Patients with BD-II, low propensity for manic/
hypomanic episodes, or previous history of response
to antidepressants may be more likely to benefit
from antidepressant treatment (Pacchiarotti et al.,
2013). Antidepressant monotherapy should be
discouraged. In general, tricyclics and tetracyclics,
along with SSRIs and norepinephrine inhibitors
(SNRIs), have elevated risk of manic switches and
should be avoided (Salvi, Fagiolini, Swartz, Maina,
& Frank, 2008). Bupropion and SSRIs (except for
paroxetine) have evidence to support an antidepres-
Copyright American Psychological Association. Not for further distribution.
sant effect in BD and are likely have the best risk–
benefit profile of the antidepressants (McInerney &
Kennedy, 2014).
While not an approved treatment for MDD or BD,
modafinil is indicated for improving wakefulness in
patients with excessive sleepiness, a symptom that
is common and functionally impairing in bipolar
depression. Further, adjunctive modafinil treatment
was demonstrated in one randomized controlled
trial (RCT) to have an acute antidepressant effect
in participants with bipolar depression that were
resistant to mood stabilizers (Frye et al., 2007).
Additionally, adjunctive modafinil was not associ-
ated with increased risk of mania compared with
the adjunctive placebo group. As such, modafinil
presents an additional option in the treatment of
bipolar depression.
Algorithm for Treatment
of Bipolar Disorder
In the following section, we describe current
evidence-based recommendations for the treatment
of BD during its various illness phases. Of note,
the most recent American Psychiatric Association
guidelines for the treatment of BD were published
in 2002 (American Psychiatric Association, 2002).
Since 2002, a large number of BD clinical trials
have been conducted. Thus, the current recom-
mendations are in accordance with the 2017–2018
Florida Best Practice Psychotherapeutic Medication
Guidelines for Adults (Florida Medicaid guidelines;
University of South Florida, Florida Medicaid Drug
Therapy Management Program, 2018), which have
integrated the results from more recent clinical trials.
Pharmacological Treatment of Bipolar Disorder
These guidelines may differ from other treatment
guidelines, as a greater emphasis has been placed on
balancing efficacy with tolerability. As such, certain
treatments that have robust evidence of efficacy may
be lower in the treatment algorithm (as compared
with previous treatment guidelines) because of
concerns around tolerability and safety (Parker
et al., 2017). Readers are encouraged to compare
and contrast other recent international BD treatment
guidelines (references provided in the Tool Kit of
Resources at the end of this chapter). However, for
clarity, only the Florida Medicaid guidelines for
the pharmacological treatment of BD are summa-
rized here. The following flow diagrams focus
on pharmacological interventions. Prior to initi-
ating any pharmacological interventions, all the
factors involved in treatment selection summarized
previously (Exhibit 8.1) should be considered.
Additionally, the use of measurement-based care
using validated scales, as summarized in Table 8.8,
is merited to more accurately evaluate treatment
response. The primary goals of BD treatment are
remission, maintenance of remission, prevention
of relapse/recurrence, and full functional recovery
while experiencing good medication tolerability.
Selection of acute treatment should take maintenance
treatment goals into account.
During the acute treatment of mania or hypo-
mania, the algorithm in Figure 8.2 may be followed.
In addition to starting an evidence-based antimanic
TABLE 8.8
Validated Measures to Evaluate Treatment
Response in Bipolar Disorder
Scales evaluating manic Scales evaluating depressive
symptoms symptoms
Young Mania Rating Scale Beck Depression Inventory
Bech-Rafaelsen Mania Rating Hamilton Rating Scale for
Scale Depression
Altman Self-Rating Mania Montgomery-Åsberg Depression
Scale Rating Scale
Self-Report Manic Inventory Patient Health Questionnaire
(PHQ-9)
Quick Inventory of Depression
Symptomatology
177
 Rosenblat and McIntyre
agent as described in that algorithm, all anti­
depressants and stimulants should be discontinued
as these agents may worsen symptoms of mania or
hypomania. Of note, there is no separate section
included on the treatment of hypomania due to
limited availability of data. As such, treatment of
hypomania should be extrapolated from evidence
and guidelines for treatment of mania. The algo-
rithm for the acute treatment of bipolar depression
and for maintenance treatment are summarized in
Figure 8.3 and Figure 8.4, respectively.
In addition to diagnosing current illness phase, the
DSM–5 allows for the specification of the presence of
Copyright American Psychological Association. Not for further distribution.
specific features (American Psychiatric Association,
2013). In BD, the most important features that directly
impact treatment selection are mixed features,
psychotic features and, to a lesser extent, anxious
distress. If psychotic features are present during any
phase of illness, the addition of an SGA is indicated
(i.e., during depression or mania with psychotic
features). Compared with psychotic features, the
treatment of mixed features remains less clear, as
the DSM–IV–TR definition of mixed states was
changed in 2013 with the publication of the DSM–5,
thus limiting the number of studies conducted with
DSM–5-defined mixed features (Rosenblat & McIntyre,
2017b). As such, treatment of mixed features in BD
is based on (a) the relatively few completed studies
using DSM–5-defined mixed features, (b) extrapola-
tion of results from studies assessing treatments of
DSM–IV–TR-defined mixed episodes, and (c) expert
opinion (Grunze et al., 2018; Stahl et al., 2017).
Integrating these three sources of data, consensus
guidelines on the treatment of mood episodes with
mixed features were recently published (Stahl et al.,
2017). When mixed features are identified, anti­
depressants and stimulants should be discontinued as
they may worsen symptoms of mania. Recommended
treatments of mixed states include agents that may
simultaneously improve symptoms of depression and
mania. Mixed states comprised of syndromal mania
and subsyndromal depression are best treated with
SGAs (e.g., asenapine, cariprazine, quetiapine) and
mixed states comprised of syndromal depression and
subsyndromal hypomania are best treated specifi-
cally with lurasidone or quetiapine. Divalproex is an
additional alternative if SGAs provide inadequate
178
control of symptoms; however, divalproex’s anti-
depressant effects are less robust and therefore may
be less helpful to simultaneously treat both mood
poles. Short-term use of benzodiazepines or hypnotics
may also be of benefit if decreased sleep, irritability,
or agitation is present. Notably, when mixed features
are identified, patients should be monitored closely,
as mixed states are associated with increased risk of
suicidality and other risky behaviors (Seo, Wang, Jun,
Woo, & Bahk, 2016).
BEST APPROACHES FOR ASSESSING
TREATMENT RESPONSE AND
MANAGING SIDE EFFECTS
When initiating any of the previously described treat-
ments, a systematic approach to assessing treatment
response and side effects is imperative to providing
optimal care. Measurement-based care using validated
scales is required to accurately evaluate treatment
response (Fortney et al., 2017). Validated scales are
summarized in Table 8.8. Baseline symptoms severity
of both manic and depressive symptoms should
be evaluated along with reassessment of symptom
severity at each visit. Given the high prevalence
of mixed features, evaluating symptoms of both
mania and depression at each visit is required, even
when treatment is currently targeted at alleviating
symptoms of one mood pole. As smart phone tech-
nology develops, it may allow for the potential use
of daily symptom monitoring to aid in evaluation
of treatment response and side effects (Grünerbl
et al., 2015).
As with the evaluation of treatment response, a
systematic approach to the evaluation of treatment
emergent side effects is indicated, as summarized
in Figure 8.5 (Ng et al., 2009). Mild, tolerable
side effects emerging early in the course of treat-
ment (e.g., mild gastrointestinal side effects, mild
headache) may provide reassurance, and treatment
should be continued as many of these side effects
may spontaneously subside after the first few days
to weeks of treatment. If significant or intolerable
treatment emergent side effects are identified (e.g.,
severe rash, significant weight gain, dyslipidemia,
insulin resistance), discontinuation of the likely
offending agent may be required, balancing the need
 Pharmacological Treatment of Bipolar Disorder

