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Insights into the

Diagnosis and Treatment


of Bipolar Disorder

HYPOMANIA

DYSTHYMIA

Sponsored by Neuroscience Education Institute


This activity is supported by an educational grant from

Released: October, 2007

CME Credit Expires: September, 2010

CME INFORMATION

Overview
This monograph is a summary of the bipolar disorder sessions previously presented at the 2007 NEI Psychopharmacology 2-Day Academies,
with a discussion of the neurobiology, diagnosis, and treatment of bipolar spectrum disorders.

Target Audience
This activity was designed for healthcare professionals, including psychiatrists, neurologists, primary care physicians, clinical psychologists,
pharmacists, psychotherapists, nurses, nurse practitioners, addiction counselors, social workers and others, who treat patients with psychiatric
conditions.

Statement of Need
The content of this educational activity was determined by rigorous assessment, including activity feedback, expert faculty assessment, literature
review, and new medical knowledge, which revealed the following unmet needs:

Thirty percent of bipolar patients are misdiagnosed. Four key areas are important for discerning if a patient may have a bipolar
spectrum disorder: sleep, treatment-response history, family history, talking to a relative. In addition, bipolar spectrum disorders are
progressive illnesses making tracking of symptoms and treatment responses necessary.

Because efcacy and tolerability of mood stabilizers, particularly atypical antipsychotic mood stabilizers, may vary depending on the
phase of illness, treatment selection and dosing may need to be state-dependent in bipolar spectrum disorders.

Evidence-based and/or rational polypharmacy techniques for treating bipolar spectrum disorders are lacking, since most of the studies
focus on monotherapy.

Learning Objectives
Upon completion of this activity, you should be able to:

Track history and progression of symptoms and treatment responses for patients with mood/behavioral symptoms
Select mood stabilizers and their doses based on patient presentation
Use neurobiologic and mechanistic rationale when combining medications to treat bipolar spectrum disorders

Accreditation and Credit Designation Statements


The Neuroscience Education Institute is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical
education for physicians.
The Neuroscience Education Institute designates this educational activity for a maximum of 2.0 AMA PRA Category 1 Credits. Physicians
should only claim credit commensurate with the extent of their participation in the activity.

Activity Instructions
This CME activity is in the form of a printed monograph and incorporates instructional design to enhance your retention of the information and
pharmacological concepts that are being presented. You are advised to go through this activity from beginning to end and then complete the
posttest and activity evaluation. The estimated time for completion of this activity is 2 hours.

Instructions for CME Credit


To receive your certicate of CME credit or participation, please complete the posttest (you must score at least 70% to receive credit) and
activity evaluation found at the end of the monograph and mail or fax them to the address/number provided. Once received, your posttest will
be graded and a certicate sent if a score of 70% or more was attained. Alternatively, you may complete the posttest and activity evaluation
online and immediately print your certicate. There is no fee for this activity.

NEI Disclosure Policy


It is the policy of the Neuroscience Education Institute to ensure balance, independence, objectivity, and scientic rigor in all its educational
activities. The Neuroscience Education Institute takes responsibility for the content, quality, and scientic integrity of this CME activity.
All faculty participating in any NEI-sponsored educational activity and all individuals in a position to inuence or control content development are
required by NEI to disclose to the activity audience any nancial relationships or apparent conicts of interest that may have a direct bearing on
the subject matter of the activity. Although potential conicts of interest are identied and resolved prior to the activity, it remains for the audience
to determine whether outside interests reect a possible bias in either the exposition or the conclusions presented.

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Individual Disclosure Statements


Author/Developer
Laurence Mignon, PhD
Medical Writer
Neuroscience Education Institute, Carlsbad, CA
No other nancial relationships to disclose.

Content Editors
Meghan Grady
Director, Content Development
Neuroscience Education Institute, Carlsbad, CA
No other nancial relationships to disclose.
Stephen M. Stahl, MD, PhD
Adjunct Professor, Department of Psychiatry
University of California, San Diego School of Medicine, San Diego, CA
Board Member: Cypress Bioscience; NeuroMolecular; Pierre Fabre; Tetragenix
Grant/Research: Alkermes; AstraZeneca; Bristol-Myers Squibb; Cephalon; Cyberonics; Eli Lilly; GlaxoSmithKline; Janssen; Jazz; Neurocrine
Biosciences; Novartis; Organon; Pzer; Sepracor; Shire; Somaxon; Takeda; Wyeth
Consultant/Advisor: Acadia; Amylin; AstraZeneca; Avera; Azur; Biovail; Boehringer Ingelheim; Bristol-Myers Squibb; Cephalon; CSC;
Cyberonics; Cypress Bioscience; Eli Lilly; Epix; Forest; GlaxoSmithKline; Janssen; Jazz; Labopharm; Neurocrine Biosciences; NeuroMolecular;
Neuronetics; Novartis; Organon; Pamlab; Pzer; Pierre Fabre; sano-aventis; Schering-Plough; Sepracor; Shire; Solvay; Somaxon; Tethys;
Tetragenix; Vanda; Wyeth
Speakers Bureau: AstraZeneca; Cephalon; CSC; Eli Lilly; Pzer; Wyeth

Peer Reviewer
Meera Narasimhan, MD
Professor, Department of Psychiatry
Director of Biological Research, Ofce of Biological Research
Department of Neuropsychiatry and Behavioral Science
University of South Carolina School of Medicine, Columbia, SC
Grant/Research: AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Forest Laboratories, Inc.; Janssen Pharmaceutica Inc.
Consultant/Advisor: Bristol-Myers Squibb Company; Eli Lilly and Company
Speakers Bureau: AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Eli Lilly and Company; Janssen Pharmaceutica Inc.

Editorial & Design Staff


Rory Daley, MPH
Program Development Associate
Neuroscience Education Institute, Carlsbad, CA
No other nancial relationships to disclose.

Jahon Jabali
Interactive Designer
Neuroscience Education Institute, Carlsbad, CA
No other nancial relationships to disclose.

Jaime Derringer
Project Manager
Neuroscience Education Institute, Carlsbad, CA
No other nancial relationships to disclose.

Nancy Muntner
Director, Medical Illustrations
Neuroscience Education Institute, Carlsbad, CA
No other nancial relationships to disclose.

Stacey L. Hughes
Director, Program Development
Neuroscience Education Institute, Carlsbad, CA
No other nancial relationships to disclose.

Steve Smith
President and COO
Neuroscience Education Institute, Carlsbad, CA
No other nancial relationships to disclose.

Disclosed nancial relationships have been reviewed by the Neuroscience Education Institute CME Advisory Board to resolve any potential
conicts of interest. All faculty and planning committee members have attested that their nancial relationships do not affect their ability to
present well-balanced, evidence-based content for this activity.

Disclosure of Off-Label Use


This educational activity may include discussion of unlabeled and/or investigational uses of agents that are not approved by the FDA. Please
consult the product prescribing information for full disclosure of labeled uses.

Disclaimer
Participants have an implied responsibility to use the newly acquired information from this activity to enhance patient outcomes and their own
professional development. The information presented in this educational activity is not meant to serve as a guideline for patient management.
Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this educational activity should not be used by
clinicians without evaluation of their patients conditions and possible contraindications or dangers in use, review of any applicable
manufacturers product information, and comparison with recommendations of other authorities. Primary references and full prescribing information should be consulted.

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Copyright 2007, Neuroscience Education Insitute. All rights reserved.


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1. Introduction
The family history of patient X reveals a history of mental illnesses. His maternal grandfather had suffered from
depression and died in a psychiatric hospital; his mother
was once hospitalized for depression and was treated
with amitriptyline for most of her life; and his fraternal
twin brother suffered from situational depression. As a
child, patient X experienced episodes where his thoughts
and reactions seemed magnied and was plagued with
behavioral problems such as impulsivity, distractibility
and hyperactivity. He was intelligent but never excelled
in school. Since he was a child, he thought that things
would grow bigger and become dangerous. The current
state of mind of patient X is that he wants to be pleasing, accepted, loved, admired, and special, and he suffers from self-esteem issues, which could uncover signs of
narcissistic personality traits. When he preaches, patient
X transcends sickness and reaches a high; at the same
time he thinks that his role as a preacher has diminished
in todays society and he feels worthless.

Patients with bipolar disorder (BPD) will often be misdiagnosed for many years, resulting in an escalation of symptoms and leading to an increased burden on the patient,
their family and society.1 In worst cases, treatment based
on an erroneous diagnosis can actually exacerbate the
state and symptoms of the patients. An early and correct
diagnosis, on the other hand, can substantially increase
quality of life and lead to a productive social life. This
monograph aims to educate the reader about the intricacies of diagnosing BPD and about the preferred use of
different medications.
2. What is Bipolar Disorder?
In the Diagnostic and Statistical Manual of Mental Disorders Version IV, Text Revision (DSM-IV-TR), BPD encompasses four distinct disorders, i.e. bipolar I (BP-I), bipolar II
(BP-II), cyclothymic disorder, and bipolar disorder not otherwise specied (BP-NOS). The lifetime prevalence of BPD
is approximately 1%2 but if the denition of the disease is
widened to include all illnesses within the spectrum, the
prevalence can be as high as 2.6% to 6.5%.3 Almost a
third (31%) of patients with BPD have been misdiagnosed
with unipolar depression, and about 35% of BPD patients
have waited 10 or more years to be accurately diagnosed.4
In general, BPD can be difcult to differentiate from other
psychiatric conditions especially unipolar depression,
and until recently it has been widely underdiagnosed.5

In the last 8 years, patient X has been given a lot of


medications, including tricyclic antidepressants, selective
serotonin reuptake inhibitors, dual serotonin and norepinephrine reuptake inhibitors, norepinephrine dopamine reuptake inhibitors, norepinephrine and specic serotonergic agents, various antipsychotics and
anticonvulsants, with varying degrees of efcacy, and
side effects. After many failed attempts and a relapse,
patient X is nally diagnosed with BP-II, and started on

Almost a third (31%) of patients with BPD have been


misdiagnosed with unipolar depression, and about 35% of BPD
patients have waited 10 or more years to be accurately
diagnosed.
The following case study illustrates how complicated it can
be to properly diagnose BPD and how important it is to
obtain a full medical and family history as well as the complete pharmacotherapeutic treatment the patient received
throughout his life. Knowing which symptoms have responded to which drug can reveal a lot about the disease.

duloxetine 60 mg/day and ziprasidone 60 mg twice


a day, and he is taking clonazepam 4 mg/nightly for
his sleep problems. Under this treatment plan patient X
does not suffer from hypomanic symptoms anymore. I
can preach and still enjoy being out in front of people,
but dont feel out of control and need to have this feeling to gain any pleasure. He also has more energy, but
still experiences periods of fatigue and residual symptoms of depression. Nonetheless, patient X can socialize
again with his wife, and lead a better life than before.

