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Advanced Center for Interventions and Services Research for Late-life Mood Disorders and the John A. Hartford Center of Excellence in Geriatric Psychiatry, Department of Psychiatry, University of Pittsburgh School of Medicine, Pennsylvania, USA
Department of Psychiatry, University of Pittsburgh School of Medicine, Pennsylvania, USA, and Center for Addiction and Mental Health, University of Toronto, Canada
Advanced Center for Interventions and Services Research for Late-Life Mood Disorders and the John A. Hartford Center of Excellence in Geriatric Psychiatry, Departmentof Psychiatry, University of Pittsburgh School of Medicine, Pennsylvania, USA
Department of Psychiatry, University of Pittsburgh School of Medicine, Pennsylvania, USA, and Rotman Research Institute, Baycrest Center for Geriatric Care, University of Toronto, Canada
Advanced Center for Interventions and Services Research for Late-life Mood Disorders and the John A. Hartford Center of Excellence in Geriatric Psychiatry, Department of Psychiatry, University of Pittsburgh School of Medicine, Pennsylvania, USA
Correspondence: Dr Eric Lenze, Western Psychiatric Institute and Clinic, 3811 O'Hara Street, Room E 823, Pittsburgh, PA15213, USA. Tel: +1 412 246 6007; fax: +1 412 246 6260; email: Lenzee{at}upmc.edu
Declaration of interest E.J.L., B.H.M., B.G.P., M.D.M. and C.F.R. have received support and/or consult for (one or more of): Forest Laboratories, Pfizer Inc., Johnson & Johnson Co., Bristol-Myers Squibb, Eli Lilly, GlaxoSmith Kline, Lundbeck, Janssen Pharmaceutica, and Sepracor (detailsin Acknowledgements).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Aims To examine whether anxiety symptoms predict acute and maintenance (2 years) treatment response in late-life depression.
Method Data were drawn from a randomised double-blind study of pharmacotherapy and interpersonal psychotherapy for patients age 70 years and over with major depression. Anxiety symptoms were measured using the Brief Symptom Inventory. Survival analysis tested the effect of pre-treatment anxiety on response and recurrence.
Results Patients with greater pretreatment anxiety took longer to respond to treatment and had higher rates of recurrence. Actuarial recurrence rates were 29% (pharmacotherapy, lower anxiety), 58% (pharmacotherapy, higher anxiety), 54% (placebo, lower anxiety) and 81% (placebo, higher anxiety).
Conclusions Improved identification and management of anxiety in late-life depression are needed to achieve response and stabilise recovery.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Beyond the high rates of coexistence, comorbid anxiety has been often cited as a clinically relevant problem owing to its impact on acute treatment response in late-life depression. Thus, several studies have found that greater severity of anxiety symptoms is associated with an increased risk of withdrawal from treatment (Fawcett, 1997; Flint & Rifat, 1997a), a decreased response to acute antidepressant treatment (Fawcett, 1997; Flint & Rifat, 1997a; Steffens & McQuoid, 2005), and a longer time to both response (Mulsant et al, 1996; Dew et al, 1997; Lenze et al, 2003) and remission (Clayton et al, 1991; Alexopoulos et al, 2005).
Although the impact of anxiety on response and recurrence of major depression has been previously studied extensively in general adult populations, its relevance to long-term treatment response in late-life depression has received much less attention (Lebowitz et al, 1997; Charney et al, 2003) and has not been examined in a controlled maintenance trial. Maintenance outcomes in late-life depression and the factors that moderate those outcomes are critical, given the brittle nature of response in this age group (Reynolds & Lebowitz, 1999; Reynolds et al, 2006). To our knowledge, the only published data addressing these long-term outcomes were obtained during a 2-year naturalistic follow-up study. In this uncontrolled study, pre-treatment anxiety symptoms were not related to time to recurrence during 2 years of open pharmacotherapy trial with nortriptyline (Flint & Rifat, 1997b).
