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Change in Cognitive Functioning After
Acute Antidepressant Treatment in
Late-Life Depression
Michelle Culang, B.S., Joel R. Sneed, Ph.D., John G. Keilp, Ph.D.,
Bret R. Rutherford, M.D., Gregory H. Pelton, M.D.,
D. P. Devanand, M.D., Steven P. Roose, M.D.
Objective: Selective Serotonin Reuptake Inhibitors (SSRIs) are the most commonly
prescribed medications for geriatric depression. The association of late-life depression
and cognitive impairment has been well documented. However, there have been few placebo-controlled trials examining the impact of SSRIs on cognitive functioning. De-
sign: Prepost neuropsychological (NP) data collected as part of an 8-week, double-blind,
placebo-controlled trial of citalopram in depressed patients aged 75 years and older were
used to examine change in cognitive functioning. Setting: University-affiliated outpa-
tient psychiatry clinics. Participants: One hundred seventy-four community-dwelling
men and women aged 75 years or older with nonpsychotic unipolar depression. Mea-
surements: NP assessments included mental status (Mini-Mental State Examination),
psychomotor speed (Wechsler Adult Intelligence Scale-III Digit Symbol Subtest), reaction
time (Choice Reaction Time), visual-spatial skill (Judgment of Line Orientation), execu- tive functioning (Stroop Color/Word Test), and memory (Buschke Selective Reminding Test). Results: Differences in the pattern of change by treatment group depended on
responder status. Citalopram nonresponders were the only group to decline on verbal
learning and psychomotor speed. Citalopram responders showed significant improve- ment in visuospatial functioning, when compared with nonresponders in either condi- tion, but their improvement was not greater than responders on placebo. Citalopram responders showed greater improvement on psychomotor speed than citalopram nonre- sponders, but their improvement was not greater than placebo responders or nonre- sponders. Conclusions: Medication may have a deleterious effect on some aspects of
cognition among patients aged 75 years and older who have not responded. This suggests
that patients should not be maintained on a medication if they have not had an adequate response. (Am J Geriatr Psychiatry 2009; ●:000 –000) Key Words: Cognitive functioning, cognitive impairment, geriatric depression, late-life
depression, citalopram
Received November 3, 2008; revised May 4, 2009; accepted June 1, 2009. From the Queens College, City University of New York (MC, JRS); and Columbia University and the New York State Psychiatric Institute (MC, JRS, JGK, BRR, GHP, DPD, SPR), NY. Send correspondence and reprintrequests to Michelle Culang, B.S., Department of Psychology, Queens College of the City University of New York, 65-30 Kissena Blvd, Flushing,NY 11367. e-mail: michelle.culang@qc.cuny.edu 2009 American Association for Geriatric Psychiatry Am J Geriatr Psychiatry ●:●, ●●● 2009 rich3/jgp-ajgp/jgp-ajgp/jgp99908/jgp0562-09z
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SelectiveSerotoninReuptakeInhibitors(SSRIs)are been few placebo-controlled trials examining this is- the first-line of treatment in the geriatric de- sue. In one study, nortriptyline and phenelzine pro- pressed due to the efficacy, safety, and tolerability of duced no change in cognition in depressed older its class. Cognitive impairment is common in late-life adults, when compared with placebo, and this effect depression (LLD), particularly in memory,1–3 vi- did not depend on responder status.8 However, the suospatial functioning,2,4 information processing small sample size and limited number of responders speed,5,6 and executive functioning.5,7 It is important made it difficult to determine the impact of responder to consider the impact that antidepressant treatment status on change in cognition. Furthermore, this study can have on cognition when treating depressed older was restricted to the use of a TCA and MAO-I. In another study, patients taking duloxetine showed sig- Research that has examined the impact of SSRIs on nificant improvement in verbal learning and memory, the cognitive functioning of depressed older adults when compared with the placebo group.15 Therefore, it has been inconclusive because most studies have is unclear what impact medication, SSRIs in particular, been limited by methodological constraints includ- ing small sample size or lack of an age-matched The purpose of this study was to examine the control group for comparison.8–11 For instance, treat- impact of antidepressant treatment on change in cog- ment of LLD with sertraline led to an improvement nitive functioning. To accomplish this aim, we used in short- and long-term memory storage and re- neuropsychological (NP) data collected as part of the trieval and speed of processing.11 Although these Old-Old Depression Study,16 a large (N ϭ 174), ran- results suggest that some aspects of cognition (i.e., domized, double-blind, placebo-controlled trial of memory and processing speed) improve with anti- citalopram in depressed older adults (age Ͼ75 depressant treatment, it is difficult to determine years). These data provided us with the methodolog- whether the improvement was a function of repeat ical strength to address two questions: 1) do patients testing or medication because the design lacked a treated with citalopram show differential change in cognitive functioning over the 8 weeks, when com- Studies using age-matched controls have shown pared with patients treated with placebo? 2) Does that cognitive functioning of depressed older adults change in cognitive performance depend on re- does not improve beyond the expected practice effect sponder status? To our knowledge, this is the first (practice effects refer to improvement due to repeat attempt to approach these issues using a placebo- testing and are defined by the performance of a controlled trial of an SSRI in an old-old (Ͼ75 years) comparison condition, either an age-matched control group12–14 or a placebo comparison group,8,15 that is not being treated with medication).12–14 For example,working and episodic memory, attention shifting,and processing speed did not improve after treat- ment with paroxetine to a greater degree than nor-mal controls did with practice, regardless of re- The procedures used in the multisite, randomized, sponder status.14 Similarly, cognitive functioning placebo-controlled trial (RCT) have been previously showed no improvement beyond a practice effect described.16–18 Briefly, 174 community-dwelling men among responders to either nortriptyline or parox- and women aged 75 years or older meeting Diagnos- etine.13 These studies suggest that depressed older tic and Statistical Manual of Mental Disorders, adults show little improvement as a function of treat- Fourth Edition criteria (based on Structured Clinical ment and cognitive impairment persists after an ad- Interview for Diagnostic and Statistical Manual of equate trial of antidepressant medication.
Mental Disorders-III-R interview) for nonpsychotic Although such designs allow us to determine unipolar depression (single or recurrent) with a base- whether cognition changes as a function of antide- line 24-item Hamilton Rating Scale for Depression pressant treatment, it does not allow us to conclude (HRSD) score Ն20 participated in this 8-week RCT.
that the change (if any) is a result of treatment due to All patients began the trial with a 1-week single- a lack of a placebo condition. However, there have blind placebo lead-in with the baseline visit con- Am J Geriatr Psychiatry ●:●, ●●● 2009 rich3/jgp-ajgp/jgp-ajgp/jgp99908/jgp0562-09z
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ducted at the end of the lead-in. Patients were ran- reflect uncertainty due to missing values and im- domized to citalopram 20 mg/day or matched placebo only if they continued to meet inclusion andexclusion criteria at the end of the placebo lead-in. At Statistical Analyses
the end of Week 4, patients with a HRSD score Ͼ10had the dose increased to two pills per day, i.e., 40 Before testing for differences in change in NP test mg of citalopram or 2 placebo pills.
performance, we used the PROC REG and PROCLOGISTIC procedures in SAS to test for differences NP Test Battery
at baseline between the two treatment conditionsand the four treatment condition by responder status The test battery was designed to assess a number groups (see later). There were no differences on age, of cognitive functions pertinent to aging and major education, gender, baseline depression severity, re- depression including mental status, psychomotor sponder status, or on any of the NP tests with the speed, reaction time, visual-spatial skill, attention, exception of baseline scores on the MMSE and Digit and memory. Three of the tests (Choice Reaction Symbol subtest of the Wechsler Adult Intelligence Time [CRT], Judgment of Line Orientation [JOLO], Scale-III. Therefore, we adjusted for baseline Digit and Stroop) were presented on a Macintosh laptop Symbol and MMSE scores in the two treatment computer and were written in the PsyScope pro- group analyses. When comparing the four patient gramming language,19 whereas the other three tests groups (responder status by treatment condition), (Mini-Mental State Exam, Buschke Selective Remind- we found differences on education and baseline ing Test [SRT], and Digit Symbol) were administered MMSE, CRT, and Buschke SRT scores. Therefore, we by hand. The tests included the 30-item