Patient X, a 67-year-old evangelist preacher married for


45 years, complains of persistent problems with depression especially in the morning, sense of dread in the stomach, lack of energy, and occasional anger. His minor
complaints include word-nding difculties and feeling
distressed and tense. In his 30s the patient had periods
during which he was unable to sleep and was prescribed
amitriptyline, which he said saved [his] life. At age 44,
patient X had a major breakdown and was diagnosed
with manic-depressive symptoms and given lithium to no
avail. Since then, he states that he has only had three
months of wellness.

3. How is Bipolar Disorder Diagnosed?


A. Diagnostic and Statistical Manual of Mental
Disorders Version IV, Text Revision (DSM-IV-TR) and
the World Health Organization International
Classication of Diseases Version 10 (WHO ICD-10)
The American Psychiatric Association DSM-IV-TR6 and

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the WHO ICD-107 have substantially different denitions of bipolar disorder leading to discrepancies in
diagnosis and treatment between both systems.

activity or psychomotor agitation, grandiosity,


inated self-esteem, pressured speech, ight of
ideas, and excessive involvement in pleasurable
activities that could have painful consequences.

i. DSM-IV-TR criteria for the diagnosis of bipolar


spectrum disorders (BSD).

ii. WHO ICD-10 criteria for the diagnosis of bipolar affective disorder (BAD).

To be diagnosed with

BP I, patients need to have experienced


at least one episode of full mania with
possibly intervening major depressive
episodes

BP II, patients need to have experienced at least one episode of hypomania and at least one episode of major
depression

Cyclothymic disorder, patients need to


present with hypomania plus subthreshold major depressive symptoms for at
least two years, and this may occur
without the progression to major
affective episodes

BP-NOS, patients need to present with


symptoms of the above disorders but
without meeting full criteria for any of
them

BAD-I is characterized by two or more episodes of


signicantly disturbed mood in conjunction with altered activity levels; which can be either an elevation
of mood with increased activity, i.e. hypomania or
mania, or a lowering of mood with decreased activity, i.e. depression. The ICD-10 then subdivides BAD
into 7 categories: 1) BAD with current episode hypomanic, 2) BAD with current episode manic without
psychotic symptoms, 3) BAD with current episode
manic with psychotic symptoms, 4) BAD with current
episode mild or moderate depression, 5) BAD with
current episode severe depression without psychotic
symptoms, 6) BAD with current episode severe depression with psychotic symptoms or 7) BAD with
current episode mixed. BAD-II on the other hand, is
classied under other bipolar affective disorders.
Thus it becomes obvious why accurate diagnosis of
BP-I and especially BP-II disorders can be problematic. Neither system allows a diagnosis of BPD to
be made without the occurrence of a full episode of
mania or hypomania even though the disorder often starts with an episode of depression without the
hypomanic state meeting the criteria of duration.4
Additionally, the DSM-IV-TR and the WHO ICD-10
systems allow for a broad diagnostic criteria for unipolar depression and a very narrow one for BPD,
thus biasing towards an underdiagnosis of the latter.4

A major depressive episode is characterized by


depressed mood and loss of interest/pleasure
for most days for two weeks, plus four of the following symptoms: insomnia/hypersomnia, difculty concentrating or thinking, indecisiveness,
psychomotor agitation or retardation, change in
appetite/weight, fatigue, and feelings of worthlessness or guilt.
A manic episode is characterized by an abnormally or persistently elevated, expansive or irritable mood that lasts at least one week, plus three to
four of the following symptoms: decreased need
for sleep, distractibility, increase in goal-directed

B. Differences between BP-I and BP-II


BPD is divided into different subtypes, the main two cat-

Figure 1: Graphic representation of the different stages seen in BP-I (A) and BP-II (B).

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egories being BP-I and BP-II. The prevalence is between


3 and 6% for the general population with a higher
prevalence in the 18- to 24-year-olds.8 In general, BP-I
patients have full blown manic episodes followed by full
depression or mixed episodes of full mania combined
with full depression (Figure 1A9), and BP-II patients present with one full blown depressive episode followed by a
hypomanic episode (Figure 1B9). Using a longitudinal study, Judd et al. found that BP-I patients experience three times more depressive states than manic
states.10 Additionally subsyndromal symptoms, whether depressive or manic, are much more frequent than
symptoms at their threshold.10 BP-I patients also exhibit
higher rates of reckless activity, distractibility, agitated activity, irritable mood and increased self-esteem,
and these 5 symptoms can correctly classify 83% of
patients as manic or BP-I and 81% of patients as hypomanic or BP-II.11 Furthermore, BP-II patients will spend
20% more time in a depressed state than BP-I patients (Table 110). In general BP-II patients show a higher lifetime
prevalence of more depressive episodes, shorter interepisode intervals, a faster onset, and a more chronic

C. Mixed episodes and rapid cycling


Around 40% of patients with BPD will experience
mixed episodes, i.e. manic and depressive episodes
occurring simultaneously. Often times, one of the two
states is the primary one, with signs of the other in the
background.4 Adding to the difculty of proper diagnosis is the fact that anxiety, personality disorder, substance misuse, and the use of antidepressants have
a high rate of comorbidity with mixed states.4 Hypomanic symptoms that are most often associated with
major depressive episode include irritability, risky activities, racing/crowded thoughts, psychomotor agitation, distractibility and suicidality.17 Major depressive episode symptoms ranging from weight gain,
overeating, hypersomnia, worthlessness, guilt, diminished concentration, indecisiveness, and thoughts
of death/suicide, on the other hand, can be associated with hypomanic symptoms.17 Mixed depression or depressive mixed states have been suggested to indicate a continuum between hypomania
as seen in BP-II and depression as seen in major

% Time (hypo)manic

% Time depressed

% Time cycling/mixed

%Time asymptomatic

BP- I

9.3%

31.9%

5.9%

52.7%

BP-II

1.3% Pure hypomanic

50.3% Pure depressed

2.3%

46.1%

Table 1: Percent time spent in Symptom Categories in BP-I versus BP-II.

In general BP-II patients show a higher lifetime prevalence of


more depressive episodes, shorter inter-episode intervals, a
faster onset, and a more chronic course of the disease.
course of the disease.12 Additionally there is a higher
comorbidity with anxiety disorders in BP-II patients.

depressive disorder, but the jury is still out.17, 18 It is


important to note, however, that there is a greater
risk of suicidality in a mixed episode than in a purely
manic phase.19

A study by Serretti and Olgiati challenged the notion of the DSM-IV-TR which describes manic episode
as being similar to hypomanic episode except more
severe.11 Additionally it is common for manic patients to undertake reckless activities due to psychomotor agitation and poor judgment,13 and uncommon for hypomanic patients to do so.14 The major
depressive episodes seen in BP-II are often mixed
with hypomanic symptoms, such as irritability, mood
liability, racing thoughts, increased sexuality and
distractibility, leading to a misdiagnosis as depressive mixed states.14 When compared to BP-I, more
than half of BP-II patients exhibit their rst symptoms
before the age of 19,8 and there is a much higher
prevalence of family history, i.e. a rst-degree relative suffering from the same illness, in BP-II compared
to BP-I (6.1% versus 1.8% respectively).15, 16

In 1974, Dunner and Fieve dened rapid cycling as a


mood disorder. To be characterized as rapid cycling,
patients have to exhibit at least four episodes of mania, hypomania or depression in one calendar year,20
all of which need to meet set duration parameters.6,
21
A period of two months between a switch from a
manic to a depressive episode, or full remission, is
required; additionally, an episode of mania has to
last one week, hypomania four days and depression
two weeks. Anything short of that will not count as
rapid cycling based on the DSM-IV-TR criteria. Clinicians, however, treat patients whose cycles are much
shorter and have proposed the following rapid cycling
denitions based on the frequency of the cycles: 1)
classical cycling lasts from three days to twelve weeks,
with at least four episodes per year; 2) ultra rapid

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cycling lasts at least three days with at least four cycles per month and 3) ultra ultra rapid or ultradian
cycling lasts less than twenty-four hours.22, 23 About
1030% of BP patients exhibit a rapid cycling pattern and 7090% of rapid cycling patients are women.24 There is also a higher risk in women (29.6%)
than in men (16.5%) to develop rapid cycling.25 In
general, BP-II patients have a higher risk (30.3%) of
developing rapid cycling compared to BP-I patients
(6%), especially if a depressive episode presented
rst.26, 27 In some patients, the rapid cycling pattern
can subside after a few years.28, 29 In summary, the
usual clinical prole of BP-II patients with rapid cycling
includes 1) being a woman, 2) presenting rst with a
depressive episode, 3) exhibiting a sequence of cycles
such as depression-mania-euthymia, 4) having a premorbid cyclo- or hyperthymic temperament and 5) in

E.

