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Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
University of Colorado, Boulder, Colorado, USA
Massachusetts General Hospital and Harvard Medical School
University of Pittsburgh, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania
Massachusetts General Hospital and Harvard Medical School
Baylor College of Medicine, Houston, Texas
University of Missouri–Kansas City School of Medicine, Kansas City, Missouri
McLean Hospital and Harvard Medical School
School of Public Health, University of Pittsburgh
University of Pittsburgh Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts,USA
the Step–Bd Investigators
Correspondence: Dr Michael W. Otto, Boston University Center for Anxiety and Related Disorders, 648 Beacon Street, 6th Floor, Boston, Massachusetts 02215-2013,USA. Email: mwotto{at}bu.edu
Funding detailed in Acknowledgements.
* No longer participating in this role in STEP–BD. 
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODRESULTSDISCUSSIONAPPENDIXACKNOWLEDGMENTSREFERENCES |
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Aims To examine the association between anxiety and course of bipolar disorder, as defined by mood episodes, quality of life and role functioning.
Method A thousand thousand out-patients with bipolar disorder were followed prospectively for 1 year.
Results A current comorbid anxiety disorder (present in 31.9% of participants) was associated with fewer days well, a lower likelihood of timely recovery from depression, risk of earlier relapse, lower quality of life and diminished role function over I year of prospective study. The negative impact was greater with multiple anxiety disorders.
Conclusions Anxiety disorders, including those present during relative euthymia, predicted a poorer bipolar course. The detrimental effects of anxiety were not simply a feature of mood state. Treatment studies targeting anxiety disorders will help to clarify the nature of the impact of anxiety on bipolar course.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONAPPENDIXACKNOWLEDGMENTSREFERENCES |
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METHOD |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONAPPENDIXACKNOWLEDGMENTSREFERENCES |
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Participants
The sample consisted of the first 1000 patients (59% women) enrolled into
STEP-BD. At study entry, participants had a mean age of 40.6 years (s.d.=12.7)
and a mean duration of bipolar illness of 23.1 years (s.d.=12.9). The majority
of the sample met DSM-IV criteria for primary bipolar I disorder (71%) or
bipolar II disorder (24%). Of the 1000 participants, 4% met criteria for
bipolar disorder not otherwise specified and 1% met criteria for
schizoaffective, cyclothymic or unspecified disorder; these patients were
excluded from analyses covarying bipolar subtype (I v. II).
At study entry, 39.8% of the sample were married or living as married, 82.3% had at least some college education and 47.0% had a college degree. Regarding occupational status, 34.5% reported full-time work outside the home, 20.0% reported part-time or homemaker status, 38.8% reported unemployment, disability or leave of absence, and 5.0% and 1.8% reported retired or `other' status respectively. The majority of the sample were White (92.6%), with 3.4% of the sample identifying themselves as Black or African American, 1.1% Asian, 0.4% Native American or Alaskan and 2.8% as mixed race or `other'; 3.7% of the sample identified themselves as Hispanic or Latino.
Assessments and procedures
The Affective Disorder Evaluation (ADE;
Sachs, 1990) includes a
modified version of the mood and psychosis modules from the Structured
Clinical Interview for DSM-IV (SCID; First
et al, 1997) intended for routine use by practising
clinicians. The ADE also assesses age at onset of mood episodes, the number of
prior episodes, periods of recovery, suicidal actions and past treatment
response. A study psychiatrist completed the ADE with each patient at study
entry; this served as the primary source of the history and characteristics of
bipolar episodes and provided the basis for assigning bipolar status.
The Mini International Neuropsychiatric Interview (MINI Plus Version 5.0; Sheehan et al, 1998) is a semi-structured interview designed to identify major Axis I psychiatric disorders, and was adapted to assess lifetime anxiety and eating disorders. In validation and reliability studies, the MINI was compared with the SCID Patient version for DSM-III-R and found to have acceptably high validation and reliability scores (Sheehan et al, 1998). In our study the MINI, administered by study clinicians, was used to confirm the bipolar-spectrum diagnosis and to identify comorbid psychiatric disorders at study entry.