Level 1 Established efficacy:

Optimize index mood stabilizer if already prescribed a mood stabilizer. Check blood
levels if appropriate.
Quetiapine or lurasidone monotherapy*
*Notes: Only quetiapine has established efficacy for bipolar II disorder. Lurasidone has
a better metabolic profile than quetiapine.
Lamotrigine monotherapy
Lurasidone or lamotrigine** adjunctive to lithium or divalproex if index mood stabilizer
has been optimized.
**Caution: There is a drug-drug interaction with use of lamotrigine and divalproex
together that requires reducing the lamotrigine dose by 50% of the typical lamotrigine
dose.
Do not utilize conventional antidepressants (e.g., SSRIs, SNRIs, TCAs, MAOIs) as a
first-line therapy.
Level 2A Established efficacy, but with safety concerns*:
Copyright American Psychological Association. Not for further distribution.

Olanzapine + fluoxetine (bipolar I disorder)

*Note: Tolerability limitations include weight gain and metabolic concerns.
Level 2B Better tolerability, but limited efficacy*:
Lithium (bipolar 1 disorder)
2 drug combination of above medications. Drugs may include either a first
generation antipsychotic (FGA) or second generation antipsychotic (SGA) but
NOT TWO antipsychotic medications
*Note: Efficacy limitations, relatively few positive randomized controlled trials.
Level 3 If Levels 1 and 2 are ineffective and/or not well tolerated*:
Electroconvulsive therapy (ECT)
*Note: Consideration is merited due to clinical need, despite even greater
efficacy/tolerability limitations than Level 1 and 2 treatments.

Level 4 If Levels 1–3 are ineffective and/or not well tolerated:

Cariprazine
FDA-approved agent for bipolar disorder + conventional
antidepressant (e.g., SSRI)*
Pramipexole
Adjunctive: modafinil, thyroid hormone (T3), or stimulants
3 drug combination
Transcranial magnetic stimulation (TMS)
*Notes:
▪ There is inadequate information (including negative trials) to
recommend adjunctive antidepressants, aripiprazole, ziprasidone,
levetiracetam, armodafinil, or omega-3 fatty acids for bipolar
depression.
▪ Preliminary evidence is available for cariprazine in the treatment
for bipolar I depression.
▪ Antidepressant monotherapy is not recommended in bipolar I
depression; recommendation is for adjunctive mood stabilizer with
antidepressant.
▪ Superiority (in other words, efficacy and safety) of antidepressant
monotherapy versus adjunctive mood stabilizer with antidepressant
for treatment of bipolar II depression is uncertain.

FIGURE 8.3.   Algorithm for the acute treatment of bipolar depression based
on Florida Medicaid guidelines. From “2017–2018 Florida Best Practice
Psychotherapeutic Medication Guidelines for Adults,” by R. S. McIntyre, 2018,
pp. 14–15 (http://www.medicaidmentalhealth.org/_assets/file/Guidelines/2018-
Psychotherapeutic%20Medication%20Guidelines%20for%20Adults%20with%20
References.pdf). Copyright 2018 by the USF Medicaid Drug Therapy Management
Program for Behavioral Health. Reprinted with permission.
179
 Rosenblat and McIntyre

Level 1 Established efficacy:

Periodic evaluation: frequency based on clinical needs
Continue with effective and well-tolerated treatment
Lithium* monotherapy
Quetiapine monotherapy
Lamotrigine* (evidence strongest for prevention of depression)
If initially stabilized on divalproex*†, maintain.
Aripiprazole or aripiprazole long-acting injectable, long-acting risperidone monotherapy
Quetiapine (for recurrence prevention) or ziprasidone (for relapse prevention) adjunctive
to (lithium* or divalproex*†)
Asenapine monotherapy
†
Note: Be aware that there are limited data on long-term efficacy of divalproex.
Level 2A Established efficacy, but with safety concerns**:
Olanzapine monotherapy
Copyright American Psychological Association. Not for further distribution.

Olanzapine adjunctive to lithium* or divalproex*†

Level 2B If Level 1 is ineffective and/or not well tolerated:
Continue effective and well-tolerated acute treatment(s) if not listed in Level 1
Lithium* and divalproex*† combination
Follow acute mania/bipolar depression guidelines to achieve remission or
partial remission
Level 3 If Levels 1 and 2 are ineffective and/or not well tolerated:
Adjunctive clozapine (avoid combining with another antipsychotic)
Electroconvulsive therapy (ECT)†
Notes:
*Caution should be used when prescribing lithium, lamotrigine, divalproex or carbamazepine to
women of reproductive age due to increased risks to the fetus with use during pregnancy, including
neural tube and other major birth defects. Please see Florida Best Practice Recommendations for
Women of Reproductive Age with Serious Mental Illness and Comorbid Substance Use Disorders
and online guideline on the Pharmacological Treatment of Mood Disorders During Pregnancy.
**Side-effect concerns with these agents include weight gain, metabolic syndrome, and extrapyramidal
symptoms (EPS). Side-effects warrant vigilance and close monitoring on the part of the clinician.
†
Long-term efficacy data are limited for the following: divalproex monotherapy, carbamazepine (drug
interaction risk), antidepressants, and electroconvulsive therapy (inconvenience/expense).

FIGURE 8.4.   Algorithm for the maintenance of bipolar disorder treatment based on
Florida Medicaid guidelines. From “2017–2018 Florida Best Practice Psychotherapeutic
Medication Guidelines for Adults,” by R. S. McIntyre, 2018, p. 18 (http://www.
medicaidmentalhealth.org/_assets/file/Guidelines/2018-Psychotherapeutic%20
Medication%20Guidelines%20for%20Adults%20with%20References.pdf). Copyright
2018 by the USF Medicaid Drug Therapy Management Program for Behavioral Health.
Reprinted with permission.

for efficacy with tolerability. Switching to another
evidence-based agent with a decreased risk of the
same problematic side effect would be advised.
MEDICATION MANAGEMENT ISSUES
The majority of this chapter focuses on initial phar-
macological management strategies in BD. However,
BD has a relapsing and remitting course with high
rates of treatment resistance. Determining the most
likely underlying causes of treatment resistance is
paramount in deciding how to optimize treatment.
The cause of apparent treatment resistance (i.e., not
improving with initially prescribed treatments) can
be secondary to (a) inadequate medication trials
(i.e., the mood stabilizer has not been prescribed
at an adequate dose or for an adequate duration),
(b) nonadherence to the prescribed treatment (i.e.,
the patient is not taking the treatment as prescribed),
(c) previously unidentified perpetuating factors

180
 Pharmacological Treatment of Bipolar Disorder

‘Basic’ parameters for all patients prior to treatment implementation

History: medical comorbidities (including CVD risk factors), smoking status, alcohol use,
pregnancy status, family history of CVD risk factors

Investigations: waist circumference and/or BMI (weight & height), BP, FBC, EUC, LFTs,
fasting glucose, fasting lipid profile

Manage any identified Selection of medication, taking

medical conditions as into consideration overall
appropriate health risk profile
Copyright American Psychological Association. Not for further distribution.

‘Add-on’ parameters according to treatment selected

Lithium Valproate and carbamazepine Atypical

antipsychoticsa
Baseline: TSH, Ca Baseline: Haematological and hepatic history
Longitudinal
Serum level: 2 levels Serum level: 2 levels to establish therapeutic monitoring
to establish dose (4 weeks apart for carbamazepine), then ▪ Weight monthly for
therapeutic dose, then as clinically indicated first 3 months, then
every 3–6 months,
every 3 months
after dose increases Longitudinal monitoring ▪ BP and fasting
and as clinically Valproate: Weight, FBC LFT, menstrual
▪ glucose every 3
indicated history every 3 months for the first year, months for first year,
then annually; BP, fasting glucose, and lipid then annually
Longitudinal profile if risk factors; bone densitometry if ▪ Fasting lipid profile
monitoring risk factors after 3 months, then
▪ EUC every 3–6 Carbamazepine: FBC, LFT, EUC monthly
▪ annually
months for first 3 months, then annually; alert to ▪ ECG and prolactin
▪ Ca, TSH, and rash especially in first few months of level as clinically
weight after 6 treatment; bone densitometry if risk factors; indicated
months, then review contraceptive efficacy where
annually applicable a
Clozapine an exception
Lamotrigine
▪ Alert to rash

CVD = cardiovascular disease; BMI = body mass index; BP = blood pressure; FBC = full blood count; EUC =
electrolytes, urea, and creatinine; LFTs = liver function tests; TSH = thyroid stimulating hormone; Ca = calcium;
ECG = electrocardiogram.