Misdiagnosis and subsyndromal symptoms

Misdiagnosis of BP-I and especially BP-II disorder often


results from a lack of clear diagnostic criteria and an
overlap of symptoms within the BSD. Depending on
the denition of a hypomanic episode, a key component of BP-II, a misdiagnosis can occur. As mentioned earlier, the DSM-IV-TR calls for a hypomanic
episode to last at least 4 days, but for a BP-II diagnosis, hypomanic episodes as short as two days should
be included.3, 34 Using structured interviews that do
not allow for a gray area can lead to misdiagnosis as well. Patients often minimize their depressive
symptoms, and do not consider their hypomanic
episodes as cumbersome; the patients actually feel
better during those episodes and seek for them to
recur.4 Of all the symptoms of hypomania, overactiv-

Diagnosing BPD in adolescents can be especially difcult due to


the high comorbidity rate (87%) with attention decit disorder.
men, having a comorbidity with anxiety disorder and
substance use.24

ity or increased goal-directed activity could be one of


the best predictors of BP-II disorder, especially when
trying to differentiate it from major depressive disorder.35 The younger the age of onset of BPD, the more
likely it is to be initiated with a depressive symptom,
and thus more often than not these patients will be
misdiagnosed with unipolar depression.36

D. Comorbidity with substance use disorder


In the Epidemiology Catchment Area study the rate of
alcohol abuse and dependence was shown to be 46%
for BP-I and 39% for BP-II patients, exceeding all other
mood disorders including schizophrenia, panic disorder and unipolar depression.30 Recently, a new study
conrmed these results and showed a 54% lifetime
prevalence of substance use disorder in patients with
BPD, with patients using substances such as alcohol,
marijuana, sedatives, hypnotics, and cocaine mainly
to alleviate their mood/anxiety symptoms, to become
euphoric or to boost energy.31 Additionally among
all psychiatric disorders, mania and hypomania are
signicantly more associated with alcohol abuse than
any other mood disorder.32 Feinman et al. investigated
three groups of patients: 1) a primary BP group who
presented only with BPD, 2) a complicated group who
had primary BPD that was complicated by substance
abuse and 3) a secondary BP group, whose BPD started after the onset of substance abuse.33 Interestingly,
when primary BP was complicated with substance
use, the patients presented with an earlier age of onset of symptoms (13.3 years) and a higher percentage
of suicide attempts (54.3% in the complicated group
versus 30.1% in the primary BP group).33 Additionally,
the complicated and the secondary BP group were
more anxious and depressed, as measured on the
Hamilton and Beck rating scales, than the primary BP
group.33 Thus, it appears that substance use worsens
the course of BPD.

Diagnosing BPD in adolescents can be especially difcult due to the high comorbidity rate (87%) with attention decit disorder.37 Additionally, children and
adolescents often present with short and frequent episodes of mania and/or depression as well as subsyndromal symptoms.38 As children exhibit less discrete
episodes of mania and depression,37 clinicians need
to look for higher rates of mixed mania (55%) and
rapid cycling (87%). Many studies have shown that
even though recovery is quite high in this population
of patients, there is also a high rate of recurrence,
despite the presence of pharmacotherapy, including many suicide attempts or completed suicides.38
Compared to adults, children and adolescents with
BP-I spend more time symptomatic, have more mixed
episodes and cycling occurrences and present with
more subsyndromal symptoms.38 There is also a higher rate of conversion between BP-I and BP-II in youth
compared to adults.38 Children will often be wrongly
characterized as temperamental and explosive with
a high degree of irritability, and non-treatment or mistreatment can be devastating to their future clinical
history.
The clinical consequences resulting from misdiagnosing BPD include the risk of suicide, substance abuse and
iatrogenic complications.15 It has been shown that of

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the people who are misdiagnosed as having unipolar


depression and treated with an antidepressant, 50%
will develop mania or hypomania and 25% will develop
rapid-cycling.39 Finally, misdiagnosing BPD has an
important economic impact on society, as BPD is the
6th leading cause of disability worldwide.15

have doubled the rate of patients diagnosed


with BPD who were originally classied as suffering from unipolar depression (the percentage
went from 22% to 40%).45, 46 Obtaining key
information from a close relative or signicant
other as well as re-interviewing the patient during a different episode can further enhance the
proper diagnosis of BP-II.47 Following the 1989
and 1994 National Institute of Mental Health
Workshops on Bipolar Disorder, an outcome
measure was developed that would quantify daily
aspects of the clinical course of BPD, namely the
National Institute of Mental Health daily prospective Life-Chart Method (NIMH-LCM-p).48 This daily report has two separate versions; one where
the patient (or self) rates himself, and one where
the clinician (or observer) rates the patient. This
allows clinicians to track the manic and depressive variations of a patient, thus providing a measure to follow the course and severity of BPD.
Additionally, a specic treatment response, or a
lag in response, can be followed as well with this
LCM-p,48 providing clinicians with a new way of
determining the efcacy of a treatment plan.

A very important aspect in treating BPD is to ascertain that the patients recover functionally and not
only syndromally. Functional recovery is the restoration of normal functioning at work, at home, and
with family and friends.40 A recent study has found
that compared to non-depressed patients, subsyndromally depressed BP patients are signicantly more
likely to be impaired at work and at home, both
in relationships with family members and with respect to home duties.41 The degree of impairment is
also signicantly correlated with the intensity of the
subsyndromal symptoms and close to that of syndromally depressed patients.41 In general, subsyndromal
depression is more common than subsyndromal mania
and there is an association between the rst subsyndromal symptoms and the subsequent mood episode
of the same polarity.16, 42 The global impact that impairment in functionality has on society16 in addition to
the poor quality of life of the patients supports the need
to assess functional recovery in patients who have subsyndromal symptoms and to consider long-term treatment of these patients.
F.

ii.

Due to the large range of symptoms presented in


the BSD and their overlap with other mood disorders, it has been difcult for physicians to accurately distinguish between various mood disorders, BP-I and BP-II. Dr. Hirschfeld helped ll this
gap by introducing the Mood Disorder Questionnaire, a simple-to-use one-page questionnaire.49 A
series of thirteen yes-or-no questions based on the
DSM-IV criteria and on clinical experience set out
to unravel a lifetime history of manic and hypomanic syndromes. A score of 7, i.e. yes to at
least seven questions, is the cutoff, as it provides
good sensitivity and good specicity. Thus, the use
of the Mood Disorder Questionnaire in addition
to an in-depth evaluation of the patient may allow
for the proper diagnosis of BPD.49 Mood charts
as well as life charts can also be very helpful for
the physician to make a proper diagnosis, and for
the patient to realize the different phases they are
in, or whether a specic event induced a specic
mood. They also allow the physician to obtain
a picture of the patients symptomatic prole between visits.

How can we achieve a better diagnosis?

A thorough evaluation of the patient and a solid grasp on


the subtleties between different mood disorders can aid in
correctly diagnosing BPD. There are a few indicators
for BPD, and these include a family history, an antidepressant-induced (hypo)mania, a hyperthymic personality prior to depression, an early age of onset and
brief episodes of the illness.17, 43 Other symptoms that
can predict BPD include hypersomnia, hyperphagia,
fatigue and sensitivity to rejection during a depressive episode. Additionally, BPD may have psychotic
features, show a seasonal pattern, exhibit severe premenstrual syndrome, and be unresponsive to antidepressants.4 An abrupt onset or end are common. Symptoms that precede the manic episodes often include
increased energy, elevated mood, disinhibition, and
racing thoughts.
i.

Mood Disorder Questionnaire

Asking the right question to the right person

The diagnosis of BP-II is improved when semistructured interviews are given to patients by
trained clinicians who focus on the symptoms
of hypomania.44 A systematic evaluation of hypomanic symptoms and the use of more elaborate checklists and alternative rating scales

4. Current Treatments in BPD


A. What is the underlying neurobiology of BPD?
The main three monoamine neurotransmitter (NT) systems norepinephrine (NE), dopamine (DA) and sero-

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tonin (5-HT) are all involved in the regulation of mood,


and deregulation in any of them can lead to depression or mania. NE, DA and 5-HT can regulate their
own release as well as the release of the other two
NTs, and they project to brain areas such as the prefrontal cortex, the basal forebrain, the hypothalamus,
the thalamus, the striatum and the nucleus accumbens,
areas regulating sleep/arousal, hyperactivity, apathy,
fatigue, weight and executive function to name a few.
All of these brain circuits are involved in one way or
another in BPD,50 and are often referred to as being
either hyper- or hypoactive in BPD. It might be more
appropriate, however, to say that these systems are
out of tune or chaotic, as they might be up in one
area and down in the other.9 The cholinergic system,
as well as stress and glucocorticoids, have also been
implicated in mood disorders. While the metabolism
of monoamines is altered in BPD patients,51 it might
be the signaling pathways within the previously mentioned systems that are defective and lead to the
pathophysiology of this mental disorder. Intracellular
signaling cascades including but not limited to the Gprotein and protein kinase C signaling, calcium levels,
glycogen synthase kinase and signaling through glutamate receptors all play a role in BPD, and most drugs
do indeed act through these pathways.50
B. What is a mood stabilizer?
Mood stabilizers have been dened by the American
Psychiatric Association's Practice Guideline for Treatment of Patients With Bipolar Disorder (Revision)52 as
drugs with both antimanic and antidepressive actions, and they are used to treat mood disorders with
rapid and unstable mood swings. Different mood stabilizers are often used in combination with each other
or with antidepressants to alleviate all the symptoms of