The Clinical Monitoring Form (CMF; Sachs et al, 2002) is a one-page assessment tool used by study clinicians to document the symptom and treatment characteristics of patients at each clinical visit. It consists of modified versions of the SCID current mood modules, associated symptoms, medical problems and comorbid conditions; selected mental status items; current medications adherence and adverse effects; laboratory data; summary scores narrative - i.e. clinical status, Clinical Global Impression - Severity (Guy, 1976) and Global Assessment of Functioning (GAF; American Psychiatric Association, 1994: pp. 758-759) and treatment plan. To be certified in use of the CMF, treating psychiatrists completed standardised training and met certification requirements for establishing interrater agreement with video-taped ratings. Once certified, treating psychiatrists were periodically monitored to help maintain rating standards (Sachs et al, 2003). The CMF was the primary source of clinical status information.
On the basis of the presence or absence of criteria based on DSM-IV, one of eight operationally defined clinical states was assigned at each clinic visit. Four clinical states corresponded to the DSM-IV definitions of major depression, mania, hypomania and mixed episodes. Patients achieving relative euthymia (up to two moderate symptoms) for at least a week were assigned a status of `recovering' or `recovered', depending on whether this status had been sustained for at least 8 weeks. Two sub-syndromal states categorised patients as either `continued symptomatic' or `roughening'. These bipolar state categories and reliability training are further discussed by Sachs et al (2003).
Quality of life and functional impairment were assessed with two scales. The short form of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q; Endicott et al, 1993) is a 16-item self-report questionnaire assessing the degree of enjoyment and satisfaction in a variety of areas of daily functioning. Higher scores indicate greater life satisfaction. Functional impairment was assessed by the clinician-rated Longitudinal Interval Follow-up Evaluation - Range of Impaired Functioning Tool (LIFE-RIFT; Leon et al, 2000), with higher scores indicating greater impairment.
Assigment of clinical status during prospective study
Although the CMF served as the primary source of clinical status
information for patients in the longitudinal phase of the study, other sources
of information were included in the assignment of `estimated days well' to
provide a continuous record for assignment of daily clinical status.
Specifically, the study's Serious Adverse Event log (e.g. psychiatric
hospitalisations) and scores on the Montgomery-Åsberg Depression Rating
Scale (MADRS; Montgomery &
Åsberg, 1979) and Young Mania Rating Scale (YMRS;
Young et al, 1978)
from quarterly independent evaluations by trained raters
(Sachs et al, 2003)
provided additional information for confirmation of the CMF status. For
example, when there was a discrepancy between the CMF score and other
assessments, the `worst' score was used (i.e. MADRS or YMRS scores indicative
of a mood episode, or a psychiatric hospitalisation, were scored as the loss
of `recovering' status). Because patients in a longitudinal naturalistic study
are assessed at variable intervals, the following procedures were used to
assign days in recovering or recovered status over study intervals, as well as
the number of days to changes in status (e.g. recovery or relapse) for
survival analyses. When two identical status ratings were present at the
beginning and end of any interval of time, each day of that interval was
assigned the same clinical status rating. When clinical status differed at the
start and end of a time interval, the midpoint of that interval was defined as
the day of change to the new clinical status. For participants completing the
full year of prospective study, the mean number of clinical CMF assessments
was 9.34 (s.d.=7.31). The mean for the entire sample was 7.28 (s.d.=6.06)
assessments.
Statistical analyses
The influence of anxiety comorbidity on the course of bipolar disorder was
examined with statistical models that took into account bipolar subtype (I
v. II) and the presence of recovering or recovered status at study
entry. We examined three related outcome variables describing the course of
bipolar disorder over time:
For the examination of days well, the presence of anxiety comorbidity was examined as a main effect, and bipolar subtype (I v. II) and recovering or recovered status at study entry were treated as covariates in mixed-model regression analyses. For assessment of days to recovery or relapse, bipolar subtype was treated as a covariate, and main effects of anxiety comorbidity were examined using Cox regression survival models.
