Elderly Depression

Is a SSRI no better than a TCA for this late-life disorder?

Original Citation

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.

Overall Study Question

In 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 Valid?

Was assignment of patients randomized?

Yes.  Randomized and stratified based on inpatient vs. outpatient status and baseline mini mental status score (24 or below vs. 25 or above)

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.

Were patients, their clinicians, and study personnel ‘blind’ to treatment?
Unable to determine.  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 procedures.
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.

Aside from the experimental intervention, were the groups treated equally?

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.

Overall, are the results of the study valid?

Yes.

What were the Results?

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 burden (as 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.

How precise was the estimate of the treatment effect?

Not applicable.

Will the Results Help Me in Caring for My Patients?

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.

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.
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.

Commentary

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 tolerating treatment”.

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