BPD. Lithium, lamotrigine and quetiapine are the most


effective mood stabilizers at treating both mania and
depression in BPD.
C. Treatment guidelines and their differences.
Depending on the geographical location of a patient
the treatment guidelines will be different as can be
shown by comparing the recommendations of the Canadian Network for Mood and Anxiety Treatments
(CANMAT), the American Psychiatric Association
(APA) and the British Association of Psychopharmacology (BAP). The clinical recommendations of these
associations are based on different categories with
varying degrees of clinical evidence, including but not
limited to double-blind randomized controlled trials
with a placebo arm, prospective non-controlled naturalistic trials and, expert opinion/anecdotal reports.
Table 2 represents the treatment guidelines of the different agencies.52-54
The Food and Drug Administration (FDA) normally approves treatment options for specic diseases based
on the results from at least 2 double blind placebo
controlled randomized clinical trials, and this evidencebased medicine is used to determine a treatments safety and efcacy. The following drugs are FDA-approved
for the treatment of acute mania in BPD: aripiprazole,
carbamezapine ER, chlorpromazine, divalproex ER,
lithium, olanzapine, quetiapine, risperidone, and ziprasidone. The only monotherapy approved by the FDA
for depression in BPD is quetiapine; while olanzapine
is approved in combination with uoxetine. As maintenance therapy for BPD, FDA-approved drugs include
aripiprazole, lithium, valproate, lamotrigine, and olanzapine. Table 3 (pages 12 and 13) gives an overview
of the different drugs used in the treatment of BPD; their

Acute Mania or
Mixed Episodes (ME)

Acute Depression

Maintenance Treatment

APA

Severe mania or ME: Li in combo with AP or


Val in combo with AP
Less severe: SGA better than FGA
Alternatives: CBZ, ZIP or QUE; psychosocial
therapy
In refractory illness consider Cloz and ECT

Initiate with Li or La; consider Li with AD


In severe cases use ECT; if unresponsive add
another AD

Li, Val, La, CBZ or maintenance ECT

BAP

Severe mania or ME: AP or Val


Mild mania: AP, Val, Li or CBZ;
If unresponsive switch AP or consider ECT

Severe: SSRI, or other AD (not TCA), ECT, and


AP if patient is psychotic
Moderate: SSRI, other AD (not TCA), consider
La
Mild: La or Li, psychosocial therapy

If mania predominates:
1) Li, Val, OLZ; 2) CBZ; 3) combo
If depression predominates:
1) La; 2) Li; 3) combo

CANMAT

Li; Val; AP or 2 drug-combo (Li or Val + AP)


If unresponsive consider CBZ, Cloz or ECT

If patient on Val or OLZ, RIS, ARI or ZIP, add


SSRI, Li or La or QUE
If patient is drug nude, use La, Li, QUE,
OLZ+SSRI, Li/Val+SSRI or Li+Val
If unresponsive, use different AD or consider
ECT

1) Li, La, Val, or OLZ


2) CBZ, Li+Val; Li+CBZ; Li/La+OLZ; ARI; RIS;
QUE; ZIP; Li+RIS/QUE; Li+La/SSRI;
3) Cloz; ECT; topiramate; omega-3-fatty acids,
gabapentin

Table 2: Treatment recommendations for BPD. AD=antidepressant; AP=antipsychotic; APA=American Psychiatric Association; ARI=aripiprazole; BAP= British Association of Psychopharmacology; CANMAT=Canadian Network for Mood and Anxiety Treatments; CBZ=carbamazepine; Cloz=clozapine; ECT=electroconvulsive
therapy; FGA=1st generation AP; La=lamotrigine; Li=lithium; ME=mixed episodes; OLZ=olanzapine; QUE=quetiapine; RIS=risperidone; SGA=2nd generation AP;
SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant; Val=valproate; ZIP=ziprasidone.

-10-

Atypical Antipsychotic Actions


in Psychotic and Nonpsychotic Mania

5HT2A

D2

Atypical Antipsychotic Actions


in Bipolar Depression

5H

M1

A
T1

M3

H
1

1
2

5HT1D

SRI

atypical
antipsychotic

NRI

5HT2C

D1

3
5HT

5HT
7

D2
D4

D3

clinical
actions

pharmacologic
actions

NE and DA
disinhibition

mood and
cognition

antihistamine
NE and DA
disinhibition

H1

5HT2A
5HT
disinhibition

H1

5HT2A

mood

2
SRI
NRI

SERT
inhibition

2C

mood
2

1D

SRI
NRI

mood

2C

NET
inhibition

mood

mood and
cognition

NE and DA
disinhibition

trophic
factors

insomnia
1A

-11-

5HT2A

1D

Atypical antipsychotics have been shown to be


effective at treating mania and depression in
BPD, and some are also used as maintenance
therapy. There are different feasible mechanisms of action that can explain the efcacy of
atypical antipsychotics. Their DA D2 receptor blocking activity is mainly responsible for reducing psychotic events, while the blocking ac-

blocks DA
hyperactivity

reduces glutamate
hyperactivity

1A

Despite its age, lithium remains the gold standard


in the treatment of BPD and is effective at relieving
manic and possibly depressive symptoms. Importantly, it is the only drug known to reduce suicidality in BP patients.56 Lithium is a very effective drug,
even if it can induce signicant side effects. When
lithium is given towards the bottom of its therapeutic window in combination with other mood stabilizers however, the occurrences of side effects can be
limited while achieving the same therapeutic value due
to synergistic effects with the other drugs. This might be
the new way to use this old drug. An anticonvulsant and
mood stabilizer, valproate is efcacious at treating acute
mania, and possibly depression in BPD and is used
for maintenance therapy.57 Valproate also has unacceptable side effects at the doses needed for monotherapy, but similarly to lithium when given in addition to other mood stabilizers at the low end of its
therapeutic range, it can be really efcacious and
improve tolerability and compliance. Thus for both
lithium and valproate, combination therapy might be
preferred as it will reduce side effects while optimizing
therapeutic value. The anticonvulsant lamotrigine,
whether as monotherapy or as adjunct, has been
shown to be very effective in preventing depressive
relapses in BPD, most likely due to its mechanism of
action prole.58, 59 At doses between 50200 mg/
day lamotrigine is well tolerated and, unlike antidepressants, does not lead to increased rates of
switching to manic or hypomanic states.59 Monotherapy with lamotrigine is also efcacious at
stabilizing mood swings and helping rapid cycling BP patients achieve euthymia, as shown
by a recent study using the NIMH-LCM-p over a
6-month period.60 Anticonvulsants are not necessarily the most efcacious monotherapy for BP mania,
however, these are useful drugs as add-ons. Some
side effects of concern need to be mentioned though:
there is a risk of developing polycystic ovarian syndrome with valproate, and carbamazepine is known
to have teratogenic effects and to lead to drug-drug
interactions which can render any form of contraception ineffective.

tions at the 5-HT2A receptors, which leads to the


reduction of glutamate within various different circuits, is probably responsible for both anti-manic
and anti-depressive actions (Figure 2A).9 Additional
mechanisms of action include increasing the neurotransmitters DA, NE and 5-HT, which can be valuable in relieving depressive symptoms (Figure 2B)9. All
atypical antipsychotics however have slightly different
binding properties giving them a variable portfolio of
actions. Understanding the pharmacological and clinical action of a specic drug by knowing which receptors it interacts with, can aid the physician in determining which drugs to combine in practice, which side
effects might result from a specic drug combination
and which can be eliminated.61

5H
T6

mechanism of action; the FDA-approved doses and


other issues to be aware of.55 Additionally, for each
drug the non FDA-approved usage has been added,
and is based on what is effective in practice.

neurogenesis?
circadian
rhythms

sleep, mood?

Figure 2: Actions of atypical antipsychotics in mania (A) and depression (B)

Drug Name, Class and Mechanism of


Action (MOA)

FDA-Approval *
(Non FDA-Approval)

Dosing

Lithium (Li) -- Original mood stabilizer

Tx of manic episodes; maintenance


Tx for manic depressive patients
with a history of mania

- acute: 1800 mg in 3 doses


- maintenance: 900-1200 mg/day in divided doses or at night
- start dosing at 300 mg 2-3X/day, then increase dose while monitoring
plasma levels

Maintenance Tx of BP-I

- monotherapy for BPD: 100-200 mg/day


- adjunctive Tx for BPD: 100 mg/day in combo with Val, or 400 mg/day
in combo with CBZ
- titrate VERY slowly up to 200 mg/day (25 mg/day for 2 wks; 50 mg/
day wk 3; 100 mg/day wk 5; 200 mg/day wk 6)

Mania; migraine prophylaxis;


maintenance Tx of BPD

- dosage to achieve therapeutic plasma level vary widely (750-3000 mg/


day)
- for acute mania start at 1000 mg/day and increase rapidly
- for less acute mania, begin with 250-500 mg/day and titrate upward
as tolerated, can go up to 1200-1500 mg/day

Tx of mania in BPD (as controlled


release formulation)

- 400 mg/day increased slowly up to 1200 mg/day to enhance tolerability of sedating SE


- can require upward dosage adjustment as it induces its own metabolism, thus lowering plasma levels during the 1st several wks/months of Tx

Schizophrenia; manic type of manicdepressive illness; combativeness


and/or explosive hyperexcitable
behavior in children; hyperactive
children; psychosis; acute mania

- 200-800 mg/day
- low dose may have more sedative effects
- ampuls and vials contain sultes that could cause allergic reactions; one
of the few AP available as suppository

Different applications in schizophrenia; acute mania and mixed


episodes associated with BPD

- 80-160 mg/day in divided doses, or 10-20 mg IM


- start oral dose of 40 mg 2X/day; on day 2 increase to 60 or 80 mg
2X/day
- too low a dose might block 5-HT2C receptors; best efcacy seen at doses
higher than 120 mg/day; best if taken with food, as food can double
bioavailability by increasing absorption and increasing plasma drug
levels

Schizophrenia and maintaining


stability in schizophrenia; acute Tx
of BP mania/mixed states

- 15-30 mg/day
- lower doses may be needed to avoid akathisia/activation and for max
tolerability
- if patient is switched from another AP to ARI, consider adding a full dose
of ARI to the maintenance dose of 1st AP for several days prior to a slow
down-titration of the 1st drug

Schizophrenia and maintaining


response; acute agitation associated
with schizophrenia; acute mania; BP
maintenance; acute agitation associated with BP-I mania; BP depression

- 10-20 mg/day (oral or IM)