Thus, given the high recurrence rate of late-life depression (Zis et al, 1980) and the increased morbidity and mortality risks associated with this disorder (Ganguli et al, 1993, 2002; Reynolds et al, 1994), as well as the lack of controlled data regarding the impact of pre-treatment anxiety on its long-term treatment, further examination of anxiety as a predictor not only of response but of recurrence would greatly benefit clinicians in planning treatment. Accordingly, we conducted an analysis to assess whether pre-treatment comorbid anxiety predicts treatment outcomes during both acute and maintenance treatment of major depression in old age. Our hypothesis was that greater pre-treatment severity of anxiety symptoms would predict poor treatment outcome, including both a longer time to response during acute treatment, and an increased rate of – and shorter time to – recurrence during maintenance treatment.
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METHOD |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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In the acute phase, patients received open pharmacotherapy and weekly interpersonal psychotherapy (Klerman et al, 1984) until they achieved response (defined as a HRSD score of 10 or less for three consecutive weeks). Pharmacotherapy consisted of paroxetine started at 10 mg/day and titrated as necessary up to a maximum of 40 mg/day. Adjunctive pharmacotherapy with bupropion, nortriptyline or lithium was used when required to achieve response (n=69). Adjunctive lorazepam (0.5–2 mg/day) was also used in 65 patients.
Patients who responded to acute treatment entered 16 weeks of continuation treatment to stabilise their response; they received the same pharmacotherapy and interpersonal psychotherapy every 2 weeks. Patients who maintained response during continuation treatment were then randomly assigned to one of four maintenance treatments:
Patients randomised to pharmacotherapy received paroxetine (with adjunctive medication if required) for the remainder of their study participation. Patients randomised to receive placebo had paroxetine (and adjunctive medication) slowly tapered over 6 weeks under double-blind conditions. All patients were allowed to remain on a stable dosage of lorazepam if it had been required during the acute or continuation treatment phases. Patients remained in maintenance therapy for 2 years or until recurrence of a major depressive episode. Recurrence required a HRSD score of 15 or over, meeting DSM–IV criteria (American Psychiatric Association, 1994) for a major depressive episode during a SCID interview, and confirmation of the diagnosis by an independent geriatric psychiatrist. Assessors were unaware of treatment assignment. All patients provided written informed consent. For this data analysis we collapsed the interpersonal psychotherapy and non-psychotherapy groups because this therapy was not shown to prevent recurrence in the primary outcome analysis, whereas paroxetine was (Reynolds et al, 2006).
Symptoms of anxiety were measured using the self-report anxiety scale from
the Brief Symptom Inventory (BSI;
Derogatis & Melisaratos,
1983). The BSI is a validated self-report scale developed from the
Symptom Checklist 90 – Revised (SCL–90–R;
Derogatis, 1983) with strong
test–retest and internal consistency reliabilities. Factor analytic
studies of the internal structure of the scale have demonstrated its construct
validity (Derogatis, 1983).
The anxiety sub-scale consists of six items: `nervousness or shakiness
inside', `suddenly scared for no reason', `feeling fearful', `feeling tense or
keyed up', `spells of terror or panic' and `feeling so restless you couldn't
sit still'. Each item is rated on a five-point scale (0 symptom not present, 4
extremely severe). We used both a categorical and a continuous form of the BSI
anxiety measure. We analysed BSI scores (Cronbach's 
=0.84 for the
present sample) on a continuum and also we also dichotomised those with higher
v. lower anxiety by using a median split (median value for the sample
1.0). We present in this paper the results based on the categorical approach
because it has more relevance to the categorical decisions clinicians are
faced with in their practice.
The analyses included data on 181 persons who participated in the acute treatment phase. Of these, 116 maintained response during continuation treatment and were randomly assigned to maintenance treatment. Pre-treatment BSI scores were available on 170 participants entering the acute phase. Of these, 109 participated in randomly assigned maintenance treatment.
Statistical analysis
We used Kaplan–Meier survival analysis to assess the effect of
pre-treatment anxiety symptoms (BSI scores) on time to response. In order to
analyse the influence of lorazepam on time to response
(Buysse et al, 1997),
we compared the time to response in the group receiving lorazepam v.
the group not receiving lorazepam. Further, we stratified the sample based on
presence or absence of lorazepam use. In order to control for other potential
confounders, we subsequently fitted Cox proportional hazards models for each
outcome, stratifying on severity of depression to estimate the unique effects
of anxiety on acute treatment outcomes. We controlled for baseline depression
severity as measured by the HRSD scores, with the four anxiety-related items
(9, 10, 11 and 15) removed (Dew et
al, 1997; Gildengers
al, 2005; Dombrovski
et al, 2007).
