Departments of Psychiatry and Obstetrics & Gynecology, The University of Texas Southwestern Medical Center, Dallas, TX, USA
Department of Psychiatry and Human Behavior, Brown University, Providence, RI, USA
Correspondence: Kimberly A. Yonkers, MD, Department of Psychiatry, Yale University School of Medicine, 15 Honeysuckle Hill Lane, Easton, CT 06612, USA. Tel: (203) 452-9762; fax: (203) 452-9762; e-mail: Kim-Charlie{at}worldnet.att.net
Declaration of interest Practical support from the Upjohn Company and the National Institute of Mental Health (see Acknowledgements).
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ABSTRACT |
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Aims To investigate variables that influence the clinical course of GAD.
Method A total of 167 patients with GAD participated in the Harvard-Brown Anxiety Research Program. Patients were assessed at intake and re-examined at six-to twelve-month intervals for five years. Kaplan-Meier curves were constructed to assess the likelihood of remission. Regression analysis was used to investigate factors predicting full or partial remission.
Results The rate of remission was 0.38 after five years. Diminished likelihood of remission was associated with low overall life satisfaction, poor spousal or family relationships, a concurrent cluster B or C personality disorder and a low global assessment score.
Conclusions Full or partial remissions were less likely to occur in patients with poor relationships and personality disorders. These patients should be given more intensive and possibly multi-modal therapy.
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INTRODUCTION |
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HARP data set
Information from participants with GAD in the Harvard-Brown Anxiety
Research Program (HARP) provides a unique data set to investigate factors
predicting illness remission because subjects are re-interviewed multiple
times at relatively short intervals (6-12 months) over the course of five
years. Using this data set, we explored whether concurrent Axis I and Axis II
psychopathology, as well as illness severity and patient characteristics,
would influence the likelihood of chronic illness. The current report expands
our previous three-year follow-up (Yonkers
et al, 1996) to five years and provides new information
on predictors of remission and recurrence.
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METHOD |
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Psychiatric evaluation
The initial comprehensive evaluation included selected items from the
Personal History of Depressive Disorders (available upon request from Dr
Hirschfeld, University of Texas Medical Branch, Department of Psychiatry,
Galveston, TX 77550, USA), the Structured Clinical Interview for DSM-III-R,
Patient Version (Non-Affective Disorders Section and Psychosis Screen)
(SCID-P; Spitzer et al,
1990) and the Research Diagnostic Criteria Schedule for Affective
Disorders and Schizophrenia - Lifetime (Affective Components) (SADS-L;
Endicott & Spitzer, 1978).
Items from the SCID-P and SADS-L were combined to create the SCALUP (available
upon request from Dr Keller, Butler Hospital, 345 Blackstone Boulevard,
Providence, RI 02906, USA). The DSM-III-R exclusion of a diagnosis of GAD in
the setting of another psychiatric disorder was set aside. Overall ratings of
well-being were assessed using the Global Assessment Scale (GAS;
Endicott et al,
1976).
Follow-up was conducted at six-month intervals for the first two years and then annually using the Longitudinal Interval Follow-Up Evaluation (LIFE-UP; Keller et al, 1987), which gathered information prospectively on syndrome and overall illness severity, treatment, non-psychiatric medical illness and psychosocial functioning.
Personality disorders were determined by administration of the Personality Disorder Evaluation (PDE; Loranger et al, 1987) given at the 12-month interview.
Psychiatric status ratings
The LIFE assesses psychopathology by employing a six-point psychiatric
status rating (PSR) scale that is scored on a week-by-week basis at each
interview. Full DSM-III-R criteria for GAD, including major disruption or
functional impairment, is indicated by a PSR score of 6. A PSR score of 5
includes full symptom criteria without major disruption or impairment in
psychosocial or work functioning. A PSR score of 4 indicates worry in
conjunction with three to five symptoms for most days or worry for less than
50% of the time and six symptoms. A PSR score of 3 indicates three symptoms
and worry for less than half the time. Occasional worry is assigned a PSR
score of 2, and lack of symptoms is assigned a PSR score of 1.
