Original ArticleDesign and implementation of a randomized.docx

Original Article
Design and implementation of a randomized
trial evaluating systematic care for bipolar
disorder
Abundant evidence demonstrates that treatments
for bipolar disorder can reduce the severity of
mood symptoms and improve daily functioning.
Specific pharmacotherapies have been proven effi-
cacious in the acute management of mania and
depression (1, 2) as well as in the prevention of
recurrence (1). For lithium, more intensive treat-
ment has been shown to improve both long-term
clinical outcomes and psychosocial functioning.
Promising evidence also supports the efficacy of
several disease-specific psychosocial interventions
for bipolar disorder (3, 4).
Unfortunately, treatments provided in everyday
practice fall far short of those proven in clinical
Simon GE, Ludman E, Unützer J, Bauer MS. Design and
implementation
of a randomized trial evaluating systematic care for bipolar
disorder.
Bipolar Disord 2002: 4: 226–236. ª Blackwell Munksgaard,
2002
Objectives: Everyday care of bipolar disorder typically falls
short of

evidence-based practice. This report describes the design and
implementation of a randomized trial evaluating a systematic
program to
improve quality and continuity of care for bipolar disorder.
Methods: Computerized records of a large health plan were used
to
identify all patients treated for bipolar disorder. Following a
baseline
diagnostic assessment, eligible and consenting patients were
randomly
assigned to either continued usual care or a multifaceted
intervention
program including: development of a collaborative treatment
plan,
monthly telephone monitoring by a dedicated nurse care
manager,
feedback of monitoring results and algorithm-based medication
recommendations to treating mental health providers, as-needed
outreach
and care coordination, and a structured psychoeducational group
program (the Life Goals Program by Bauer and McBride)
delivered by the
nurse care manager. Blinded assessments of clinical outcomes,
functional
outcomes, and treatment process were conducted every 3 months
for
24 months.
Results: A total of 441 patients (64% of those eligible)
consented to
participate and 43% of enrolled patients met criteria for current
major
depressive episode, manic episode, or hypomanic episode. An
additional
39% reported significant subthreshold symptoms, and 18%

reported
minimal or no current mood symptoms. Of patients assigned to
the
intervention program, 94% participated in telephone monitoring
and 70%
attended at least one group session.
Conclusions: In a population-based sample of patients treated
for bipolar
disorder, approximately two-thirds agreed to participate in a
randomized
trial comparing alternative treatment strategies. Nearly all
patients
accepted regular telephone monitoring and over two-thirds
joined a
structured group program. Future reports will describe clinical
effectiveness and cost-effectiveness of the intervention program
compared
with usual care.
Gregory E Simona, Evette
Ludmana, Jürgen Unützerb
and Mark S Bauerc
aCenter for Health Studies, Group Health
Cooperative, Seattle, WA, bUCLA
Neuropsychiatric Institute, Los Angeles, CA,
cProvidence Veterans Affairs Medical Center
and Brown University, Providence, RI, USA
Key words: algorithm – bipolar disorder – case

management – cost-effectiveness –
effectiveness – group psychotherapy –
randomized trial
Received 3 July 2001, revised and accepted for
publication 18 October 2001
Corresponding author: Gregory Simon, Center for
Health Studies, 1730 Minor Ave. #1600, Seattle,
WA 98101-1448, USA. Fax: 206-287-2871;
e-mail: [email protected]
Bipolar Disorders 2002: 4: 226–236
Copyright ª Blackwell Munksgaard 2002
BIPOLAR DISORDERS
ISSN 1398-5647
226
efficacy studies. Among patients treated with mood
stabilizers, treatment interruptions and unplanned
medication discontinuation are the rule rather than
the exception (5, 6). Long gaps between follow-up
visits are common, even among patients in need of
close monitoring (e.g. those recently hospitalized
or those recently discontinuing mood stabilizer
treatment) (5). Promising disease-specific psycho-
therapy programs have not been disseminated into

community practice.
Shortcomings in the management of bipolar
disorder are actually quite similar to those seen in
the management of other psychiatric (7) and
general medical illnesses (8). Studies of care for
unipolar depression also document poor medica-
tion adherence (9), sporadic follow-up monitoring
(9, 10), and slow dissemination of proven depres-
sion-specific psychotherapies. Similar deficiencies
are seen in the management of chronic medical
disorders such as diabetes, asthma, and congestive
heart failure (8). While treatment of bipolar
disorder may present unique challenges, many of
the shortcomings in current treatment reflect defi-
ciencies in the organization of care for chronic
psychiatric and general medical disorders. A
system focused on urgent or acute needs may not
devote sufficient attention to long-term treatment
adherence and to sustained and systematic follow-
up of non-urgent patients. Those who discontinue
treatment prematurely are too often out of sight
and out of mind.
Key elements of effective management are also
similar across a wide range of chronic illnesses.
Wagner and VonKorff (8, 11) have described a
comprehensive model of chronic illness manage-
ment that includes the following:
• re-organization of care to promote active follow-
up (e.g. systematic monitoring, telephone out-
reach)
• information systems (such as disease registries)
to support patient tracking and active follow-up

• ready access to evidence-based expertise – either
human or computerized ‘expert systems’
• support for patient-self management (e.g. sys-
tematic patient education, psychosocial inter-
ventions to promote better self-care).
We describe here the design and implementation of
a randomized trial evaluating the effectiveness and
cost-effectiveness of such a systematic treatment
program for bipolar disorder. Our intent was to
identify and enroll a representative, population-
based sample of patients treated for bipolar disor-
der. The multicomponent treatment program was
designed to address the shortcomings in everyday
practice described above while respecting the
structure and resource limitations of everyday
practice.
Study methods
Study setting
The study is being conducted at four of the six
outpatient mental health clinics of Group Health
Cooperative (GHC) of Puget Sound, a prepaid
health plan serving approximately 450 000 mem-
bers in western Washington state. Most members
are covered through employer-purchased plans,
but the enrollment includes approximately 45 000
Medicare members and 35 000 members covered
by Medicaid or by Washington’s Basic Health Plan
(a state program for low-income residents). The
GHC members are similar to area residents except

for higher educational level and less representation
of high-income residents.
All providers are paid by salary with no
individual financial incentives tied to specialty
mental health utilization or referral. The four
outpatient specialty mental health clinics included
in the study emphasize short-term individual psy-
chotherapy, pharmacotherapy, and group therapy.
Approximate outpatient mental health staffing
ratios per 100 000 members are: 5.5 psychiatrists,
2.5 psychiatric nurse practitioners, 2.5 psychiatric
nurses, 2.5 psychologists, and 15 masters-level
psychotherapists (ratios similar to other group/
staff model health plans). Psychiatric inpatient,
partial hospitalization, and day treatment services
are provided by contracted community providers.
Typical coverage arrangements for outpatient
psychotherapy allow 10–20 visits per year subject
to $10–$20 visit copayments. Psychiatric visits for
medication management are covered at parity with
general medical visits (same copayment level, no
annual limits). Typical coverage arrangements for
inpatient mental health care provide for up to
30 days hospitalization per year copayments or
coinsurance of $50–$75 per day.
Previous research at GHC demonstrated that
0.42% of all members received treatment for
bipolar disorder during a 1-year period from
1995 to 1996 (12). The majority of treated patients
received specialty mental health services and treat-
ment with mood stabilizing medications (5, 12).
Sampling and recruitment

The health plan’s computerized visit and hospital
discharge records were used to identify all members
aged 18 and over with inpatient or outpatient
diagnoses of bipolar disorder during the previous
Systematic care for bipolar disorder
227
12 months. Eligible diagnoses for initial screening
included bipolar disorder (DSM-IV codes 296.0,
296.4, 296.5, 296.6, 296.7, 296.8, 296.89), schizoaf-
fective disorder (295.7), and cyclothymic disorder
(301.13). Diagnoses of schizoaffective disorder and
cyclothymia were included at the screening stage to
completely capture patients with true bipolar
disorder. Diagnosis was subsequently confirmed
by structured interview (see below). Those sampled
were classified into three strata according to recent
treatment history, (1) any psychiatric hospitaliza-
tion during the past 12 months, (2) any emergency
room visit with psychiatric diagnosis or psychiatric
hospitalization between 12 and 24 months previ-
ously, and (3) all others. For all potentially eligible
patients, the responsible prescribing mental health
provider (psychiatrist or nurse-practitioner) was
asked to confirm a diagnosis of bipolar disorder.
Specifically, providers were asked to exclude pa-
tients with no clear history of manic or hypomanic
disorder as defined by DSM-IV or a clear diagnosis
of schizoaffective disorder (psychotic symptoms
persisting in the absence of a mood episode). All
remaining patients were mailed an invitation letter.

Baseline assessment
Each eligible patient was invited to complete a
baseline assessment at his or her usual behavioral
health clinic. Compensation of $25 was offered for
time and travel expenses. The assessment included:
• relevant modules of the Structured Clinical
Interview for DSM-IV (13) or SCID (Mood
Episodes, Psychotic Symptoms, Alcohol and
Other Substance Use Disorders)
• The SF-36 functional status questionnaire (14)
• Questions regarding time missed from employ-
ment or household responsibilities because of
illness (15)
• A 10-item version of the Health Care Climate
Questionnaire (16, 17) (a measure of patients’
perceptions that providers support autonomous
illness self-management) adapted for patients
with bipolar disorder (18)
• An 11-item questionnaire assessing participants’
confidence regarding self-management of bipolar
disorder developed for this study
• The 12-item Patient Satisfaction Index focused
on mental health care (19)
• Questions regarding services received (outpatient
and inpatient mental health treatment, psycho-
tropic drug prescriptions) outside of the GHC
health plan in the past 3 months

This baseline assessment was relatively brief in
comparison with most clinical trials – approxi-
mately 50 min of interview time followed by
15 min for completion of self-report question-
naires. Our intent was to maximize acceptability
to potential participants in order to enroll as
representative a sample as possible. Achieving this
goal required that we sacrifice detailed informa-
tion on past history and comorbid psychiatric
diagnoses.
The primary eligibility criterion was a diagnosis
of Type I or Type II Bipolar Disorder by DSM-IV
criteria. If SCID interview confirmed such a
diagnosis, the patient was immediately invited to
participate in the randomized trial. If SCID
interview did not confirm an eligible diagnosis
(e.g. no history of definite manic or hypomanic
episode, hypomania only with no history of defin-
ite major depressive episode) the treating provider
was asked to review the clinical record. If the
clinical record clearly documented an eligible
diagnosis, the patient was considered eligible and
invited to participate. If an eligible diagnosis could
not be confirmed by record review, the patient was
considered ineligible. This procedure was designed
with the expectation that some patients with true
bipolar diagnoses might not clearly recall prior
mood episodes. Patients were included regardless
of current mood state (depression, mania, mixed
state) or severity of current mood symptoms. No
patients were excluded because of comorbid
psychiatric, general medical, or substance use
disorder.

Treatment assignment
All eligible and consenting patients were randomly
assigned to either continue in usual care or to be
offered the intervention program described below.
Randomization was accomplished by the study
database administrator using three computerized
random number tables (one for each of the clinical
strata described above).
Usual care
Patients assigned to the usual care group were
expected to continue existing treatment and could
receive any and all services normally available
either inside or outside the GHC health plan. No
additional services were provided, but no services
usually available were withheld.
Care typically provided to GHC patients with
bipolar disorder is described in an earlier publica-
tion (5). At two of the four participating clinics,
unstructured support groups for patients with
bipolar disorder were available. Otherwise, no
special programs for bipolar disorder were in
Simon et al.
228
operation, and no staff (physicians, nurses, or
psychotherapists) either specialized in or were
specifically assigned to the care of patients with
bipolar disorder.

Intervention design
The intervention program was intended to address
previously identified shortcomings in the care of
bipolar disorder discussed above (inadequate
patient education, absence of structured psycho-
therapy programs, inadequate follow-up visit fre-
quency, high rates of medication non-adherence,
poor adherence to laboratory monitoring guide-
lines). We designed a multifaceted package of
services with the expectation that not all patients
would accept every component of the program.
The intervention program was delivered by three
nurse care managers (each spending 26–30 h/week
on this program) in collaboration with patients’
regular care providers (psychiatrists, nurses, nurse-
practitioners, and psychotherapists). Nurse care
managers were responsible for an initial assessment,
regular telephone monitoring contacts, and leader-
ship of group sessions (as described below). Case-
load sizes for the three specialized nurses ranged
from 60 to 85 patients. All care mangers were
registered nurses with at least 5 years of experience
in outpatient and inpatient psychiatric care.
The intervention program began with an
in-person visit to the nurse care manager. This
visit included an explanation of the intervention
program and a comprehensive assessment of cur-
rent clinical condition, current treatment, and past
treatment history. The nurse and patient worked
together to complete a structured care plan inclu-
ding:

• Members of treatment team and expected visit
frequencies
• Current medications
• Personal warning signs of depression and mania/
hypomania
• Personal strategies for coping with depression
and mania/hypomania
• Family members or significant others to contact
in case of emergency
Telephone monitoring, support, and care management
Nurse care managers contacted every patient at
least once per month to complete a brief, struc-
tured clinical assessment. Over 95% of assessments
were completed by telephone, but a few patients
made occasional in-person visits. These monitoring
contacts included:
• Clinical ratings of depression and mania/hypo-
mania over the last month using the 6-point
Psychiatric Status Rating scale from the Longi-
tudinal Interval Follow-up Examination (20) or
LIFE
• The Internal State Scale (21), a self-report
measure of mood symptoms developed by Bauer
and colleagues
• Assessment of current medication use (medica-
tion actually consumed rather than prescribed)
• Structured assessment of medication side-effects

with severity rated on a 4-point scale (None,
Easily tolerated, Significant but tolerable, and
Intolerable)
• Assessment of plans for follow-up (appoint-
ments already scheduled or expectations about
scheduling next appointment)
Phone calls might also include brief support or
review of problems discussed at group meetings
(see below). One telephone contact per month was
expected, and additional phone contacts were
added at the discretion of the nurse care manager.
Following each contact, the nurse care manager
provided written, structured feedback to all current
providers (psychiatrist, nurse practitioner, psycho-
therapist) regarding current clinical condition,
medication use, medication side-effects, and plans
for follow-up. These feedback reports included
algorithm-based recommendations regarding me-
dication adjustment and laboratory testing (see
details below). When clinically indicated (e.g.
severe symptoms, unplanned medication discon-
tinuation) the nurse care manager also made
immediate contact with the responsible provider
(either by telephone or face-to-face). Nurses also
provided as needed outreach and support in
between scheduled monthly phone contacts.
When appropriate (and with permission of parti-
cipating patients) nurses also contacted family
members or significant others to assist with
outreach and care coordination.
This system of assessment, feedback, and rec-
ommendations was intended to support (rather

than replace) care by patients’ usual providers
(psychiatrists and psychiatric nurse practitioners).
Intervention group patients continued in treatment
with existing providers (physicians, nurses, and
psychotherapists). Usual providers remained re-
sponsible for all decisions regarding pharmaco-
therapy (initiating or changing medications, dosage
adjustments). No providers other than the nurse
care-manager were specifically assigned to the
treatment of intervention patients. Both interven-
tion and usual care patients were free to transfer
between existing providers.
229
The telephone monitoring program was suppor-
ted by an intranet-based computer application
developed for this project. This application tracked
contact schedules for each patient, guided nurses
through the structured assessment, used an evi-
dence-based algorithm to assign treatment recom-
mendations, and generated structured feedback
reports to providers. The recommendations algo-
rithm considered current clinical state (depression,
mixed state, etc.), medication doses and blood
levels, and medication side-effects to generate
recommendations for individual medications. In
total, this algorithm considered 804 different scen-
arios (e.g. mania with psychosis, atypical antipsy-
chotic drug prescribed at moderate dose, mild side-
effects). Recommendations for specific clinical
scenarios were based on treatment guidelines

developed by the American Psychiatric Association
(22), the Texas Medication Algorithms Project
(23), and the Veterans Administration (2). For
example, a scenario of moderate manic symptoms,
use of lithium alone with a blood level of 0.5 and
mild lithium side-effects would lead to a recom-
mendation to ‘Consider increasing dose of lithium.’
A similar scenario with more severe side-effects
would lead to a recommendation to ‘Consider
medication switch or augmentation for lithium.’
Absence of a blood level following a change in
valproate dose would lead to the advice that ‘Dose
has changed since last valproate level.’
Structured group program
All patients were invited to participate in the Life
Goals Program (4, 24), a structured group psycho-
therapy program for bipolar disorder developed by
Bauer and McBride.
Phase I of the program consists of five 1-h
psychoeducational sessions focused on increasing
basic understanding of the illness, describing and
clarifying each individual’s personal course of
illness, identifying personal early warning signs
and typical precipitating events, and developing
specific action plans for self-management of illness
episodes. The specific agenda for each phase I
session includes:
• Session 1 – Description of symptoms and pat-
terns of bipolar disorder, emphasis on normal-
izing symptoms and reducing stigma, basic
summary of pathophysiology and treatment
options

• Session 2 – Symptoms and early warning signs of
depression, relationship of depression to perso-
nal stresses or triggers, emphasis on self-moni-
toring
• Session 3 – Description of adaptive and mal-
adaptive responses to symptoms of depression,
develop idea of weighing costs and benefits of
various coping responses, recognition of sub-
stance use and suicidal behavior as maladaptive
responses
• Session 4 – Symptoms and early warning signs of
mania/hypomania, relationship of mania/hypo-
mania to personal stresses or triggers, emphasis
on self-monitoring
• Session 5 – Description of adaptive and mal-
adaptive responses to symptoms of mania/hypo-
mania, develop idea of weighing costs and
benefits of various coping responses, recognition
of substance use as a maladaptive response
In discussing each topic, group leaders begin with a
brief description and ask group members to
provide specific examples. Discussion moves from
the more general and less threatening (What
symptoms might people experience when they feel
high or manic?) to the more personal (What
symptoms have you experienced when you’ve felt
high or manic?).
Phase II of the program consists of 1-h group
sessions scheduled bi-monthly. This phase of the
program is designed to address specific functional

deficits and promote self management. Phase II
sessions are less structured than phase I, but are
organized around a problem-solving approach
toward attainment of specific goals. At each
session, patients are asked to identify a specific
goal or problem. Group members then work
together to address specific problems using a
variety of strategies (breaking larger problems
into smaller pieces, brainstorming solutions, listing
of pros and cons). Group leaders encourage
participation and use of specific problem-solving
skills while avoiding advice-giving. As appropriate,
phase II groups include review of topics initially
discussed in phase I (e.g. effective and ineffective
strategies for responding to symptoms of depres-
sion). Phase II groups continue for the duration of
the intervention program (up to 24 months), and
patients are encouraged to continue group partici-
pation throughout.
Outcome assessment
All randomized patients were contacted for
blinded outcome assessments every 3 months until
24 months following randomization (total of eight
assessments). Assessments were conducted at each
participant’s usual behavioral health clinic, and
participants were reimbursed $20 for time and
transportation expenses.
Simon et al.
230

Each outcome assessment included the following
measures:
• The Mood Episodes module of the SCID (13)
focused on symptoms present during the last
2 weeks
• Alcohol and Other Substance Use Disorders
modules of the SCID (13) focused on symptoms
present during the last month
• Separate week-by-week symptom timelines (one
for depressive symptoms, one for manic/hypo-
manic symptoms) adapted from the LIFE (20).
Interviewers rated severity of symptoms for each
week since the last assessment
• The SF-36 functional status questionnaire (14)
• Questions regarding time missed from employ-
ment or household responsibilities because of
illness (15)
• A 10-item version of the Health Care Climate
Questionnaire (16, 17) adapted for patients with
bipolar disorder
• An 11-item questionnaire assessing participants’
confidence regarding self-management of bipolar
disorder developed for this study
• The 12-item Patient Satisfaction Index focused
on mental health care (19)
• Questions regarding services received (outpatient
and inpatient mental health treatment, psycho-
tropic drug prescriptions) outside of the GHC

health plan
Assessments were relatively brief – 45 min of
interview time followed by 15 min for completion
of self-report questionnaires. Our experience sug-
gests that brief questionnaires are helpful in
maintaining relatively high rates of participation
in follow-up data collection over 2 years.
All interviewers were experienced mental health
clinicians with a minimum of 2 years experience in
psychiatric assessment. Training included approxi-
mately 8 h of didactic instruction and role-play
interviews followed by observation of at least five
assessments. All interviewers completed at least five
interviews under supervision before certification.
Given the nature of the intervention, partici-
pants could not be blinded to treatment assign-
ment. Interviewers, however, remained blinded to
treatment assignment throughout the study. Prior
to each blinded outcome assessment, each partici-
pant received a reminder letter including a request
not to discuss any information regarding treatment
during the assessment interview. Interviewers also
began each assessment with an explanation of the
need for blinding and a warning against revealing
any information about treatment.
While use of prospective daily mood ratings
might yield more precise measurement rapid mood
changes, daily ratings would present two problems
in this randomized trial. First, reliance on daily
mood ratings would limit our sample to patients
willing and able to complete daily mood diaries.

Those unwilling or unable would either be exclu-
ded from participation or largely excluded from
analyses because of missing data. Those unable or
unwilling to complete daily mood diaries may be
those most likely to benefit from a systematic care
improvement program. Secondly, encouraging (or
requiring) participants to complete daily mood
ratings might have a significant intervention effect.
In fact, promotion of regular self-monitoring is one
component of the Life Goals Program. We are
concerned, however, about the accuracy of recall
over several months. For that reason, we chose a 3-
month recall period rather than the 6-month
period used in some previous studies. In addition,
a substudy will use randomly spaced brief tele-
phone assessments to examine the accuracy of
mood recall during the 3-month interviews between
in-person assessments.
Informed consent
Informed consent was obtained at several points
during the recruitment and evaluation process. The
invitation letter included a brief description of the
overall study and a phone number patients might
call to refuse further contact. Prior to the baseline
assessment, all participants provided written in-
formed consent. This consent document also
included a detailed description of the baseline
assessment and a brief description of the random-
ized trial and intervention program. Patients invi-
ted to participate in the randomized trial
completed a second consent procedure following
the baseline assessment. This consent document
included a detailed description of the randomiza-
tion procedure, the blinded outcome assessments,

and the intervention program. Patients were ad-
vised, however, that consenting to participate in
the randomized trial did not necessarily imply
willingness to accept any particular components of
the intervention program. Finally, patients ran-
domly assigned to the intervention completed an
additional consent procedure at the first interven-
tion contact. This consent document included a
detailed description of the intervention program
and requested specific consent to share clinical
information with the patient’s treatment providers
and designated family members or significant
others.
There were several motivations for this multistep
consent process. First, dividing the overall consent
process into three components eliminated the need
231
for a single lengthy and complex consent docu-
ment. Secondly, this process allowed potential
participants to weight the risks and benefits of
each separate decision (participating in the baseline
assessment, agreeing to random assignment and
blinded follow-up assessments, participating in the
intervention program). At each step, consent
documents focused on information relevant to the
decision at hand. Finally, our goal was to enroll as
representative a sample as possible rather than
restricting participation to those willing to accept
some or all of the intervention program.

Results to date
Recruitment
Patients were enrolled from four of GHC’s seven
specialty behavioral health clinics. Mailing of
invitation letters began in August 1999 and all
baseline interviews were completed by September
2000 (13 months overall).
Invitation letters were mailed to 945 potential
participants. Of this number, 81 (9%) could not be
contacted by telephone and 79 (8%) were found to
be ineligible. Most common reasons for ineligibility
were disenrollment from the health plan and/or
moving out of the area. Of the remaining 785
patients, 509 (65%) agreed to complete a baseline
assessment and 276 (35%) declined. Compared
with those not contacted and those refusing, those
completing the baseline assessment did not differ
significantly in mean age (44.5 versus 43.0 years),
proportion female (68 versus 62%), proportion
with psychiatric hospitalization in the prior
12 months (10 versus 9%) or proportion with
psychiatric emergency room visit in the prior
12 months (14 versus 15%).
Of the 509 patients completing the baseline
assessment, 59 (12%) were found ineligible because
a diagnosis of bipolar disorder could not be
confirmed by structured interview or medical
records. Of the 450 patients found eligible, 410
(92%) met criteria for Bipolar Disorder Type I or
Type II by SCID interview, and 33 (8%) were

found eligible based on provider diagnosis and
chart review. Of those eligible, 441 (98%) agreed to
participate and were enrolled in the randomized
trial. Consequently, the estimated overall partici-
pation rate was 64% (65% participation rate
among those eligible for baseline assessment
times 98% participation rate among those eligible
for randomization).
Baseline clinical characteristics of participants
Demographic and baseline clinical characteristics
of enrolled patients are shown in Table 1. The age
(mean ¼ 44 years) and sex distribution (approxi-
mately 68% female) are similar to those we have
reported earlier for all GHC patients treated for
bipolar disorder (12). Approximately one-third of
patients met DSM-IV criteria for current major
depressive episode and one-fifth met criteria for
current hypomanic or manic episode. When symp-
toms of depression and mania were considered
together, 40% met criteria for current DSM mood
episode (Psychiatric Status Rating of Definite or
Severe) and 22% were in remission (Psychiatric
Status Rating of Mild or None). Those assigned to
the intervention and usual care groups did not
differ significantly with respect to age, sex, ethni-
city, or baseline severity of depressive symptoms,
or baseline rating of manic/hypomanic symptoms.
Intervention program implementation
The intervention program has been successfully
implemented in all four clinics over a period of
12 months. Of patients assigned to the intervention

Table 1. Demographic and baseline clinical characteristics of
enrolled patients
Intervention Group (n ¼ 212) Usual Care Group (n ¼ 229) Test
statistic (p-value)
Mean age (SD) 44.1 (13.4) 44.3 (12.9) t ¼ 0.1 (p ¼ 0.92)
% Female (n) 68% (144) 69% (157) v2 ¼ 0.02 (p ¼ 0.89)
% Caucasian (n) 87% (184) 90% (206) v2 ¼ 1.08 (p ¼ 0.30)
Current depression rating v2 ¼ 0.18 (p ¼ 0.91)
% Definite or severe (n) 34% (71) 35% (81)
% Marked or partial (n) 40% (85) 39% (90)
% None or mild (n) 26% (56) 25% (58)
Current mania rating v2 ¼ 1.24 (p ¼ 0.54)
% Definite or severe (n) 12% (26) 15% (35)
% Marked or partial (n) 34% (72) 30% (69)
% None or mild (n) 54% (114) 55% (125)
Simon et al.
232
program, 94% completed the initial contact with
the nurse care manager. Of patients enrolled in the
study for more than 12 months, 91% continued to
participate in monthly telephone monitoring. Ap-
proximately 70% of patients enrolled have atten-
ded at least one group session, and approximately
60% have completed phase I (initial five sessions)
of the Life Goals Program.
Within the telephone monitoring program,

intensity of contact varied widely. Duration of
phone contacts ranged from 10 min (for patients in
remission) to 40 min (for patients requiring more
complex assessment or significant additional sup-
port). In some cases, completing a telephone
contact required multiple telephone attempts and/
or mailed reminders. If clinically indicated, nurse
care managers arranged additional brief telephone
contacts between scheduled monthly calls.
Discussion
Our experience illustrates several of the compro-
mises necessary in the design and execution of
treatment effectiveness research. While population-
based sampling and recruitment improves repre-
sentativeness and ultimate generalizability, it may
yield a less severely ill patient sample than seen in
most treatment efficacy trials. The baseline assess-
ment must balance the need for more detailed
clinical information against the probability that
lengthy assessments will exclude those with lower
motivation to participate, leading to an unrepre-
sentative sample. The intervention protocol must
be specific enough to permit reliable replication but
flexible enough to accommodate the range of
patients seen in a ‘real world’ sample. Outcome
assessments must be brief enough to maintain high
participation rates and infrequent enough that the
assessment process does not become an interven-
tion in itself. Because the essential components of
the intervention involve greater contact between
patients and providers, neither patients nor pro-
viders can be blinded to treatment group assign-
ment. Outcome assessments can, however, be
conducted by raters blinded to treatment group

assignment.
Initial data analyses will be conducted when all
participants have completed 12 months of follow-
up. The intervention and usual care groups will be
compared in terms of process of care, treatment
outcomes, functional outcomes, satisfaction, self-
efficacy, and costs of care. Primary analyses of
costs will examine mental health treatment costs
including intervention program costs, psychotropic
medications, and all costs of specialty mental
health care. Secondary analyses will examine total
health services costs. Cost data will be collected
from GHC’s cost accounting records as well as
participants’ reported use of non-GHC health
services. Data on incremental cost (i.e. difference
between intervention and control care groups) and
incremental effectiveness will be used to calculate
cost-effectiveness of the intervention compared
with usual care. The appropriate unit for assess-
ment of incremental cost is relatively straightfor-
ward: dollars discounted to account for medical
inflation during the study period. The appropriate
unit for defining incremental effectiveness, how-
ever, is not well established. We propose to use
LIFE Psychiatric Status Ratings to classify pa-
tients on a 0 to 1 scale from ‘Complete Remission’
to ‘Completely Symptomatic’. Data for individual
weeks will then be summed to yield an overall sum
of ‘Days Free of Mood Disorder’ over the follow-
up period. This follows the method described by
Lave and colleagues (25) for calculation of ‘De-
pression Free Days.’ Parallel analyses will be
conducted using the longer-term follow-up data
(months 13–24).

All data analyses will be based on initial assign-
ment or intent-to-treat, regardless of level of
participation in the intervention program. We
have no plans to analyse outcomes according to
treatment actually received (e.g. ‘completers’ ana-
lysis). While such an approach may have some
value in more structured efficacy studies, it is
inappropriate in the analysis of effectiveness trials
such as ours. Patients who decline to participate in
some or all of the intervention program almost
certainly differ in important ways from those who
participate, and any analysis which excluded these
non-participants from the intervention group
would be liable to significant bias. The question
we address is ‘Should all patients with bipolar
disorder be offered a systematic treatment
program?’ rather than ‘What is the efficacy of the
treatment program among those who participate?’
Comparisons of the intervention and usual care
groups will consider the entire intervention as
package, and no analyses will allow us to examine
the effects of individual components of the inter-
vention program. While participation in some
specific component may be associated with more
or less favorable outcomes, such observations do
not support any definite conclusions about clinical
effectiveness. For example, more favorable out-
comes among those attending more group sessions
could reflect self-selection rather than any causal
relationship. A finding of better outcomes among
intervention patients would certainly raise ques-
tions about relative effectiveness of individual
components. Such questions could only be

233
addressed by further study of specific components
(e.g. random assignment to group program alone,
telephone monitoring program alone, or the com-
bination).
The sample of patients enrolled in this study
differs significantly from those included in most
treatment efficacy studies (26–28). Patients were
included regardless of current mood state (depres-
sion, mania, mixed state). There was no threshold
for current symptom severity leading to inclusion
of many patients with minimal or no current mood
symptoms. Patients with comorbid psychiatric,
general medical, or substance use disorder were
not excluded. The resulting heterogeneous sample
might not be appropriate for testing a specific
efficacy question (e.g. efficacy of a new drug for
bipolar depression), but such a representative
sample is ideal for evaluating the ‘real world’
effectiveness of a systematic care improvement
program.
Our experience demonstrates the feasibility of
recruiting a population-based sample of patients
with bipolar disorder into a randomized clinical
trial. Approximately two-thirds of patients contac-
ted volunteered to attend an initial assessment and
nearly all of those found eligible agreed to parti-
cipate in the randomized trial. Approximately 35
patients were enrolled into the randomized trial per

month. Given the current randomized trial evi-
dence, most clinical decisions in the management
of bipolar disorder are based on clinical experience
and expert opinion. Developing evidence to guide
common clinical decisions is a high priority. Given
the need for additional evidence from randomized
trials, it is encouraging that a majority of patients
treated for bipolar disorder in this health plan were
willing to participate in a randomized trial com-
paring alternative treatment strategies. Approxi-
mately 35% of patients contacted declined to
participate in the initial assessment, but only 2%
of those found eligible at the initial assessment
declined to participate in the randomized trial.
Acceptance of the multicomponent intervention
program by patients and mental health providers
has been generally good. Over 95% of patients had
some intervention contact, and over half partici-
pated in both main components of the program
(telephone monitoring and group program). As
expected, participation in the telephone monitoring
program was considerably higher than participa-
tion in groups. We believe this difference reflects
several factors. Participation in telephone con-
tacts required much less time and effort than
did attendance at group sessions. While group
participants often valued the support and sense
of community in group sessions, many group
non-participants expressed concerns about privacy
and confidentiality. While nurse case managers
made every effort to recruit patients into group
sessions, telephone outreach was naturally more
effective for increasing participation in telephone
monitoring than for increasing group participa-

tion. In reporting these treatment participation
rates, we should emphasize the difference between
this population based sample and the samples
traditionally included in treatment efficacy trials.
Samples recruited via referral or response to
advertisement would be expected to have higher
motivation to participate in treatment.
Our hope is that this intervention program (if
proven effective) could be implemented across a
range of health care systems. We believe the
various intervention components could be easily
adapted to other managed care mental health
clinics, Veterans Affairs clinics, or community
mental health centers. We do, however, see some
barriers to implementation in traditional fee-for-
service outpatient practice – especially solo or
small group practice. First, the program requires a
relatively large group of patients with bipolar
disorder at a single facility in order to form and
maintain effective groups. Secondly, telephone
outreach and monitoring (a core component of
the program) is not currently reimbursable under
fee-for-service arrangements.
Implementation of this (or any other) care
improvement program for bipolar disorder will
depend on the balance of added costs and added
clinical benefits. The primary cost components of
the intervention program include the time of nurse
care managers, costs of clinical supervision, and
costs of maintaining the computerized care man-
agement system. Using actual caseload, salary,
fringe benefit, and overhead (e.g. facilities) costs,
we estimate the cost of nurse care manager time at
approximately $585 per patient per year. Estimated

cost of supervision time (also based on actual
salary, fringe benefit, and overhead costs) is
approximately $25/patient/year. Estimated cost of
maintaining the computerized care management
system is approximately $21/patient/year (although
this cost would decline if fixed costs were spread
over a larger number of patients). The sum of these
components ($621/patient/year) compares with
total health services costs of approximately $3500/
year in an earlier sample of patients with bipolar
disorder treated in the same health plan (29).
Relatively few randomized trials have evaluated
the effectiveness (rather than efficacy) of treat-
ments for bipolar disorder. In contrast, numerous
effectiveness trials have evaluated a range of
strategies to improve care of unipolar depression.
Simon et al.
234
With few exceptions (30, 31), interventions limited
to traditional didactic provider education have
yielded disappointing results (32–34). More inten-
sive educational interventions such as academic
detailing or continuous quality improvement pro-
grams have also failed to improve clinical out-
comes (35, 36). Reminder or feedback programs
have also had no significant clinical benefit (37–
39). Several studies, however, have demonstrated
that more intensive multicomponent interventions
lead to significant improvements in patient (39–
45) outcomes as well as a favorable balance of

added benefits to added costs (46–48). Common
elements of these effective care improvement
programs include: systematic patient education,
specific treatment algorithms, active follow-up
care, and ongoing support for effective patient
self-management. Our intervention program for
bipolar disorder attempted to incorporate these
core elements of effective programs for unipolar
depression.
Effectiveness trials such as this one are an
intermediate step in the path from treatment
efficacy to widespread dissemination. Again,
research on treatment of unipolar depression
illustrates this range. Efficacy trials (49) have
established the clinical benefits of antidepressant
pharmacotherapy and depression-specific psycho-
therapies when those treatments are provided
under ideal conditions. Subsequent effectiveness
trials (40, 41, 50) demonstrated the clinical and
economic effects of these treatments under more
natural practice conditions. Finally, recent dissem-
ination studies (44, 45) show that evidence-based
treatments can be implemented by existing staff in
community practice settings. We hope the current
randomized trial will demonstrate the effectiveness
of our multicomponent intervention for bipolar
disorder. If so, additional research will be needed
to evaluate strategies for dissemination.
Acknowledgements
This work was supported by NIMH Grant MH59125.
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