Folstein included these variables as covariates in the four Mini-Mental State Examination (MMSE)20 to esti- group analyses. We also adjusted for site of study in mate global cognitive functioning, the Wechsler all analyses, which we know from previous reports Adult Intelligence Scale-III Digit Symbol Subtest21 as a measure of psychomotor speed, the CRT test To test for differences in change in NP test perfor- adapted from Thorne et al.,22 the Stroop Color/Word mance, we used data from the multiply imputed Test23 to assess the response inhibition component of datasets and adopted a partial or regressed change executive functioning, the JOLO24 as a measure of approach to analyzing two time-point data29 using spatial judgment, and the Buschke SRT25 as a mea- the PROC REG procedure in SAS. According to this approach, the endpoint NP test score is treated as theoutcome variable, and the baseline test score istreated as a covariate. This effectively removes all Missing Data
correlation of the endpoint score from the baseline Missing data at baseline ranged from 0.6% on the score and represents an improvement over simple MMSE and Buschke SRT to 9.8% on the JOLO and change scores (subtracting baseline from endpoint), from 11.5% on the MMSE to 19.0% on the Stroop at which tend to overcorrect the endpoint score by the follow-up. To accommodate missing data, we used baseline score due to unreliability of measurement.29 multiple imputation using the PROC MI and We first tested for differences in endpoint scores MIANALYZE procedures in SAS. Multiple imputa- between treatment conditions using a dummy coded tion is a simulation technique that replaces each (citalopram ϭ 1 and placebo ϭ 0) variable. To test missing datum with a set of m Ͼ1 plausible values.26 whether change in NP test performance depends on This report is based on five imputed datasets (m ϭ 5), responder status (50% reduction from baseline which is sufficient to obtain excellent results unless HRSD score), we again used a dummy coded vari- rates of missing data are exceptionally high.27 The able to designate the four patient groups (citalopram imputed datasets are analyzed using standard statis- responders, citalopram nonresponders, placebo re- tical analyses, and results from the analyses from the sponders, and placebo nonresponders). Each covari- m complete datasets are combined using Rubin’s ate was centered at its respective mean, so the inter- rules26,28 to generate valid statistical inferences that cept corresponded to the mean of the reference Am J Geriatr Psychiatry ●:●, ●●● 2009 rich3/jgp-ajgp/jgp-ajgp/jgp99908/jgp0562-09z
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group at endpoint and the unstandardized regres- Hypothesis Testing
sion weights reflected the difference between thegroups included in the model and the reference Table 2 shows the unadjusted means and standard group (excluded from the model). All significance deviations for all NP tests both pre and posttreat- tests were evaluated at the 5% level.
ment for the citalopram and placebo groups and thefour patient groups (treatment group by responderstatus). Adjusting for site and baseline MMSE and Digit Symbol, there was a statistically significant dif-ference between the placebo and citalopram condi- Descriptive Statistics
tions at endpoint on the Buschke SRT. Specifically,patients treated with citalopram scored lower at end- Table 1 presents baseline demographic and clinical point than patients treated with placebo (B ϭ Ϫ2.74, characteristics of the total sample, placebo and cita- SE ϭ 1.41, t[1,087] ϭ Ϫ1.94, 95% CI: Ϫ5.52 to 0.03, lopram groups, and the four groups of patients clas- sified by treatment condition and responder status.
We next compared the four groups of patients The average study participant was 79.57 years and classified according to treatment condition and re- completed about 2 years of college. Approximately sponder status on endpoint NP test performance. As 58% of the sample were women, average baseline can be seen in Table 2, citalopram responders scored depression severity was 24.32 on the 24-item HRSD, significantly higher than both citalopram nonre- and 40% of the sample was classified as responders.
sponders (B ϭ Ϫ2.54, SE ϭ 0.97, t[80.46] ϭ Ϫ2.54, The average MMSE score of the sample at baseline 95% CI: Ϫ4.38 to Ϫ0.53, p ϭ 0.01) and placebo non- was 27.99, and 6.9% had a score of 24 or below.
responders (B ϭ Ϫ2.47, SE ϭ 0.89, t(217.31) ϭ Ϫ2.77, To facilitate interpretation of the pattern of change 95% CI: Ϫ4.23 to Ϫ0.71, p ϭ 0.01) on the JOLO at in NP test performance as a function of treatment endpoint. However, citalopram responders were not group, all NP scores were converted to z-scoresbased on mean values at baseline in the total sample.
