Fluoxetine Versus Trazodone in

Depressed Geriatric Patients

William E. Falk, MD; Jerrold F. Rosenbaum, MD; Michael W. Otto, PhD;
Paul M. Zusky, MD; Jeffrey B. Weilburg, MD; Ralph A. Nixon, MD

Abstract .
A total of 27 subjects began active treatment in this double-blind study comparing the efficacy and safety of trazodone and
fluoxetine in geriatric depressed patients, but only 13 completed 6 weeks on study medication. Both agents were effective
according to weekly and endpoint analyses, and there was no evidence of significant effects on blood pressure, pulse, or weight.
Separate analysis of patients who had received an adequate trial of medication indicated a trend toward relatively more
fluoxetine-treated patients meeting clinical criteria for resolved depression. (
J Geriatr Psychiatry Neurol 1989;2:208-214.)

treatment of major depression in the elderly
he is more complicated than it is for younger pa-
tients. When prescribing antidepressants to geriatric
patients, physicians must take into account age-related
changes in drug metabolism, altered pharmacokinetic
and pharmacodynamic effects, and greater susceptibil-
ity to side effects.’ Furthermore, since elderly patients
frequently require medications for other medical prob-
lems, the risk of drug interactions is increased.
Cyclic antidepressants vary in the intensity of
anticholinergic effects., postural hypotension, and di-
rect cardiac effects produced, but all have some degree
of these unwanted characteristics. Monoamine oxidase
inhibitors, while low in anticholinergic and cardiac ef-
fects, are frequently associated with postural hypoten-
sion and have the potential for severe drug or food
interactions. Despite these drawbacks and risks, both
classes of agents are used effectively in treating elderly
depressed patients.
Among currently available antidepressants, trazo-
done is one that is considered to be well tolerated in
geriatric depressed patients.2 In studies comparing it to
imipramine3 and amitriptyline,4 trazodone-treated pa-
tients had fewer cardiovascular side effects, including
no increase in heart rate, little effect on cardiac conduc-
Received April 24, 1989. Received revised July 7,
cepted for publication Sept 6, 1989.
From the Department of Psychiatry, Harvard Medical School,
and the Massachusetts General Hospital, Boston, MA.
Address correspondence to Dr William E. Falk, Clinical
Psychopharmacology Unit, ACC 715,Massachusetts General Hospi-
tal, Boston, MA 02114.
tion, and less postural hypotension. Its low anti-
cholinergic profile diminishes the likelihood of cogni-
tive deficits, narrow angle glaucoma, urinary retention,
constipation, and other uncomfortable or potentially
serious side effects. In addition, its relative safety in
overdose is attractive for an antidepressant agent. All of
these factors encourage the use of trazodone in the eld-
erly, but this agent is not without potential side effects,
including an increase in preexisting ventricular irritabil-
ity, priapism, sedation, gastrointestinal distress, and
symptomatic orthostasis.5 As such, the consideration of
the relative efficacy of other antidepressant agents for
the elderly is relevant.
,
Fluoxetine is one such agent. Fluoxetine is a selec-
tive inhibitor of serotonin reuptake that has virtually no
affinity for muscarinic, noradrenergic, or dopaminergic
receptors, and although the drug does down-regulate
5-HT1 receptors over time, it does not by itself appear
to down-regulate (3-receptors.b These pharmacody-
namic characteristics are of potential importance for the
side effect profile of this medication. Fluoxetine ap-
pears to be relatively benign in overdose and does not
appear to lower seizure threshold. In addition, fluoxe-
tine has not been associated with cardiovascular
changes, postural dizziness, or sedation. Fluoxetine,
like trazodone, is free of anticholinergic effects but is
associated with increased reports of nausea and
1989. Ac-
headaches.
Fluoxetine has proven effective in double-blind,
placebo controlled trials comparing it to imipramine
and amitriptyline.7-9 In a study of nongeriatric de-
pressed patients, its efficacy was comparable to that of