Because the Q-LES-Q and the LIFE-RIFT were administered on a quarterly basis during the year of the study, we used a mixed-model regression analysis that examined all four prospective quarterly assessments (3, 6, 9 and 12 months) as outcome in a model that adjusted for within-subject correlations of measurement. In the respective models of prospective Q-LES-Q and LIFE-RIFT, baseline Q-LES-Q or LIFE-RIFT score was entered as a covariate, along with bipolar subtype and recovering or recovered status. Anxiety comorbidity was examined in the context of this model.
The presence of a current anxiety disorder was first examined using the variable `any anxiety disorder', defined as having met DSM-IV criteria at study entry for currently having one of the following: panic disorder with or without agoraphobia, agoraphobia without panic disorder, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD) or generalised anxiety disorder. Subsequently, these six disorders were examined individually for their significance in predicting longitudinal bipolar status.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONAPPENDIXACKNOWLEDGMENTSREFERENCES |
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At entry into the study 489 participants were categorised as recovering or recovered, 248 as depressed, 145 as hypomanic, manic or `mixed' and 117 met criteria for one of the transitional categories between these states. One participant's clinical status at study entry was unknown. Owing to the heterogeneity and limited sample size for detailed analyses of anxiety comorbidity in the hypomanic/manic/mixed group, only the sample of those rated as depressed at study entry was included in the time to recovery analyses.
Loss to follow-up
In the year of the study, participants provided a mean of 300.7 days
(s.d.=109.6) of follow-up data, with 67.9% of the sample providing a full year
of data. Loss to follow-up was not significantly associated with recovering or
recovered status at baseline, bipolar subtype (bipolar I v. II) or
the presence of `any current anxiety disorders'. Of the individual anxiety
disorders, only a PTSD diagnosis in interaction with baseline recovery status
was linked to longitudinal study withdrawal; patients with PTSD who were not
assigned recovering or recovered status tended to leave the study earlier,
with a mean of 41.7 weeks (s.d.=16.4) of assessment for patients with current
PTSD and 44.6 weeks (s.d.=15.3) for patients without PTSD. The examination of
the proportion of days well during study participation (days well/days of
observation) was used to complement analyses of the absolute number of days
well; identical patterns of significance were obtained, except where
noted.
Estimated days well and anxiety comorbidity
The mean number of estimated `days well' for the sample as a whole was
199.2 days (s.d.=117.8). The predictive significance of any current anxiety
disorder was examined in the context of a model that took into account the
impact of baseline recovering/recovered status and bipolar subtype (I &
II). These results are summarised in Table
1.
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A clinical status of recovering or recovered at study entry was associated with 83 additional days well (F=117.4, d.f.=1,816; P=0.0001). Bipolar subtype was not significantly associated with the number of days well (F=2.48, d.f.=1,816; P=0.1160), but a trend towards a worse course was significant when assessed as the proportion of days well: bipolar II subtype predicted 4.1% fewer days well by this measure.
Having at least one current anxiety disorder was associated with a loss of 39.3 days well (F=22.4, d.f.=1,816; P=0.0001). Moreover, having multiple anxiety disorders had an additive influence on the loss of days well, with a loss of 27.6 days for a single anxiety disorder, 43.5 days for two current anxiety disorders and 56.9 days for three or more current anxiety disorders. Of the individual anxiety disorders, all were significant predictors of fewer days well except for agoraphobia without panic disorder, which reflected only a trend towards a poorer course (P=0.085). A `days well' loss of 29-30 days was found for panic disorder and generalised anxiety disorder; and a loss of 34-44 days was found for social anxiety disorder, obsessive-compulsive disorder and PTSD.
Risk of relapse
Of the participants who met criteria for recovering or recovered status at
study entry, 165 (41.4%) relapsed during the year of prospective study.