statistically significantly different than placebo re- As can be seen in Fig. 1, NP test performance im- sponders at endpoint (B ϭ Ϫ1.81, SE ϭ 1.02, t[111.56] ϭ proved on each test in the placebo group, which is Ϫ1.78, 95% CI: Ϫ3.83 to 0.20, p ϭ 0.08). Looking at consistent with a practice effect. For the purposes of endpoint performance on the Buschke SRT, citalo- this report, practice effects refer to improvement in pram nonresponders were the only group to decline performance due to repeat testing and are defined on from pretest to posttest. Specifically, citalopram non- the basis of the performance of the placebo group.
responders scored lower (3.64 points) than placebo Differences from the placebo group (both positive and nonresponders at study end (B ϭ Ϫ3.64, SE ϭ 1.83, negative) reflect deviations from a practice effect and t(472.15) ϭ Ϫ1.99, 95% CI: Ϫ7.23 to Ϫ0.05, p ϭ 0.05).
represent either improvement beyond a practice effect Similarly, citalopram nonresponders were the only or the absence of a practice effect, possibly even de- group to decline from pretest to posttest on the Digit cline. As can be seen in Fig. 1, the citalopram group Symbol. In particular, citalopram nonresponders improved on some tests and declined on others.
scored lower than citalopram responders at endpoint Baseline Clinical and Demographic Characteristics of the Total Sample, the Citalopram and Placebo Conditions, and
the Four Patients Groups Classified by Treatment Condition and Responder Status
Total Sample
Citalopram
Citalopram
Citalopram
Variable
(n ؍ 174)
Responders
Nonresponders
Responders
Nonresponders
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FIGURE 1.
Change in Cognitive Performance From Pre to Posttreatment in the (a) Placebo Condition and (b) Citalopram
Condition Across Six Neuropsychological Tests
(B ϭ Ϫ5.62, SE ϭ 2.65, t(233.31) ϭ Ϫ2.12, 95% CI: nonresponders on medication. Therefore, these find- ings suggest that patients should not be maintainedon a medication if they have not had an adequateresponse.
One possible explanation for the observed decline DISCUSSION
in verbal learning and psychomotor speed is that the This was the first study to examine the impact of overall level of cognitive functioning in the sample antidepressant treatment on change in cognitive was low and the citalopram group had a dispropor- functioning in depressed adults aged 75 years and tionately high number of cognitively impaired pa- older using data from an 8-week RCT. Although the tients. This might explain why there was inconsistent placebo group showed a distinct practice effect from improvement in the citalopram condition and why baseline to endpoint on all NP tests, the citalopram this study differs from previous placebo-controlled group improved on some tests but declined on oth- trials.8,15 However, the average MMSE score at base- ers. However, the pattern of change depended on line for the sample was 28, which is well within responder status. Specifically, citalopram nonre- normal limits. Moreover, although there was a sig- sponders were the only group to decline in perfor- nificant difference in MMSE scores between the treat- mance on verbal learning (Buschke SRT) and psy- ment groups at baseline, it was the citalopram group that scored higher at baseline than the placebo responders showed significant improvement in visuospatial functioning (JOLO), when compared Another possibility is that brain lesions, which are with nonresponders in either condition, but their associated with age30 and other risk factors such as improvement was not greater than responders on hypertension and diabetes,31 were disproportion- placebo. Similarly, citalopram responders showed ately represented in the citalopram condition. White greater improvement on psychomotor speed (Digit matter hyperintensities (WMH) that are characteris- Symbol) than citalopram nonresponders, but their tic of LLD may interrupt frontal-striatal pathways improvement was not greater than placebo respond- that mediate cognitive functions that are commonly ers or nonresponders. The findings indicate that the impaired in LLD. Furthermore, cognitive impair- practice effect is impaired in some domains among ment is associated with the presence of WMH in LLD Am J Geriatr Psychiatry ●:●, ●●● 2009 rich3/jgp-ajgp/jgp-ajgp/jgp99908/jgp0562-09z
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and deficits worsen as the lesions become more se- vere.2,5 However, there were no statistically signifi- cant differences in the percentage of patients in the citalopram group and the placebo group classified as having high lesion load, which was defined as a deep Nonresponders
WMH rating of 2 or a subcortical gray matter rating of 3 on the Fazekas modified Coffey Rating Scale for The decline in verbal learning may be particularly attributed to the anticholinergic effects of SSRIs. SSRIs have unique nonserotonergic pharmacologic profiles Subsamples