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trazodone, although onset of benefit was somewhat
delayed.10 It was also found to be as beneficial as
doxepin geriatric depressed patients.ll Doses as low
in
as 20 mg have been demonstrated to be effective in
some patients, while other patients have improved on
doses of 40 to 80 mg.12 Side effects appear to increase at
the higher dosages.
The clinical efficacy of fluoxetine, as well as its side
effect profile, suggests it may be an attractive agent for
the treatment of depression in geriatric patients, and
raises questions whether it may offer clinical benefits
similar to or beyond that of trazodone. For these rea-
sons, we undertook a study to compare the safety, effi-
cacy, and tolerability of fluoxetine and trazodone in
older depressed patients.
Methods
Male and female outpatients at least 62 years old were
invited to participate in a study comparing fluoxetine to
trazodone. To be included, a subject had to meet criteria
for Diagnostic and Statistical Manual o f Mental Disorders,
ed. 3 (DSM-III) unipolar major depressive disorder, ei-
ther single episode or recurrent, and to have experi-
enced the present episode for at least 4 weeks. Subjects
also had to achieve a score of at least 20 on the 21-item
Hamilton Rating Scale for Depression (HAM-D).13
Exclusion criteria were serious medical illness that
could be adversely affected by the study drugs, glau-
coma, unstable cardiac arrhythmias, seizure disorder,
antihypertensive agents (ie, guanethidine, reserpine,
clonidine, and methyldopa), and history of allergy to
either drug. Psychiatric exclusions included patients
with severe psychosis, suicidal symptoms, or DSM-III
diagnoses of schizophrenia, schizoaffective illness, bi-
polar disorder, organic mental disorder, substance
abuse disorders within the past year, or paranoid
disorders.
Patients were excluded if they took either study
drug in the month preceding entry, monoamine oxidase
inhibitors in the prior 14 days, or other antidepressants
at the time of entry. Aside from the use of benzo-
diazepines or chloral hydrate for sleep, no other
psychotropic agent could be taken during the study.
After providing informed consent, each subject re-
ceived a medical and psychiatric examination, as well
as laboratory testing (complete blood count, chemistry
profile, urinalysis, and ECG). Physical examination and
laboratory testing were repeated at the time of study
exit. Blood pressure, pulse, and weight were obtained
weekly throughout the course of the study.
The study duration was 7 weeks, during which
there were eight weekly visits. All patients were given
placebo capsules during the first week between visit 1
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(entry) and visit 2 (baseline). From visit 2 onward, all
patients received active drug by random assignment.
Each subject was given study medication in three bot-
tles marked for morning, noon, or evening administra-
tion. All capsules were identical and contained either 20
mg of fluoxetine, 50 mg of trazodone, or placebo. In the
fluoxetine-treated patients, noon and evening bottles
actually contained placebo, while for the trazodone- -
treated group, morning medication was placebo.
For the first 3 weeks of active drug treatment, the
daily dosage regimen could not be adjusted. Starting at
week 4 of active drug treatment (visit 5), the daily dos-
age could be adjusted to achieve maximum therapeutic
response. For fluoxetine, dosage through week 3 was
kept at 20 mg, during week 4 it could range from 20 to
40 mg, and at weeks 5 and 6 it could range from 20 to
60 mg. For trazodone, 100 mg. was administered on
days 1 through 3, 150 mg on days 4 through 7, 200 mg
on days 8 through 10, and 250 mg on days 11 through
21. During weeks 4 through 6 of active drug treatment,
dosage could be titrated between 50 and 400 mg.
Weekly assessments included the 21-item HAM-D
and patient- and physician-rated Clinical Global Im-
provement (CGI),14 7-point scale ranging from
a
marked improvement (1) to markedly worse (7), with
no change denoted by 4. Side effects were evaluated
using the Treatment Emergent Side-effect Scale (TESS).
Continuous response variables were analyzed by t-
tests, and categorical response variables by Fisher exact
tests,15 A significance level of .05 was used for all t-
tests. As the Fisher exact tests were one-tailed, a signifi-
cance level of .025 was adopted for these tests. Alpha
probabilities between .025 and .05 were termed mar-
ginally significant.
Results
Patient Attrition
Thirty-six patients were entered for the single-blind,
placebo washout phase of the study. By the end of this
phase, nine patients dropped out or were excluded
from further participation: HAM-D scores decreased to
less than the criteria of 20 for two patients, medical
problems precluded participation for three patients,
and four patients discontinued because of &dquo;side effects,&dquo;
concerns of family members, or unwillingness to re-
main free of excluded medications. Of the 27 patients
continuing in the protocol, four men and 10 women
were assigned to fluoxetine treatment, and three men
and 10 women were assigned to trazodone treatment.
There was no significant difference in age between the
treatment groups: 69.1 ± 6.2 years for the fluoxetine-
treated patients and 67.5 ± 4.0 years for the trazodone-
209
treated patients. Likewise, there were no significant TABLE 1
differences between treatment groups in age at onset of Reasons for Discontinuation of Medication
first episode, number of episodes, or duration of the
’

present episode.
One patient from each treatment group failed to re-
turn at visit 3, leaving a total of 25 patients available for
outcome analysis. Of these, five patients on trazodone
and two on fluoxetine dropped out at visit 3 (after one
week of active drug treatment). Five additional patients
dropped out before termination, leaving only 13 pa-
tients completing the entire protocol, three on trazo-
done and ten on fluoxetine (Table 1). The average dose
of medication at visit 8 was 350 mg for trazodone and
48 mg for fluoxetine. The number of completers was
significantly different between the two groups (P =