Bipolar subtype (I v. II) did not significantly predict risk of
relapse. Any current anxiety disorder was associated with significantly
greater risk of an earlier relapse, with a hazard ratio (HR) of 1.764
(
2=10.9, P=0.001)
(Fig. 1). There was evidence of
increasing risk for number of anxiety disorders: HR=1.55 for one disorder and
HR=2.17 for two or more disorders. Of the individual anxiety disorders, only
social anxiety disorder (HR=2.07; 2=11.6; P=0.0001)
and PTSD (HR=2.45; 2=6.1, P=0.013) were significantly
associated with an elevated risk of relapse
(Table 2).
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Recovery from depression
Of the patients who were depressed at study entry, 151 (80.7%) recovered
during the 12-month observation period. The presence of any current anxiety
disorder was significantly associated with a lower likelihood of a timely
recovery (HR=0.661; 2=5.41, P=0.020)
(Fig. 2). Of the individual
anxiety diagnoses, only social anxiety disorder was associated with a
significantly lower likelihood of timely recovery (HR=0.452;
2=11.17, P=0.0008). These results are summarised in
Table 3.
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Quality of life and role functioning
In addition to assessing the impact of anxiety disorders on the course of
bipolar disorder, we also evaluated their impact on quality of life and role
functioning. Scores on the Q-LES-Q at study entry ranged from 7 to 100, with a
mean score of 54.25 (s.d.=19.58). After adjusting for scores at study
initiation, quality of life as assessed by the Q-LES-Q was significantly lower
(approximately 5.6 points) for patients with at least one current anxiety
disorder (F=9.61, d.f.=1,438, P=0.0021). In addition, the
presence of two anxiety disorders was associated with even lower scores
(P=0.004). Of the individual anxiety disorders, social anxiety
disorder (P=0.007) and PTSD (P=0.002) were each associated
with lower quality-of-life scores.
Scores on the LIFE-RIFT at study entry ranged from 4 to 20, with a mean score of 11.70 (s.d.=3.87). Poorer role functioning over the course of the study was also linked to the presence of anxiety comorbidity. Relative to levels at study initiation, LIFE-RIFT impairment scores were significantly higher (about 0.6 points) for patients with at least one current anxiety disorder (P<0.0001). The presence of two or more anxiety disorders was associated with even poorer functioning. As found for the Q-LES-Q, social anxiety disorder (P<0.0001) and PTSD (P<0.005) were individually linked to poorer functioning as assessed by the LIFE-RIFT.
Controlling for substance use
Previously we have shown that substance use and anxiety disorders co-occur
in individuals with bipolar disorder
(Simon et al,
2004b; Kolodziej
et al, 2005) and substance use disorders are associated
with a worse course (Weiss et al,
2005). To clarify the independent association between anxiety
disorders and course of bipolar disorder, we included alcohol and other
substance use disorders as covariates in the above analyses. All significant
effects for anxiety disorders were retained, with the single exception of the
reduction of the significance of PTSD as a predictor of relapse to a marginal
level (P<0.058).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONAPPENDIXACKNOWLEDGMENTSREFERENCES |
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The consistency of our results across bipolar subtypes (I v. II) and phases of the disorder (recovering or depressed) is of particular importance for the understanding of the nature of the association between anxiety disorders and bipolar disorder. Our results indicate that the predictive significance of anxiety comorbidity is not simply due to a misattribution of the anxiety, panic, agitation or rumination that can co-occur with depressive, (hypo)manic or mixed states (see Perugi et al, 2001). In our study we documented a negative impact of anxiety disorders on bipolar course, even when anxiety was assessed during periods of relative euthymia. Because mood state and comorbidity are often confounded in cross-sectional data, our study documents the cost of anxiety comorbidity to bipolar course in a way that cross-sectional studies cannot.