that are associated with distinct effects on cognitive Responders
functioning.33 Paroxetine, for example, may cause impairment in delayed verbal recall in healthy mid- dle-aged adults and elderly subjects, whereas sertra- line is associated with improvement in immediateand ncy.34,35 Although administration of citalopram is Citalopram
associated with improvement in working memory in depressed adults36 and increased memory consolida- Citalopram
Nonresponders
tion in healthy adults,37 it is still unclear what effect citalopram can have on cognitive functioning of the geriatric depressed, a population that is especially Endpoint
vulnerable to the adverse effects of antidepressant The observed decline in verbal learning and psy- chomotor speed in the citalopram group is consistent Baseline
Citalopram
Responders
with a recent report from an epidemiological study Responder
of elderly depressed patients examining the relation- ship among depressive symptoms, cognitive impair- ment, and antidepressant use.39 Findings revealed that baseline depression scores predicted future mild cognitive impairment (MCI) but only among those Condition
using antidepressant medications at baseline. Taken Performance
together, these findings support the contention that nonresponders should not be maintained on medi- Treatment
cation that may have a negative impact on some aspects of cognitive functioning, which may facilitatethe development of MCI.40 This study should be interpreted in the context of According
several limitations. First, there were statistically sig- nificant differences between the two treatment con- Neuropsychological
ditions and the four patient groups at baseline on Classified
Citalopram
several NP tests. However, these differences were adjusted for in the statistical models by including Unadjusted
those tests as covariates. Second, it may be possible that including a small number of MCI patients (MMSE Յ24) in this study (N ϭ 12) might have influenced our results. However, we ran the analyses Am J Geriatr Psychiatry ●:●, ●●● 2009 rich3/jgp-ajgp/jgp-ajgp/jgp99908/jgp0562-09z
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with and without this group of patients, and the respond on medication. Although responders on results were not different. Third, there was missing medication may improve in some domains, their data, as is typically the case in clinical trials, and we improvement does not exceed the expected practice accommodated for missing data using multiple im- effect observed in patients randomized to placebo.
putation, a far superior method compared with tra- This raises the important clinical issue that, although ditional approaches using mean substitution or com- two treatments may be equivalent with regard to plete case analysis. Fourth, a somewhat limited NP response, they may have differential effects on cog- battery was used. Only one aspect of executive func- nitive functioning, especially in a cognitively vulner- tioning (i.e., response inhibition) was evaluated, and able population. Our findings suggest that nonre- no formal test of attention was included in the study.
sponders should not be maintained on medication However, these limitations are balanced by using that may have a negative effect on some aspects of data from the only randomized, placebo-controlled clinical trial of antidepressant treatment among de-pressed patients aged 75 years or older. Moreover, This work was supported by a grant from Forest unlike other studies, there were an approximately Laboratories and National Institute of Mental Health equal number of responders in both treatment con- grants T32 MH20004 (to SPR) and K23 MH075006 (to ditions, allowing for an adequate test of whether JRS) and from Eli Lilly and Novartis (to DPD). change in cognitive function across two treatments SPR has received consultant fees from Forest Labo- ratories, Wyeth Pharmaceuticals, Sanofi-Anventis, Pfizer, Our findings indicate that citalopram may inter- and Sierra Pharmaceuticals and DPD has received con- fere with the normal practice effect in verbal learning sultant fees from Glaxosmithkline, Acadia, and Sanofi- and psychomotor speed among patients who do not References
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1—Kindly check whether the minor edit made to the article title is appropriate.
2—Kindly spell out the first name of the author “D.P. Devanand.” 3—Please note that the page foot note has been moved to the text as per journal style.
4 —Kindly spell out TCA and MAO-I.
5—Kindly check whether tables are OK as typeset.
6 —Kindly check whether the grant information and the disclosure are OK as typeset.
7—Please note that Ref. 19 (original number) has been deleted as it seemed to be repetition of Ref.
16 and also the corresponding references have been renumbered as to make it sequential perjournal style.
8 —Kindly provide department/division name (if any) for the affiliations.

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