.012, one-tailed), but the difference in dropouts due to

complaints of adverse effects (five in the trazodone
group and two in the fluoxetine group) was not signifi-
cant according to Fisher exact test analysis.
Depression
The high dropout rate found in this sample of elderly
patients presents problems for the analysis of between-
treatment differences. Few subjects are left for compari-
son at the last treatment visit, leaving little power for
the detection of differences in treatment efficacy.
Nonetheless, as a high rate of attrition is common to
studies of geriatric depressives, 16 the use of endpoint
analysis (carrying the last visit forward) does provide a
realistic index of the average improvement that a sam-
ple of geriatric patients entering treatment may achieve
over a short-term drug trial.
After 1 week of active drug treatment.
Treatment outcome was assessed by HAM-D scores
and physician-rated CGI scores. Mean scores for these
variables are presented in Table 2. Two statistical com-
parisons were of interest: (1) a within-subjects compari-
son of the significance of changes in these depression
ratings occurring since the baseline period for the
groups pooled together, and (2) a between-subjects
comparison of whether these changes were signifi-
cantly different between the treatment groups. In addi-
tion to endpoint analysis, these within-subjects
comparisons were examined at each week, and
between-subjects comparisons were examined when-
ever the overall sample size was 16 subjects or more (to
visit 7). Figures 1 and 2 illustrate these comparisons of

TABLE 2
HAM-D and CGI Scores for All Patients at Each Visit and Endpoint

HAM-D =
Hamilton Rating Scale for Depression; CGI =
Clinical Global Improvement.
&dquo;Baseline.
tLast visit carried forward.

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FIGURE 1
Change in Hamilton Rating Scale for Depression scores between baseline and each subse-
quent visit. Numbers within the columns refer to sample size. No between-group differ-
ences were significant. At all visits, the within-subjects change from baseline scores was

significant (P < .001) for the treatment groups pooled together.

FIGURE 2
Change in Clinical Global Improvement scores between baseline and each subsequent visit.
Numbers within the columns refer to sample size. No between-group differences were sig-
nificant. At all visits, the within-subjects change from baseline scores was significant (P <
.01 for visit 3, P < .001 for all other visits) for the treatment groups pooled together.

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change (baseline visit minus treatment visit)
scores more patients in either treatment group) are listed in
across the treatment
period. Table 3. According to Fisher exact test analysis, there
Within-subjects analysis indicated a significant im- was a trend toward relatively more reports of insomnia

provement in depression across treatment as assessed in the fluoxetine-treated group (P .046, one-tailed)
=

by changes in HAM-D scores at endpoint (t [23] = 6.77, and relatively more reports of constipation in the
P < .001) and as assessed individually at weeks 3 trazodone-treated group (P = .039, one-tailed). No
through 8.* No differences between the
significant other side effects approached significance for compari-
treatment groups obtained at endpoint, (t[23] _
were sons between treatment groups. None of the side ef-

1.02, P < .32) or at any point during the study. Parallel
results were obtained for the CGI assessment of
depression.
These comparisons, however, do not fully capture a
variable of clear interest to the clinician: the number of
patients in each treatment condition who received an
adequate dose and duration of medication and
achieved resolution of depression. To examine this vari-
able, resolution of depression was defined -as a greater
than 50% reduction in HAM-D score and a final
HAM-D score less than 10, criteria that have been de-
scribed elsewhere. 17 Of the six patients treated with
trazodone at a dose of 300 mg or more, only one met
these criteria. In contrast, eight of 11 patients treated
with 40 mg of fluoxetine met these criteria. The differ-
ence in the treatment groups was marginally significant
by a one-tailed Fisher exact test (P = .043).
Side-Effects
Three variables from the physical examination were ex-
amined : postural blood pressure change, pulse, and
weight change. For data analysis, postural blood pres-
sure change was defined as the change in systolic blood
pressure between supine and standing assessments and
was examined pretreatment, at visit 3 (allowing the
comparison of the greatest number of subjects at the
same time period), and at endpoint (last visit carried
fects were so severe as to be medically dangerous to any
patient.
Discussion
Using &dquo;most generous&dquo; criteria, Gerson and colleagues
were able to find only 25 controlled studies of antide-
pressant usage in elderly patients between 1964 and
1986.18 They and others have noted that a high attrition
rate is a common problem in studies of geriatric pa-
tients. Forexample, in a study by Feighner and Cohn,11
61 % of doxepin-treated patients did not complete the
study, while 47% of fluoxetine-treated patients termi-
nated early. Spivak and colleagues reported that all
eight elderly depressed patients with medical problems
whom they treated with trazodone at a dose of 300 mg
or less had to discontinue the drug due to clinically sig-
nificant side effects.44
In our study, 75% of trazodone-treated patients did
not complete the study, while 23% of fluoxetine-
treated patients terminated early. A principal reason for
our high dropout rate appeared to be the intolerance of
even low-intensity side effects, which were not consid-
ered sufficient reason for discontinuation by the rater.
Given our high dropout rate and the apparent preva-
lence of such problems in the study of this population,
we came to appreciate the need for involving signifi-