Interrater reliability and validity
All intake interviews were conducted by experienced clinical interviewers
who underwent an initial three- to six-month training period. Ongoing
monitoring for interrater reliability included review and comparison of raw
data with an interview summary and one video-taped interview per month. The
latter was rated independently by other monitors who also met to discuss
ratings. Three sub-studies to assess interrater reliability, subject recall
and validity of the LIFE-UP PSRs were conducted using subjects already
enrolled in HARP (Warshaw et al,
1994). Median intraclass correlation ranges for PSRs according to
disorders were: PD=0.67-0.88, AWOPD=0.49-0.64, SP=0.75-0.86, MDD=0.73-0.74,
GAD=0.78-0.86 and GAS=0.72-0.77. The long-term test-retest reliability of
subjects' retrospective recall over a one-year period found excellent
reliability for GAD (range 0.97-1.00) and very good to excellent reliability
for all other index disorders and for MDD (0.89-1.00). An independent external
validity assessment comparing the summed PSRs to the GAS found a significant
inverse correlation (lower GAS scores reflect lower functioning, whereas
higher PSR scores are indicative of greater impairment) of 0.57
(P=0.0001).
Definitions of remission and relapse
Full remission is defined as occasional or no symptoms (PSR=1 or 2) for
eight consecutive weeks, a period of time that can detect noticeable changes
in morbidity and minimise transient changes in psychopathological state.
Partial remission is defined as a decrease in symptoms to PSR=3 (i.e. worry
less than 50% of the time accompanied by three symptoms).
Patients were considered to be in an episode at intake if they met full criteria (PSR=5 or 6) for GAD at any point during the six months before intake and had not met the full remission criteria outlined above. This meant that some patients who were considered in episode at intake (PSR>2) may not have met full criteria at the moment of intake because they never fully remitted.
Patients who experienced a full remission were designated as relapsed if their PSR score increased to either 5 or 6 (full criteria) for 2 weeks.
Predictor variables
Information regarding marital status (married or living together,
divorced/widowed/separated or never married), quality of relationship with
spouse, satisfaction with life, socio-economic status and gender were culled
from the LIFE at the intake interview. Satisfaction with life and quality of
relationships were rated on a scale of 1-5, with 5 reflecting the lowest
satisfaction. The severity of illness was determined from the intake GAS
score. Intake concurrent Axis I psychopathology was determined by the SCALUP,
as was information on length of illness, age of illness onset and age at
intake. Axis II diagnoses were determined by the PDE. These covariates were
used to predict remission. Too few subjects experienced a relapse to
investigate adequately the predictor variables for this event, although the
rate of relapse is reported.
Statistical analysis
All statistical analyses were conducted using SAS Version 6.07 (SAS
Institute, Carey, NC) using PROC FREQ, PROC NPAR1WAY, PROC TTEST and PROC LIFE
TEST. Longitudinal data were analysed using standard survival analysis
techniques (Kalbfleish & Prentice,
1980). Kaplan-Meier life tables were constructed for times to
remission and time to relapse. Cox regression analysis was applied to
continuous variables to identify predictors of remission and relapse.
Subjects
A total of 179 subjects were entered into the study with a lifetime
diagnosis of GAD. Of these, 167 patients had at least one follow-up interview
and this constitutes the study cohort for this report: 159 (95%) were
interviewed at one year, 150 (90%) at two years, 130 (78%) at three years, 118
(71%) at four years and 105 (63%) at five years. Seventy-two per cent of
subjects with GAD were female and the average age at illness onset was 21
years (range 2-61). At intake, the average age was 41 years (range 19-75).
