1. Read Chapters 6 and 7 in DSM-5 in Action.
Dziegielewski, S. F. (2014). DSM-5 in action (3rd ed.). John Wiley & Sons.
2. Read pages 123-188 in the DSM-5.
Diagnostic and statistical manual of mental disorders: DSM-5 (5th ed.). (2013). American
Psychiatric Publishing.
3. Read "Combining Medication Treatment and Cognitive-Behavior Therapy for Bipolar Disorder,"
by Basco, Ladd, Myers, and Tyler, from Journal of Cognitive Psychotherapy (2007).
https://lopes.idm.oclc.org/login?url=https://search-proquestcom.lopes.idm.oclc.org/docview/89071100?accountid=7374
4. Explore the Diagnostic and Statistical Manual of Mental Disorders website.
http://www.dsm5.org/Pages/Default.aspx
5. Read “Elevated Reward-Related Neural Activation as a Unique Biological Marker of Bipolar
Disorder: Assessment and Treatment Implications” by Nusslock, Young, & Damme, from
Behaviour Research and Therapy (2014). https://www-sciencedirectcom.lopes.idm.oclc.org/science/article/pii/S0005796714001405?via%3Dihub
6. Read "Predictors of Suicidal Ideation and Attempt Among Patients With Major Depressive
Disorder at a Tertiary Care Hospital, Puducherry," by Lalthankimi, et al., from Journal of
Neurosciences in Rural Practice (2021).
https://lopes.idm.oclc.org/login?url=https://search.ebscohost.com/login.aspx?direct=true&db=
a9h&AN=148381753&site=eds-live&scope=site&custid=s8333196&groupid=main&profile=eds1
7. Read “Differential Diagnosis of Bipolar Disorder and Major Depressive Disorder” by Hirschfeld,
from Journal of Affective Disorders (2014).
https://www-sciencedirectcom.lopes.idm.oclc.org/science/article/pii/S0165032714700047?via%3Dihub
8. Read “Diagnostic Utility of Worry and Rumination: A Comparison Between Generalized Anxiety
Disorder and Major Depressive Disorder” by Yang, Kim, Lee, Lee, Yu, Jeon, & Kim, from
Psychiatry and Clinical Neurosciences (2014).
https://lopes.idm.oclc.org/login?url=http://search.ebscohost.com/login.aspx?direct=true&db=a
9h&AN=97637640&site=ehost-live&scope=site
9. Read “Managing Major Depressive Disorder Through the Use of Adjunct Therapies” by Katzman,
Psychiatry Research (2014). https://www-sciencedirectcom.lopes.idm.oclc.org/science/article/pii/S0165178114700010?via%3Dihub
10 Read “An Update on the Diagnosis and Treatment of Bipolar Disorder, Part 1: Mania” from
Psychiatric Times (2015).
https://lopes.idm.oclc.org/login?url=http://search.ebscohost.com/login.aspx?direct=true&d
b=ofs&AN=112070371&site=ehost-live&scope=site
11 Read the “Case Study: Jack” document in preparation for this week’s discussion question.
November 2015
All other clinicians
either will receive a
CME Attendance
Certificate or may
choose any of the
types of CE credit
being offered.
PREMIERE DATE: November 20, 2015
EXPIRATION DATE: November 20, 2016
This activity offers CE credits for:
1. Physicians (CME)
2. Other
An Update on the Diagnosis and Treatment
of Bipolar Disorder, Part 1: Mania
by Philip G. Janicak, MD and Joseph Esposito, MS, MD
Dr Janicak is Director of the Transcranial Magnetic Stimulation Center at
Edward/Elmhurst Healthcare and is on the faculty of the department of psychiatry and behavioral sciences at Northwestern University Feinberg School
of Medicine in Chicago; Dr Esposito is a First-Year Resident at the
Delaware Psychiatric Center in New Castle, Del.
I
n this 2-part article, we consider bipolar disorder symptom manifestations
in light of the changes in DSM-5. We review the management of acute
mania and hypomania, as well as subsequent maintenance strategies.
Throughout, we also consider the implications of course specifiers (eg, rapid
cycling, mixed or psychotic features) for altering treatment approaches
(Table 1). In Part 2 (December 2015 issue of Psychiatric Times) we will
discuss the management of bipolar depression and cyclothymic disorder, the
role of psychotherapy, and future directions.
Diagnosis of bipolar disorder
The lifetime prevalence of bipolar disorder is estimated to be 1.6%.1 This
illness typically begins early in life and is characterized by acute exacerba-
ACTIVITY GOAL
This article reviews DSM-5 changes to
symptom criteria for bipolar disorder. The
primary focus is on the diagnosis and treatment of mania and hypomania.
LEARNING OBJECTIVES
At the end of this CE activity, participants should be able to:
• Understand the various bipolar specifiers
• Identify bipolar diagnostic categories
• Identify FDA-approved indications for pharmacologic management
of bipolar mania
• Distinguish which intervention (pharmacotherapy or psychotherapy)
is best for each patient
TARGET AUDIENCE
This continuing medical education activity is intended for psychiatrists,
psychologists, primary care physicians, physician assistants, nurse
practitioners, and other health care professionals who seek to improve
their care for patients with mental health disorders.
CREDIT INFORMATION
CME Credit (Physicians): This activity has been planned and implemented in accordance with the Essential Areas and policies of the
1511PT206973AJanicak_CME.indd 29
tions of mania, hypomania, and depression; a chronic, recurrent course with
substantial interepisodic morbidity; an increase in other psychiatric (eg, substance abuse) and medical (eg, cardiovascular disease) comorbidities; and a
heightened risk for suicide. As a result, bipolar disorder negatively affects
functioning in multiple spheres of activity, health status, and quality of life.
A manic episode experienced even once in a lifetime qualifies for a diagnosis of bipolar I disorder. While these patients may experience hypomanic
and major depressive episodes as well, these are not required criteria. Despite this, depression typically is the more predominant mood disturbance.
A diagnosis of bipolar II disorder requires both a hypomanic and a major
depressive episode. It is important to emphasize that bipolar II is not a less severe
form of bipolar I, but rather a distinct disease process that can be just as detrimental to psychosocial functioning, particularly in the depressive phase. While patients with bipolar I and bipolar II disorder may experience major depressive
episodes and hypomania, bipolar II patients never experience mania.
Bipolar disorder usually presents as discrete episodes. Thus, mania and
hypomania often occur with a relatively sudden and recognizable change in
behavior clearly out of character from the patient’s baseline mood state.
While mania and hypomania share many of the same symptoms, a key difference is severity (Table 2). True mania must be present for at least 1 week
Accreditation Council for Continuing Medical Education (ACCME)
through the joint providership of CME Outfitters, LLC, and Psychiatric
Times. CME Outfitters, LLC, is accredited by the ACCME to provide
continuing medical education for physicians.
CME Outfitters designates this enduring material for a maximum of 1.5
AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
(Please see Mania, page 30)
Philip G. Janicak, MD, reports that he has received grant support from,
and is on the speakers bureau for, Neuronetics Inc, Sunovion, and OrthoMcNeil/Janssen; he is also a consultant for Neuronetics Inc.
Joseph Esposito, MS, MD, has no disclosures to report.
Michael Gilin, MD, (peer/content reviewer) reports that he is on the
speakers bureau for Otsuka.
Note to Nurse Practitioners and Physician Assistants: AANPCP and
AAPA accept certificates of participation for educational activities
certified for 1.5 AMA PRA Category 1 Credit™.
Applicable Psychiatric Times staff and CME Outfitters staff have no
disclosures to report.
DISCLOSURE DECLARATION
It is the policy of CME Outfitters, LLC, to ensure independence, balance, objectivity, and scientific rigor and integrity in all of their CME/
CE activities. Faculty must disclose to the participants any relationships with commercial companies whose products or devices may
be mentioned in faculty presentations, or with the commercial supporter of this CME/CE activity. CME Outfitters, LLC, has evaluated,
identified, and attempted to resolve any potential conflicts of interest
through a rigorous content validation procedure, use of evidencebased data/research, and a multidisciplinary peer-review process.
Faculty of this CME/CE activity may include discussion of products or
devices that are not currently labeled for use by the FDA. The faculty
have been informed of their responsibility to disclose to the audience
if they will be discussing off-label or investigational uses (any uses
not approved by the FDA) of products or devices. CME Outfitters,
LLC, and the faculty do not endorse the use of any product outside of
the FDA-labeled indications. Medical professionals should not utilize
the procedures, products, or diagnosis techniques discussed during
this activity without evaluation of their patient for contraindications or
dangers of use.
The following information is for participant information only. It is not
assumed that these relationships will have a negative impact on the
presentations.
Questions about this activity?
Call us at 877.CME.PROS (877.263.7767)
UNLABELED USE DISCLOSURE
11/2/15 9:52 AM
30
PSYCHIATRIC TIMES
NOVEMBER 2015
CATEGORY 1
Mania
Continued from page 29
with associated increases in energy or activity and marked functional impairment that results in a substantial loss of social and occupational functioning.
Psychotic features may also be present in more severe episodes and often require hospitalization. Alternatively, hypomania should last at least 4 days with
symptoms that are not as severe as mania in terms of social or occupational
impairment. Psychotic features are never present in bipolar II patients, and
hospitalization is a specific exclusion criterion. Per DSM-5, if either mania or
hypomania presents with at least 3 criteria for a depressive episode, they
would warrant a mixed specifier designation as well.
Clarifying whether there has been a manic or hypomanic episode may be
difficult. This is in part because patients may not consider hypomania or mild
mania to be problematic. Clinicians need to carefully explore for possible past
episodes, using collateral sources of information whenever possible. Screening instruments such as the Mood Disorders Questionnaire and the prospective Life Chart Method are also helpful.2,3
Cyclothymic disorder is characterized by at least 2 years (1 year in children
and adolescents) of periodic hypomanic and depressive symptoms that are
distinct from each other. Neither mood phase, however, ever meets the full
criteria for a hypomanic or depressive episode. During this time, there are no
periods of normal mood that last more than 2 months. These mood disturbances should also lead to problems in social or occupational functioning.