To assess the effect of comorbid symptomatic anxiety on time to recurrence during maintenance treatment, we stratified the sample based on randomisation to paroxetine or placebo and performed Kaplan–Meier analyses in four groups: pharmacotherapy with lower BSI scores (n=35); pharmacotherapy with higher BSI scores (n=23); placebo with lower BSI scores (n=31); and placebo with higher BSI scores (n=20).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Effect of symptomatic comorbid anxiety on response during acute treatment
At baseline, 82 patients had higher BSI scores (above the median split) and
88 had lower BSI scores. Among patients with higher BSI scores, 52%
(n=43) achieved response and began maintenance treatment; among those
with lower BSI scores 75% (n=66) achieved response and began
maintenance treatment (
2=6.09, d.f.=1, P=0.01)
(Table 2). Patients with higher
BSI scores had a median time to response significantly longer than those with
lower scores (Fig. 1): 11.0
(95% CI 7.7–13.9) v. 6.7 (95% CI 5.9–7.9) weeks (Wilcoxon
2=6.26, d.f.=1, P=0.01).
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Effects of adjunctive lorazepam
Patients who received adjunctive lorazepam (n=65) had a median
time to response significantly longer than those who did not (n=120):
12.4 weeks (95% CI 8.4–14.7) v. 6.9 weeks (95% CI
5.6–7.9); Wilcoxon 2=16.81, d.f.=1,
P<0.0001. The mean daily dosage of lorazepam received by patients
with higher or lower BSI scores did not differ significantly: 1.03 mg
(s.d.=0.60) v. 0.92 mg (s.d.=0.44); t=–0.75, d.f.=61,
P=0.45. However, as would be expected, lorazepam use was correlated
with higher BSI scores (phi=0.31). Therefore, we analysed post hoc
the time to response separately in patients who received and did not receive
lorazepam, contrasting those with higher and lower BSI scores. Among patients
who received lorazepam, those with higher BSI scores had a median time to
response significantly longer than those with lower scores: 13.9 weeks (95% CI
11.0–17.1) v. 7.9 weeks (95% CI 5.9–13.6); Wilcoxon
2=4.48, d.f.=1, P=0.03. Among patients who did not
receive lorazepam, the difference in time to response between patients with
higher v. lower BSI scores was not significant (Wilcoxon
=0.0858, d.f.=1, P=0.77). The mean final daily dosage of
paroxetine received by patients with higher or lower BSI scores did not
differ: 26.3 mg (s.d.=10.9) v. 24.2 mg (s.d.=10.4)
(t=–1.27, d.f. =168, P=0.21). The effect of
symptomatic anxiety on time to response remained significant in our Cox model,
stratifying on baseline HRSD score (minus anxiety items): hazard ratio 0.65,
(95% CI 0.45–0.93), P=0.02.
Effect of symptomatic comorbid anxiety on recurrence during maintenance treatment
A higher BSI score predicted an increased rate of recurrence (Wald
2=7.05, d.f.=1, P=0.008; 95% CI hazard ratio
1.22–3.72). Time to recurrence from randomisation
(Fig. 2) differed across the
four groups, with the higher BSI group having a shorter time to recurrence
(log-rank 2=15.00, d.f.=3, P=0.002). Recurrence rates
(adjusting for censoring) were 29% (pharmacotherapy with lower BSI scores),
58% (pharmacotherapy with higher BSI scores), 54% (placebo with lower BSI
scores) and 81% (placebo with higher BSI scores). Among patients receiving
pharmacotherapy, time to recurrence was significantly shorter for those with
higher BSI scores than for those with lower scores (log-rank
2=5.66, d.f.=1, P=0.02). Among patients given
placebo, time to recurrence did not differ significantly between those with
higher or lower BSI scores (log-rank 2=2.54, d.f.=1,
P=0.11). Among patients with higher BSI scores, time to recurrence
did not differ between those given placebo or paroxetine (log-rank
2=1.95, d.f.=1, P=0.16). Among patients with lower
BSI scores, time to recurrence was significantly shorter for those in the
placebo group than for those taking paroxetine (log-rank
2=5.28, d.f.=1, P=0.02).