forward). Resting heart rate was also examined at these cant others, suchspouses and children, in the de-
as

times. No significant differences were found between cision to participate in the study and in ongoing
or within subjects for the change in these variables be-
treatment decisions.
tween baseline and visit 3 or between baseline and
TABLE 3
endpoint evaluations. Treatment-Emergent Side Effects Reported by Three or More
To avoid contamination by length of treatment,
Patients on the TESS
weight change was assessed in completers only. The
___

mean weight change was almost identical in each treat-

ment group, -2.7 ± 3.0 pounds for the fluoxetine-
treated and -2.8 ± 1.8 pounds for the trazodone-
treated group. This apparent decrease in weight across
treatment was not
statistically significant.
Complaints of treatment-emergent side effects in-
dicated by the TESS (noted only if reported by three or

*As equal population variances could not be assumed and sam-

ple sizes were unequal, critical values for these within-subject tests
and the corresponding tests of the CGI data were corrected using an TESS = Treatment-Emergent Side-Effect Scale.
adjustment to degrees of freedom as outlined by Hayes.l5 *P < .05 and > .025, one-tailed test.

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 In addition to being a general problem for the study
of geriatric depression, the high dropout rates raise cau-
tions for the interpretation of the data. As such, we
view our conclusions as tentative but important, given
the difficulties with research with this population.
_
Both trazodone and f luoxetine were associated
with clinical improvement in depression as measured
by endpoint analysis and analysis of changes from
>
baseline evident at each visit. Part of this apparent anti-
depressant effect may be attributed to placebo re-
sponse, as no placebo control group was used. Yet,
rather than replicate previous examinations of the ab-
solute efficacy of these medications, 2-4, 7-9 this study
was designed to compare the relative efficacy and side
effect profiles of fluoxetine and trazodone in a geriatric
population. Although statistical comparisons were
hampered by small sample size, examination of mean
scores at each week of treatment did not indicate that
fluoxetine was differentially effective compared to
trazodone. Separate analysis of patients receiving an
adequate trial of medication indicated a trend toward
relatively more patients on fluoxetine than on trazo-
done meeting a clinical criteria for resolved
depression.
Given this evidence that fluoxetine is at least as ef-
fective as trazodone in this geriatric population, atten-
tion is turned to the side effect profile for each
medication. The present study did not indicate cardiac
effects for either medication as determined by physical
examination data, ECG, and from patient reports. Like-
wise, analysis of weight change indicated no significant
change across treatments. No side effects were associ-
ated with medical risk. Of minor adverse effects, there
were trends toward relatively more complaints of in-
somnia with fluoxetine and more complaints of consti-
pation with trazodone. Overall, these data indicate that
fluoxetine had a side effect profile that was roughly
comparable to that of trazodone and. did not differen-
tially affect attrition rates or the health of the patient.
This is an important finding, as trazodone has been
identified as a generally well-tolerated antidepressant
in the treatment of the elderly depressed patient.
Conclusion
Although conclusions are tentative given the small
sample size, fluoxetine demonstrated efficacy in this
geriatric population that was at least comparable to that
of trazodone in terms of both antidepressant action and
tolerability. As indicated by the high dropout rate even
during the placebo washout phase of this study, geriat-
ric depressed patients remain a difficult population to
study. As such, our study is consistent with the conclu-
sions of Rockwell and colleagues that I1geriatrtc research
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is undoubtedly complicated by many factors affecting
the older patient, but further studies are essential to de-
termine optimal strategies for drug treatment in the
elderly.&dquo;19 Our findings encourage further investigation
of the use of fluoxetine as a useful and safe alternative
to trazodone in depressed geriatric patients.
Acknowledgments
This research was supported by a grant from Eli Lilly and Com-
pany. The authors appreciate the clinical and administrative support
of Laura Pill, BS, manuscript preparation of Margaret O’Brien, and
statistical assistance of Bruce Dornseif, PhD.
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