Differential diagnosis
Bipolar disorder can be difficult to distinguish from other psychiatric conditions because there is often substantial symptomatic overlap. Acute schizo-
phrenia can mimic a more severe episode of mania and requires careful attention to the patient’s psychiatric history to help clarify the diagnosis. While
similar symptoms may occur in both disorders, schizophrenia more commonly presents with hallucinations and fixed delusions.
Schizoaffective disorder is distinguished from acute mania with psychosis
by a period of psychotic symptoms that lasts at least 2 weeks in the absence
of significant mood symptoms. Over the long-term course of schizoaffective
disorder, however, there should be a substantial proportion of time (> 50%)
when mood symptoms are present.
MDD and bipolar depression are often clinically indistinguishable. MDD,
however, involves only depressive episodes, whereas bipolar depression requires a history of mania or hypomania. Obtaining a thorough personal and
family history, including premorbid functioning, may help clarify the diagnosis.
Other disorders (eg, ADHD, conduct disorder, stimulant use) may also
include certain symptoms of hypomania or mania and, to further complicate
the diagnosis, often occur as comorbidities with bipolar disorder. Various
substances, medications, and medical conditions can mimic the symptoms of
bipolar disorder and have their own specific diagnostic categories. For example, manic or hypomanic symptoms due to the effects of cocaine would not
be given a bipolar diagnosis unless the symptoms persisted well after the
drug’s effects subsided.
Table 3 lists and briefly describes DSM-5 categories for bipolar disorder.
Management of bipolar mania and hypomania
Treatment recommendations
Several reviews, professional guidelines, pragmatic studies, and treatment algorithms serve as the basis for our suggested treatment approaches. The strategies recommended in these publications are based primarily on the strength of
Table 1 – Bipolar specifiers
Type
Symptoms
Comments
With anxious distress
Tenseness, restlessness, poor concentration due to
worry, impending misfortune, fear of loss of control
Number of symptoms: mild, 2; moderate, 3; moderate to severe,
4 or 5; severe, 4 or 5 with motor agitation
With mixed features during mania
or hypomania
Manic or hypomanic episode plus depressed mood,
decreased pleasure in activities, psychomotor retardation, fatigue, worthlessness or guilt, thoughts of death
with or without a specific plan
At least 3 symptoms present for the majority of the days during
an episode
With mixed features during
a depressive episode
Elevated mood, grandiosity, talkativeness, racing
thoughts, increased goal-directed activity, risky
behavior, decreased need for sleep
At least 3 symptoms present for the majority of the days during
an episode
With rapid cycling
Four or more mood episodes in the past 12 months
Each episode must be separated by either a period of full
remission or a switch to the opposite polarity
With melancholic features
Loss of pleasure in activities OR no reactivity to events
that should be pleasurable AND 3 or more melancholic
symptoms
Melancholic symptoms: distinct quality of depression that is
worse in the morning, early morning awakening, psychomotor
changes, anorexia, weight loss, or excessive or inappropriate
guilt
With atypical features
Mood reactivity AND at least 2 other symptoms
Symptoms such as increased appetite or weight gain,
hypersomnia, heavy feeling of the arms and legs, sensitivity
to rejection
With mood-congruent
psychotic features
Delusions or hallucinations
Should be in line with what is expected for the current episode
(eg, grandiosity during mania)
With mood-incongruent
psychotic features
Delusions or hallucinations
Should not fit with the current mood episode or are mixed with
some congruent features
With catatonia
Catatonic features present for most of the episode
May occur with mania or depression
With peripartum onset
Mood episode during pregnancy or up to 4 weeks
after delivery
Depressed episode may be associated with severe anxiety
or panic attacks
With seasonal pattern
Mood episodes and remissions that only occur at a
certain time of the year
There is an absence of off-cycle episodes in at least the past 2
years and more seasonal episodes compared with non-seasonal
episodes overall
Adapted from DSM-5.
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Table 2 – Mania and hypomania
diagnostic criteria
31
Table 3 – Bipolar diagnostic categories
Criteria
Maniaa
Hypomaniab
Diagnosis
Description
Minimum timeframe for diagnosis
1 week
4 days
Bipolar I disorder
Number of symptoms for diagnosis
At least 3
At least 3
Diagnosis requires at least 1 true manic
episode with or without episodes of
depression or hypomania
Grandiosity
Yes
Yes
Bipolar II disorder
Decreased need for sleep
Yes
Yes
More talkative
Yes
Yes
Diagnosis requires at least 1 hypomanic
episode AND 1 major depressive episode
in the absence of any lifetime history of
mania
Flight of ideas
Yes
Yes
Cyclothymic disorder
Distractibility
Yes
Yes
Increased goal-directed activity
Yes
Yes
2 years (1 in children and adolescents)
of hypomanic and depressive symptoms
that fall short of meeting DSM criteria for
either mood state
Risky behavior
Yes
Yes
Marked impairment of
social/occupational functioning
Yes
No
Substance/medication-induced
bipolar and related disorders
A disturbance in mood that develops
during or soon after substance
intoxication or withdrawal
Psychotic features
Yes
No
May require hospitalization
Yes
No
Bipolar and related disorders
due to another medical
condition
The disturbance is a direct pathophysiological consequence of another medical
condition
Other specified bipolar and
related disorders
Symptoms that fall short of meeting
criteria for bipolar I or II disorder
(eg, short hypomanic episodes, belowcriteria hypomanic symptoms with major
depression, hypomania without major
depressive episode, cyclothymic
symptoms occurring less than 2 years
[1 in children and adolescents] )
Unspecified bipolar and
related disorders
Diagnosis used until a more specific
diagnosis can be obtained (ie, limited
information, emergency department
setting)
More severe.
Less severe.
Adapted from DSM-5.
a
b
evidence from placebo- and/or active comparator-controlled trials involving
various medications or psychotherapeutic approaches. In some cases, however,
there is a lack of such data and information of lesser strength forms the basis
for recommendations. In particular, guidelines for the management of certain
patient subgroups (eg, rapid cyclers) are often based on results from fewer and
less well-controlled trials. One additional caveat is that the preponderance of
evidence derived from controlled trials is industry sponsored.
Emergency interventions
Manic patients who present with severe agitation or aggression may require
immediate pharmacologic intervention to prevent harm to themselves and
others. Second-generation antipsychotics are generally preferred over firstgeneration (typical) agents because of their lower short-term adverse effect
burden. Benzodiazepines may also be used as adjuncts to quickly calm an
agitated patient, to reduce the amount of antipsychotic required, or to prevent
withdrawal symptoms when alcohol or other substances are involved.
When possible, oral formulations should be offered initially and acute
parenteral formulations reserved for those unwilling or unable to tolerate oral
therapy.4 Alternatively, the combination of lower doses of haloperidol (eg, 2
to 5 mg) and lorazepam (eg, 2 mg) may be used either orally or parenterally.
A recent study indicated that successful remission of postpartum psychotic
mania may require combined treatment with lithium, an antipsychotic, and a
benzodiazepine.5 In more emergent situations such as manic delirium, ECT
can be life-saving.6
Stabilization strategies
Once the safety of the patient and others is assured, attention turns to resolution of an acute episode (Figure). If the patient is currently taking an antidepressant, it should be discontinued (preferably by taper rather than by abrupt
cessation) to prevent persistent manic symptoms and a greater risk for relapse.
Most published strategies to manage acute, mild to moderate manic or
mixed episodes (and to a lesser extent hypomania) recommend lithium, valproate, or a second-generation antipsychotic as first-line monotherapies. Of
note, recent evidence supports lithium’s potential neuroprotective properties
and lower non-suicide mortality risk compared with anticonvulsants.7,8 In
patients with more severe symptoms, associated psychosis, or schizoaffective disorder, a second-generation antipsychotic alone or in combination with
other mood stabilizers plus a benzodiazepine are usually recommended (eg,
lithium or valproate plus an antipsychotic). Second-generation antipsychot-
1511PT206973AJanicak_CME.indd 31
Adapted from DSM-5.
ics are usually preferred to first-generation antipsychotics to minimize adverse effects, particularly neuromotor; or to lithium, valproate, or carba
mazepine during pregnancy. With insufficient benefit, clozapine as
monotherapy or augmentation therapy may also be an alternative.9 Finally,
ECT alone or combined with an atypical antipsychotic can control episodes
of psychotic mania and severe refractory episodes, and constitutes a safer
alternative during pregnancy.10,11
Lithium and valproate appear to be comparably effective in treating pure
manic episodes, while valproate may be more effective for mixed or rapid
cycling presentations.12 Carbamazepine with or without an antipsychotic is
usually recommended as second-line therapy because it is limited by its adverse effect profile and the risk of significant interactions with other psychotropic and nonpsychotropic medications.12 In this context, oxcarbazepine—a
structurally similar analog of carbamazepine—may be an alternative based
on promising but limited data from preliminary studies, primarily because of
its lower adverse effect profile and fewer drug interactions.13
Once the initial target dose or blood level is achieved, medication adjustments may be considered within 1 to 2 weeks if there is insufficient improvement. When feasible, dose adjustments of the initial medication(s) should be
attempted before the addition of another medication to minimize adverse
effects, drug interactions, and unnecessarily complicated treatment regimens—all of which may exacerbate adherence problems. At times, however,
the combination of lithium plus valproate will more effectively control acute
symptoms. This strategy is usually done in a sequential fashion rather starting both medications simultaneously.
(Please see Mania, page 32)
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Mania
Continued from page 31
Maintenance treatment
The agent(s) used to successfully control a manic episode are typically continued for maintenance purposes. Thus, the most commonly recommended
treatments mirror those used for acute management and include lithium, valproate, and second-generation antipsychotics. In addition, risperidone longacting injectable formulation (alone or in combination with lithium or valproate) may be considered for patients with a history of poor oral absorption
or inadequate adherence. At times, combined treatments may enhance efficacy but often at the cost of a greater adverse effect burden. In this context,
the results of the BALANCE study indicate that lithium alone is more likely
to prevent relapse than valproate alone.14 However, it is unclear whether lithium alone is as effective in preventing relapse as the combination of lithium
and valproate. In addition, psychotherapy to address residual mood symptoms and comorbid conditions such as substance use disorders is critical to
achieving and maintaining a successful outcome.