- start with 5-10 mg 1X/day, then increase by 5 mg/day 1X/week until
desired efcacy is reached
- raising the usual dose to 15 mg/day can be efcacious for agitated or
Tx- resistant patients with little SE
- for IM dosing: start with 10 mg, followed by 2nd injection of 5-10 mg
given 2 hrs later; do not take more than 20 mg/day and no more than 3
injections/24 hrs
- for non-responding patients dose can be increased to 30 mg/day
(which is above approved limit of 20 mg/day)

Schizophrenia; acute mania; BP


depression

- for acute BP mania: 400-800 mg/day in divided doses


- on 1st day, start dosing with 2X/day with max of 100 mg/day total,
then increase in increments of 100 mg/day to 400 mg/day on day 4,
adjust dosage up to 800 mg/day by day 6
- is often underdosed; initial doses of 400-800 mg/day might optimize
chances of success in acute mania; higher doses generally achieve
greater response, some patients may need more than 800-1000 mg/day

Schizophrenia and delaying


relapses in schizophrenia; other psychotic disorders; acute mania

- 2-8 mg/day orally for acute psychosis and BPD


- 0.5-2.0 mg/day for children/elderly
- 25-50 mg depot IM every 2 wks
- start with 1 mg/day in 2 doses, increase each day by 1 mg/day until
desired efcacy is reached; max effect seen at 4-8 mg/day; max oral
dose is 16 mg/day
- can decrease dose in patients with SE without loosing efcacy; best
efcacy seen around 2-6 mg/day orally
- only use long-acting risperidone if patients tolerate 2mg/day oral risperidone

MOA: complex; alters sodium transport across


cell membranes in nerve and muscle cells;
inhibits NT via phosphatidyl inositol 2nd
messenger system

Lamotrigine (La) Anticonvulsant


Ca++
Na+

K+

Na+ channel
unit

MOA: blocks VSSCs; interacts with open


channel conformation of VSSCs at the alpha
pore-forming subunit; inhibits Glu release

(BP depression, adjunctive Tx in major


depressive disorder, vascular headache, neutropenia)

(BD depression; BP mania (adjunctive


and 2nd line); psychosis; adjunctive Tx
in schizophrenia)

glu

Valproate (Val) Anticonvulsant; mood stabilizer


Na+
Ca++

MOA: increases brain concentrations of GABA


by blocking VSSCs

(BP depression; psychosis; adjunctive


Tx in schizophrenia)

glu
GABA

Carbamazepine (CBZ) -- Anticonvulsant


Ca++
Na+
K+

GABA

MOA: blocks VSSC; interacts with open


channel conformation of VSSCs at the alpha
pore-forming subunit; inhibits Glu release

(BPD; psychosis; adjunctive Tx in


schizophrenia)

Na+ channel
unit

Chlorpromazine (Chlor) -- Conventional AP


M1

MOA: blocks D2 receptors; combo of D2, H1


and cholinergic M1 blockade in vomiting
center may reduce nausea/vomitin

H1
1

D2

Ziprasidone (ZIP) -- AAP; mood stabilizer


A
T1
5H
PA

5HT2A

5HT1D

SRI

NRI

5HT2C

D2
5HT

D3

MOA: blocks D2 and 5-HT2A receptors; interactions at 5-HT2C; 5-HT1A and 1D receptors may
contribute to efcacy in cognitive and affective
symptoms

Aripiprazole (ARI) -- Partial DA agonist; mood stabilizer


A
T1
5H
PA

5HT2A

D2
D3

PA

MOA: D2 partial agonist; D3 agonist, 5-HT1A


partial agonist; 5-HT2A antagonist which could
lead to enhanced DA release in certain brain
regions

Olanzapine (OLZ) -- AAP; mood stabilizer


X

M1

M3

5HT2A

5HT2C

D2

5H

T6

5HT

D1

D4

D3

MOA: blocks D2 and 5-HT2A receptors,


causing site-specic enhancement of DA
release; has antagonist actions at 5-HT2C
receptor

Quetiapine (QUE) -- AAP; mood stabilizer


T1
5H

MOA: blocks D2 and 5-HT2A receptors,


causing site-specic enhancement of DA
release; also acts at 5-HT1A receptors,
which could improve cognitive and affective
symptoms

A
X?

PA

M1

M3?
H

5HT2A

1
2

5H

5HT
7

T6

D2

Risperidone (RIS) -- AAP; mood stabilizer


X?

5HT2A

1
2

5HT7

D2

MOA: blocks D2 and 5-HT2A receptors, causing site-specic enhancement of DA release;


alpha2 antagonist properties may lead to AD
action

(BPD)

(BP maintenance; BP depression;


behavioral disturbances in children
and adolescents; disorders associated with impulse control, and other
psychotic disorders

(BP depression; various behavioral


disturbances; disorders associated
with problems with impulse control; BP
maintenance)

(other psychotic disorders; AD-resistant


unipolar depression; various behavioral disturbances; disorders associated
with problems with impulse control)

(other psychotic disorders; BP maintenance; various behavioral


disturbances including in Parkinsons
disease; disorders associated with
problems with impulse control)

(BP maintenance and BP depression;


various behavioral disturbances; disorders associated with problems with
impulse control)

Table 3: Drugs used in the treatment of BPD, their mechanism of action, FDA-approved doses, and side effects and special considerations.
*these drugs have additional FDA-approved uses not mentioned in the table. For additional information please refer to Stahl SM (2005) Essential Psychopharmacolgy. The Prescriber's Guide. Cambridge:
Cambridge University Press.
(1) Risk categories in Pregnancy -- Risk Category C: some animal studies show adverse effect, no controlled studies available in humans; Risk Category D: positive evidence of risk to human fetus, during
1st trimester may increase risk of neural tube defects or congenital anomalies

-12-

Side Effects and Special Considerations (SC)


Most common: ataxia, dysarthria, delirium, tremor, memory problems, polyuria and polydipsia (nephrogenic diabetes insipidus), diarrhea, nausea, and weight gain
Life-threatening: lithium toxicity, renal impairment, cardiovascular changes
SC: closely monitor patients as therapeutic window is very narrow; not recommended in patients with renal and cardiac impairments; elderly will most likely require
lower dose and may be more sensitive to SE; no safety and efcacy assessment in children under 12; risk category D in pregnancy(1); discontinue drug or bottle feed
BUT lithium is very effective at decreasing suicide attempts in unipolar, BP-I and BP-II patients and often under-prescribed as it is an old drug
Most common: benign rash (+/- 10%), sedation, blurred vision, dizziness, ataxia, headache, tremor, insomnia, poor coordination, fatigue, nausea, vomiting, abdominal pain
Life-threatening: serious rash with greater risk in pediatric patients
SC: use caution when giving to patients with renal, hepatic or cardiac impairment; elderly will most likely require lower dose and may be more sensitive to SE; risk
category C in pregnancy(1); discontinue drug or bottle feed; may be best rst line Tx for BP depression, appears effective at preventing both manic and depressive
relapses; may be best tolerated mood stabilizer with little weight gain or sedation; use lamotrigine at dose when given with valproate as valproate can double
lamotrigine levels
Most common: sedation, tremor, dizziness, ataxia, asthenia, headache, abdominal pain, nausea, vomiting, diarrhea, constipation, alopecia (unusual)
Life-threatening: rare hepatotoxicity with liver failure (especially in children under 2), rare and sometimes fatal pancreatitis
SC: be alert to symptoms of hepatotoxicity and pancreatitis; contraindicated in patients with hepatic impairment; elderly will most likely require lower dose; look for
sedation in elderly and monitor uid intake and nutritional intake; not generally indicated for children under 10; risk category D in pregnancy(1); drug found in breast
milk, but generally safe to continue breastfeeding if infant is monitored for adverse effects; 1st line of Tx and best for patients with mixed states of BPD or with rapid
cycling BPD; more effective in Tx of manic versus depressive episodes of BPD; may be more effective in preventing manic versus depressive relapses; also used to
treat aggression, agitation and impulsivity in BPD and schizophrenia. When valproate is given in combination with lamotrigine, reduce lamotrigine to the dose, as
valproate can double lamotrigine levels
Most common: sedation, dizziness, confusion, unsteadiness, headache, nausea, vomiting, diarrhea, benign leucopenia (up to 10%), rash
Life-threatening: rare aplastic anemia, agranulocytosis, rare but severe dermatologic reactions, SIADH
SC: monitor patients for signs of unusual bleeding and bruising; use with caution in patients with renal, hepatic and cardiac impairment; elderly patients may tolerate
lower doses better; approved to be used in children for epilepsy with the same therapeutic plasma levels as in adults; risk category D in pregnancy(1); discontinue
drug or bottle feed; 1st anticonvulsant widely used for Tx of BPD, but use is declining; may be effective in people who fail to respond to lithium or other mood stabilizer; preferred as 2nd or 3rd line treatment for mania; not clearly effective for depressed phase of BPD
Most common: neuroleptic-induced decit syndrome, akathisia, priapism, EPS, parkinsonism, TD, galactorrhea, amenorrhea, dizziness, sedation, impaired memory,
dry mouth, constipation, decreased sweating, sexual dysfunction, hypotension, tachycardia, syncope, weight gain
Life-threatening: rare neuroleptic malignant syndrome, rare jaundice, agranulocytosis, rare seizures
SC: use with caution in patients with renal and hepatic impairment; cardiovascular toxicity or orthostatic hypotension may occur; use lower doses in elderly patients
and monitor them; use cautiously in children and adolescents; risk category C in pregnancy(1); discontinue drug or bottle feed; dystonia, TD and sedation have been
observed in breastfed infants
Most common: dizziness, EPS, sedation, dystonia, nausea, dry mouth, asthenia, skin rash, rare TD, orthostatic hypotension
Life-threatening: rare neuroleptic malignant syndrome and rare seizures
SC: no dose adjustment needed in patients with renal or hepatic impairment; contraindicated in patients with cardiac impairment, especially with a history of QTc
prolongation; not ofcially recommended for patients under the age of 18, but may be safe and effective for behavioral disturbances in children and adolescents if
monitored closely; risk category C in pregnancy(1); unknown if ZIP found in breast milk, best to discontinue drug or bottle feed; well-accepted in clinical practice,
especially if weight gain is an issue, causes less weight gain than other AAP; monitor patient even though less risk of diabetes and dyslipidemia; more activating that
other AP at low doses, and 1 of only 2 AP with a short-acting IM formulation