Individual anxiety disorders
There was evidence that all of the individual anxiety disorders studied had
an impact on outcome, except for agoraphobia without panic attacks. In
estimates of the hazard for lower recovery and higher relapse as well as
disruptions in quality of life and role functioning, PTSD and social anxiety
disorder had prominent roles. Although social anxiety disorder has received
relatively less attention in bipolar disorder
(Perugi et al, 1999),
it has been associated with poorer outcome for unipolar depression. For
example, in a 12-month prospective study, Gaynes et al
(1999) found that the presence
of anxiety disorder (primarily social phobia) enhanced the risk of persisting
depression for patients who were depressed at study entry. Similar results
have been reported for other anxiety disorders in patients with unipolar
depression (Coryell et al,
1992; Frank et al,
2000).
The potentially complex relationship between anxiety disorders and bipolar disorder is reflected in recent studies of comorbid PTSD. As reviewed by Otto et al (2004), patients with bipolar disorder are characterised by high rates of risk factors for PTSD. Likewise, PTSD itself is associated with a number of factors associated with a worse course of bipolar disorder, including emotional lability, hyperarousal, sleep disruption, substance use, and avoidance, with the potential for increased social isolation. This potential for a reciprocal negative influence of anxiety comorbidity and bipolar disorder could serve to maintain the anxiety disorder and worsen the course of bipolar disorder. Substance use disorders may also arise as a consequence of the anxiety disorders (e.g. Sung et al, 2004), but as noted, in this study we showed that the predictive significance of anxiety comorbidity remained after controlling for the influence of comorbid substance use disorders.
Our study does not address whether anxiety disorders are themselves a product of a unique subtype of bipolar disorder distinct from type I or II status (e.g. MacKinnon et al, 2002; Rotondo et al, 2002). For example, a worse course of bipolar disorder in people with anxiety comorbidity may not be a result of the effects of the anxiety disorder directly (e.g. increased affective instability and increased role and social challenges because of anxiety and avoidance), but may reflect a unique biological subtype of bipolar disorder that is manifested by anxiety comorbidity, early age at onset and a poorer illness course. Our study supports the need for work targeting the treatment of anxiety comorbidity, to clarify the effects of this separate treatment on the course of the mood disorder. Both cognitive-behavioural and pharmacological strategies hold promise for this treatment goal (Otto et al, 2004).
Our study did not examine the link between anxiety comorbidity and the type and intensity of pharmacotherapy received over the course of the year of prospective study. At study entry, the presence of anxiety disorders was not significantly associated with the adequacy of mood stabiliser use or the presence of antipsychotic or stimulant medications, but was linked to greater use of antidepressant and benzodiazepine medications (Simon et al, 2004a). None the less, we cannot rule out the possibility that the presence of anxiety disorders is associated with greater drug sensitivity, leading to differential treatment over the course of study.
Concluding remarks
In a large, prospective study we found evidence for a worse course of
bipolar disorder among patients with comorbid anxiety disorders. Our data
further demonstrated that anxiety disorders present during relative euthymia
are implicated in higher rates of bipolar relapse, suggesting that the
detrimental effects of anxiety do not simply represent a feature of current
mood states. Most of the individual anxiety disorders were implicated in this
relationship, with even greater mood disruption and disability associated with
a greater number of comorbid anxiety conditions. Of the individual anxiety
disorders, social anxiety disorder and PTSD had prominent roles. Treatment
outcome studies targeting anxiety comorbidity have the potential to clarify
further the nature of the relationship between anxiety comorbidity and course
of bipolar disorder.
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APPENDIX |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONAPPENDIXACKNOWLEDGMENTSREFERENCES |
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STEP–BD Clinical Coordinating Center
Gary S. Sachs, MD; Mark S. Bauer, MD (coinvestigator); Leslie
Leahy,* PhD; Jane N. Kogan, PhD; Ellen B. Dennehy, PhD; Jennifer A.
Conley, MA; Jaimie L. Gradus, BA; Stephen M. Gray,* BA; Jacqueline
Flowers,* BA; Mandy Graves, BA.
STEP–BD Data Coordinating Center
Stephen Wisniewski, PhD.