In the absence of persistent psychosis, adjunctive antipsychotics used for
acute control may be slowly tapered after a reasonable period of mood stability is achieved. If benzodiazepines are used for acute stabilization, they
should also be slowly discontinued when symptoms are resolved. Maintenance ECT may be continued after a successful acute treatment course at the
lowest possible frequency, if symptoms are not adequately controlled with
medication(s) and psychotherapy.
Maintenance treatment should be continued for at least 6 to 12 months
after complete remission of a manic episode before assessing the need for
Figure. Treatment Strategy for Acute Mania
Treatment strategy
Clinical presentation
Acute mild to moderate mania
Start
Lithium (0.8-1.2 mEq/L) or valproate (50-125 μg/mL) or
second-generation antipsychotic;
withdraw antidepressant if being used
Insufficient response
Moderate to severe episode;
psychotic symptoms;
primary mood stabilizer(s) insufficient
Start
Second-generation antipsychotic ± mood stabilizer
± benzodiazepine
Insufficient response
Poor oral absorption;
inadequate adherence
to oral medications
Consider
Risperidone long-acting injectable ± mood stabilizer
± benzodiazepine
Insufficient response or intolerable adverse effects
Mood stabilizer not tolerated
May start
Second-generation antipsychotic monotherapy
± benzodiazepine
Insufficient response
Prior nonresponse to lithium;
rapid cycling; mixed state;
medical contraindication to lithium;
patient is not pregnant
May start
Valproate/carbamazepine ± antipsychotic
± benzodiazepine
Insufficient response
Combined mood stabilizers ± antipsychotic
± benzodiazepine
Insufficient response
Clozapine ± valproate or lithium
Insufficient response
Immediate danger (eg, manic delirium);
previous good response to ECT;
medical contraindication to
pharmacotherapy; patient is pregnant
May start
ECT
Insufficient response
ECT plus second-generation antipsychotic
Adapted from Janicak et al.1
1511PT206973AJanicak_CME.indd 32
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ongoing treatment. Given the high relapse rates with discontinuation, however, it is generally recommended that maintenance therapy continue indefinitely. If lithium is discontinued, it should be done by a slow taper over several weeks to decrease the risk of relapse.
Pharmacotherapy
Lithium
While lithium’s exact mechanism of action is unknown, its ability to modulate various aspects of brain chemistry is consistent with many current models of the pathogenesis of bipolar disorder. Lithium exerts multiple biochemical effects at a variety of targets owing to its relatively simple nature.
Because of its similarity to other cations (eg, Na+, K+, Ca++, Mg+), lithium
can alter ion channels and pumps in cell membranes. It is also implicated in
the modulation of neurotransmitters and neuropeptides such as lithium-induced decreases in beta-adrenergic receptor number, beta-adrenergic activity through inhibition of thyroid hormone, dopamine receptor supersensitivity, and glutamate-mediated calcium signaling; and increases in serotonin
release.
In addition, lithium interacts with G-protein and second messenger systems leading to downstream effects on DNA transcription, which may serve
to explain its long-term therapeutic effects. Neuroprotective properties such
as increasing neuronal viability in the context of glutamate cytotoxicity and
the expression of brain-derived neurotrophic factor are also associated with
sustained lithium treatment.15
Lithium is rapidly absorbed in the gastrointestinal tract, is not protein
bound, and distributes throughout total body water with peak serum concentrations at 1 to 2 hours after administration (4 to 5 hours for slow-release
preparations). It has no metabolites and is almost entirely excreted by the
kidneys. Its typical half-life in a healthy adult is about 24 hours, and steady-
33
state serum levels are usually achieved in 4 to 5 days.
Lithium is usually started at 300 mg, 2 or 3 times daily, and gradually
increased 300 to 600 mg every 1 to 5 days based on response to treatment,
blood levels, and tolerability. Optimal dosing generally falls between 900
and 1900 mg daily to achieve a target serum concentration of 0.8 to 1.2
mEq/L. If dose adjustments are made, a lithium trough (10 to 12 hours after
the last dose) level should be drawn 5 to 7 days after the change to properly
reflect the new steady-state concentration.
Lithium is contraindicated in patients with significant renal impairment,
dehydration, and low sodium levels, because these states increase the likelihood of acute toxicity. Lithium should also be avoided in patients with significant cardiovascular disease because of its impact on the heart’s conduction system.
Lithium is associated with a number of adverse effects even at therapeutic
levels. Nausea is most commonly managed by encouraging food intake with
each dose or the use of extended-release formulations. Tremor, which can
also be an early sign of toxicity, may be managed by dividing doses and
avoiding exacerbating factors such as anxiety, stress, and caffeine. Weight
gain, loose stools, and cognitive impairment can also occur and may require
dose adjustment. Renal function should be assessed once or twice a year
because lithium may cause impairment with long-term use. Lithium also
affects the thyroid and parathyroid glands, reducing thyroid hormone release
and increasing parathyroid hormone activity.
In the context of pregnancy, lithium is listed as a category D drug owing
to the risk of cardiac defects such as Ebstein’s anomaly. During pregnancy
(particularly the first trimester), the developing fetus should be closely monitored for cardiac defects. Doses will need adjustment, particularly near par(Please see Mania, page 34)
Table 4 – FDA-approved indications for pharmacologic management of bipolar mania
Bipolor mania
Drug
Acute
Maintenance
Usual dose
range (mg)
Lithium
A
A
600-2400
Usual therapeutic serum range: 0.8-1.2 mEq/L for acute mania; teratogenic
potential; requires ongoing monitoring of weight, renal and thyroid function
Divalproex
A
–
750-2000
Usual therapeutic serum range: 50-125 µg/L for acute mania; teratogenic
potential; requires ongoing monitoring of weight, CBC count, LFTs, and
menstrual history
Divalproex ER
A, B
–
750-2000
Usual therapeutic serum range: 85-125 µg/L for acute mania; teratogenic
potential; requires ongoing monitoring of weight, CBC count, LFTs and
menstrual history
Carbamazepine XR
A, B
–
800-1600
Possible therapeutic serum range: 4-12 µg/mL; requires ongoing monitoring
of weight, CBC count, LFTs, electrolytes; several AEs; teratogenic potential
and drug-interaction issues limit usefulness
Chlorpromazine
A
–
200-800
Approval not based on present-day FDA criteria
Olanzapine
A, B, C, D
A
5-20
Sedation; cardiometabolic AEs
Risperidone
A, B, C
–
1-6
Neuromotor AEs; hyperprolactinemia
Risperidone LAI
A
A,C
25-50a
May resolve absorption and adherence issues; may be used as monotherapy
or in combination with lithium or divalproex; hyperprolactinemia
Quetiapine
A, C, D
C
400-800
Sedation and cardiometabolic AEs
Quetiapine XR
A, B, C
C
400-800
Sedation and cardiometabolic AEs
Ziprasidone
A, B
C
80-160
Cardiometabolic risks reduced
Aripiprazole
A, B, C, D, E
A, C
5-30
Agitation/anxiety; akathisia; cardiometabolic risks reduced
Asenapine
A, B, C
C
10-20
Sublingual formulation only
Comments
A, monotherapy; B, mixed states; C, adjunct to lithium or valproate; D, pediatric/adolescent; E, acute parenteral.
CBC, complete blood cell; LFT, liver function test; ER, extended release; XR, extended release; AEs, adverse effects; LAI, long-acting injectable.
a
Every 2 weeks.
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Mania
Continued from page 33
turition and postpartum because of changes in metabolism and fluid volumes. When neonates are breastfed while their mother is taking lithium, they
should be assessed for lethargy, as well as growth and feeding problems.
Valproate
As with lithium, the mechanism of action for valproate as a mood stabilizer
is not fully understood. Two actions that may be relevant include blockade
of voltage-dependent sodium ion receptor channels and enhancement of
gamma-aminobutyric acid activity by increasing its synthesis and release.
Valproate is well absorbed with greater than 80% bioavailability after oral
administration and may be administered after meals because food delays
absorption, lessening adverse effects. It is highly protein bound and remains
mainly in the extracellular fluid. Peak serum levels occur between 1 and 4
hours after administration, and half-life ranges between 6 and 16 hours.
Valproate is metabolized by the liver and excreted through the kidneys.
Valproate is usually started at a dose of 250 mg, 2 or 3 times daily, and
titrated every few days until a dose of 1500 to 2500 mg/d is reached. Valproate can also be orally loaded at 20 to 30 mg/kg daily to more rapidly achieve
therapeutic levels. Optimal therapeutic plasma levels of valproate generally
fall between 50 and 125 µg/mL and should be checked 2 to 5 days after a
dose increase, 12 hours after the last dose.
Mania, hypomania, and mixed
episodes can be managed initially
with 1 of 3 strategies: lithium,
valproate, or a second-generation
antipsychotic either as monotherapy
or in various combinations.
Valproate can cause nausea, vomiting, hair loss, easy bruising, and tremor. Valproate-associated weight gain and insulin resistance can lead to metabolic syndrome. More rarely, it may cause liver toxicity, elevations in ammonium levels, pancreatitis, thrombocytopenia, and coagulation problems.
It is contraindicated in persons with liver disease and those with mitochondrial disorders. Liver function tests should be performed before starting
treatment and repeated during the first few months if indicated.
In the context of pregnancy, valproate is listed as a category D drug because of a 9% risk of development of major malformations.16 Women of childbearing age should use adequate contraceptive methods while taking valproate and should receive folic acid. If pregnancy does occur, the patient should
be switched to an alternative treatment and the fetus monitored for cardiac
anomalies. Valproate also carries an increased risk of polycystic ovary syndrome, which is particularly relevant in women of childbearing age.
Carbamazepine
The hypothetical mechanism of action of carbamazepine in bipolar disorder
may relate to its binding of sodium ion channels, enhancing the inactivated
state and blocking the propagation of rapid action potentials. It is absorbed
slowly, with peak serum levels occurring 6 to 8 hours after administration
and a bioavailability of 85%, and is metabolized in the liver by cytochrome
P450 (CYP450) 3A4. Its half-life during the initial stages of treatment ranges from 25 to 65 hours, but may decrease to 12 to 17 hours after several
weeks owing to autoinduction. For this reason, serum levels should be measured at 3, 6, and 9 weeks after starting treatment.
Oxcarbazepine is usually fully absorbed and not affected by food with
peak serum concentrations achieved 4 to 6 hours after administration and a
half-life of 8 to 12 hours. Oxcarbazepine also undergoes hepatic metabolism
but is less likely to induce liver enzymes than carbamazepine.
Carbamazepine is usually started at an oral dose of 400 to 600 mg daily
with dose increases of 200 mg every 3 to 5 days until a clinical effect is
achieved or adverse effects become intolerable. Although target serum levels
1511PT206973AJanicak_CME.indd 34
for patients with epilepsy typically range from 4 to 12 µg/mL, clinical response and tolerability should take priority over levels in those with bipolar
disorder. Starting doses of oxcarbazepine are generally 300 to 600 mg daily,
which can be increased by up to 600 mg per day weekly with a range of 300
to 3000 mg daily.
Common adverse effects of carbamazepine include nausea, vomiting,
headache, diarrhea, hyponatremia (possibly higher risk with oxcarbazepine),
rash, pruritus, fluid retention, and low testosterone in males. More serious
effects include Stevens-Johnson syndrome, agranulocytosis, and aplastic
anemia, which often present within the first few months of treatment. Carbamazepine can lead to multiple clinically relevant drug interactions, primarily
through CYP450 3A4 induction. Pharmacogenetic testing (eg, HLAB*1502, HLA-A*31:01) can prevent carbamazepine-induced hypersensitivity reactions (ie, Stevens-Johnson syndrome) in certain ethnic groups (eg,
Han Chinese, Europeans).
In the context of pregnancy, carbamazepine is labeled as a category D
drug owing to an increased risk of spina bifida, craniofacial defects, cardiovascular malformations, developmental delays, and hypospadias. Women of
childbearing age should use adequate contraceptive methods while taking
carbamazepine and should receive folic acid. While carbamazepine enters
the breast milk as its active metabolite and is detected in the serum of breastfed infants, it is generally thought to be safe. However, mothers are encouraged to discontinue breastfeeding if the neonate begins to experience related
adverse events (eg, transient hepatic dysfunction).
Oxcarbazepine is a category C drug found to cause adverse effects in animal studies, but with no specific malformations identified in humans. It is
also transferred to newborns in small amounts through breast milk.
Antipsychotics
First-generation antipsychotics preceded the availability of lithium in the US
by almost 20 years and were the mainstay of medication treatment for bipolar disorder during this period. Indeed, chlorpromazine still has an FDAapproved indication for this disorder. With the advent of lithium, however,
the primary role of antipsychotics was to serve as adjunctive therapy for more
severe episodes. With extended experience, lithium was found insufficiently
effective and/or poorly tolerated in a substantial proportion of patients with
bipolar disorder. This ushered in a series of studies with anticonvulsant
agents and second-generation antipsychotics to ascertain their potential as
alternative mood stabilizers. Theories on the mechanism of action of secondgeneration antipsychotics focus on their multiple neuroreceptor effects, particularly related to the dopamine and serotonin systems.
A series of controlled trials considered olanzapine as either monotherapy
or adjunctive therapy for bipolar disorder, particularly for acute mania. The
consistently positive results with olanzapine led to studies with other secondgeneration antipsychotics. While the most common adverse effects of antipsychotics include neuromotor, sedative, hormonal, and metabolic complications, they vary substantially among the different agents. For example,
haloperidol and risperidone can increase the risk of acute extrapyramidal side
effects and hyperprolactinemia, while agents such as olanzapine and quetia
pine may be more likely to cause sedation, weight gain, and related cardiometabolic effects. Table 4 lists the agents approved by the FDA for acute and
maintenance treatment of mania and hypomania; phases of the illness for
which antipsychotics have approved indication(s) as either monotherapy or
adjunctive therapy; their usual dosing ranges; and other clinically relevant
considerations.
Conclusion
The defining characteristic of bipolar disorder is the presence of mania or
hypomania. Bipolar I disorder is primarily distinguished from bipolar II disorder by meeting the criteria for a full manic episode. Conversely, bipolar II
disorder must meet criteria for both a hypomanic and a depressed episode.
Cyclothymic disorder consists of more chronic mood disturbances that do
not meet the full criteria for hypomania, mania, or depression.
Treatment approaches depend on the illness phase and symptom severity.
Mania, hypomania, and mixed episodes can be managed initially with 1 of 3
strategies: lithium, valproate, or a second-generation antipsychotic either as
monotherapy or in various combinations. Short-term use of antipsychotics
and/or benzodiazepines may also address associated symptoms (eg, agitation, psychosis, drug or alcohol withdrawal) during an acute exacerbation.
Successful maintenance strategies usually require a combination of pharma-
11/2/15 9:52 AM
35
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cologic and psychotherapeutic approaches customized to meet the needs of
a given patient.
Serotonin: How Psychiatry Got Over
Its “High School Crush”
Continued from page 28
References
1. Janicak PG, Marder SR, Pavuluri MN. Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011:351-462.
2. Hirschfeld RM, Calabrese JR, Weissman MM, et al. Screening for bipolar disorder in the community. J Clin
Psychiatry. 2003;64:53-59.
3. Denicoff KD, Leverich GS, Nolen WA, et al. Validation of the prospective NIMH-Life-Chart Method (NIMHLCM-p) for longitudinal assessment of bipolar illness. Psychol Med. 2000;30:1391-1397.
4. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT)
and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the
management of patients with bipolar disorder: update 2013. Bipolar Disord. 2013;15:1-44.
5. Bergink V, Burgerhout KM, Koorengevel KM, et al. Treatment of psychosis and mania in the postpartum
period. Am J Psychiatry. 2015;172:115-123.
6. Jacobowski NL, Heckers S, Bobo WV. Delirious mania: detection, diagnosis, and clinical management in
the acute setting. J Psychiat Pract. 2013;19:15-28.
7. Gerhard T, Devanand DP, Huang HM, et al. Lithium treatment and risk for dementia in adults with bipolar
disorder: a population-based cohort study. Brit J Psychiatry. 2015;207:46-51.
8. Smith EG, Austin KL, Kim HM, et al. Mortality associated with lithium and valproate treatment of US Veterans Health Administration patients with mental disorders. Brit J Psychiatry. 2015;207:55-63.
9. Li XB, Tang YL, Wang CY, de Leon J. Clozapine for treatment-resistant bipolar disorder: a systematic review.
Bipolar Disord. 27 Oct 2014; (Epub ahead of print).
10. Hirschfeld R. Guideline watch: practice guideline for the treatment of patients with bipolar disorder. 2005.
http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/bipolar-watch.pdf.
Accessed September 29, 2015.
11. Medda P, Toni C, Giorgi M, et al. Electroconvulsive therapy in 197 patients with a severe, drug-resistant
bipolar mixed state: treatment outcome and predictors of response. J Clin Psychiatry. 2015;76:1168-1173.
12. Grunze H, Vieta E, Goodwin GM, et al. The World Federation of Societies of Biological Psychiatry (WFSBP)
guidelines for the biological treatment of bipolar disorders: update 2009 on the treatment of acute mania.
World J Biol Psychiatry. 2009;10:85-116.
13. Kakkar AK, Rehan HS, Unni KE, et al. Comparative efficacy and safety of oxcarbazepine versus divalproex
sodium in the treatment of acute mania: a pilot study. Eur Psychiatry. 2009;24:178-182.
14. Geddes JR, Goodwin GM, Rendell J, et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet.
2010;375:385-395.
15. Dwivedi T, Zhang H. Lithium-induced neuroprotection is associated with epigenetic modification of specific BDNF gene promoter and altered expression of apoptotic-regulatory proteins. Front Neuroscience.
2014;8:457.
16. Hernandez-Diaz S, Smith C, Shen A, et al. Comparative safety of antiepileptic drugs during pregnancy.
Neurology. 2012;78:1692-1699. ❒
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nized the complexities of sorting out psychosocial causes from biological effects—which can in turn become new causes or predispositions. They wrote:
. . . it is . . . conceivable that early experiences of the infant or child may
cause enduring biochemical changes, and that these may predispose some
individuals to depressions in adulthood. It is not likely that changes in the
metabolism of the biogenic amines [dopamine, norepinephrine, and serotonin] alone will account for the complex phenomena of normal or pathological affect.11
The causal chain in the genesis of major depression is almost certainly
long and complex—probably beginning with a genetic predisposition to depression, exacerbated by psychosocial stressors and losses, and worsened by
dysfunctional personality traits and poor social supports. And while the “selfdefeating cognitions” posited by cognitive theorists may not be a proximal
cause of depression, their presence may deepen or prolong the person’s depression.12 Recently, psychiatrists have also focused on socio-economic,
educational, and cultural factors that contribute to the risk, and perhaps the
onset, of clinical depression. In their recently released book, The Social Determinants of Mental Health, psychiatrists Michael T. Compton, MD, and
Ruth S. Shim, MD,13 cite the following risk factors for depression: racial
discrimination, poverty, unemployment, lack of social skills, reduced frustration tolerance and self-regulation, and food insecurity.14
All this is nothing radically new—it’s really an elaboration of the biopsychosocial model that has dominated academic psychiatry since the 1980s.
Clearly, this multi-level model bears little resemblance to a simplistic chemical imbalance theory. And it gives the lie to those who claim that psychiatry
has become reductionistic, hostile to the role of the “mind,” or void of psychodynamic understanding. On the contrary, this expanded biopsychosocial
model opens the possibility for therapeutic interventions at several links in
the causal chain. Thus, antidepressants—and perhaps, someday, anti-inflammatory agents—may ameliorate the biological components of depression,
while psychotherapy reduces the experiential aspects of the illness, such as
pathological guilt and self-loathing.
In short, if serotonin was once American psychiatry’s “high school crush,”
the field now appears wedded to a more mature model of biological and
psychosocial understanding.
Dr Pies is Editor in Chief Emeritus of Psychiatric Times and a Professor in the psychiatry departments at SUNY Upstate Medical University in Syracuse, NY and Tufts University School of
Medicine in Boston.
References
1. LeBano L. Inflammation, mood disorders, and disease model convergence. Psych Congress Network (interview with Dr Roger McIntyre). http://www.psychcongress.com/article/depression-inflammation-connectiondiabetes-and-disease-model-convergence-23649. Accessed September 11, 2015.
2. Pies R. Doctor, is my mood disorder due to a chemical imbalance? Psych Central. http://psychcentral.com/
blog/archives/2011/08/04/doctor-is-my-mood-disorder-due-to-a-chemical-imbalance/. Accessed September 11, 2015.
3. Pies R. Nuances, narratives, and the “chemical imbalance” debate. Psychiatric Times. April 11, 2014. http://
www.psychiatrictimes.com/couch-crisis/nuances-narratives-chemical-imbalance-debate. Accessed September 11, 2015.
4. American Psychiatric Association. Let’s talk facts: what is mental illness? 2005. https://www.cpp.
edu/~healthcounseling/Documents/mental-illness-b1.pdf. Accessed September 11, 2015.
5. Understanding Science: How Science Really Works. http://undsci.berkeley.edu/article/howscienceworks_19. Accessed September 11, 2015.
6. Healy D. Serotonin and depression. BMJ. April 21, 2015. http://www.bmj.com/content/350/bmj.h1771.
long. Accessed September 11, 2015.
7. Grohol JM. The problem with Google’s health knowledge graphs. Psych Central. http://psychcentral.com/blog/
archives/2015/08/21/the-problem-with-googles-health-knowledge-graphs/. Accessed September 11, 2015.
8. Gong Q, He Y. Depression, neuroimaging and connectomics: a selective overview. Biol Psychiatry.
2015;77:223-235.
9. Borchard T. Is the link between serotonin and depression a myth? Psych Central. http://psychcentral.com/blog/
archives/2015/09/01/is-the-link-between-serotonin-and-depression-a-myth/. Accessed September 11, 2015.
10. Raison CL, Miller AH. Role of inflammation in depression: implications for phenomenology, pathophysiology and treatment. Mod Trends Pharmacopsychiatri. 2013;28:33-48.
11. Schildkraut JJ, Kety SS. Biogenic amines and emotion. Science. 1967;156:21-37.
12. Ellis A, Harper RA. A Guide to Rational Living. Los Angeles: Wilshire Book Co; 1961.
13. Compton MT, Shim RS. The Social Determinants of Mental Health. Washington, DC: American Psychiatric
Association Publishing; 2015.
14. Bailey RK. Book Forum. Review of The Social Determinants of Mental Health. Am J Psychiatry.
2015;172:913-914. ❒
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Journal of Cognitive Psychotherapy: An International Quarterly
Volume 21, Number 1 • 2007
Combining Medication Treatment and
Cognitive-Behavior Therapy for Bipolar
Disorder
Monica Ramirez Basco, PhD
University of Texas at Arlington
Gretchen Ladd, PhD
Cook Children's Medical Center
Diane S. Myers, PhD
David Tyler, MD
University of Texas Southwestern Medical Center at Dallas
Bipolar disorder (BPD) is a severe, recurrent psychiatric illness characterized by a chronic course
of vacillating episodes of major depression and mania that impair functioning across many
psychosocial domains (DSM–IV; DSM–IV-TR). Within each type of episode, changes occur
in mood, cognitive processing, and regulation of vegetative functioning. Typical mood shifts
include sadness (in depression) or euphoria (in mania). Either state can produce irritability, anxiety, and anger. In addition, both the process and the content of cognitive functioning are altered.
Typical changes in process include decreased speed of thought in depression and increased speed
of thought in mania. Content changes include negativity in depression and in mixed states, and
grandiosity or paranoia in manic states. According to the cognitive-behavioral model of BPD
(Basco & Rush, 2005), these changes in mood and cognition are accompanied by behavioral
changes, typically increases in activity in mania and decreases in activity in depression. These
behavioral changes, in turn, generally have a negative impact on the individual’s psychosocial
functioning, such as slowed work productivity, neglect of household or family responsibilities,
and reduced involvement in social activities, bring negative consequences to patients as well as
those in their primary support groups. In mania, risk taking, disorganized behavior, sleep loss,
and reduced medication adherence quickly exacerbate symptoms, reduce quality of functioning,
and create significant psychosocial problems. BPD is sensitive to stress (Goodwin & Jamison,
1990). As symptoms alter functioning, new stressors are created as a consequence. Added stress
exacerbates symptoms, and functioning may decline further.
Keywords: cognitive therapy; bipolar; medication; noncompliance
P
atients suffering from BPD have often been ill for quite some time prior to accurate diagnosis and treatment. Given that many have already married and begun families at the time
of symptom onset, it is no surprise that when adequate care is finally offered, the clinician
© 2007 Springer Publishing Company
7
8
Therapy for Bipolar Disorder
may need to spend as much time on marital and parenting issues as on medically treating the
underlying disorder. Indeed, it is probably uncommon for purely medical management to suffice
in any patient with newly diagnosed BPD.
Early on in the treatment of a patient with BPD, medication management may have to take
first priority, because the patient may simply be too ill to benefit from or tolerate psychotherapy.
Patients with severe mania, those who cycle very rapidly, those with psychosis, and those with
profound depression may require the improvement that comes from beginning a medication
regimen and the stabilization and decrease in symptom intensity that usually follows. Once this
is achieved, formal psychotherapy can begin. During this early phase, when the severity of symptoms may interfere with psychotherapy, much useful psychotherapeutic work can be done with
patients’ families. Education about the disorder as well as support by the management team can
help prepare the family for further psychotherapeutic work after the patient is stabilized.
There is no absolute rule for when to begin psychotherapy. In general, manic or mixed patients
need to be relatively free of intense psychotic symptoms and stable enough to tolerate 15–20 minutes of interaction without becoming agitated or irritable. Early in treatment with a very ill patient,
the sessions may be quite brief. Some outpatients can benefit from several brief office visits during
a week rather than one hour-long session. Some patients suffering from depression may benefit
little from psychotherapy until psychosis and intense psychomotor retardation have improved.
An example is Jim, who was referred for treatment in an effort to avoid rehospitalization. Jim had
been hospitalized several weeks before and had been released once his suicidal ideation subsided.
However, his depression continued to be so severe that it was difficult for him to make conversation
or maintain eye contact. He was unable to sustain his energy to participate in full therapy sessions.
Therefore, he was provided with brief supportive therapy until his cognitive functioning and energy
improved. Those who have been ill for years with many failed trials of medications can present the
greatest challenge. All medication trials must be reviewed in as much detail as possible with the
patient and loved ones, as some useful medications may have been tried and discarded without
sufficient reason. In addition, the long-term use of antidepressants may make it impossible to know
if concurrent mood stabilizers were of value.
Pharmacotherapy is obviously an essential component of the treatment of BPD. However,
its efficacy is often limited by poor patient adherence. Research suggests a 40%–60% risk of
nonadherence throughout the course of treatment for patients with BPD (Basco & Rush, 1995).
Further, symptom breakthroughs commonly occur even in patients who take their medications as prescribed (Maj, Pirozzi, & Magliano, 1996). Often, symptom recurrence or relapse is
foreshadowed by the early emergence of subsyndromal symptoms of depression and mania. If
recognized, these early indicators can provide an opportunity for proactive intervention.
COGNITIVE-BEHAVIOR THERAPY (CBT) FOR BIPOLAR DISORDER
Several studies demonstrate that CBT is an effective complementary treatment to pharmacotherapy in BPD. The cognitive-behavioral formulation of BPD (Basco & Rush, 1996) focuses on an
exacerbating cycle in which reactions to cognitive and affective symptoms decrease functioning
and create psychosocial problems. Stress related to these psychosocial problems can cause symptoms to worsen. The goal of CBT in this context is to target cognitive, behavioral, and affective
changes in depression and mania, and to help the patient effectively manage BPD by stopping
the progression of episodes.
One target of CBT in treating BPD is psychoeducation about the disorder, the pharmacological treatments, and the ways in which environmental factors and the patient’s behaviors and
cognition affect the course of the illness. The second component of CBT is to help patients to
develop an early warning system that allows them to anticipate the onset of depression or mania
Ramirez Basco et al.
9
and to respond accordingly. The third element involves improving and maintaining adherence
to pharmacological treatments, psychosocial interventions, and lifestyle modifications critical to
managing the illness. These include stimulation reduction and good sleep hygiene. After progress
has been made in expanding the patient’s knowledge about BPD, improving the patient’s ability
to self-monitor symptoms, and increasing the patient’s adherence to prescribed treatment, the
fourth piece of the intervention, cognitive and behavioral management of symptoms, can be
conducted more effectively. The final goal of CBT is to teach patients methods for resolving and
preventing common psychosocial problems associated with the disorder, including relationship-,
financial-, and work-related difficulties (Basco, 2006; Basco & Rush, 2005).
Several preliminary studies have demonstrated the feasibility and usefulness of CBT in treating BPD. However, most have studied CBT as an add-on to pharmacotherapy versus pharmacotherapy alone and, therefore, have generally not controlled adequately for attention and other
nonspecific effects of psychotherapy. While the conclusions may seem promising, no definitive
statements can be made about the efficacy of CBT in BPD.
One of the first studies of CBT in BPD was conducted by Cochran (1984). She tested the
effectiveness of six weeks of CBT plus pharmacotherapy against pharmacotherapy alone, by
targeting attitudes that interfered with medication compliance during the maintenance phase of
treatment. Outcome assessments, which consisted of a composite assessment of medication compliance, appointment attendance, and serum lithium levels, showed that the CBT plus pharmacotherapy group had better composite adherence scores than the control group, and the effect was
still evident at 6 months post-treatment. The CBT plus pharmacotherapy group was less likely to
terminate treatment against medical advice and had fewer hospitalizations and noncomplianceprecipitated affective episodes as compared to the control condition.
The short-term nature of CBT interventions makes them attractive for treating patients in
acute episodes and there is some evidence that the intervention can be delivered in a cost-effective
group format. Patelis-Siotis et al. (2001) evaluated the efficacy of group CBT aimed at improving
psychosocial functioning in patients with BPD. Forty-nine patients were placed in groups of 7–12
and given fourteen 2-hour sessions of group CBT. At baseline, patients were mildly depressed or
euthymic and there was no significant change in symptoms from pre- to post-treatment. Study
completers did, however, show significant improvements in psychosocial functioning. Though
there was no control group in this study and patients were relatively asymptomatic, the results
suggest that group CBT interventions may be beneficial for improving quality of life for bipolar
patients and for maintaining stability in symptoms.