Most common: dizziness, insomnia, akathisia, activation, nausea, vomiting, occasional orthostatic hypotension, theoretical risk of TD
Life-threatening: rare neuroleptic malignant syndrome, rare seizures
SC: dose adjustment not necessary in patients with renal and hepatic impairment; use in patients with cardiac impairment not studied; not ofcially recommended for
patients under 18, but clinical experiences suggest it is safe and effective; risk category C in pregnancy(1), probably found in breast milk, best to discontinue drug or
bottle feed; well accepted in clinical practice especially as it results in less weight gain, and leads to less sedation as most AP; may not have diabetes or dyslipidemia
risk; favorable tolerability prole
Most common: risk for diabetes mellitus and dyslipidemia, dizziness, sedation, dry mouth , constipation, weight gain, joint, back and chest pain, abnormal gait,
peripheral edema, tachycardia, rare orthostatic hypotension, rare TD, rare rash due to sunlight exposure
Life-threatening: hyperglycemia, rare cases associated with ketoacidosis or hyperosmolar coma and death, increased incidence of cerebrovascular event, increased
incidence of mortality in elderly patients with dementia-related psychosis, rare neuroleptic malignant syndrome, rare seizures
SC: women have decreased clearance of OLZ; lower dose for patients with hepatic impairment and monitor liver function tests; no adjustment for patients with renal
impairment; use with caution in patients with cardiac impairment due to orthostatic hypotension; lower dose in elderly; increased risk of stroke in elderly; not ofcially
recommended for children under 18, but clinical experience suggests it is safe for Tx of behavioral disturbances in children and adolescents, if monitored closely; risk
category C in pregnancy(1); may be preferable to anticonvulsants during pregnancy; best to discontinue drug or bottle feed, monitor infants closely if breast-fed; useful
in Tx-resistant cases, efcacious as augmenting agent to SSRI (uoxetine) in BP depression; causes more weight gain than other AP; less sedation; cigarette smoking
decreases OLZ levels; 1 of only 2 AP with a short-acting IM formulation
Most common: may increase risk of diabetes and dyslipidemia, dizziness, sedation, dry mouth, constipation, dyspepsia, abdominal pain, weight gain, tachycardia,
orthostatic hypotension
Life-threatening: hyperglycemia, in some case with associated ketoacidosis or hyperosmolar coma and death, rare neuroleptic malignant syndrome, rare seizures
SC: no dose adjustment in patients with renal impairment; downward dose adjustment in patients with hepatic impairment; use with caution in patients with cardiac
impairment due to orthostatic hypotension; lower doses used in elderly; not ofcially recommended in children under 18; but safe for Tx of behavioral disturbances in
children and adolescents, if monitored closely; risk category C in pregnancy(1); may be preferable to anticonvulsants during pregnancy; best to discontinue drug or
bottle feed, monitor infants closely if breast fed; preferred AP for psychosis in Parkinsons disease and Lewy Body dementia; efcacious in Tx-resistant patients, efcacy
often underestimated as it is often underdosed; induces more sedation than other APs, no motor SE or prolactin elevation
Most common: may increase risk for diabetes and dyslipidemia, dose-dependent EPS, dose-related hyperprolactinemia, rare TD, dizziness, insomnia, headache,
anxiety, sedation, nausea, constipation, weight gain, rare orthostatic hypotension, tachycardia, sexual dysfunction
Life-threatening: hyperglycemia, sometimes associated with ketoacidosis or hyperosmolar coma and death, increased incidence of cerebrovascular event, increased
incidence of mortality in elderly patients with dementia-related psychosis, rare neuroleptic malignant syndrome, rare seizures
SC: oral solution not compatible with cola/tea; in patients with renal or hepatic impairment and in elderly start drug at 0.5 mg/day 2X/day for 1 wk, increase to 1
mg/day 2X/day during 2nd wk; look for orthostatic hypotension in patients with cardiac impairment; most frequent AP used in children/adolescents; safe for Tx of
behavioral disturbances in children and adolescents, if monitored closely; risk category C in pregnancy(1); may be preferable to anticonvulsants during pregnancy;
best to discontinue drug or bottle feed, monitor infants closely if breast-fed; well accepted for Tx of agitation and aggression in elderly demented patients and for
behavioral symptoms in children/adolescents; useful in Tx-resistant patients; only AAP to raise prolactin levels; hyperprolactinemia in women with low estrogen could
accelerate osteoporosis; monitor sedation and weight gain in pediatric patients; problematic in Parkinsons disease or Lewy Body dementia; the only AAP with longacting depot formulation
Abbreviations:
5-HT=serotonin; 5-HT(1A, 2A, 2C, 1D)=specic serotonin receptors; AAP=atypical antipsychotics; AP=antipsychotic; ARI=aripiprazole; CBZ=carbamazepine; Chlor=chlorpromazine; DA=dopamine;
D(2,3)=specic dopamine receptors; EPS=extrapyramidal side effects; GABA=gamma-aminobutyric acid; Glu=glutamate; H1=histamine receptor; hrs=hours; IM=intramuscular; La=lamotrigine;
Li=lithium; M1=muscarinic receptor; MOA=mechanism of action; NT=neurotransmitter; OLZ= olanzapine; QUE=quetiapine; RIS=risperidone; SC=special consideration; SE=side effects;
SIADH=syndrome of inappropriate antidiuretic hormone secretion; TD=tardive dyskinesia; Tx=treatment; Val=valproate; VSSCs=voltage-sensitive sodium channels; Wk(s)=week(s); ZIP=ziprasidone.

-13-

When following FDA guidelines does not lead to


improvements in patients, clinicians often adopt alternatives depending on the patients symptoms,
and use drugs off label.62, 63 Because some patients
do not readily respond to one treatment or another, physicians have to make educated guesses
as to which treatment plan to adopt next. Physicians are even more inclined to use drugs off label
when treating BP depression as there are fewer
FDA-approved drugs for the treatment of BP depression when compared to BP mania, but the patients

example start with 46 mg and not 1216 mg as per


drug insert. Risperidone is advantageous due to its
very rapid onset of action, despite the need to watch
for extrapyramidal side effects. Low doses (25 mg)
of long-acting injections of risperidone are useful in
the maintenance treatment of patients, as seen in a
recent 12-month follow-up study.65 Both oral and IM
formulations of olanzapine are very effective in the
treatment of acute mania; however the recommended 10 mg per day is often too low, and needs to be
raised to 20 or 30 mg to be efcacious. Olanzap-

When following FDA guidelines does not lead to improvements


in patients, clinicians often adopt alternatives depending on the
patients symptoms, and use drugs off label.
spend more time in the depressed state. Additionally,
while FDA-approved drugs do show positive results
in clinical trials, the doses used in these trials, and
thus the doses appearing on the labels, might not always be the most effective ones. Often times the best
dosing strategies are determined after the drug has
hit the market. Clinical know-how and years of experience has led to off-label use of the drugs mentioned
in Table 3 in the treatment of mania or depression in
BPD.
Intramuscular (IM) injections (1060 mg) of ziprasidone have robust antimanic effects without the
sedative actions of other atypicals, and they allow
for easy transitions to oral formulations. After two to
three days of 2040 mg IM ziprasidone, a patient
can be switched to 160 mg oral at bed time, and
if need be the dose can be titrated up to 240 mg.
These doses have been shown to be benecial in
the clinic even if they are much higher than what the
drug inserts specify (i.e.160 mg). With drugs such
as ziprasidone, it can be tricky to nd the correct
dose, as both too low and too high of a dose can
induce side effects. For oral dosages, it might be best
to start with 80 mg at bedtime, and if patients have
trouble with insomnia or show side effects such as
akathisia, then the drug should be switched to the
morning or the dose lowered, respectively. Starting with 80 mg allows the physician to dial up or
down depending on the patients response. Either
way, ziprasidone needs to be taken with food, as
this will aid in its absorption and ascertain that the
entire dose is actually metabolized. When compared to other atypical antipsychotics, the most
clinically signicant advantage of ziprasidone is its
tendency to induce less or no weight gain.64
If risperidone is chosen in the treatment of acute mania, it is preferable to start low and go slow; for

-14-

ine, though, can be problematic due to its metabolic


side effects and weight gain. Olanzapine in combination with the SSRI uoxetine, is one of two drugs
that has been FDA-approved for BP depression. The
other drug approved for the treatment of BP depression is quetiapine. On label, quetiapine, can be used
as rst line monotherapy at a dose of 300 mg/day,
however, this dose can induce sedation and weight
gain. The weight gain with quetiapine is linear, thus
lowering the dose can reduce weight issues. Off label, quetiapine can be used at lower doses and in
combination with other mood stabilizers or atypical
antipsychotics for the treatment of disorders along
the bipolar spectrum. It can be advantageous to use
atypicals as monotherapy in BP depression as there
is no risk of switching patients into mania. The doses
of quetiapine needed to treat acute mania are quite
high (400800 mg), can be sedating and may have
effects on the metabolic system. The slow release formulation of quetiapine has been approved for the
treatment of schizophrenia and might be advantageous in BPD as well. Finally, aripiprazole is an interesting drug and has often been termed the atypical
atypical because it has the unique pharmacology of
being a partial DA agonist or DA system stabilizer.
Aripiprazole is available in tablets, oral solution and
as an IM formulation. While the oral formulation is
normally used for acute and maintenance treatment
of schizophrenia and BPD, the IM formulation lends
itself well for the treatment of agitation in both disorders.66 While aripiprazole is effective and exhibits
fewer side effects than some of the other atypicals,
it can be hard to dose properly due to its non-linear
dose response curve. To treat mania the strategy for
in-patients is to use a loading dose of 30 mg at bedtime; however, this treatment regimen can be tricky
for out patients especially if they are hypomanic.
Additionally, the doses should be lowered for mixed
states. When it comes to dosages for the treatment of

BP depression, the off label use with aripiprazole is


only 5 mg, which is much lower than the dose recommended by the manufacturer.
D. Antidepressants, combination therapies and
treatment-resistant cases
The fact that manic patients like their manic state
and do not want them to fade away pharmacologically, as they spend most of their time depressed, is
a reason why noncompliance is an issue in BPD. At
the same time, BP patients rarely respond to only one
drug, and thus need a combination of drugs for alleviation of all symptoms. Unfortunately a treatment
regimen that requires taking multiple doses at different intervals, might further lead to noncompliance.
However, it has been shown that even with complicated treatment regimens, combination therapies
can actually increase compliance.67 For the treatment of acute mania in a hospital setting, polypharmacy combining an atypical antipsychotic, a mood
stabilizer and possibly a high potency benzodiazepine, is often recommended. The rationale for using combination therapies versus monotherapy in
BPD relies on the symptom-based treatment algorithm, where a diagnosis is broken into the differ-

sant treatment might be warranted no matter what.