FIGURE 8.5.   The International Society for Bipolar Disorders consensus guidelines for the
safety monitoring of bipolar disorder treatments. From “The International Society for Bipolar
Disorders (ISBD) Consensus Guidelines for the Safety Monitoring of Bipolar Disorder Treatments,”
by F. Ng, O. K. Mammen, I. Wilting, G. S. Sachs, I. N. Ferrier, F. Cassidy, . . . International Society
for Bipolar Disorders, 2009, Bipolar Disorders, 11, p. 562. Copyright 2009 by Wiley. Reprinted
with permission.

181
 Rosenblat and McIntyre
that are driving the illness course (e.g., substance
misuse, other medications, worsening psychosocial
environment, comorbid psychiatric or medical diag-
noses), or (d) biological treatment resistance (i.e.,
the appropriate medication combination has yet to
be identified; Gitlin, 2006; Nemeroff, 2007).
If nonadherence occurs, understanding the reasons
behind nonadherence is essential for improving
adherence. For example, often patients stop taking
prescribed medications because of intolerable side
effects (e.g., sexual side effects, weight gain, sedation)
that they have not disclosed to their prescriber. In this
scenario, providing appropriate psychoeducation and
Copyright American Psychological Association. Not for further distribution.
switching to a more well-tolerated medication may
quickly correct the difficulties with adherence, and
subsequently lead to treatment response when serum
levels are consistently therapeutic (i.e., when the
patient is taking the medication as prescribed). Other
factors, such as cost or remembering to take the medi-
cation, should also be considered when nonadherence
is suspected. If remembering to take the medications
is identified as a barrier, simplifying the medication
regimen and collaborating with the pharmacy (e.g.,
use of blister packs or other medication reminders)
may be helpful. Alternatively, if nonadherence is
secondary to lack of capacity to make the appropriate
treatment decision, assertive treatment with a
substitute decision maker may be required.
When nonadherence is identified, the use of
depot antipsychotics (i.e., long acting injectable
antipsychotics) may also be explored. Of the SGA
depots, risperidone (given every 2 weeks) and
aripiprazole (given every 4 weeks) have specifically
been demonstrated to be efficacious in BD
(Calabrese et al., 2017; Kishi, Oya, & Iwata, 2016).
Additionally, many clinicians extrapolate the efficacy
results of risperidone to assume that paliperidone is
similarly efficacious, given that it is an active metabo-
lite of risperidone. As such, the off-label use of long
acting paliperidone (available in two formulations,
given every 4 weeks or every 12 weeks) may also
be appropriate; however, there is minimal direct
evidence to support efficacy in BD (Nikolić, Page,
Akram, & Khan, 2017).
The presence of previously unidentified
perpetuating biological and psychosocial factors
may contri­bute to the inhibition of remission and
182
recovery. From a biological perspective, commonly
unidentified perpetuating factors include the use
and misuse of substances (e.g., cocaine, alcohol),
coprescribed medications (e.g., antidepressants,
stimulants, steroids, interferon), and unidentified
contributing medical disorders (e.g., sleep apnea,
anemia, hypothyroidism or hyperthyroidism) and
psychiatric disorders (e.g., personality disorders,
eating dis­orders, anxiety). Careful attention to each
of these categories may reveal the underlying etiology
of the apparent treatment resistance. Identifying
and then correcting the underlying cause may lead
to significant improvements in overall treatment
outcomes (Gitlin, 2006; Nemeroff, 2007). Numerous
psychosocial factors also may perpetuate the mood
episode, especially with treatment-resistant bipolar
depression. Evidence-based psychosocial inter-
ventions are further discussed in the Integration
of Pharmacotherapy With Nonpharmacological
Approaches section of this chapter.
Some patients may still experience persistent
symptoms, even with perfect adherence and treat-
ment of other perpetuating factors. The Florida
Medicaid guidelines presented above show an algo-
rithm to follow when adequate trials of first-line
treatments fail. Unfortunately, the evidence base for
treatment resistant and treatment refractory BD is
limited, as most RCTs have either assessed mono-
therapies or dual therapy dual therapy with various
combinations of divalproex, lithium, lamotrigine,
SGAs, and antidepressants. As such, after a few failed
medication trials, the prescriber is often left to try off-
label combinations based on expert opinion, as there
is minimal evidence to guide treatment at this stage.
EVALUATION OF PHARMACOLOGICAL
APPROACHES ACROSS THE LIFESPAN
The current chapter has focused on the treatment of
BD in the adult population (i.e., age 18–65), as the
majority of available evidence is for this age group.
However, there are notable differences in the treat-
ment of geriatric (i.e., older than 65) and pediatric
(i.e., younger than 18) populations. Over the past
decade, there has been a substantial increase in the
amount of research being conducted in the treatment
of BD with both of these age categories. There has