Personality disorders were common in this cohort and about 36% had a
concurrent personality disorder (Dyck
et al, 2000). As reported earlier, comorbid Axis I
disorders occurred frequently in HARP probands (83% had another active anxiety
disorder) and individual Axis I diagnoses of any type ranged from 5% to 41%
(Yonkers et al,
1996).
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RESULTS |
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Predictors of full remission
In a univariate model, higher scores (more impairment) on the following
quality-of-life variables significantly predicted a lower likelihood of full
remission during the five-year follow-up period: worse overall satisfaction
with life (risk ratio=0.67, 95% CI=0.51-0.89; P=0.006), poorer
quality of relationship with spouse (risk ratio=0.58, 95% CI=0.38-0.87,
P=0.008) and worse quality of relationship with relatives (risk
ratio=0.65, 95% CI=0.48-0.89, P=0.003). Concurrent personality
disorders also significantly predicted remaining in an episode of illness.
Patients with at least one concurrent personality disorder had a risk ratio of
0.30 (95% CI=0.14-0.61, P=0.001), a cluster B personality disorder
led to a risk ratio of 0.23 (95% CI=0.06-0.94, P=0.04) and a cluster
C personality disorder was associated with a risk ratio of 0.31 (95%
CI=0.15-0.66, P=0.002) for remitting from GAD. Finally, a higher GAS
score indicated an increased likelihood of remission (risk ratio=2.15, 95%
CI=1.19-3.89, P=0.01) (see Fig.
1). Covariates that were not significant included age of onset,
length of illness, male gender, marital status, socio-economic, status,
general medical health at intake, recreational enjoyment, comorbid MDD,
dysthymic disorder, post-traumatic stress disorder (PTSD),
obsessive-compulsive disorder (OCD), SP or PD.
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When the above positive predictor variables were entered into a multivariate model, having a cluster C personality disorder and poor relationship with relatives remained significant predictors of remaining ill.
Given the findings by others that MDD predicted chronicity, we explored
whether the use of selective serotonin reuptake inhibitor (SSRI) biased our
results and obscured meaningful differences. Of the 65 subjects with MDD and
GAD, 29% took an SSRI, whereas 18% of GAD subjects who had no concurrent MDD
took an SSRI. There was a trend towards a difference in groups
(2=3.08, P=0.79).
Partial remission
The following quality-of-life variables predicted a lower likelihood of
partial remission during the five-year follow-up period: worse overall
satisfaction with life (risk ratio=0.62, 95% CI=0.47-0.81, P=0.0005),
worse quality of relationship with spouse (risk ratio=0.68, 95% CI=0.49-0.94,
P=0.02) and poorer quality of relationship with relatives (risk
ratio=0.72, 95% CI=0.55-0.95, P=0.02). As with full remission, the
existence of any concurrent personality disorder lowered the probability of
partial remission (risk ratio=0.48, 95% CI=0.27-0.84, P=0.01).
Specifically, a cluster B personality disorder (risk ratio=0.35, 95%
CI=0.13-0.98, P=0.05) and a cluster C personality disorder (risk
ratio=0.54, 95% CI=0.30-0.96, P=0.04) increased the likelihood that a
patient would remain ill. Greater well-being at baseline predicted partial
remission, as illustrated by the GAS (risk ratio=1.9, 95% CI=1.14-3.20,
P=0.015). Covariates that were not significant included age of onset,
length of illness, relationship with friends, male gender, martial status,
socio-economic status, general medical health at intake, recreational
enjoyment, comorbid SP, MDD, dysthymic disorder, PTSD, OCD or PD.
As above, significant predictors were entered into a multivariate model and covariates that remained significant were worse satisfaction with life and impaired relationships with relatives.
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DISCUSSION |
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Others (Angst & Vollrath, 1991) have found, although we did not, that an enduring illness is a predictor of future chronic course. Different findings from those studies may be due to diverging methodologies; for example, the Zurich study was an epidemiological study and the percentage of patients who were very ill may have been lower than it was in HARP. In addition, data in that report included only one follow-up assessment rather than multiple assessments over time. On the other hand, the frequent contact with mental health researchers during HARP follow-up visits may have had a therapeutic effect, thus lessening the deleterious effects of a prior chronic illness course.