Interestingly though, antidepressants, without the
addition of mood stabilizers, are the most commonly prescribed drugs in the treatment of BP,69
especially since BP is often initially misdiagnosed as unipolar depression. Gijsman and colleagues performed a
systematic review of randomized, controlled trials to
get to the point of the antidepressant issue.70 Similar to what Goodwin and Jamison had noticed in the
90s,71 Gijsman and colleagues showed that different
classes of antidepressants appear to have a higher
propensity of inducing switches to mania, with tricyclic antidepressants having the highest rates (rate of
switching of 10% versus 3.2%, respectively); monoamine oxidase inhibitors inducing less mania than tricyclic
antidepressants, and SSRI being most efcacious
in treating depression in BPD.70 On the other hand,
Ghaemi et al. found that antidepressant treatment
in BP versus unipolar depression resulted in more
switches to mania and cycle accelerations, and that
co-treatment with mood stabilizers only partly prevented the manic switches.72 Recently, the effectiveness of short-term treatment of major depressive episodes in BP patients was evaluated by the National
Institute of Mental Health with the Systematic Treatment
Enhancement Program for Bipolar Disorder (STEP-BD).

BP patients rarely respond to only one drug, and thus need a


combination of drugs for alleviation of all symptoms.
ent symptoms the patient is suffering from, with each
symptom being then matched to a certain brain and
neurotransmitter pathway causing these symptoms.
Pharmacotherapies targeting these different mechanisms can then be used to alleviate each symptom one at a time.9 Thus by looking at the different
mechanisms of action of various drugs, it might be
useful to use a mood stabilizer in combination with
an atypical antipsychotic, or a mood stabilizer, an
antipsychotic and an antidepressant or different
mood stabilizers. In general, atypical antipsychotics have shown superiority compared to placebo in
reducing manic symptoms when given as add-on
medication to mood stabilizers with risperidone,
olanzapine and quetiapine having the best results.68
Additionally, when using combination therapies it is
sometimes possible to reduce the doses of all agents
and still get a good response due to the synergy
between the drugs,9 which can also lead to fewer
and less serious side effects.
The use of antidepressants in BP patients is greeted with
mixed reviews, with some believing that it might cause the
patients to enter hypomania or lead to more cycling. This notion is debated, and depending on
the severity of the patients symptoms antidepres-

-15-

The study showed that the use of bupropion or paroxetine in conjunction with a mood stabilizer was as efcacious as a mood stabilizer alone when treating BP
depression, and that neither treatment option led to an
increase in switches to mania. Unfortunately, though,
the study did not look at the use of antidepressants without mood stabilizer.73 In general, patients on an antidepressant in addition to a mood stabilizer or an atypical
antipsychotic were more likely to respond and reach
remission, supporting a positive efcacy for antidepressants in BPD.70 Finally the selegiline transdermal system
might be an interesting choice in the treatment of BP depression, as it does not lead to manic switches at low
doses. There are however various drug-drug interactions
to be aware of with the patch formulation.74 Thus it has
become accepted that when an antidepressant is
to be used, it is best to rst start patients on a mood
stabilizer and then add the antidepressant as this
might reduce the risk, if any, of a manic switch,
and because the mood stabilizer itself can prove to
have antidepressive action.75 Additionally the switch
rate is much lower in BP-II than in BP-I patients,
suggesting that antidepressant treatment in BP-II patients
may be accepted, especially in light of the fact that BP-II
patients spend more time in the depressed state.75 Figure 3 exemplies the most common, but certainly not

the only, combinations of drugs used by clinicians that have both evidence- and practicebased rationales, and that have been the most
efcacious.9 Rationale differences between
various drug combinations might also exist
depending on the geographical location of
physicians and patients (Boston Bipolar Brew;
California Careful cocktail or Tennessee mood
shine).9
Finally, various other agents need to be mentioned, as studies are currently underway to
determine their efcacy in the treatment of
BPD. These include memantine and amantadine, both NMDA glutamate receptor antagonists, with amantadine having the additional
property of releasing DA. Consistent data
however are still required to ascertain their efcacy in BPD. The anesthetic ketamine might
be an interesting drug for treatment-resistant
depression in BPD, as it shares the NMDA receptor antagonism of the two previous drugs,
and has also proven benecial in treatmentresistant unipolar depression.76 By blocking
phosphokinase C activity, omega-3 fatty acids share their mechanism of action with valproate. Despite a high heterogeneity in results,
omega-3 fatty acids have shown to be efcacious in unipolar and BP depression and they
have additional health benets important for
psychiatric patients.77 Inositol might be useful
as an augmenting agent to an antidepressant,
especially as this product is also linked to the
signal transduction cascade of 5-HT2A receptors; one of the main receptors of atypical
antipsychotics. L-methylfolate, the active form
of the folate vitamin, can increase levels of
5-HT, DA and NE and has shown to enhance
the therapeutic efcacy of antidepressants.78
Additionally some patients may lack folate
vitamin, as anticonvulsants can interfere with
both the absorption and the metabolism of
folate, thus adding it to anticonvulsants
might be a good idea. Finally the T3 thyroid hormone has shown mood stabilizing
properties in some patients but should be
studied in more detail. The DA D2/D3 agonist pramipexole, currently FDA-approved
for the treatment of Parkinsons disease and
Restless Leg Syndrome, has been tested in the
treatment of BPD, because its mechanism of
action of enhancing DA release and having
neurotrophic effects could potentially be very
useful in BPD. When added to mood stabilizers, such as lithium and valproate, pramipexole (at a dose between 0.3754.5 mg/day)
signicantly reduces depressive symptoms

Evidence Based Bipolar Combos

+
atypical-lithium
combo

atypical

lithium

DPA

+
atypical-valproate combo

atypical

valproate
divalproex

DPA

Practice Based Bipolar Combos

+
Li-Do

divalproex

lithium

+
La-Do

lamotrigine

caution

divalproex

+
La-Li

lamotrigine

lithium

+
La-Li-Do

lamotrigine

divalproex

lithium

Boston bipolar brew


(any combo
but antidepressant)

caution

antidepressant

California careful cocktail


(any combo
with antidepressant)

antidepressant

caution

+
Tennessee mood shine
(atypical + antidepressant)

atypical

antidepressant

Buckeye Bipolar Bullets

lamotrigine
monotherapy

stealth treatment

+
lami-quel

Lamictal/
lamotrigine

Seroquel/
quetiapine

quel kit
(any combo containing
quetiapine)

quetiapine

+
modafinil lamotrigine

+
modafinil

modafinil combo

+
lamotrigine/Quetiapine

antidepressant

reluctant combo

Figure 3: Different drug combinations used in the treatment of bipolar disorder.

-16-

quetiapine modafinil lamotrigine

quetiapine

in BP-II patients.79 In 67% of patients, pramipexole


when given in addition to lithium, valproate, carbamazepine, lamotrigine, and/or topiramate, leads
to a 50% reduction in depressive symptoms with
a median response time of four weeks.80 The use of
pramipexole in the treatment of depression in treatmentresistant BP patients appears to be safe overall; however patients should be monitored for the occurrence of
manic episodes.81
E.

Psychosocial therapies

It can be very tricky to impossible to treat manic patients with psychotherapy, as they might not be receptive to it. Psychotherapy is most efcacious when
patients are euthymic or depressed. There are different types of psychosocial therapies available and the
main goal is to educate the patients about how their
lifestyle can impact their disorder. For some patients,
psychotherapy can be a good alternative to polypharmacy as it does not have any side effects. It is
important to note, though, that psychosocial therapy
requires trained clinicians and can be expensive.

rate of relapses, of both manic and depressive episodes, and had fewer hospitalizations than patients in the control group.86
Interestingly, when PE is given to the family and
caregivers, it not only allows the family to understand and support the patient, but this added
support also translates into better outcomes for
the patients, such as lower rate of relapse, longer inter-episodes intervals and better treatment
adherence.87 Finally, suicide attempts are signicantly reduced in patients on pharmacotherapy,
especially lithium, when it is coupled with PE, as
the patients can better recognize the beginning of
a relapse and they feel supported by the environment providing this education.88
ii.

Cognitive-behavior therapy

Cognitive-behavior therapy (CBT) was originally


developed and used in the treatment of unipolar
depression, and focuses on changing the patients
bad behaviors that could lead to further mood
episodes. When adapted for BPD, CBT aims at

When PE is given to the family and caregivers, it not only allows


the family to understand and support the patient, but this
added support also translates into better outcomes for the
patients, such as lower rate of relapse, longer inter-episodes
intervals and better treatment adherence.

i.