been increasing interest in and need for under-
standing the efficacy and tolerability of psychiatric
treatments in older patients (Sajatovic et al., 2015),
and interest has also grown in evaluating treatments
for pediatric BD. Historically, there has been signifi-
cant debate about the existence of pediatric BD.
Critics of pediatric BD have suggested that symptoms
of mania in this population are better explained by
other childhood disorders, such as impulse control
disorders (e.g., attention-deficit/hyperactivity
disorder [ADHD]) and behavioral disorders (i.e.,
conduct disorder and oppositional defiant disorder).
However, more recently the existence of pediatric BD
Copyright American Psychological Association. Not for further distribution.
has become widely accepted as replicated evidence
has demonstrated the importance of recognizing,
diagnosing, and treating BD in this age group
(Goldstein et al., 2017).
Given the previous controversy and recent accu-
mulation of evidence regarding diagnosis and treat-
ment of pediatric BD, the ISBD formed a task force to
summarize and contextualize findings in pediatric BD
(Goldstein et al., 2017). From a treatment perspec-
tive, there is Level I evidence (i.e., positive effect
demonstrated by at least one well-designed RCT) to
support the use of SGAs in the treatment of manic
and mixed episodes in pediatric BD. Risperidone,
aripiprazole, quetiapine, olanzapine, and asenapine
are FDA-approved for the acute treatment of mania
in youth (age 10–17). Notably, however, children and
adolescents appear to be more prone to metabolic
side effects with SGAs and require close metabolic
monitoring (Correll, Sheridan, & DelBello, 2010).
Another important difference observed in pediatric
BD is that conventional mood stabilizers (i.e., lithium
and anticonvulsants) are less effective in the acute
treatment of mania compared with adults (Correll
et al., 2010).
Significantly less data is available for the treatment
of bipolar depression and maintenance treatment in
pediatric BD. Only OFC is FDA approved for the acute
treatment of bipolar depression in youth. Additionally,
in a published RCT of 347 youth (age 10–17),
lurasidone was found to have a significant anti­
depressant effect at the end of a 6-week trial (DelBello
et al., 2017). Quetiapine has also been evaluated
for bipolar depression in youth in two large RCTs,
but with negative results, showing no benefit above
Pharmacological Treatment of Bipolar Disorder
the placebo response rate (DelBello et al., 2009;
Findling, Pathak, Earley, Liu, & DelBello, 2014). As
with adults, the use of antidepressant monotherapy
is discouraged, especially in youth as there is an
increased risk of treatment emergent suicidality
(Goldstein et al., 2017).
In older patients, continuing treatment that was
effective and well tolerated during earlier adult-
hood is usually indicated (Aziz, Lorberg, & Tampi,
2006). However, lower doses may be required, as
there is increased risk of toxicity (Valiengo, Stella,
& Forlenza, 2016). The risk of treatment-emergent
cardiac arrhythmia and resultant sudden cardiac death
is also increased, and therefore electrocardiograms
are indicated with any changes in medications (Straus
et al., 2006). Lower serum levels of lithium are also
indicated. Older patients are at increased risk for falls
and therefore medication associated with heavy seda-
tion (summarized in Table 8.7) or orthostatic hypo-
tension (e.g., quetiapine and olanzapine) should be
avoided or used with caution (Woolcott et al., 2009).
CONSIDERATION OF POTENTIAL
SEX DIFFERENCES
The relative prevalence of BD in men and women
is similar, with a male-to-female prevalence ratio of
1.1:1 (Blanco et al., 2017). Studies investigating sex
differences in BD are notably sparse compared with
those for MDD (Kawa et al., 2005). Recommended
treatments for BD are the same in men and women,
with no consistently reported differences in efficacy;
however, there are some differences in side effect
profiles (Diflorio & Jones, 2010). For example,
women are at risk of treatment-emergent PCOS with
divalproex, with significant potential sequelae
such as amenorrhea, hyperandrogenism, weight
gain, and insulin resistance (Zhang, Li, Li, & Zou,
2016). Other mood stabilizers with significant meta-
bolic effects (see Figure 8.1) may also increase the
risk of developing PCOS.
Additionally, special considerations must be made
for women of childbearing age within the context
of pregnancy and breastfeeding (Payne, 2017).
Preconception counseling is recommended to eval-
