Psychiatric Research Clinic, Frederiksberg Hospital, Denmark
International Clinical Research, H. Lundbeck A/S, Denmark
Correspondence: Marc Andersen, Biostatistics Department, International Clinical Research, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. Tel: +45 36 30 1311, ext. 2302; fax: +45 36 44 0787; e-mail: ma{at}lundbeck.com
Declaration of interest Funded by H. Lundbeck A/S.
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ABSTRACT |
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Aims To compare the prophylactic efficacy of citalopram and placebo in elderly patients; to evaluate long-term tolerability of citalopram.
Method Out-patients, 65 years, with unipolar major depression
(DSMIV: 296.2 x or 296.3 x) and
MontgomeryÅsberg Depression Rating Scale score
22 were
treated with citalopram 20-40 mg for 8 weeks. Responders continued on their
final fixed dose of citalopram for 16 weeks before randomisation to
double-blind treatment with citalopram or placebo for at least 48 weeks.
Results Nineteen of the 60 patients using citalopram v. 41 of the 61 patients using placebo had recurrence. Time to recurrence was significantly different between citalopram- and placebo-patients, in favour of citalopram (log-rank test, P<0.0001). Long-term treatment was well tolerated.
Conclusions Long-term treatment with citalopram is effective in preventing recurrence of depression in the elderly and is well tolerated.
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INTRODUCTION |
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Only a few placebo-controlled studies have investigated the effect of maintenance treatment in the elderly; not all have followed the scheme outlined above. However, the reported studies have shown a beneficial effect of prophylactic treatment (Georgotas et al, 1989; Reynolds et al, 1999). This study investigated the efficacy of citalopram in recurrence prevention in elderly patients with major depression, using the three-phase scheme outlined above.
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METHOD |
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Patient population
Patients were recruited from the Copenhagen and Frederiksberg
municipalities in Denmark between March 1996 and December 1997. A letter was
sent out to all citizens aged 65 years aimed at identifying undiscovered
depression in that population. Those who were found to be depressed and
fulfilled the entry criteria for the screening procedure at the research
clinic were eligible for the study. All patients gave written informed consent
before being included in the study.
Patients included had a unipolar major depressive episode (MDE; DSM-IV:
296.2x or 296.3x; American
Psychiatric Association, 1993) at a severity corresponding to a
total score of 22 on the MontgomeryÅsberg Depression Rating
Scale (MADRS; Montgomery &
Åsberg, 1979).
Patients were excluded from the study if the index episode had lasted more
than 12 months; if they had a history of schizophrenia, mania, hypomania,
epilepsy, drug or alcohol misuse; or if they had severe somatic disorders.
Similarly, patients were excluded if they had received fluoxetine within 5
weeks or other antidepressants within 3 days of the start of the study,
lithium, carbamazepine or valproate within 2 weeks of the study,
electroconvulsive therapy within 8 weeks of the study or sumatriptan or
anticoagulants at study start. Finally, patients were excluded if they had a
score of 5 on MADRS item 10 (suicidality).
Study design
The study consisted of three periods: Period I was 8 weeks of open, acute
treatment with citalopram; Period II was 16 weeks of open continuation
treatment with citalopram to consolidate remission; Period III consisted of
double-blind treatment with citalopram or placebo for a potential minimum of
48 weeks. The patients continued with double-blind treatment until the last
patient had been treated for 48 weeks or had discontinued for any reason
(June, 1999).
In Period I, the initial dose of citalopram was 10 mg/day for the first 3
days, then increased to 20 mg/day. After 1 week, the dose could be decreased
to 10 mg/day in case of intolerable adverse events; otherwise, the patient
continued on 20 mg/day. After 3 weeks, the daily dose was increased to 20 mg
for patients on 10 mg. For the remaining patients, the dose was increased by
10 mg after 3 and/or 5 weeks to a maximum of 40 mg, if there was either an
increase or no change in Clinical Global Impressions of severity of illness
score (CGI-S; Guy, 1976),
compared with the score 3 weeks earlier, or if the absolute score was 5.
Patients with intolerable adverse events at the increased dose were
withdrawn.
At week 8, patients entered Period II if their total MADRS score was 11
(Montgomery, 1994); if not,
they were withdrawn. However, patients who showed a partial remission were
allowed to continue for 4 weeks in Period II before the final assessment about
remission was made. Patients who then had a MADRS total score
11 continued
in the study whereas those with a score >11 were withdrawn. During Period
II, the daily dose of citalopram remained fixed at the dose reached in Period
I, i.e. 20, 30 or 40 mg/day. Patients experiencing a relapse (MADRS
22,
confirmed after 3-7 days) in Period II were withdrawn.
