Evidence Based Review Article
The Journal of Informed Pharmacotherapy
Elderly depression: Is a SSRI no better
than a TCA for this late-life disorder?
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Reviewer: David Gardner, Pharm.D.
Reviewer's email address: email@example.com
Reviewer's profession/specialty: Psychopharmacology
Mulsant BH, Pollock BG, Nebes RD, Miller MD, Little JT, Stack J, Houck PR,
Bensasi S, Mazumdar S, Reynolds CF 3rd. A double-blind randomized
comparison of nortriptyline and paroxetine in the treatment of late-life
depression: 6-week outcome. J Clin Psychiatry 1999;60 Suppl
Overall Study Question
mild to moderately depressed elderly inpatients and outpatients, is there a
difference in clinical effectiveness between selective serotonin reuptake
inhibitors (SSRI) and tricyclic antidepressants (TCA)?
Are the Results of the Study
1. Was assignment of patients randomized?
and stratified based on inpatient vs. outpatient status and baseline mini mental
status score (24 or below vs. 25 or above).
2. Were all patients who entered the trial properly accounted for and
attributed at its conclusion?
Yes. Eighty consenting
patients (43 nortriptyline (NOR) and 37 paroxetine (PAR)) received at least
one dose of a randomly allocated treatment regimen and this represented the
intention to treat study group. Two analyses were completed, one for the
intention to treat group and the second for a "completer" group.
The authors stated that
patient were "assigned to treatment under double-blind conditions",
however, they did not clarify whether dosage forms were identical.
Nortriptyline was given at night and was adjusted according to response and
serum drug concentrations. Conversely, paroxetine was given in the
morning. Dosing strategies differed based on inpatient vs. outpatient
status. Considering these differences in dosing methods, it is difficult
to understand how blinding was established and maintained. The authors
did not discuss any tests to determine the effectiveness of the blinding
3. Were patients, their clinicians, and study personnel 'blind' to
- Unable to determine.
4. Were the groups similar at the start of the trial?
Overall, yes. However there were some notable differences between groups
including differences in onset of illness (NOR 62.4 years vs. PAR 54.0,
p=0.06) and incidence of patients with recurrences (49 NOR 49% vs. PAR
58%). Baseline depression scores (17 item HAM-D), cognitive
functioning (MMSE) and duration of episodes were similar between groups.
5. Aside from the experimental intervention, were the groups treated
Generally, yes. However, the nortriptyline dosing was adjusted
based on feedback from serum levels and the authors did not state whether or
not the paroxetine patients had mock serum levels undertaken in order to
maintain similar procedures between groups.
6. Overall, are the results of the study valid?
What were the Results?
1. How large was the treatment effect?
Eighty patients completed this 6-week study. The mean age was 75 years
and the average HAM-D 17 score at baseline was 22.5. There were no
significant differences between the two treatments in terms of antidepressant
response (as measured by change in HAM-D score) or the proportion of patients achieving a HAM-D
score of 10 (by intention to treat or per protocol analyses). The side effect
measured by the UKU side effects scale) was similar among completers who
received at least 4 weeks of treatment. 14/43 PAR recipients and 10/37 NOR
recipients dropped out of the study prematurely, with 8/43 and 5/37
discontinuing therapy due to adverse drug reactions, respectively. These
differences were not significant.
2. How precise was the estimate of the treatment effect?
Will the Results Help Me in Caring for My Patients?
1. Can the results be applied to my patient care?
- Yes. Depression is common among the elderly. In this
study, patients were excluded if they had an obvious contraindication to
either of the interventions or had a recent history of alcohol dependence or
misuse. Included were patients with a presumptive diagnosis of dementia,
as long as their MMSE was greater than 17. The investigators dosed both drugs
appropriately, including adjusting nortriptyline doses based on target levels
of 50-150 ng/mL. Lorazepam was given for anxiety or insomnia.
2. Were all clinically important outcomes considered?
- The authors appropriately focused on the relevant outcomes of response and tolerability.
The authors also categorically evaluated the proportion of patients who
achieved "near remission" (HAM D < 10). Considering the
population sampled, an evaluation of cognitive functioning (MMSE) was
prudent. However, the study did not address some important outcomes
including: recurrence rates (i.e. stability of response), functional status,
quality of life or pharmacoeconomic impact. To do so, a larger study of
involving longer term assessments would be required. The authors will be
reporting the 12-week results at a later date, however, this will not fully address
these methodological shortcomings.
3. Are the likely treatment benefits worth the potential harms and costs?
- Unable to determine. For most patients, SSRI are now used as first
line treatment more commonly than most other antidepressants (especially the
TCA) and this includes the treatment of elderly patients. The
equivocal findings of this study in terms of both effect and tolerance
suggest , as do many other studies, that the abandonment of the TCA in the
last decade has been premature. Based on the average daily doses used
in this study (NOR 51 mg and PAR 23 mg), the difference in drug acquisition
cost is approximately three-fold. This difference is likely to be important
to individuals who must pay for their medications and to third-party
payers. It is not possible to determine from this study the
pharmacoeconomic impact (from a societal perspective) of selectively using
either one of these agents in the treatment of depression in the
elderly. To do so, a much larger study involving a longer assessment
period with a more precise evaluation of small differences in benefits,
harms and costs.
This study was rigorously designed and advances the clinicians knowledge of how
SSRI and TCA compare in the elderly. Some studies concluded that TCA were
superior to SSRI in the severely depressed elderly. A regression analysis
completed by the authors of this study did not reveal that response was associated
with treatment choice or severity of depression. The previous studies had major
design flaws. The primary limitation of this current study is its short
duration of outcome evaluation. This is important as treatment response can be
delayed in the elderly. The authors have now presented the 12-week follow-up
outcome data (American Psychiatric Association
meeting, Chicago, USA, May 2000) and found that the earlier lack of difference in overall treatment
response between groups persisted. These findings indicate that TCA and
SSRI appear to be equally
effective in the elderly with mild to moderate depression, and that choice
should be based on factors other than "probability of responding to and
Copyright © 2000 by the Journal of Informed
Pharmacotherapy. All rights reserved.