uate treatment options prior to becoming pregnant
(Temming, Cahill, & Riley, 2016). Adequate discussion
183
 Rosenblat and McIntyre
and planning may allow for folate supplementation
and, if needed, medication changes prior to concep-
tion to minimize risk of teratogenicity. With BD, the
postpartum period is high risk for relapse of severe
mood episodes and psychosis (Wesseloo et al.,
2016). As such, having adequate mood stabilizing
treatment is usually advised.
Lithium and anticonvulsants have known risks
for causing fetal abnormalities when taken during
pregnancy. Early poorly designed studies showed a
400-fold increase in risk of cardiac malformation
with fetal exposure to lithium; however, more
recent studies with improved study design suggest
Copyright American Psychological Association. Not for further distribution.
that lithium poses a low absolute risk, with only
1% to 4% of lithium-exposed fetuses developing
cardiac malformation (McKnight et al., 2012). As
such, lithium may often be continued during preg-
nancy with an adequate informed consent discus-
sion (Wald, Muzyk, & Clark, 2016). If lithium is
continued during pregnancy, the serum lithium
levels should be monitored closely and adjusted
accordingly to maintain therapeutic levels, given
the changes in blood volume during pregnancy.
Additionally, lithium use is contraindicated while
breastfeeding as high levels of lithium may be found
in breast milk. As such, either bottle feeding or
discontinuation of lithium would be advised.
Anticonvulsants pose a greater risk and are usually
advised against in women planning to become preg-
nant, as valproate and carbamazepine are associated
with significantly elevated risk of fetal neural tube
defects (Tomson et al., 2011). Conversely, anti-
convulsants are frequently used during lactation
as a relatively safe option with added monitoring
of the newborn, with monitoring of infant blood
levels if concerns arise (Temming et al., 2016).
Among the BD treatment options, SGAs are
likely the safest during both pregnancy and lacta-
tion; however, effects of SGAs on infants when
used during pregnancy and lactation remain under-
studied (Smith & Dubovsky, 2017). One concern
with some SGAs is increasing the risk of gestational
diabetes, but this risk is usually less of a concern
and is treatable compared with potential irreversible
fetal malformations with anticonvulsants. Similar to
anticonvulsants, SGAs may be used during lactation
with added monitoring of the newborn.
184
There are also notable phenomenological differ-
ences, which will only be briefly summarized herein.
Compared with men, women with BD are more
prone to depressive episodes, suicide attempts, mixed
features, and rapid cycling (Diflorio & Jones, 2010).
Similar to MDD, women may also experience exacer-
bations of mood symptoms during the premenstrual
period, which may be associated with a more severe
illness course (Perich et al., 2017). The perimeno-
pausal period is also associated with worsening
depressive symptoms (Freeman et al., 2002). Women
are more likely to have atypical depressive symp-
toms as well, with increased appetite and weight
gain being common symptoms associated with
depressive episodes (Miller et al., 2015). Rates of
comorbidity also vary between men and women,
as comorbid anxiety and eating disorders are more
common in women and substance use disorders are
more common in men (Baldassano, 2006).
INTEGRATION OF PHARMACOTHERAPY
WITH NONPHARMACOLOGICAL
APPROACHES: BENEFITS
AND CHALLENGES
Pharmacotherapy remains the cornerstone of treat-
ment for BD. Adjunctive nonpharmacological treat-
ments should also be considered during all phases
of illness. Nonpharmacological approaches can
broadly be categorized into (a) brain stimulation
and (b) psychosocial interventions. Both catego-
ries have evidence supporting efficacy in BD, with
specific interventions demonstrating antidepressive
and antimanic effects along with preventing relapse
and recurrence.
Brain stimulation represents one of the oldest
treatment modalities of BD. More specifically, electro-
convulsive therapy (ECT) was the earliest treatment
for acute mania that demonstrated a potent and rapid
antimanic effect (Mukherjee, Sackeim, & Schnur,
1994). While ECT is still effective, pharmacotherapy
has largely replaced ECT in the acute treatment of
manic and mixed episodes given the invasiveness,
cost, and cognitive dysfunction associated with ECT.
However, ECT may still be indicated if manic or
mixed symptoms are refractory to medications or if
the use of medications is contraindicated, as there are

no absolute contraindications to ECT. For treatment
resistant/refractory bipolar depression, ECT has
demonstrated antidepressant efficacy (Medda, Toni,
& Perugi, 2014). ECT is also indicated for severe
depression with acute suicidality when a rapid
effect is needed and oral medications might not be
feasible. Additionally, ECT is usually the treatment
of choice for catatonia secondary to BD (Luchini
et al., 2015).
More recently, the role of repetitive transcranial
magnetic stimulation (rTMS) has been investigated
with mixed results. While initial observational data
and open label studies showed promising results
Copyright American Psychological Association. Not for further distribution.
(Pallanti et al., 2014; Rachid, Moeglin, & Sentissi,
2017; Rostami, Kazemi, Nitsche, Gholipour, &
Salehinejad, 2017; Zendjidjian et al., 2014), RCTs
have failed to demonstrate efficacy compared with
placebo (Fitzgerald et al., 2016). There also have
been concerns about potential rTMS treatment-
emergent mania/hypomania in the absence of
adequate mood stabilizer treatment, suggesting that
rTMS monotherapy (or in combination with an
antidepressant) should be avoided in BD (Rachid,
2017). Magnetic seizure therapy has also been of
interest, but has only case report-level evidence
(Noda et al., 2014).
Psychosocial interventions are important and
efficacious adjunctive treatments of BD as well.
Most current BD treatment guidelines suggest
that all patients should receive, at a minimum,
comprehensive psychoeducation (Parker et al.,
2017). Psychoeducation should provide patients
with information about the signs and symptoms
of relapse along with strategies to decrease risk of
relapse. Key counseling topics include, but are not
limited to, the importance of sleep hygiene, exer-
cise, maintaining a healthy diet, avoiding substance
use, and encouraging social interaction. In addition
to psychoeducation, the use of evidence-based
psychotherapy may be of great benefit, especially
for the treatment and prevention of bipolar depres-
sive episodes (Miklowitz, 2008). In the treatment
of bipolar depression specifically, cognitive behav-
ioral therapy (CBT), mindfulness, interpersonal
and social rhythm therapy, and family-focused
therapy have demonstrated antidepressant effi-
cacy along with anxiolytic effects (Salcedo et al.,
Pharmacological Treatment of Bipolar Disorder
2016). Taken together, a comprehensive treat-
ment plan for patients with bipolar depression
includes these therapies in addition to appropriate
pharmacotherapy.
INTEGRATED APPROACHES
FOR ADDRESSING COMMON
COMORBID DISORDERS
In BD, psychiatric and medical comorbidity is the
rule rather than the exception. The effective treat-
ment of comorbidities starts with adequate screening
of common comorbidities. Replicated evidence
has demonstrated high rates of comorbidity with
anxiety disorders, ADHD, substance use dis­orders,
eating disorders, and personality disorders (McIntyre
et al., 2012; Rosenbluth et al., 2012). As per the
Canadian Network for Mood and Anxiety Treatments
(CANMAT) guidelines on management of comorbidity
in mood disorders, several principles should be consid-
ered including, but are not limited to: establishing the
diagnosis, risk assessment, establishing the appropriate
setting for treatment, chronic disease management,
concurrent treatment, and measurement-based care
(McIntyre et al., 2012). Importantly, comorbid psychi-
atric disorders should be concurrently managed during
the treatment of BD. For example, providers should
not wait for comorbid substance use to be adequately
treated prior to providing BD treatment, and vice versa.
Toward this end, both psychosocial and psycho-
pharmacological treatments should be utilized to treat
comorbid conditions.
For comorbid anxiety disorders, CBT and
mindfulness are effective options, if available.
Pharmacologically, doses of SGAs and/or conven-
tional mood stabilizers may be further optimized
to control comorbid symptoms of anxiety. SGAs are
particularly effective at mitigating anxiety during all
illness phases, including during euthymic periods.
Gabapentin and pregabalin represent alternative treat-
ments for comorbid anxiety without the risk of manic
switches associated with antidepressant treatment
(Rakofsky & Dunlop, 2011). Intermediate or longer
half-life benzodiazepines may be required for short-
term utilization only for moderate to severe anxiety.
If these approaches inadequately alleviate symptoms
of anxiety, first-line antidepressants for anxiety
185
 Rosenblat and McIntyre
(e.g., sertraline, escitalopram) may be required
with the risk of a manic switch.
For ADHD, first-line stimulants (e.g., methyl-
phenidate, lisdexamfetamine) may still be effectively
and safely used with the added caution to monitor
for potential manic/hypomanic switches (McIntyre
et al., 2012). A key consideration is that stimulants
should be used in combination with an adequate dose
of a mood stabilizer. Stimulants should be avoided in
patients with rapid cycling, mixed features, or active
psychosis. Stimulants (e.g., lisdexamfetamine) may
also be cautiously prescribed for comorbid binge
eating disorder with a relatively low risk of treatment-
Copyright American Psychological Association. Not for further distribution.
emergent mania (McIntyre et al., 2013).
For comorbid personality disorders, dialectical
behavioral therapy may be particularly effective,
specifically for borderline personality disorder
(BPD). In some cases, long-term psychodynamic
psychotherapy may also be indicated (Rosenbluth
et al., 2012). Of note, a careful assessment is
required in patients with BD with comorbid BPD,
as manic symptoms or mixed features may at times
be confused with BPD-related affective dysregulation
(Bayes, Parker, & McClure, 2016).
EMERGING TRENDS
Several novel treatments for BD are currently being
investigated, providing hope for improved efficacy
and tolerability. Novel emerging treatments for
bipolar depression are of particular interest and
importance, as they may satisfy an essential unmet
need in the treatment of BD. Modulation of the
glutamate system as well as the immune system
are particularly promising treatment targets for
bipolar depression.
Over the past decade, mounting evidence has
strongly implicated immune dysfunction in the
pathoetiology of numerous neuropsychiatric
disorders, including BD (Rosenblat & McIntyre,
2017a). Targeting the immune system has been
proposed as a potential way to modify the disease
course of BD by targeting the underlying cause
(i.e., inflammation) of BD rather than only the
downstream effects (e.g., neurotransmitter levels;
Rosenblat & McIntyre, 2016). Several proof-of-
186
concept clinical trials have demonstrated anti­
depressant effects of anti-inflammatory agents when
used in BD (Rosenblat et al., 2016). Of the anti-
inflammatories, N-acetylcysteine (NAC) has shown
the most consistent results for demonstrating an anti-
depressant effect in BD and is already recommended
as adjunctive treatment in some guidelines (Yatham
et al., 2013). Minocycline, infliximab, celecoxib,
pioglitazone, and liraglutide have shown promising
antidepressant effects in preliminary studies as well.
There has also been significant interest in omega-3
fatty acids given their anti-inflammatory effects and
excellent tolerability profile (Bloch & Hannestad,
2012). In BD, results have been mixed, with some
trials showing an antidepressant effect (Frangou,
Lewis, & McCrone, 2006; Stoll et al., 1999) and
others reporting no effect compared with conven-
tional therapy alone (Frangou, Lewis, Wollard,
& Simmons, 2007; Hirashima et al., 2004; Keck
et al., 2006). The mixed results of these studies
may suggest that omega-3s (and likely all anti-
inflammatory agents) are beneficial in only a subset
of those with BD. In an RCT with unipolar depres-
sion, omega-3s were found to have a significant
antidepressant effect in the subset of participants
with elevated inflammatory markers (Rapaport et al.,
2016). Intriguingly, in participants with normal
inflammatory marker levels, placebo had a greater
antidepressant effect compared with omega-3s,
leading to an overall negative study outcome (i.e.,
no significant antidepressant effect was found when
including the entire sample). While this study
was on unipolar depression, it is likely that a
similar effect may be observed in BD in that only
patients with elevated inflammatory markers may
benefit from anti-inflammatory treatments such
as omega-3s, but further study is still required
to confirm or refute this hypothesis in the BD
population.
Targeting the glutamate system has also become
of great interest in recent years with both bipolar
and unipolar depression (Caddy et al., 2015).
Interest in the glutamate system grew out of the
identification of ketamine as a rapid acting anti-
depressant with potent antidepressant effects in
both bipolar and unipolar depression (Kishimoto