Psychoeducation

The goal of psychoeducation (PE) is 1) to provide


the patient with information about the illness and
2) to render the patient an active collaborator in
the treatment of the illness.82, 83 Helping the patients
understand the history of their disease will allow
for better recognition of future symptoms. Additionally, enticing the family to participate in this education is very important as a broader understanding
of the disease by all affected members leads to
better treatment. It is best if PE is given to the patients during a euthymic phase, mainly as a prophylactic treatment, as this will increase information assimilation.82, 83 Different positive results have
been obtained by combining PE with pharmacotherapy, such as better compliance to lithium therapy and less variable serum levels.84 While some
studies show improvement only in the manic
or only in the depressive state of BP following
PE, a recent study favored PE as it improved
mood stability in general and prevented relapses up to one year in 80% of the patients.85
Patients undergoing PE presented with a lower

-17-

increasing awareness of mood, recognizing subsyndromal symptoms and signs of upcoming episodes, and preventing the escalation to full blown
episodes.88, 89 Adding CBT to pharmacotherapy
results in better adherence to medical treatment,
fewer hospitalizations and relapses and less uctuations in mood.90, 91
iii.

Family-focused treatment

The family-focused therapy (FFT) was developed


by Miklowitz and colleagues and combines PE
with communication skills training and problem
solving along with an assessment of the family, as
family emotions, which tend to be unsupportive,
can induce relapses in patients.89, 92 FFT appears
to be useful in addition to pharmacotherapy, and
patients undergoing FFT show fewer relapses, longer time to relapse, improvement in depressive
symptom and more medication adherence over a
two-year period.87, 93

iv.

Interpersonal and social rhythm therapy

family and society, and therefore we need to improve our


knowledge about the disease and its treatments.

An adaptation from the interpersonal therapy


by Frank and colleagues94 led to the development of the Interpersonal and social rhythm
therapy (IPSRT) for BPD, a specically designed
treatment therapy that includes PE, social rhythm
therapy and interpersonal psychotherapy with
a special emphasis on understanding the link
between mood and life events and their impact
on BPD.89 When offered in conjunction with
lithium, IPSRT has been shown to signicantly
reduce suicidality over a two-year period.88
Thus psychosocial therapies in general, when
given in addition to pharmacotherapy, are benecial in reducing the number of relapses, increasing the interval between relapses and
increasing treatment adherence, as well as
educating the patient and the family about disease
progression and the importance of treatment.
F.

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16.

In patients with comorbid substance use, treatment


can often be difcult, mainly because of noncompliance. In a recent pilot study on BP patients abusing
cocaine, it was determined that valproate signicantly improved the percentage of cocaine and alcohol
abstinent days and signicantly decreased the use
of marijuana. Additionally, signicant improvements
were observed in manic, depressive and sleep symptoms.95 Valproate has also been shown to be benecial in reducing the number of days drinking and the
number of drinks per day in BP patients suffering from
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Abbreviations:
5-HT=serotonin; 5-HT(1A, 2A, 2C, 1D)=specic serotonin receptors; AAP=atypical
antipsychotics; AD=antidepressants; AP=antipsychotic; APA=American
Psychiatric Association; ARI=aripiprazole; BAD=Bipolar Affective Disorder;
BAP=British Association of Psychopharmacology; BPD=Bipolar Disorder;
BSP=Bipolar Spectrum Disorder; BP-I=Bipolar I disorder; BP-II=Bipolar II
disorder; BP-NOS=Bipolar disorder not otherwise specied;
CANMAT=Canadian Network for Mood and Anxiety Treatments;
CBT=Cognitive-Behavior Therapy; CBZ=carbamazepine; Chlor=chlorpromazine;
Cloz=clozapine; DA=dopamine; D(2,3)=specic dopamine receptors; DSM-IV
(TR)=Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text
revision; ECT=electroconvulsive therapy; EPS=extrapyramidal side effects;
FDA=Food and Drug Administration; FFT=Family-Focused Treatment; FGA=rst
generation antipsychotic; GABA=gamma-aminobutyric acid; Glu=glutamate;
H=histamine; H1=histamine receptor; IM=intramuscular; IPSRT=Interpersonal
and Social Rhythm Therapy; La=lamotrigine; Li=lithium; M1=muscarinic
receptor; ME=mixed episodes; MOA=mechanism of action; Na=sodium;
NE=norepinephrine; NMDA=N-methyl-d-aspartate; NIMH-LCM-p=National
Institute of Mental Health daily prospective Life-Chart Method;
NT=neurotransmitter; OLZ=olanzapine; PE=Psychoeducation; QUE=quetiapine;
RIS=risperidone; SC=special consideration; SE=side effects; SGA=second
generation antipsychotics; SIADH=syndrome of inappropriate antidiuretic
hormone secretion; SSRI=selective serotonin reuptake inhibitor; TD=tardive
dyskinesia; Tx=treatment; Val=valproate; VSSCs=voltage sensitive sodium
channels; Wk=week; WHO ICD-10=World Health Organization International
Classication of Diseases Version 10; ZIP=ziprasidone.

-19-

Posttest and Activity Evaluation


To receive your certicate of CME credit or participation, please complete the posttest and activity evaluation answer sheet found
on the back cover ap and return by postage-paid mail or fax it to 760-931-8713. Upon receipt, your posttest will be graded
and, along with your certicate (if a score of 70% or more was attained), returned to you by mail. Alternatively, you may complete these items online and immediately print your certicate at www.neiglobal.com/pt/07bipolarmonograph.
(Please circle the correct answer on the answer sheet provided.)
1. Compared to patients with BP-I, patients with BP-II
A.
B.
C.
D.
E.

7. The usual clinical prole of a BP-II patient is:

Spend more time in the depressed state


Spend less time cycling or in a mixed state
Spend more time in the manic state
A and B
B and C

A.
B.
C.
D.
E.

2. Children and adolescents with bipolar disorder

Being a woman
Having a manic episode at onset
Hyperthymic temperament
A and C
A, B and C

8. Which statement is false?

A. Have shorter episodes, and are often misdiagnosed

A. Psychoeducation works best in depressed patients as

with attention decit disorder


B. Have longer episodes, and are often misdiagnosed
with attention decit disorder
C. Are never misdiagnosed with attention decit
disorder
D. Always adhere to their treatment

they are more willing to assimilate new information


B. Psychoeducation combined with pharmacotherapy

shows positive results


C. Psychoeducation is benecial in decreasing treatment

adherence, the number of relapses and the relapse


interval
D. Involving the family through psychoeducation can be
helpful to the patient

3. Which of the following drugs are normally started at a

lower dose than the package insert recommends?


A.
B.
C.
D.

9. When co-administering valproate and lamotrigine, one

Risperidone and olanzapine


Aripiprazole and olanzapine
Risperidone and aripiprazole
Quetiapine and olanzapine

needs to be cautious, because:


A.
B.
C.
D.

4. The rate of suicide attempts is greatest in which

Lamotrigine can double the levels of valproate


Both drugs act as agonists at the glutamate receptors
Valproate can double the levels of lamotrigine
Both drugs should be given at lunch time

disorder?
10. Which 2 antipsychotics have intramuscular

A. Unipolar depression
B. Bipolar I
C. Bipolar II

formulations?
A.
B.
C.
D.

5. According to the DSM-IV the parameters for rapid

cycling are as follows:

Ziprasidone and aripiprazole


Quetiapine and risperidone
Ziprasidone and risperidone
Olanzapine and ziprasidone

A. Mania that lasts 3 days, hypomania that lasts 3


11. Which antipsychotic does not act at the 5-HT1A

days; depression that lasts 3 days; with at least four


episodes in one month
B. Mania that lasts 1 week, hypomania that lasts 4
days; depression that lasts 2 weeks; with at least four
episodes in one year
C. Mania that lasts 24 hours, hypomania that lasts 24
hours; depression that lasts 3 days; with many
episodes in one month

receptor?
A.
B.
C.
D.
E.
F.

6. Ultradian cycling refers to:


A. Circadian rhythm of the patient
B. Ultra ultra rapid cycling that lasts less than 24 hours
C. Switching between treatment therapies in BP patients

-20-

Olanzapine
Aripirazole
Risperidone
Ziprasidone
A and C
B and D

Insights into the Diagnosis and Treatment of Bipolar Disorder


Posttest and Activity Evaluation
To receive your certicate of CME credit or participation, please complete the posttest (you must score at least 70% to recieve credit) and activity evaluation answer sheet
found on this page and return by postage-paid mail or fax it to 760-931-8713. Upon receipt, your posttest will be graded and, along with your certicate, returned
to you by mail. Alternatively, you may complete these items online and immediately print your certicate at www.neiglobal.com/pt/07bipolarmonograph. (Circle the
correct answers)

Posttest
1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

Activity Evaluation
Please rate the following, using a scale of:
1-poor

2-fair

3-good

4-very good

5-excellent

1.

The overall quality of the content was

1 2 3 4 5

2.

The relevance of the content to my professional needs was

1 2 3 4 5

3.

The level at which the learning objective was met of teaching me to track history and progression of symptoms and treatment
responses for patients with mood/behavioral symptoms

1 2 3 4 5

4.

The level at which the learning objective was met of teaching me to select mood stabilizers and their doses based on patient
presentation

1 2 3 4 5

5.

The level at which the learning objective was met of teaching me to use neurobiologic and mechanistic rationale when combining
medications to treat bipolar spectrum disorders

1 2 3 4 5

6.

The level at which this activity was objective, scientically balanced, and free of commercial bias was

1 2 3 4 5

7.

The overall quality of this activity was

1 2 3 4 5

8.

Based on my experience and knowledge, the level of this activity was:


Too Basic

9.

Basic

Appropriate

Complex

Too Complex

Based on the information presented in this activity, I will:


A.
B.
C.
D.

Change my practice
Seek additional information on this topic
Do nothing as current practice reects activitys recommendations
Do nothing as the content was not convincing

10. What barriers might keep you from implementing changes in your practice youd like to make as a result of participating in this activity?

11. The following additional information about this topic would help me in my practice:

12. How could this activity have been improved?

13. Additional comments:

Name:

Credentials:

Specialty:
Address:
City, State, Zip:
Email:

Phone: