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Clinical Significance of Lifetime Panic Spectrum Symptoms in the Treatment of Patients With Bipolar I Disorder
Ellen Frank, PhD;
Jill M. Cyranowski, PhD;
Paola Rucci, DStat;
M. Katherine Shear, MD;
Andrea Fagiolini, MD;
Michael E. Thase, MD;
Giovanni B. Cassano, MD, FRCPsych;
Victoria J. Grochocinski, PhD;
Bryan Kostelnik, BA;
David J. Kupfer, MD
Arch Gen Psychiatry. 2002;59:905-911.
ABSTRACT
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Background Given the observed association between panic disorder and bipolar disorder
and the potential negative influence of panic symptoms on the course of bipolar
illness, we were interested in the effects of what we have defined as "panic
spectrum" conditions on the clinical course and treatment outcome in patients
with bipolar I (BPI) disorder. We hypothesized that lifetime panic spectrum
features would be associated with higher levels of suicidal ideation and a
poorer response to acute treatment of the index mood episode in this patient
population.
Methods A sample of 66 patients with BPI disorder completed a self-report measure
of lifetime panic-agoraphobic spectrum symptoms. Patients falling above and
below a predefined clinical threshold for panic spectrum were compared for
clinical characteristics, the presence of suicidal ideation during acute treatment,
and acute treatment response.
Results Half of this outpatient sample reported panic spectrum features above
the predefined threshold. These lifetime features were associated with more
prior depressive episodes, higher levels of depressive symptoms, and greater
suicidal ideation during the acute-treatment phase. Patients with BPI disorder
who reported high lifetime panic-agoraphobic spectrum symptom scores took
27 weeks longer than those who reported low scores to remit with acute treatment
(44 vs 17 weeks, respectively).
Conclusions The presence of lifetime panic spectrum symptoms in this sample of patients
with BPI disorder was associated with greater levels of depression, more suicidal
ideation, and a marked (6-month) delay in time to remission with acute treatment.
Alternate treatment strategies are needed for patients with BPI disorder who
endorse lifetime panic spectrum features.
INTRODUCTION
A GROWING BODY of evidence indicates that patients with unipolar (UP)
depression and co-occurring panic display greater symptom severity,1-4 more
suicidal ideation,5-7
and a poorer response to both psychotherapeutic2, 8-9
and pharmacological2, 4, 9-11
treatments, compared with patients without such comorbidity. Chen and Dilsaver12 found the prevalence of panic disorder among community
samples with bipolar (BP) disorder to be 2.1 times higher than among individuals
with UP depression, and 26 times higher than that of control probands with
no history of mood disorder. Indeed, a recent study indicated that 20% of
patients with BPI disorder report a lifetime history of panic disorder and/or
agoraphobia, although only 9% meet current panic disorder criteria.13
Clinically, panic and anxiety have often been associated with mixed
BP states. For example, panic disorder has been observed to occur more frequently
in patients with dysphoric or mixed mania than in patients with pure mania,14 although rates of panic disorder have been noted
to be elevated in patients with BP depression as well.15
Nevertheless, surprisingly little research has attempted to map the clinical
and prognostic significance of panic symptoms in patients with BP disorder.
For the past several years, we have been interested in the concept of
spectrum conditions linked to DSM-IV mood16 and anxiety9, 17-20
disorders, and the influence of these conditions on illness course and treatment
outcome. By spectrum conditions we refer to a dimensional
view of psychopathology that includes a broad array of manifestations of the
target disorder, including its core and most severe symptoms as well as a
range of more subtle features related to the core condition. The latter may
include temperamental traits, prodromal indicators, or residual symptoms.17 Though associated with specific DSM-IV disorders, these enduring spectrum conditions are also found
in individuals who have never met full DSM-IV diagnostic
criteria. We have recently operationalized many of these spectrum conditions
for assessment with interview and self-report instruments, such as those developed
to assess lifetime panic-agoraphobic spectrum symptoms (Panic-Agoraphobic
Spectrum–Self-Report [PAS-SR]).9, 17-18
Previous analyses had pointed to an association between medical record–reviewed
anxiety symptoms and treatment outcome among our patients with BPI disorder.21 Given the evidence from UP depression research,2-6,8
our own examination of panic spectrum symptoms in UP depression,9
and the earlier medical record–review results,21
we expected that patients with BP disorder endorsing higher scores on a comprehensive
panic-agoraphobic spectrum assessment22 would
display higher levels of suicidal ideation and a poorer response to treatment
than patients without such panic spectrum features. The current report examines
the occurrence and clinical significance of lifetime panic spectrum symptoms
among patients with BPI disorder treated in an outpatient psychiatric clinic.
PATIENTS AND METHODS
PATIENTS
The study group consisted of 66 patients participating in a larger randomized,
controlled trial (MH29618, E.F., principal investigator),23
36 of whom were included in our earlier report on the influence of medical
record–reviewed anxiety symptoms on treatment outcome among individuals
with BPI disorder.21 Patients in the larger
treatment trial were recruited via medical referrals, referrals from inpatient
mood disorder units and outpatient clinics at the Western Psychiatric Institute
and Clinic, Pittsburgh, Pa, and media announcements. Of the 66 patients included
in the current study, 23 (34.8%) were recruited from inpatient units, while
43 (65.2%) were recruited from outpatient sources. Treatment outcome data
reported herein are drawn from the acute (or preliminary) treatment phase
of the protocol. Data on panic spectrum symptoms are drawn from a single cross-sectional
assessment that occurred when patients were at various points in this long-term
protocol. In most cases (92%), this assessment followed completion of the
acute treatment phase or termination from the study protocol.
To be enrolled in the larger protocol, patients were required to be
between the ages of 18 and 65 years, to meet Research Diagnostic
Criteria24 for BPI or schizoaffective
manic disorder, and to be in an acute affective episode. The index episode
had to meet severity criteria (ie, a Hamilton Depression Rating Scale [HDRS]
score of  15 or a Bech-Rafaelsen Mania Scale score of 15). Exclusion
criteria included the following: pregnancy, current rapid cycling (4 affective
episodes per year), lifetime diagnosis of schizophrenia or antisocial personality
disorder, current drug or alcohol abuse (unless confined to affective episodes),
and significant medical illness that would preclude protocol pharmacotherapy.
TREATMENT PROTOCOL
After giving written, informed consent, participants were randomly assigned
to the acute-treatment phase consisting of algorithm-based pharmacotherapy
accompanied by either intensive clinical management or interpersonal and social
rhythm therapy (IPSRT).25 Protocol pharmacotherapy
began with the administration of lithium carbonate and ultimate stabilization
receiving lithium monotherapy was encouraged. Patients who could not tolerate
lithium therapy received either divalproex sodium or carbamazepine, or a combination
of mood stabilizers. Patients with depression who failed to stabilize while
receiving a mood stabilizer alone received either tranylcypromine sulfate
or, if they were unwilling to take a monoamine oxidase inhibitor, paroxetine
or another antidepressant in addition to their mood stabilizer. Neuroleptics
were given as adjunctive medication to patients with manic, mixed, or psychotic
symptoms who could not be stabilized using a mood stabilizer alone.
Intensive clinical management has been described as a nonspecific low-dose
therapy aimed at providing education and support, reviewing symptoms, reinforcing
medication adherence, and assisting patients in the management of any adverse
effects of the medications. In contrast, IPSRT is a procedurally specified
psychotherapy that focuses on problems in interpersonal relationships, the
link between mood and life events, the importance of maintaining regular daily
routines, and the identification and management of potential precipitants
of rhythm dysregulation.25 Both clinical management
and IPSRT were provided in the format of weekly individual sessions, both
subject groups were treated according to identical pharmacotherapy guidelines,
and in both conditions patients met with their therapist and psychiatrist
at each visit. Because preliminary analyses on 124 patients randomly assigned
to these 2 treatment conditions showed no difference in either the percentage
of patients who remit with treatment or time to remission,21
treatment group is not controlled for statistically in subsequent analyses.
ASSESSMENTS
Clinical History and Status
Both current status and lifetime history of DSM-IV diagnoses were assessed via Structured Clinical
Interview for the DSM-IV Axis I Disorders (SCID)26
performed at study enrollment by SCID-trained clinical evaluators (master's-
or doctoral-level nurses, social workers, or clinical psychologists). Following
stabilization of the index episode, National Institute of Mental Health Life
Charting Interviews27-28 were
performed to supplement patient medical records and SCID interview data, and
to obtain a more comprehensive account of patients' lifetime mood episode
history.
Throughout treatment, patients were assessed by independent clinical
evaluators at each weekly clinic visit. Depressive symptoms were rated on
both the 17-item and 25-item versions of the HDRS.29-30
Manic symptoms were assessed with the 12-item Bech-Rafaelsen Mania Scale.31 Full clinical remission is defined by an average
17-item HDRS score of 7 or less and an average Bech-Rafaelsen Mania Scale
score of 7 or less over a period of 4 consecutive weeks. For the present analyses,
time to remission was defined as the number of weeks from the first treatment
session to the onset of this 4-week period of stabilization.
Panic-Agoraphobic Spectrum
The lifetime experience of panic-agoraphobic spectrum symptoms was assessed
in a cross-sectional sample of 66 patients using the Panic-Agoraphobic Spectrum–Self-Report
(PAS-SR). The term "panic-agoraphobic spectrum"17-18
refers to a broad array of features associated with DSM-IV panic disorder, including typical and atypical manifestations of core
panic symptoms (such as paniclike somatic symptoms, anxious expectation, and
agoraphobia), as well as a range of related temperamental or behavioral features
(categorized as separation anxiety, stress sensitivity, medication sensitivity,
illness-related phobias, and reassurance seeking). The PAS-SR, a 114-item
self-report scale, assesses the lifetime experience of panic-agoraphobic symptoms
and features across 8 specified domains (Table 1).
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Table 1. Example Items From the Panic-Agoraphobic Spectrum Scale-Self-Report
(PAS-SR)*
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The interview version of this measure has been shown to have excellent
psychometric properties,22, 32
and the 8 panic-agoraphobic spectrum subscales have been shown to display
a strong pattern of convergent and discriminant validity with existing panic
and anxiety assessment measures across multiple diagnostic groups and control
subjects who were never psychiatrically ill.32
The self-report version of this instrument has been shown to agree very well
(intraclass correlation coefficient = 0.94) with the interview version.32 Data obtained from a subset of 23 patients in the
current sample indicated excellent test-retest reliability for the PAS-SR
instrument over a 2- to 3-month period (Spearman  = 0.92, P<.001) (range, 50-91 days; mean [SD], 80.8 [9.5] days). In receiver
operating characteristic curve analyses reported previously, a cutoff score
of 35 was determined to best distinguish between psychiatric outpatients with
and without clinically significant lifetime panic spectrum features.9
STATISTICAL ANALYSES
High (35) and low (<35) PAS-SR scorers were compared across demographic
and clinical characteristics using  2 and t tests. Yates correction was applied to 2 tests in
2 x 2 tables, and the Mann-Whitney test was used in place of t tests when the distribution of data was significantly skewed. When
an association between categorical variables and PAS-SR scores was hypothesized
a priori, we reported the odds ratios. Finally, for a subset of 45 patients
on whom life charting data were available, associations between total PAS-SR
scores and lifetime days depressed, manic, and "ill" (either depressed or
manic) were assessed using the Pearson product-moment correlation coefficients.
Kaplan-Meier survival analyses were conducted to compare the median
time to remission between patients above and below the cutoff for panic-agoraphobic
spectrum. Dropouts were treated as censored data. Given our previous finding
that patients treated for BP depression and mixed-cycling profiles take longer
to achieve remission than those treated for manic episodes,33
a Cox proportional hazards regression model was used to examine the association
between PAS-SR scores and time to stabilization, adjusted for the predominant
mood state being treated. Similarly, to check whether the association between
time to stabilization and PAS-SR score was related to a longer duration of
illness, we used a Cox regression model with total PAS-SR score and time spent
depressed or manic as independent variables. All tests were 2-tailed, and
an  level of .05 was used to determine statistical significance.
RESULTS
CHARACTERISTICS OF PARTICIPANTS
A cross-sectional sample of 76 patients who had completed or nearly
completed the acute-treatment phase of the protocol described earlier were
invited to complete PAS-SRs. Of the 76 patients approached, 66 returned completed
questionnaires for a response rate of 86.8%. Nonrespondents did not differ
from respondents for age, sex, baseline psychiatric severity, or time to remission.
Of the 66 respondents, 37 were female and 29 were male. Mean (SD) age of patients
was 35.1 (11.0) years (range, 18-61 years). During the acute treatment phase,
33 of the patients were predominantly treated for depression, 21 for mania,
and 12 for mixed-cycling episodes.
Using the PAS-SR cutoff score of 35, 33 (50%) were categorized as low
PAS-SR scorers and 33 (50%) were categorized as high PAS-SR scorers. The median
PAS-SR score among the low group was 19 (mean [SD], 17.97 [9.0]; range, 1-34),
while the median PAS-SR score among the high PAS-SR group was 52 (mean [SD],
51.45 [13.4]; range, 35-87). Only 8 patients (12.1%) reported a lifetime history
of DSM-IV panic disorder. All of these patients had
PAS-SR scores above the threshold of 35.
DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF HIGH VS LOW PAS-SR SCORERS
Patients with high PAS-SR scores were significantly more likely to be
female and to report more lifetime depressive episodes and greater depressive
symptoms at baseline (Table 2).
Life charting data available for a subset of 45 patients indicated a significant
correlation between higher PAS-SR scores and a greater number of lifetime
days depressed (r = 0.39, P
= .01) and lifetime days ill (ie, depressed or manic; r = 0.36, P = .02); however, the correlation
between PAS-SR scores and lifetime days manic did not reach significance (r = 0.23, P = .14). Finally, patients
with high PAS-SR scores were significantly more likely to have been treated
for an affective episode that included depressive components (ie, BP depression
or mixed-cycling presentations) during the acute treatment phase of the protocol
(60% vs 28.6%, 21 = 4.5, P
= .03).
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Table 2. Demographic and Clinical Characteristics of 66 Patients With
Bipolar Disorder*
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DEPRESSIVE SYMPTOMS AND SUICIDALITY
To examine the relationship between lifetime panic spectrum symptoms
and the affective presentation of these patients, we compared weekly HDRS
scores averaged across the acute treatment phase. As expected, high PAS-SR
scorers reported higher levels of depression than low PAS-SR scorers (Table 3).
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Table 3. Clinical Outcomes During the Acute Treatment Phase for 66
Patients With Bipolar Disorder*
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This finding may have been influenced by 2 potential confounds. First,
high PAS-SR scorers were more likely to have been treated for depressed or
mixed-cycling presentations (rather than pure mania) during the acute treatment
phase. However, a 2-way analysis of variance (ANOVA) including both the PAS-SR
group and the predominant state treated indicated that a high PAS-SR score
was significantly associated with higher mean HDRS scores even after controlling
for the predominant mood state treated (Table 3). A second potential confound was that a larger proportion
of female patients were categorized as high PAS-SR scorers. Given the robust
sex difference in lifetime rates of depressive episodes among men and women
with BP disorder, sex (rather than panic spectrum symptoms per se) could have
accounted for this difference in depression scores. However, a 2-way ANOVA
including both the PAS-SR group and sex indicated that a high PAS-SR score
was significantly associated with higher mean HDRS scores even after controlling
for sex (Table 3).
As predicted, high PAS-SR scorers were significantly more likely than
low PAS-SR scorers to report suicidal ideation. Reports of suicidal ideation
were derived from clinician ratings on item 3 of weekly HDRS evaluations.
Any rating of suicidal ideation of 2 to 4 (ie, from mild to severe) obtained
during the acute treatment phase was scored as a positive indication of suicidal
ideation. Sixteen (48.5%) of the high PAS-SR scorers reported mild to severe
suicidal ideation during the acute treatment phase compared with 6 (18.2%)
of the low PAS-SR scorers. This finding was not surprising, given the fact
that high PAS-SR scorers were more likely to be treated for depressed or mixed
states (rather than mania) in the acute treatment phase. However, a subsequent
analysis restricted to patients treated for either BP depression or mixed-cycling
presentations (n = 45) indicated that high PAS-SR scorers were still nearly
4 times more likely to report suicidal ideation than their low PAS-SR counterparts
(Table 3).