Patients completing Period II with a MADRS score 11 were randomised on
a 1:1 basis, using a block size of 10, to receive double-blind treatment with
identical looking tablets of either placebo or citalopram in Period III (same
dose as in Period II, randomisation irrespective of dose).
No concomitant psychotropic medication was allowed, except for benzodiazepines and other hypnotics, the dose of which was to remain unchanged after week 8 of Period II. Treatment with benzodiazepines and other hypnotics could not be started during Periods II or III except in case of relapse/recurrence, if the investigator felt that intervention was needed before relapse (Period II) or recurrence (Period III) was confirmed.
Visits and assessments
In Period I, patients were seen for a screening and a baseline visit, and
also at weeks 1, 3, 5 and 8. In Period II, patients were seen upon entry
(=last visit in Period I), and at weeks 4, 8, 12 and 16. In Period III,
patients were seen at entry (=last visit in Period II) and at weeks 2 and 4,
and subsequently every 4 weeks until discontinuation or completion. In
addition, all patients were seen for a discontinuation or completion
visit.
Patients were assessed by the CGI-S, MADRS, the 17-item Hamilton Depression Rating Scale (HDRS; Hamilton, 1960), and the Melancholia Scale (MES; Bech et al, 1986) at baseline, at all subsequent visits in all periods (except for the visit at week 1 in Period I) and at premature discontinuations. Concomitant medication and adverse events were noted at each visit. Patient history and physical examination were registered at baseline. Laboratory tests were performed at the screening visit in Period I, at entry into Period III and at discontinuation/completion. Vital signs were assessed at entry into Period I, at week 8, at completion of Period II and at the end of each 24-week period in Period III. Height and body weight were recorded at baseline.
Outcome measures and definitions
The primary measure of prophylactic efficacy was the time to recurrence of
a depressive episode from the start of Period III. Recurrence of depression
was defined as the patient reaching a MADRS total score of 22, confirmed
after 3-7 days.
The assessment of safety and tolerability of citalopram during prophylactic treatment was based on reporting of adverse events, vital sign measurements and laboratory assessments. Adverse events were either reported spontaneously by the patient, observed by the investigator, or elicited by the investigator using open questioning.
Statistical analysis
In the primary analysis, the log-rank test was used to compare the time to
recurrence of depression for patients treated with citalopram or placebo.
Survival curves were estimated using the KaplanMeier method and overall
treatment effect was estimated using the Cox proportional hazard model
(Andersen et al, 1993;
SAS Institute Inc., 1997).
In order to have a power of at least 90% at a 5% significance level for the primary analysis, a minimum sample size of 150 patients randomised into Period III (75 patients/group) was estimated (Goldman & Hillman, 1992). This was calculated to require inclusion of approximately 300 patients. The actual number of patients included in the study was 230. The power at a 5% significance level was re-estimated to be 60-75%.
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RESULTS |
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The primary reasons for discontinuation in Period I were adverse events (13%) and withdrawal of consent (10%), whereas in Period II the main reasons were withdrawal of consent (15%), lack of efficacy (8%) and adverse events (5%).
All patients randomised into Period III were included in the intention-to-treat (ITT) population for analysis of efficacy. This population comprised 23% males and 77% females, which is a good representation of a population of elderly patients with depression (Brown et al, 1995).
Demographics and baseline characteristics of patients
Demographics and baseline characteristics of the patients were similar for
the two treatment groups (Table
1). A total of 15% of the randomised patients in both groups had a
history of previously diagnosed MDEs, of whom none reported having had more
than two. In both treatment groups, the great majority of patients were
moderately ill or markedly ill at baseline (CGI-S
ratings), with about half the patients in each of these categories.
Approximately 18% of the patients in both groups had previously received
pharmacological treatment for depression (except one citalopram patient who
had had electroconvulsive therapy). However, none of the patients had been
treated with psychotropics within the last 3 months. A family history of major
depression was noted for 15% (citalopram) and 11.5% (placebo) of the patients,
respectively.
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Concurrent medical conditions and medication
There was no significant difference between treatment groups in respect of
concurrent diseases and concomitant drug therapy. Approximately 72% of the
patients in both treatment groups had an ongoing medical condition at
baseline, and about 78% of the patients in both groups were continuing with at
least one kind of medication upon entry into Period III.
MADRS, HDRS and MES scores
For the ITT population, the baseline total MADRS scores (s.d.) at entry
into Periods I and III were 27.0 (3.4) and 4.7 (3.7), respectively, in the
citalopram group and 26.7 (3.1) and 3.9 (3.5), respectively, in the placebo
group. The total HDRS scores were 17.2 (2.8) and 3.3 (2.7) (citalopram) and
17.2 (3.2) and 2.9 (2.6) (placebo), respectively, and the total MES scores
were 16.3 (2.8) and 3.6 (2.8) (citalopram) and 16.7 (2.9) and 3.0 (2.7)
(placebo), respectively.