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2=0.49, d.f.=1, P=0.48). The power to detect a
moderator effect was low (0.22) and the hazard ratio for the interaction was
1.5 (95% CI 0.48–4.68). We repeated the analysis for both acute and maintenance phases using BSI score as a continuous measure, with similar results (further details available from the authors).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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We found that patients with higher BSI scores and adjunctive lorazepam treatment had increased time to response. The use of lorazepam per se probably did not prolong time to response, because patients receiving adjunctive lorazepam but having lower BSI scores had similar time to response as patients not receiving adjunctive lorazepam. This observation is consistent with our previous study (Buysse et al, 1997), which reported that adjunctive lorazepam did not slow the antidepressant response in elderly patients with depression. However, patients with higher BSI scores not receiving adjunctive lorazepam had a shorter time to response than those with higher scores who received lorazepam. One possible explanation that deserves further exploration is that the patients with higher BSI scores who needed adjunctive lorazepam differed clinically from the patients with higher scores who did not need adjunctive lorazepam. This difference might be related to a higher preponderance of symptoms of general anxiety disorder in the group who needed adjunctive lorazepam, as general anxiety disorder more often than other anxiety disorders is associated with worse outcomes (Beekman et al, 2000; Lenze et al, 2000).
Strengths and limitations
Our study was limited in its power to detect a moderator effect –
that is, interactions between treatment and coexisting anxiety. We were able
to detect main effects of pharmacotherapy and of anxiety on recurrence, but
the study lacked sufficient power to detect interaction between
pharmacotherapy and anxiety.
This study is the first randomised controlled trial to demonstrate the limited efficacy of standard pharmacotherapy in late-life depression with coexisting anxiety to make and keep patients well. It is important to emphasise that patients treated in this study received intensive management, with clinicians and psychiatrists reviewing cases weekly and refining treatment plans to minimise attrition and maximise response. Also, adjunctive pharmacotherapeutic strategies, which were instrumental in many patients achieving response and which were continued during the maintenance phase, were still not enough to protect most patients with comorbid anxiety from recurrence of depression. Even under these intensive treatment conditions, which go well beyond regular clinical care, comorbid anxiety had a prominent negative effect on acute and long-term outcomes.
Future directions
Overall, our findings suggest limited efficacy of current medications with
regard to mitigating the impact of comorbid anxiety on response and
recurrence, even though selective serotonin reuptake inhibitors (such as
paroxetine, used in this study) are indicated for the treatment of both
anxiety and depression. It is also worth noting that adding lorazepam to
paroxetine in cases of patients with higher anxiety did not improve outcomes.
Alternative treatment options should be considered for these patients. Given
the detrimental effect of anxiety on long-term course of depression and the
limited benefit demonstrated here even with optimal treatment, clinicians are
left with the challenge of deciding what they can do to improve outcome in
this group of patients (Tyrer et
al, 2004). Expert consensus guidelines
(Alexopoulos et al,
2001) recommend maximising the dosage of antidepressant. It is
possible that dosages of paroxetine higher than those used in this study would
have yielded better outcomes in anxious patients
(Baldwin & Polkinghorn,
2005). However, older adults may not tolerate high doses of
antidepressants, given the frequent medical comorbidity and sensitivity to
medications' side-effects in this population. Further research involving
possible pharmacological alternatives such as adjunctive use of
second-generation antipsychotic agents
(Adson et al, 2005;
Wetherell et al,
2005a) as well as learning-based psychotherapies such as
problem-solving therapy and cognitive–behavioural therapy
(Stanley et al, 2003;
Wetherell et al,
2005b) is warranted.
In conclusion, replicating and extending the results of previous studies, our findings indicate a need for active identification and aggressive treatment of anxiety symptoms in late-life depression, as well as the need for further research to identify optimal treatment. In order to improve outcomes in elderly patients with anxious depression, we need to develop and test treatment algorithms that would involve both psychosocial and pharmacological alternative treatments.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Received for publication June 7, 2006. Revision received November 3, 2006. Accepted for publication November 14, 2007.
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