Scott, Garland, and Moorhead (2001) tested a relapse-prevention-focused intervention with
patients who were randomly assigned to CBT plus pharmacotherapy (n = 21) or medication
alone (n = 21). Sixty percent of participants had comorbid personality disorders and several
had a strong history of medication noncompliance, although all were actively treatment with
pharmacotherapy at study enrollment. Relative to the control group, the therapy plus medication
group showed significantly fewer symptoms and improved social functioning after 6 months of
CBT. The control subjects were provided CBT after completion of a 6-month observation period
to assess within-person changes. This group showed similar improvement in symptoms and
functioning from pre- to post-CBT and had significantly fewer hospitalizations at 12 months
post-treatment relative to their 6-month wait-list period prior to initiating CBT.
Scott and colleagues (2006) were unable to replicate these positive results. Across five treatment sites, 253 patients with BPD were randomized to receive either 22 sessions of medication treatment as usual (TAU; n = 126) or CBT plus TAU (n = 127). TAU varied across the five sites, with
some providing additional clinician contact time. Patients with more severe psychopathology, such
as those with acute mania, borderline personality disorder, or rapid cycling BPD, and those current
abusing illicit drugs were excluded from the sample. Some patients were not receiving medication
treatment at the time of the trial. Contrary to their previous studies (e.g., Scott & Tacchi, 2002; Scott
10
Therapy for Bipolar Disorder
et al., 2001), Scott and colleagues (2006) found no between-group differences in recurrence rate, level
of medication adherence, or symptom control over the 18 months of follow-up. A post hoc analysis
showed that patients in the CBT plus pharmacotherapy group with fewer than 12 lifetime episodes
of illness had a longer time to first recurrence than those with more than 12 episodes. Given that the
interepisode length often shortens with the duration of the illness (Goodwin & Jamison, 1990), their
finding might reflect the greater chronicity and cyclicity of BPD over time. Still, this larger scale study
calls into question the effect size of CBT interventions for BPD when added to pharmacotherapy.
Lam et al. (2001) evaluated a 12–20 session adjunctive CBT intervention utilizing symptom management skills (n = 13) against standard outpatient medication treatment alone (n = 12) for patients
in the maintenance phase of treatment. Relative to the control group, at post-treatment and 6-month
follow-up, patients receiving CBT with their medication treatment had fewer bipolar episodes and
better coping skills for prodromal symptoms, and were more adherent to pharmacotherapy.
Lam et al. (2003) examined the effect of CBT on relapse prevention in patients reporting
noncompliance with pharmacotherapy. Over a 12-month period, 103 participants were randomly assigned to medication management alone or to medication management with adjunctive
CBT. Those in the CBT with medication group received 14 sessions during the first 6 months
and 2 booster sessions in the second 6 months. They found that the CBT with medication group
had significantly fewer bipolar episodes, fewer days in an episode, and fewer hospital admissions.
Patients who received CBT along with medication also reported higher social functioning, fewer
mood symptoms, and less fluctuation in manic symptoms. Lam et al. concluded that CBT is a
useful treatment in preventing relapse in conjunction with mood stabilizers.
At 18 months following completion of treatment, Lam, Hayward, Watkins, Wright, and
Sham (2005a) found that that patients treated with CBT had fewer days in bipolar episodes relative to the control group and had better ratings of mood and better psychosocial functioning, and
demonstrated better management of prodromal symptoms. However, there was no difference in
relapse rates between groups at the 18-month follow-up.
The cost-effectiveness of this intervention was also evaluated (Lam, Wright, & Kerr, 2005b).
Relative to the control group, those receiving CBT in addition to medication had better clinical
outcomes, but incurred similar treatment costs. Taking into consideration the value of symptom-free days, which allow for greater productivity, their analyses showed that CBT was a costeffective adjunctive intervention, particularly when the costs of CBT could be lessened.
The presence of residual symptoms following an affective episode may increase the likelihood
of relapse (Fava, 1999). Fava, Bartolucci, Rafanelli, and Mangelli (2001) conducted an uncontrolled
study of the long-term efficacy of CBT aimed at reducing residual symptoms in 15 medicationcompliant patients with BPD who had relapsed while on lithium prophylaxis. Patients were treated
in the acute phase with antidepressants or antipsychotics, which were tapered off as CBT began.
Ten 30-minute CBT sessions were provided after symptom stabilization. A follow-up evaluation
indicated a significant decrease in residual symptoms and a significant increase in the number of
months before relapse following CBT, as compared to baseline levels. While all 15 patients had
relapsed within 30 months of the initial lithium therapy and prior to beginning any psychosocial
interventions, only 5 of these patients relapsed within 30 months after CBT was initiated. Without a
control condition it is difficult to determine if the positive effect was due to CBT specifically or the
nonspecific effects of psychotherapy, including attention and monitoring of symptoms.
In a randomized controlled trial of 6 months of CBT plus treatment as usual with mood
stabilizers versus medication alone in 52 individuals with BPD, Ball, Mitchell, Corry, Skillecorn, and
Malhi (2006) found that CBT participants had significantly less severe depression and mania scores,
improved attitudes, better self-control, better treatment adherence, and a lower relapse rate. A longer
time before depressive relapse approached significance. The effect was strongest in the first 12 months
of the intervention. However, the two groups had similar outcomes at 18 months. Their findings suggest that continuation and/or maintenance treatment may be needed to secure a more lasting effect.
Ramirez Basco et al.
11
Bernhard et al. (2006) tested a cognitive-psychoeducational program for individuals with
BPD and their family members. Sixty-two patients received fourteen 90-minute biweekly
sessions, while their relatives (N = 49) participated in two 4-hour workshops, and both
interventions focused on increasing the knowledge of BPD and its treatment. Although no
control group was utilized, between-subject comparisons from pre- to post-treatment showed
improvements in patients’ and relatives’ knowledge. Both groups rated the intervention as satisfactory. There was no change in subjective burden or expressed emotion at post-treatment.
However, at the 12-month follow-up, relatives reported less of a burden and improvements in
expressed emotion.
In summary, research on CBT for BPD suggests that CBT can be beneficial in increasing
medication adherence, in managing symptoms, in improving psychosocial functioning, and
perhaps in reducing the risk of relapse when used in conjunction with pharmacotherapy.
Unfortunately, studies to date have not controlled for attention and other nonspecific effects
of psychotherapy. In addition, they have been limited by small sample sizes and stringent
inclusion/exclusion criteria, as is common in psychotherapy development efforts. Patients
with comorbid disorders and those with rapid cycling or mixed states were excluded in many
studies thereby calling into question the generalizability of the findings. Nonetheless, these
studies demonstrate the feasibility of CBT as an adjunct to medication treatment in patients
with BPD. Whether CBT is delivered in an individual or a group format, it has the potential
to complement and enhance the effectiveness of the pharmacological management of the
disorder.
CHALLENGES OF INITIATING TREATMENT FOR BIPOLAR DISORDER
There are many challenges that face people who have BPD, beginning at the time of diagnosis and
the initiation of medical treatment. Being unfamiliar with the symptoms of BPD, the experiences
of mania and depression, especially in the presence of psychotic symptoms, can be overwhelming, confusing, and frightening. Depending on their knowledge and level of sophistication as well
as the manner in which they came to the attention of clinicians, patients may be ready to understand and accept the diagnosis or may reject it outright. Psychotherapy can be particularly useful
at this juncture in helping people to make sense of their experience, to understand the nature of
their illness, and to cope with the distress associated with the treatment experience, often a first
hospitalization, as well as the assignment of a diagnostic label such as BPD.
To facilitate the initiation of pharmacotherapy, education about the illness and its treatment should be provided and reviewed periodically (Basco, 2006; Basco & Rush, 2005).
Particularly useful is information about how a diagnosis was derived, what the treatment
entails, and what the individual will need to do to engage in the treatment process. While
generic information about BPD is useful, identification of the specific symptoms of depression or mania experienced by the patient may be more informative. The symptom summary
worksheet method proposed by Basco and Rush (1996, 2005) can help patients to identify
their specific symptoms of depression and mania and to contrast those symptoms with their
normal or usual state. This exercise can also aid in the early detection of future episodes, if the
patient and his or her family members or friends are vigilant in watching for changes from
usual habits to symptomatic behaviors. Mood graphs can also be useful in sensitizing patients
to fluctuations in affect and can help in monitoring the effects of pharmacotherapy. Generally,
the initiation of medication treatment for BPD requires adjustments in the type, amount, and
number of medications. Mood graphs can help patients and physicians track the effects of
medication as these changes are made. Rather than relying on patients’ retrospective reports,
mood graphs can more accurately reflect subjective experiences of symptom improvement or
worsening that occur as the medication regimen changes.
12
Therapy for Bipolar Disorder
Another challenge that can be addressed in psychotherapy is the emotional adjustment
required to accept a diagnosis of BPD. In addition to realizing that he or she has a stigmatizing
mental illness, the person may become aware that his or her life will not turn out as planned;
that is, that lifelong medication will be needed to achieve mood stability. Loss of emotional and
mental normalcy is as difficult a concept to accept as having a chronic physical illness. While the
psychopharmacologist takes on the challenge of symptom stabilization, support from others who
have been down this path, as in therapy or support groups, can facilitate acceptance of the illness
and its treatment. Individual therapy can provide the extra time needed to process the emotions
stimulated by the illness as well as the diagnostic and treatment experiences.
CASE STUDY
Albert is a 24-year-old, newly married, Caucasian male, who was brought to the attention
of mental health professionals when he recently experienced an episode of mania. He had
always been a very creative and outgoing person, the life of the party, and seemed to have
more energy than his wife and his peers. His usual gregarious nature took a different turn
after he started a new job at a city newspaper’s photojournalism desk. He began working
the evening shift, covering accidents, fires, and burglaries. This was a significant change
from his prior work taking photos of civic activities and other more mundane events. His
new job was exciting and a bit overstimulating, making it hard for Albert to fall asleep
at night. He would go to bed at midnight with his wife, but after tossing and turning for
several hours, he would make his way to the living room to watch television, play video
games, or listen to music until he could fall asleep. He tried to wake up early in the morning to spend time with his wife before she went off to work. Eventually, the sleep loss got
the best of him and he became edgy, irritable, and unable to function well at work. People
at work noticed his change in demeanor and suspected that he was using drugs. When his
wife confronted him with this, Albert exploded at her and then drove off in his car. He was
stopped by police some time later when he was found trying to get into the locked executive parking lot at the newspaper office. Uncertain if he was mentally ill or intoxicated, the
police took him to a local emergency room and he was admitted to the psychiatric ward
and diagnosed with mania.
After a few days on the ward and the initiation of medication treatment, his mania
lessened and he was able to sleep. His wife met with the attending psychiatrist, who
explained the diagnosis and treatment. Albert had been told about his diagnosis of
BPD, but he did not fully understand what it meant at the time. He was discharged
and referred for follow-up medication treatment and for psychotherapy to learn more
about the management of his illness. Albert was skeptical about the whole experience.
He did not remember being manic and could only vaguely recall the events leading up
to his admission to the hospital. He thought that it was all a big mistake and that he
had been wronged by the police and the hospital. He did not like the medication he had
been prescribed and didn’t want to keep taking it. He only agreed to see the therapist to
please his wife. She also wanted to believe that nothing was wrong, but she had observed
a change in Albert that did not make sense and she needed to know if it would happen
again.
Albert’s wife accompanied him to the first individual psychotherapy session. They
discussed the nature of BPD and although Albert was not ready to accept it, he did
acknowledge that something had happened to him that needed an explanation. He agreed
to attend three additional sessions for the purpose of “getting to the truth” about what
happened. During the course of these sessions, Albert was able to recall more and more
Ramirez Basco et al.
13
about the changes he had experienced before going to the hospital. A review of Albert’s
experiences with manic-like symptoms proved informative. The more he talked about his
past, the more he was able to recall definite “up” periods, when he was more productive
than usual, didn’t sleep as much, and had a lot of energy.
The therapist’s process was to encourage the exploration of experiences with depression
and mania without forcing the issue that BPD was the appropriate diagnosis. She asked
the couple to think of alternative explanations for Albert’s experiences and asked them to
consider how they might be able to tell the difference between normal ups and downs and
BPD. Each alternative explanation was discussed and rejected by Albert until, by process of
elimination, BPD became the working hypothesis to explain his symptoms. They all agreed
that the true test of the diagnosis would be time. BPD tended to recur and if Albert had the
illness, he would likely have another episode of depression or mania at some point in time.
This prospect frightened Albert and his wife, but also motivated them to learn more about
the illness and prepare for its possible return.
The second part of therapy involved discussion of common precipitants of mania and
depression, such as sleep loss and overstimulation, and precautions that could be taken to
avoid them. To be successful in his job, Albert would have to be available to go after the big
stories, even if they happened at night. He hated the idea of taking medication, but he was
unwilling to go through another manic episode caused by sleep loss. So he agreed to take
medication to help him fall asleep at night so that he would not run that risk. In addition,
the therapist taught Albert some techniques for slowing his thoughts at night and relaxing
his body so that he could more easily fall asleep.
The final part of Albert’s therapy was to identify his specific signs and symptoms
of depression and mania so that he and his wife would be able to see a recurrence as it
developed. The symptom summary worksheet that lists the person’s unique changes in
thoughts, actions, physical symptoms, and emotions that come with depression and mania
was completed and a copy provided for Albert, his wife, the therapist, and Albert’s psychiatrist. If Albert or his wife noted any changes in his demeanor or habits, they were to review
the list and call the doctor or therapist if more than one or two symptoms were emerging.
When and if that occurred, Albert could be taught methods for containing his symptoms
and reducing the risk of a complete relapse.
Throughout this process and with his written consent, Albert’s therapist and psychiatrist
discussed his progress. The therapist was able to relay information about Albert that helped
the psychiatrist to confirm his diagnosis. In turn, the psychiatrist explained the medication
treatment plan so that the therapist could help Albert maximize his adherence to treatment. Albert, his wife, the psychiatrist, and the therapist maintained open communication
so they could function efficiently as a treatment team.
MAINTENANCE PHASE TREATMENT
Maintenance treatment of BPD often includes psychosocial interventions, such as group therapy
or individual psychotherapy in combination with continued pharmacotherapy. Although most
studies have examined interventions delivered during individual therapy, there have been
some that support the efficacy of group-based interventions. One such model is used at the
University of Texas Southwestern Medical Center at Dallas where psychiatrists and therapists
(e.g., psychologists or social workers) function as cofacilitators in group psychotherapy. The aims
of this treatment modality are to increase self-management skills, decrease episode frequency
and severity, and improve overall quality of life while addressing medication issues, such as side
effects and waning adherence.
14
Therapy for Bipolar Disorder
The selection of individuals appropriate for group treatment is based upon joint assessment
by the psychiatrist and therapist. Candidates for group therapy should have relative mood stability and not have active substance abuse or psychotic symptoms. Often a period of brief individual
psychotherapy may precede inclusion in a group, to ensure a basic understanding of the illness
and assess readiness for the group.
The collaborative nature of the group allows the clinicians to model problem solving and
open communication, providing a safe place to discuss functional, occupational, interpersonal,
and psychosocial issues. Emphasizing enhanced symptom awareness and recognition; the role
of lifestyle, stress, and illness management; and practical problem solving, communication, and
anger management strategies, group members work together to identify environmental triggers,
encourage self-monitoring of symptoms, and enhance awareness of personal illness patterns.
Group maintenance psychotherapies for BPD, such as those evaluated by Cochran (1984)
and Patelis-Siotis et al. (2001), can be also be facilitated solely by social workers, nurses, or other
mental health professionals in a psychiatric clinic. In another treatment model, case managers in
community mental health centers serve as communication links between patients, psychiatrists,
and rehabilitation program staff. The multidisciplinary team approach developed by Mark Bauer
and Linda McBride (2003), which utilizes a nurse case manager, is another model for supplementing pharmacotherapy with an adjunctive intervention aimed at improving compliance and
early symptom detection, which leads to earlier medical intervention to prevent relapse.
CONCLUSION
Pharmacotherapy is the mainstay of treatment for BPD. However, the addition of psychotherapy
in an individual or group format can enhance treatment adherence, teach coping skills, improve
symptom detection early in the course of new episodes, and provide the education and support
needed to ease adjustment to the illness and its treatment. Several studies have provided support
for the efficacy of a multidisciplinary team approach to the treatment of this disorder. However,
there is a need for randomized trials that control for the nonspecific effects of psychotherapy in
a consistent manner.
Clinically, an argument can be made for the combination of pharmacotherapy and
psychotherapy in BPD to maximize the effectiveness of treatment. Therapists can facilitate
communication between patient and physicians, reinforce the physician’s instructions, and troubleshoot adherence problems. Therapists can also help in the detection of relapse, as they may
be able to see patients with greater frequency than the psychiatrist and can reinforce their relapse
prevention plans. Also, when psychiatrists are trained in CBT they can provide psychotherapy
along with medication as an integrated method of treatment.
Therapeutic innovations in psychotherapy and psychopharmacology continue to evolve and
refinements continue to be made. Clinicians no longer have to feel helpless in the face of this
complicated and persistent mental illness. Most importantly, people with this illness are getting
the message that they can be active participants in their care.
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Correspondence regarding this article should be directed to Monica Ramirez Basco, PhD, 4104 Ambleside Ct.,
Colleyville, TX 76034. E-mail: MABasco@Comcast.net
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Psychiatry and Clinical Neurosciences 2014; 68: 712–720
doi:10.1111/pcn.12193
Regular Article
Diagnostic utility of worry and rumination: A comparison
between generalized anxiety disorder and major depressive
disorder
Min-Jeong Yang, MA,1† Bin-Na Kim, MA,1† Eun-Ho Lee, MA,2 Dongsoo Lee,
Bum-Hee Yu, MD, PhD,1 Hong Jin Jeon, MD, PhD2 and Ji-Hae Kim, PhD1*
MD, PhD,1
1
Department of Psychiatry, and 2Depression Center, Department of Psychiatry, Samsung Medical Center, Sungkyunkwan
University School of Medicine, Seoul, South Korea
Aim: Although previous reports have addressed
worry and rumination as prominent cognitive processes in generalized anxiety disorder (GAD) and
major depressive disorder (MDD) and their distinct
correlation with anxious and depressive symptoms,
the differential association of worry and rumination
with the diagnosis of GAD and MDD remains
unclear. The purpose of this study was to investigate
the distinct features of worry and rumination in
factor structure and their predictive validity for the
diagnosis of GAD and MDD.
Methods: Four hundred and sixty-eight patients with
GAD (n = 148) and MDD (n = 320) were enrolled
and the diagnoses were confirmed with the Structured Clinical Interview for DSM-IV. Participants
completed the Penn State Worry Questionnaire and
Ruminative Response Scale and the severity of
anxiety and depressive symptoms was assessed via
clinician ratings.
HE NOSOLOGIC RELATIONSHIP between generalized anxiety disorder (GAD) and major
depressive disorder (MDD) has been a controversial
topic, due to high rates of comorbidity and overlapping diagnostic criteria in the DSM-IV.1,2 In an extensive review, Hettema showed that overall lifetime
T
*Correspondence: Ji-Hae Kim, PhD, Department of Psychiatry,
Samsung Medical Center, Sungkyunkwan University School of
Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, South Korea.
Email: jihae0931.kim@samsung.com
†
Both authors contributed equally to this article.
Received 3 September 2012; revised 10 January 2014; accepted 11
April 2014.
712
Results: In joint factor analysis using the Penn State
Worry Questionnaire and Ruminative Response Scale
items, worry and rumination emerged as distinct
factors. In logistic regression analyses, worry contributed to a higher probability of the diagnosis of GAD
than rumination, as rumination did in MDD than
worry.