et al., 2016). Ketamine, a dissociative anesthetic,
modulates the glutamate system as an N-methyl-
D-aspartate (NMDA) antagonist. Modulation of
the glutamate system is believed to be ketamine’s
primary mechanism of action mediating its anti-
depressant effects (Tokita, Yamaji, & Hashimoto,
2012). Replicated RCTs have provided Level I
evidence (e.g., established efficacy) for the use
of ketamine in the acute treatment of depression
(Kishimoto et al., 2016), but several limitations
prevent its use (Sanacora et al., 2017). Gold stan-
dard ketamine treatments for depression are via
the intravenous (IV) route (ketamine 0.5 mg/kg IV
Copyright American Psychological Association. Not for further distribution.
infused over 40 minutes) and therefore are resource
intensive and more invasive compared with other BD
treatments (i.e., orally administered medications).
Additionally, most RCTs assessed only a one-time
dose of IV ketamine and therefore the long-term
risks and benefits are yet to be adequately studied.
As such, providing long-term ketamine treatments
for depression is an inappropriate extrapolation of
currently available evidence (Sanacora et al., 2017).
The risk for misuse (given that ketamine also has
abuse liability) and potential dissociative effects are
also of concern.
Given these concerns, other agents targeting
the glutamate system (e.g., D-cycloserine, riluzole,
CP-101,606, CERC-301, basimglurant, JNJ-40411813,
dextromethorphan, nitrous oxide, rapastinel,
esketamine) are also currently under investigation
(Lener, Kadriu, & Zarate, 2017). For example,
dextromethorphan, an oral over-the-counter cough
suppressant, is also an NMDA antagonist and has
been evaluated in the acute treatment of bipolar
depression with promising preliminary results (Kelly
& Lieberman, 2014; Lee et al., 2017). However,
compared with ketamine, no other glutamate
modulating agent has demonstrated the same
reproducible and robust rapid antidepressant effects
(Lener et al., 2017).
Another emerging area in BD is evaluating treat-
ments specifically for BD-II. As shown in Figure 8.3,
only quetiapine has robust evidence for efficacy in the
treatment of BD-II depression. Results from RCTs in
BD-I are often extrapolated in the treatment of BD-II,
but emerging evidence suggests that these distinct
Pharmacological Treatment of Bipolar Disorder
disorders may require different treatment approaches
(Grande, Berk, Birmaher, & Vieta, 2016).
TOOL KIT OF RESOURCES
Bipolar Disorder
Patient Resources
Depression and Bipolar Support Alliance:
http://www.dbsalliance.org/
MindShift phone app: https://www.anxietybc.com/
resources/mindshift-app
Moodgym phone app: https://moodgym.com.au/
Mayo Clinic Patient Care & Health Information,
Diseases & Conditions: Bipolar Disorder: https://
www.mayoclinic.org/diseases-conditions/
bipolar-disorder/symptoms-causes/syc-20355955
National Institute of Mental Health, Health and
Education, Mental Health Information: Bipolar
Disorder: https://www.nimh.nih.gov/health/topics/
bipolar-disorder/index.shtml
Clinician Resources
2017–2018 Florida Best Practice Psychotherapeutic
Medication Guidelines for Adults (Florida Medicaid
guidelines): http://www.medicaidmentalhealth.org/
_assets/file/Guidelines/2018-Psychotherapeutic%20
Medication%20Guidelines%20for%20Adults%20
with%20References.pdf
CANMAT Treatment Guidelines: http://dx.doi.org/
10.1111/bdi.12025
World Federation of Societies of Biological Psychiatry
Treatment Guidelines: http://dx.doi.org/10.1080/
15622975.2017.1384850
Consensus guidelines for mixed depression: http://
dx.doi.org/10.1017/S1092852917000165
Mood Disorder Questionnaire (MDQ): http://
www.sadag.org/images/pdf/mdq.pdf
Hypomania Checklist (HCL-32): http://www.oacbdd.org/
clientuploads/Docs/2010/Spring%20Handouts/
Session%20220b.pdf
Young Mania Rating Scale (YMRS): https://
www.outcometracker.org/library/YMRS.pdf
Altman Self-Rating Mania Scale (ASRM):
http://www.cqaimh.org/pdf/tool_asrm.pdf
187
 Rosenblat and McIntyre
Bipolar Depression Rating Scale (BDRS):
http://www.barwonhealth.org.au/bdrs
Patient Health Questionnaire (PHQ-9): http://
www.cqaimh.org/pdf/tool_phq9.pdf
Quick Inventory of Depression Symptomatology (QIDS):
http://www.ids-qids.org/
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