STEP–BD site principal investigators and co-principal investigators
Lauren B. Marangell, MD, and James M. Martinez, MD, at Baylor College of
Medicine; Joseph R. Calabrese, MD, and Melvin D. Shelton, MD, at Case Western
Reserve University; Michael W. Otto,* PhD; Andrew A. Nierenberg,
MD, and Gary S. Sachs, MD, at Massachusetts General Hospital and Harvard
Medical School; R. Bruce Lydiard,* MD, at the Medical University of
South Carolina; Joseph F.
Goldberg,* MD, at New
York Presbyterian Hospital and Weill Medical College of Cornell University;
James C.-Y. Chou, MD; and Joshua Cohen, DO, at New York University School of
Medicine; John
Zajecka,* MD, at
Rush–Presbyterian St Luke's Medical Center; Terence A. Ketter, MD, and
Po W. Wang, MD, at Stanford University School of Medicine; Uriel
Halbreich,* MD, at
State University of New York at Buffalo; Alan
Gelenberg,* MD, at
University of Arizona; Mark
Rapaport,* MD, at
University of California, San Diego; Marshall Thomas, MD; Michael H. Allen,
MD, and David J. Miklowitz, PhD, at University of Colorado Health Sciences
Center, Rif S. El-Mallakh, MD, at University of Louisville School of Medicine;
Jayendra Patel, MD, at University of Massachusetts Medical Center; Kemal
Sagduyu, MD, at University of Missouri–Kansas City, School of Medicine,
Western Missouri Mental Health Center; Mark D. Fossey, MD, and William R.
Yates, MD, at University of Oklahoma College of Medicine; Laszlo Gyulai, MD,
and Claudia Baldassano, MD, at University of Pennsylvania Medical Center;
Michael E. Thase, MD, and Edward S. Friedman, MD, at University of Pittsburgh
Western Psychiatric Institute and Clinic; Peter Hauser, MD, at Portland VA
Medical Center; and Charles L. Bowden, MD; and Cheryl L. Gonzales, MD, at
University of Texas Health Science Center at San Antonio.
STEP–BD Executive Committee
Mark S. Bauer, MD, Charles L. Bowden, MD, Joseph R. Calabrese, MD, Ellen B.
Dennehy, PhD, Maurizio Fava, MD, Gary Gottleib, MD, Ellen Frank, PhD, Jennifer
Harrington, MA, Terence A. Ketter, MD, Jane N. Kogan, PhD, David Kupfer, MD,
Lauren B. Marangell, MD, David J. Miklowitz, PhD, Michael W. Otto, PhD,
Jerrold F. Rosenbaum, MD, Matthew V. Rudorfer, MD, Gary S. Sachs, MD, Linda
Street, PhD, Michael E. Thase, MD, Sean Ward and Stephen Wisniewski, PhD.
National Institute of Mental Health liaisons to STLP–BD
Matthew V. Rudorfer, MD; Joanne Severe, MS; Linda Street, PhD.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONAPPENDIXACKNOWLEDGMENTSREFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONAPPENDIXACKNOWLEDGMENTSREFERENCES |
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Received for publication December 15, 2004. Revision received May 31, 2005. Accepted for publication June 2, 2005.
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  D. J. Miklowitz, M. W. Otto, E. Frank, N. A. Reilly-Harrington, S. R. Wisniewski, J. N. Kogan, A. A. Nierenberg, J. R. Calabrese, L. B. Marangell, L. Gyulai, et al. Is Psychosocial Management Effective? Reply Arch Gen Psychiatry, December 1, 2007; 64(12): 1452 - 1453. [Full Text] [PDF]
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D. J. Miklowitz, M. W. Otto, E. Frank, N. A. Reilly-Harrington, S. R. Wisniewski, J. N. Kogan, A. A. Nierenberg, J. R. Calabrese, L. B. Marangell, L. Gyulai, et al. Psychosocial Treatments for Bipolar Depression: A 1-Year Randomized Trial From the Systematic Treatment Enhancement Program Arch Gen Psychiatry, April 1, 2007; 64(4): 419 - 426. [Abstract] [Full Text] [PDF]
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