Recurrence of depression in the double-blind Period III
In the 60 patients randomised to continue on citalopram, there were 19
recurrences (32%) in contrast to 41 recurrences in the 61 patients randomised
to placebo (67%). The total observation time from randomisation into Period
III until recurrence, completion or discontinuation for other reasons than
recurrence, was 53.8 (citalopram) and 30.3 (placebo) person-years,
respectively. At week 48, 18 patients in the citalopram group and 38 patients
in the placebo group had experienced a recurrence of depression
(Table 2). The estimated
probability of no recurrence within 48 weeks was 0.67 for patients treated
with citalopram and 0.27 for placebo-treated patients. The time to recurrence
in Period III differed significantly between the treatment groups, in favour
of citalopram (log-rank test, 2 value 18.45, d.f.=1,
P<0.0001; Fig. 2). The
hazard ratio (citalopram v. placebo) was estimated at 0.32 (95% CI 0.19-0.56)
using a Cox regression model with treatment as the only predictive factor.
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Although the study was not powered for subgroup analysis, and despite the fact that a limited number of patients received 20 mg/day, the difference in time to recurrence between citalopram- and placebo-treated patients was statistically significant at all three dose levels (log-rank test, 20 mg/day, P=0.0009; 30 mg/day, P=0.0227; 40 mg/day, P=0.0188). In the 20 mg/day group, none of the patients continuing on citalopram experienced a recurrence whereas all the patients switched to placebo did.
Discontinuation in the double-blind Period III
The majority of discontinuations in Period III occurred in the placebo
group (55 (90%), compared with 37 (62%) in the citalopram group). The most
frequent reason was recurrence of depression (citalopram 19 (32%); placebo 41
(67%)) followed by withdrawal of consent (about 24% in both groups). A few
patients discontinued because of adverse events (citalopram 10%; placebo 13%)
with no difference in time to withdrawal between the two groups (log-rank
test, P=0.1842).
Safety and tolerability
In Period I, the most frequent adverse events (5%) were nausea,
diarrhoea, headache, increased sweating, tremor, dizziness and fatigue
(Table 3). Similar symptoms,
but with a reduced frequency, were seen in Period II. Sexual side-effects
(spontaneous reporting) were rare and weight gain/loss was reported by only
two patients.
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Although data should be interpreted with caution, given the low number of events and the longer exposure time (about twice as long) for patients treated with citalopram than for patients on placebo, the pattern of adverse events for those who continued in Period III was similar in the two treatment groups (Table 3). The only events occurring in Period III at a frequency >5% and at least twice as frequently in the citalopram group as in the placebo group, were back pain and influenza-like symptoms. None of these events were considered to be related to treatment. The events most consistently rated as treatment- related were nausea, diarrhoea, headache, increased sweating, tremor, dizziness and fatigue, consistent with the known adverse event profile of citalopram (Noble & Benfield, 1997). Of these, only increased sweating, tremor and fatigue were seen with a statistically higher frequency in the citalopram group compared with the placebo group in Period III.
Changes in laboratory or vital sign parameters were seen occasionally but were generally all single-parameter changes, unlikely to be related to the use of citalopram. A total of 8 of the 230 patients had alanine aminotransferase values out of normal range after baseline. However, three of these patients already had abnormal values at baseline, and all values were only slightly increased. One patient discontinued prematurely because of an increase in alanine aminotransferase, which the investigator considered probably to be related to treatment. The parameter had normalised 4 months later.
The abrupt discontinuation of citalopram in patients randomised to the placebo group neither induced new adverse events nor resulted in an increased intensity of adverse events present at randomisation.
A total of 34 serious adverse events were reported in 28 patients during the study, of which 18 were reported during the open treatment periods and 16 (11 in the citalopram group and 5 in the placebo group) during the double-blind treatment period. There were two serious adverse events with outcome death: one from oesophageal carcinoma, occurring during the open treatment period; and one for unknown reasons, occurring in a placebo patient. Neither of these deaths nor the other serious adverse events were judged by the investigator to be related to treatment.
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DISCUSSION |
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Comparison with studies in 18- to 65-year-olds
Essentially similar results were obtained in a recent placebo-controlled
citalopram study of the same design in 18- to 65-year-old patients with
recurrent depression (Hochstrasser et al,
2001). Reynolds et al
(1994) also found that
outcomes of maintenance therapy were remarkably similar in elderly and younger
patients with depression. Compared with the 18- to 65-year-olds
(Bougerol et al, 1997), elderly
patients tended to need a longer time to respond to acute treatment and a
shorter time to recurrence. Both a longer time to remission
(Reynolds et al, 1996) and a
higher and more rapid rate of recurrence with older age have been reported
previously (Reynolds et al,
1999).
Only 15% of the randomised elderly patients in this study had a history of previously diagnosed depression. Furthermore, a family history of depression was about half as frequent in this study as in a comparable study in 18- to 65-year-olds (Hochstrasser et al, 2001) consistent with the known profile in late-onset depression (Small, 1998). In spite of the absence of these known risk factors for recurrence of depression, the results of the present study demonstrate that the population it included was at high risk of recurrence. The results confirm that the risk of recurrence in geriatric patients is high, even after first-episode depression (Flint & Rifat, 1999; Reynolds et al, 1999).
Study design
This study was designed to allow sufficient time to resolve symptoms of an
episode of unipolar major depression and to distinguish relapse of an episode
from recurrence of a new episode
(Montgomery et al, 1988).
Period I was designed to optimise response to citalopram (flexible dose and
treatment extension up to 12 weeks), possibly explaining why only 3% of the
patients discontinued because of lack of efficacy, reflecting the fact that a
long time for resolution of symptoms could be required in some patients
(Quitkin, 1992). Period II was
designed to consolidate remission from the present depressive episode
(Montgomery et al, 1988). The
following 48-week minimum duration of prophylactic therapy was chosen on the
basis of the current knowledge of the time to recurrence seen in most
depressive patients (about 24 weeks), but allowing enough time to obtain
knowledge of recurrences occurring at later time-points; and of statistical
power calculations.
Treatment
The doses of 20, 30 or 40 mg/day citalopram were chosen on the basis of
previous 12-week studies of citalopram in elderly patients with depression
(Kyle et al, 1998) and on the
well-established long-term efficacy and safety of doses of 20-40 mg/day
citalopram in 18- to 65-year-old patients
(Robert & Montgomery,
1995). The dose to which patients responded during acute
treatment, and remained well on during continuation treatment, was maintained
during prophylactic treatment, as studies have indicated that a full dose of
anti-depressants is more effective than a reduced dose during prophylactic
treatment (Franchini et al,
1998).
Relapse versus recurrence
It might be questioned whether the depressive episodes recorded in Period
III were relapses rather than recurrences. However, because the design of the
study followed the recommendations given by the experts in this field
(Montgomery et al, 1988), new
depressive episodes occurring in Period III were regarded as recurrences. This
is further substantiated by the fact that the duration of an untreated
depressive episode is usually considered to be 6-8 months
(American Psychiatric Association,
1993). When patients entered Period III in this study, their index
episode had started at least 6.5 months earlier. Furthermore, if the patients,
although symptom free, were still in the depressive phase of their index
episode when they entered Period III, it is most likely that the patients
randomised to placebo would relapse very early. Thus, the difference in
treatment effect of citalopram and placebo should be greatest at the time
immediately following randomisation. The fact is, however, that a substantial
part of the recurrences occurred in weeks 8-12 after randomisation, and
citalopram was superior to placebo in preventing recurrence throughout the
observation period.
Safety and tolerability of prophylactic treatment
Prophylactic treatment with citalopram was well tolerated in the elderly
patients in this study. This is an important finding, given the particular
vulnerability of elderly patients to adverse drug reactions and the high
frequency of concurrent diseases and concomitant drug therapy in these
patients (Pollock, 1999).
The pattern of adverse events was in agreement with other results regarding long-term safety of SSRIs (Zajecka et al, 1999) and was comparable to the adverse events seen in placebo-treated patients. Notably, sexual symptoms, a common and bothersome reaction to SSRIs (Kennedy et al, 2000), were reported with very low frequency. However, the frequency could have been underestimated because specific enquiries were not made about these events. Weight gain was only reported by one patient (citalopram) in Period III in agreement with a previous long-term study (Hochstrasser et al, 2001).
Premature discontinuation
Apart from recurrence, the most common primary reasons for premature
discontinuations in Period III were withdrawal of consent and adverse events,
which is to be expected in a long-term study in an elderly population. It is
of major importance that the abrupt discontinuation of citalopram in patients
randomised to the placebo group caused no worsening of the adverse event
profile. Although the sample size was small and the study was not designed to
investigate this, it indicates that abrupt discontinuation of citalopram in
the elderly is not associated with discontinuation symptoms.
In conclusion, citalopram effectively reduces the rate of recurrence of depression in elderly patients. Moreover, long-term treatment with citalopram is well tolerated. This study confirms available data indicating that maintenance treatment in patients with depression is efficacious in reducing recurrence rates and is beneficial even after first-episode depression.
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication November 15, 2001. Revision received March 18, 2002. Accepted for publication March 21, 2002.