In contrast to the work of others, Axis I disorders and specifically concurrent MDD, OCD or PTSD did not significantly inhibit the chances of remission (Angst & Vollrath, 1991; Mancuso et al, 1993; Durham et al, 1997). In HARP, comorbidity in general was high (83% had an additional anxiety disorder), possibly obscuring a specific effect for MDD (Yonkers et al, 1996). In addition, treatment was not controlled in HARP and therapeutic interventions aimed at other conditions could have reduced the untoward effects of psychiatric comorbidity on the course of generalised anxiety. This is especially likely because the subjects with a greater number of disorders are more likely to receive aggressive treatment. We found a trend towards greater SSRI use in patients with concurrent MDD and GAD; these and other agents also could have been used in the past.
Predictors of full remission were similar to those for partial remission, with the exception that cluster C personality disorders were significant in the multivariate model only for full remission, and life satisfaction was significant in the multivariate model for partial remission. Findings from these models should be interpreted cautiously, given the limited number of remission events that occurred. Even so, others have suggested that comorbid personality disorders worsen the course of GAD (Barlow et al, 1986a; Mancuso et al, 1993). Results from Mancuso et al (1993) are in agreement with our findings that probands with cluster B and C personality disorders are less likely to remit from GAD. Another study comparing patients with MDD to either mixed anxiety and depression or non-panic chronic anxiety found higher rates of cluster C disorders (avoidant and dependent PD) in the chronic anxiety group (Alnaes & Torgersen, 1990). Gasperini et al (1990) did not find any particular personality disorder to be associated with chronic GAD, but their study did not evaluate prospectively the effects of personality disorders on clinical course.
Generalised anxiety disorder in the setting of a personality disorder results in greater morbidity, which perhaps leads to a lower likelihood of remission. The co-occurring personality disorder may cause disruptions in an individual's interpersonal relationships, which can sustain anxiety and psychiatric illness. We find some support for an association between personality disorders and disrupted relationships in our data. The variable disturbed martial relationships was no longer significant in the multivariate model, suggesting that it is not independent of a cluster C personality disorder. On the other hand, patients with dependent or avoidant personality disorders may be more vulnerable to anxiety if intimate relationships are disturbed.
As in our study, Mancuso et al (1993) found that poor overall life satisfaction and impaired ratings of the individual's relationships were more highly associated with continuing to suffer from GAD. Durham et al (1997) found that marital tension predicted a less favourable outcome. The consistency of these findings with ours strengthens the association between these predictors and the course of GAD.
This study has a number of strengths, including the large sample size, thorough assessments using standardised instruments and multiple regular-interval follow-up interviews over a period of five years. Weaknesses include primarily the possibility that follow-up and uncontrolled treatment may have influenced the course of illness. Second, although the reliability in HARP for diagnoses was generally good across raters, the interrater reliability in HARP for diagnoses was generally good across raters, the interrater reliability of agoraphobia without a history of panic was lower, leading us potentially to underdiagnose comorbidity with this disorder. Third, we did not have an ongoing assessment of life stressors, which have been postulated to play a role in the onset of GAD (Angst & Vollrath, 1991). However, variables important in the onset of a disorder may not be germane to maintaining the illness (Wittchen & Zerssen, 1988, cited in Angst & Vollrath, 1991; Mancuso et al, 1993).
In summary, we find that over the five years of follow-up, less than 50% of people with GAD experience either a full or partial remission. Relapse rates are substantial at three years (27%), supporting a chronic relapsing course for GAD. As with previous research, our study finds that personality disorder comorbidity (particularly cluster C disorders), life satisfaction and relationship with spouse and family are significant predictors of clinical course.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication October 24, 1998. Revision received August 6, 1999. Accepted for publication August 17, 1999.