TREATMENT RESPONSE
As hypothesized, high PAS-SR scores were associated with a significantly
longer median time to remission (44 weeks vs 17.1 weeks for patients with
low PAS-SR scores) in a Kaplan-Meier survival analysis (Breslow test = 13.6,
degrees of freedom [df] = 1, P<.001; Figure 1). A separate
Kaplan-Meier survival analysis indicated that patients treated for mixed-cycling
and depressive presentations also took significantly longer to remit (32.8
and 32 weeks, respectively) than patients treated for mania (13 weeks; Breslow
test = 16.5, df = 2, P<.001).
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Figure 1. Censored data include 4 patients
who dropped out of the acute treatment phase (data censored at point of termination
from study) and 5 patients who were active in the acute treatment phase at
the time of analysis (data censored at number of weeks of active treatment
completed). PAS-SR indicates Panic-Agoraphobic Spectrum–Self-Report.
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To examine the effect of PAS-SR scores on time to remission within the
depressed and mixed-cyling groups only (ie, excluding manic subjects, who
tended to show lower PAS-SR scores and a quicker time to remission), a subsequent
Kaplan-Meier survival analysis was conducted for this subgroup (n = 45). This
analysis indicated that high PAS-SR scorers still took significantly longer
to remit than low PAS-SR scorers (45.4 weeks vs 22.9 weeks, respectively;
Breslow test = 11.9, df = 1, P<.001; Figure 2).
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Figure 2. Censored data include 2 patients
who dropped out of the acute treatment phase (data censored at point of termination
from study) and 5 patients who were active in the acute treatment phase at
the time of analysis (data censored at number of weeks of active treatment
completed). PAS-SR indicates Panic-Agoraphobic Spectrum–Self-Report.
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In line with these findings, a Cox regression model including dichotomous
(high vs low) PAS-SR scores and predominant state treated as covariates was
found to fit the data significantly better than the baseline model with no
covariates (overall 23 = 22.5, P<.001). This model indicated that high PAS-SR scores and having
a depressed clinical presentation as the predominant state treated were significantly
and independently associated with a longer time to remission (for PAS-SR score,
risk ratio [RR] = 0.33, df = 1, P = .003; for depressive vs manic state, RR = 0.39, df = 1, P = .005; for mixed-cycling vs manic
state, RR = 0.44, df = 1, P
= .06).
In contrast, a Cox regression model including the total PAS-SR score,
lifetime days depressed, and lifetime days manic indicated that while total
PAS-SR score was positively associated with a longer time to remission (RR
= 0.97, df = 1, n = 45, P
= .04 for total PAS-SR score), neither cumulative history of depression nor
of mania (RR = 1, df = 1, n = 45, P = .40 for lifetime days depressed; RR = 1, df
= 1, n = 45, P = .86 for lifetime days manic) was
associated with time to remission.
COMMENT
The prevalence of clinically significant panic-agoraphobic spectrum
features in this sample of patients with BPI disorder exceeds that observed
in a previous report on patients with UP disorder assessed with the PAS-SR
instrument.9 This is consistent with epidemiologic
findings of Chen and Dilsaver12 and clinical
findings of Pini et al.34 More important, the
prevalence of these panic spectrum features was more than 4 times as great
as that of lifetime panic disorder in these patients. Clinically significant
lifetime panic spectrum was associated with female sex, higher levels of depression,
a greater risk of suicidality, and a much longer time to remission of the
index mood episode in this sample. These effects could not be explained by
the increased likelihood of high PAS-SR scorers to be treated for depressed
or mixed-cycling states15 rather than pure
mania (that was associated with lower HDRS scores and the lowest rates of
suicidal ideation). Analyses restricted to only those patients treated for
depressed or mixed-cycling episodes showed that high PAS-SR scorers were still
nearly 4 times more likely than low PAS-SR scorers to report suicidal ideation
during the acute treatment phase and took more than 5 months longer than low
PAS-SR scorers to remit from the acute mood episode (time to remission, 10.5
months vs 5.3 months, respectively). These findings highlight the crucial
importance of assessing a broader range of panic features than those represented
by the DSM-IV criteria for panic disorder and of
monitoring suicidal symptoms in patients with BP disorder who present with
depressed or mixed symptom profiles complicated by panic spectrum features.