Conclusion: This is the first comprehensive study
investigating the diagnostic utility of worry and rumination in a well-defined clinical sample of both GAD
and MDD. Our results suggest that worry and rumination are distinct cognitive processes and play a differential role in the diagnosis of GAD and MDD,
distinguishing them at the cognitive level.
Key words: anxiety disorders, cognition, depressive
disorder,
depressive
symptoms,
differential
diagnosis.
comorbidities have been reported to be as high as
70–90% and that GAD has substantial overlap with
MDD in the areas of genetics, childhood environment, demographics, and personality traits as well as
shared pharmacologic efficacy of antidepressants.3
Despite high comorbidity and similarities between
GAD and MDD, some evidence of differences and
disorder-specific pathological processes has been
reported.3,4 Among them, worry has been considered
to be a key cognitive process that characterizes GAD,
whereas rumination has traditionally been related to
depression.5,6 Worry is defined as ‘a chain of thoughts
and images, negatively affect-laden and relatively
uncontrollable’7 and excessive and uncontrollable
© 2014 The Authors
Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2014; 68: 712–720
Worry and rumination 713
worry is the cardinal diagnostic feature of DSM-IV
GAD. Studies have pointed out that worry contributes to the maintenance and aggravation of anxiety
by interfering with emotional processing.8 On the
other hand, rumination is defined as ‘repetitively
focusing one’s attention on one’s depressive symptoms and on the implications of these symptoms’
and has been found to be a salient cognitive feature
of dysphoria, including MDD. Many studies have
provided empirical support for the hypothesis that
rumination prolongs and worsens depressed mood
and predicts future depressive episodes.9
However, worry and rumination, although differing in degree, are prevalent in other disorders as
well.10 Furthermore, due to apparent commonalities
(e.g., repetitive thoughts in response to negative
affect, maintenance or prolongation of pre-existing
negative affect), the assertion of a distinctive role of
the two constructs has been challenged.
Accordingly, recent studies started to investigate the
similarities and differences between worry and rumination and their relationship with anxious and
depressive symptoms more systematically. Using
structural equation modeling, Segerstrom et al.11
found that both worry and rumination loaded onto a
latent variable labeled as ‘repetitive thought’ and specific factors of worry and rumination failed to differentially relate to anxiety and depression. Fresco et al.12
reported that worry and rumination are distinct
factors in joint factor analysis; however, when their
relations to symptoms were examined, both worry
and rumination showed an undifferentiated pattern
of strong associations with both anxiety and depression, consistent with the study by Segerstrom et al. On
the other hand, other joint factor analysis studies
controlling for the overlap between worry and rumination in analysis, demonstrated that worry and/or
rumination have a differential association with
anxiety and depression.13,14 In summary, results from
previous studies converged on the conclusion that
both worry and rumination are fairly similar, albeit
not identical, cognitive processes, that impact anxiety
and depression symptoms. However, methodological
limitations prevent greater generalizability of previous findings to a clinical population. Most involved
non-clinical student samples12–14 and in a study
including a small clinical sample, the selection
depended not on the structured clinical interview but
on the self-referral problem.11 Also, whether worry
and rumination are differentially related to the diagnosis of GAD and MDD has not been addressed and
thus remains unclear, as previous studies focused only
on symptom level in non-clinical samples. To date, no
study examined whether two constructs can have differential value in diagnosis in a large patient sample
diagnosed via formal structured diagnostic interview.
As previous investigations recruited chiefly US or
European participants, whether those results can be
generalized to a Korean sample is another question
that needs to be explored. Prevalence rates of MDD
and GAD in East Asian countries, including South
Korea, are reported to be lower than those in the
West.15–17 Although explanations for such difference
are relatively scant owing to the lack of enough crosscultural studies, different symptom phenomenology
might be a factor. Koreans with MDD expressed more
symptoms of ‘low energy’, ‘concentration difficulty’
or somatic symptoms and less symptoms of
‘depressed mood’.15 Nevertheless, this does not mean
that the DSM criteria are invalid. The DSM MDD in
Korea showed good internal consistency and discrimination, but showed a higher diagnostic threshold and different symptom presentations.15 With
regard to GAD, even though the number and content
of worry domains were reported to vary crossculturally, cross-cultural similarities in the Penn State
Worry Questionnaire (PSWQ) scores indicate equivalent total level of worry across ethnic groups.16 In the
present study, we used the DSM-IV criteria for diagnosis and PSWQ and Ruminative Response Scale
(RRS) to assess worry and rumination, all of which
are widely utilized measures worldwide and translated and validated in Korean.
This study aims to replicate and integrate the
current findings and to test the diagnostic utility of
worry and rumination in well-defined GAD and
MDD patient groups in South Korea. Specifically, we
tested the following hypotheses. First, worry and
rumination would load onto different latent variables in joint factor analysis, despite a significant
correlation. Second, in logistic regression, worry
would contribute to a higher probability of the diagnosis of GAD than rumination, while rumination
would increase the probability of the diagnosis of
MDD than worry.
METHODS
Participants
Four hundred and sixty-eight Korean participants
were enrolled at Samsung Medical Center (SMC)
© 2014 The Authors
Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology
714 M-J. Yang et al.
Psychiatry and Clinical Neurosciences 2014; 68: 712–720
Table 1. Demographic variables in GAD and MDD (n = 468)
Total sample
Age (mean, SD)
Sex
Men
Women
Education
Less than elementary school
Less than high school
Less than graduate school
Socioeconomic status
Low
Below average
Average
Above average
High
Missing
49 (15.80)
GAD (n = 148)
45.53 (15.15)
MDD (n = 320)
50.60 (15.85)
χ2
3.26
P
†
0.001
162 (34.6%)
306 (65.4%)
55 (37.2%)
93 (62.8%)
107 (33.4%)
213 (66.6%)
1.05
0.592
76 (16.2%)
203 (43.4%)
189 (40.4%)
21 (14.2%)
72 (48.6%)
55 (37.2%)
55 (17.2%)
131 (40.9%)
134 (41.9%)
2.50
0.286
28 (6.0%)
64 (13.7%)
272 (58.1%)
73 (15.6%)
14 (3.0%)
17 (3.6%)
7 (4.7%)
21 (14.2%)
86 (58.1%)
27 (18.2%)
6 (4.1%)
1 (0.7%)
21 (6.6%)
43 (13.4%)
186 (58.1%)
46 (14.4%)
8 (2.5%)
16 (5.0%)
7.61
0.179
†
Statistics for ANOVA.
GAD, generalized anxiety disorder; MDD; major depressive disorder.
between April 2006 and July 2011. The participants
gave written informed consent before participating in
the study, which was approved by the Institutional
Review Board of SMC. With regard to the ethnicity,
although different symptom presentation and relatively lower prevalence were reported in a Korean
sample with either MDD or GAD, DSM MDD criteria
and the core feature of GAD, which is worry, have
been found to be reliable in a Korean sample.15,16 All
participants, therefore, were diagnosed using the
Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I)18 carried out by a trained clinical
psychologist. The primary inclusion criteria were the
diagnoses of GAD and MDD. The inclusion criteria
for MDD were patients with both single and recurrent
episodes, while MDD patients with psychotic features
or in full remission, and with comorbid anxiety disorders were excluded. In case of GAD, we decided to
include GAD patients with comorbid MDD in order
to increase the statistical power of the study, as
excluding them would result in a much smaller
sample size due to the high comorbidity of GAD and
MDD. In order to control the severity of symptoms,
we excluded the individuals with Hamilton Anxiety
Rating Scale (HAM-A) score of less than 14 in the
GAD group and the individuals with Hamilton
Depression Scale (HAM-D) score of less than 17 in
the MDD group.19,20 Of the enrolled 468 participants,
148 patients fulfilled the DSM-IV criteria for GAD,
and 320 patients fulfilled the DSM-IV criteria for
MDD. While there were no significant differences in
sex, education level, and socioeconomic status, age
was significantly different between the groups
(Table 1).
In logistic regression, we restricted the scope of
analysis to the sample of GAD without MDD (n = 93)
in order to make a clear comparison, while the MDD
group (n = 320) was still composed of patients only
diagnosed with MDD. This means that we excluded
GAD patients with comorbid MDD from the GAD
group, because these patients with both the diagnoses would confound the differential role of worry and
rumination in binary prediction of GAD versus MDD
and vice versa.
Measures
PSWQ
The PSWQ is a 16-item self-report scale that assesses
the generality, excessiveness, and uncontrollability of
pathological worry.21 Items are rated on a five-point
Likert scale and high score (range from 15 to 80)
means a more frequent tendency to worry. Lim et al.22
validated the Korean version (Cronbach’s α = 0.92).
The total PSWQ score is a sum of the scores of positively worded and reversed scores of negatively
worded items.
© 2014 The Authors
Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2014; 68: 712–720
Worry and rumination 715
ware.29 Statistical significance was defined at the 0.05
level, two-tailed.
First of all, we performed the joint exploratory
factor analysis using items from both the PSWQ and
RRS. Maximum likelihood extraction with Quartimax
rotation was chosen to allow for the anticipated correlation between factors. We adapted Thurstone’s criteria30 to define a well-loaded item, and the cleanest
factor structure was determined if a factor included
more than three items. The number of factors was
determined by the Eigenvalues greater than 1.0, scree
plot and interpretability of the factor.31 Afterwards,
logistic regression analysis was conducted to identify
the constructs prognostic of the diagnosis of GAD
versus MDD and MDD versus GAD. Total PSWQ and
RRS scores were entered simultaneously into an enter
model and odds ratios (OR) were adjusted for
HAM-A and HAM-D scores.
RRS
The RRS is a 22-item scale, a subscale of the original
Response Style Questionnaire.23 Each item is rated on
a four-point Likert scale with higher total score (range
from 22 to 88) indicating more prominent rumination response style. Kim et al.24 showed good internal
consistency, test–retest reliability (Cronbach’s
α = 0.89 and 0.59, respectively) of the Korean
version.
HAM-A
The HAM-A is a 14-item clinician rating scale,
designed to measure the severity of anxiety symptoms.25 Items are rated on a four-point Likert scale
and the total score ranges from 0 (remission) to 56
(moderate–severe). The psychometric properties of
the Korean version have been demonstrated by...
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