For the current report, an empirically defined cutoff was used to distinguish
between high and low PAS-SR scorers. The spectrum approach, however, was developed
to provide a more dimensional assessment of underlying symptom constellations.
Although a score of 35 may be a useful clinical indicator, continuous PAS-SR
scores should provide more sensitive information to the clinician and the
researcher. Indeed, continuous PAS-SR scores powerfully predicted time to
remission in the current sample (using a Cox regression model, odds ratio,
0.96; 95% confidence interval, 0.95-0.95; P<.001).
Although Parker et al35 postulated that
symptoms of anxious (UP) depression were likely rooted in temperament, they
noted the difficulty of identifying definitional markers encompassing not
only symptoms but also related personality patterns and temperamental features.
Such difficulties highlight the advantages of the spectrum approach. Categorical
classification of panic disorder often fails to capture the broad array of
atypical symptoms and related, yet enduring, temperamental features that can
be associated with this core condition. In contrast, the PAS-SR casts a "wide
net" to capture the lifetime experience of both classic panic symptoms as
well as related, yet subtle, manifestations of this core condition. Moreover,
the PAS-SR approach allows for the assessment of panic-related personality
features without necessitating the clinical diagnosis of DSM-IV personality disorder. This may be advantageous, given the contention
of Akiskal,36 Savino et al,37
and others that the affective instability and common anxiety-mood comorbidities
of patients with BP disorder are often misdiagnosed as Axis II personality
disorders, such as borderline personality disorder. Perhaps the strongest
evidence for the clinical usefulness of the PAS-SR assessment approach is
evident in our treatment outcome findings. From the outset of our efforts
to create structured assessments for spectrum disorders we have argued that
such assessment could be useful in predicting clinical course and treatment
decision making.
The current study is limited by the cross-sectional nature of the PAS-SR
assessments; however, patients with high and low scores on the PAS-SR did
not differ with regard to their current status in the study. In addition,
our analytic approach was limited by the small sample size (n = 66). Future
studies with larger sample sizes may be able to examine the potential mechanisms
by which lifetime panic-agoraphobic symptoms complicate the treatment of acute
symptoms. Indeed, given existing theories regarding the role of temperamental
factors and anxiety comorbidity in BPII disorder,38
future research on the prevalence and significance of panic spectrum features
in patients with BPII disorder would be informative.
Our present findings, nevertheless, point to the clinical validity and
potential usefulness of panic spectrum assessment in the management and treatment
of patients with BPI disorder, and highlight the need for development of alternate
treatment strategies for these particularly challenging patients.
AUTHOR INFORMATION
Submitted for publication December 13, 2000; final revision received
September 26, 2001; accepted October 2, 2001.
This study was supported in part by the Bosin Memorial Fund of The Pittsburgh
Foundation and by grants MH29618 (Dr Frank), MH30915 (Dr Kupfer), and training
grant MH60473 (Dr Cyranowski) from the National Institute of Mental Health,
Rockville, Md, and grants from Pfizer USA, New York, NY (Drs Frank and Shear).
This study was presented in part at the Fifth Annual Conference of Societa'
Italiana di Psicopatologia, Rome, Italy, February 25, 2000.
Reprints: Ellen Frank, PhD, Western Psychiatric Institute and Clinic,
3811 O'Hara St, Pittsburgh, PA 15213 (e-mail: franke{at}msx.upmc.edu).
From the Department of Psychiatry, Western Psychiatric Institute and
Clinic (Drs Frank, Cyranowski, Rucci, Shear, Fagiolini, Thase, Grochocinski,
and Kupfer), and the Department of Psychology (Dr Frank and Mr Kostelnik),
University of Pittsburgh, Pittsburgh, Pa; and the Departments of Psychiatry,
Neurobiology, Pharmacology, and Biotechnology, University of Pisa, Pisa, Italy
(Drs Rucci and Cassano).
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