Working Memory in Patients with Major Depressive Disorder

doi:10.4236/psych.2012.329115

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Psychology

2012. Vol.3, Special Issue, 75 8-761

Published Online September 2012 in SciRes (http://www.SciRP.org/journal/psych) http://dx.doi.org/10.4236/psych.2012.329115

758

Working Memory in Patients with Major Depressive Disorder

Yasuhiro Ka neda

Department of Psychiatry, Iwaki Clinic, Tokushima, Japan

Email: [email protected]

Received May 2nd, 2012; revised June 4th, 2012; accepted July 7th, 2012

Objective: Patients with major depressive disorder (MDD) have been reported to perform less well in

neurocognitive tests than normal control subjects. The author tested the hypotheses that verbal working

memory (WM) is predictive of the functional outcome in patients with MDD. Methods: In this naturalis-

tic longitudinal study, the subjects consisted of 22 adult outpatients receiving paroxetine as antidepressant

therapy. Functional outcome was rated on a scale of 0 (non-impaired) to 3 (severely impaired). Results: 1)

At 12 weeks, nine of the 22 patients currently experiencing MDD exhibited full remission; 2) signifi-

cantly decreased 7-item Hamilton Rating Scale for Depression (HAM-D7) scores were observed during

the 12-week study period, while Digit Sequencing Task (DST) scores increased significantly; 3) at base-

line, functional outcomes correlated significantly with HAM-D7 scores, but, at 12 weeks, correlated sig-

nificantly with bo th HAM-D7 and DST scores. Furthermore, when looking at only pa tients in full or partial

remission (mild depression), functional outcome correlated more strongly with DST than with HAM-D7

scores. Conclusions: A deficit of verbal WM correlated with the functional outcome after treatment in pa-

tients with MDD. Antidepressant therapy with paroxetine might contribute to improvement of verbal WM.

Keywords: Depression; Functional Outcome; Paroxetine; Symptomatlogy; Working Memory

Introduction

Major depressive disorder (MDD) is a significant health

problem, with major economic implications, and estimates of

the economic burden of depression range from $52 billion in

1990 to $83 billion in 2000 (Malone, 2007). Among others, the

effect on employment is considered to have a great impact on

the societal costs of depression, due to lost income, lost produc-

tivity, and disability income payments.

In previous studies (Kaneda et al., 2009, 2010), the author

demonstrated that neurocognitive performance was more im-

portant than the clinical symptoms in predicting the future em-

ployment status in patients with schizophrenia, and among the

neurocognitive functions, verbal working memory (WM) was

found to be the most important for determining the employment

outcome. Patients with MDD also have been reported to per-

form less well in neurocognitive tests than normal control sub-

jects, even after their depression is successfully treated with

newer-generation antidepressants (Gualtieri et al., 2006, Rep-

permund et al., 2009, Porter et al., 2003). Recently, Gualtieri &

Morgan (2008) reported that substantial numbers of patients

with depression exhibit cognitive impairment. However, until

date, little attention has been paid to the relation between neu-

rocognitive performance and the psychosocial or functional

outcomes in studies of depression compared to those of bipolar

disorder (Kennedy et al., 2007). Kitagawa & Koyama (2009)

have suggested a relationship between functional outcomes and

neurocognitive functions in depression, but their result has not

been duplicated.

Thus, the author first tested the hypothesis that the deficit of

neurocognitive performance, namely verbal WM, existed even

after remission (Kaneda, 2009b). In this naturalistic cross-sec-

tional study, the subjects consisted of 54 clinic adult out-patients

and 54 age- and sex-equated healthy comparison subjects. The

assessments were performed using the 7-item Hamilton Rating

Scale for Depression (HAM-D7) for the severity of depression,

and the Digit Sequencing Task (DST) for evaluation of verbal

WM (methodological details are described below). The DST

scores were significantly less in both patients with current epi-

sode of MDD and in full remitted or partial remitted (mildly

depressed) patients than in controls. Also there were no signify-

cant correlations between DST scores and the dose of antide-

pressants or benzodiazepines in full remitted or partial remitted

(mildly depressed) patients.

Since verbal WM was demonstrated to be poorly performed

in patients with MDD, another study was conducted to verify

the suggestion that verbal WM is predictive of the functional

outcome in patients with MDD after remission.

Methods

Subjects

Twenty-two consecutive adult outpatients (21 - 64 years of

age) were enrolled in this prospective, open-label study. All

subjects satisfied the DSM-IV (American Psychiatric Associa-

tion, 1994) criteria for a current episode of unipolar MDD (non-

psychotic) and were receiving paroxetine with or without sul-

piride or benzodiazepines. Patients had no co-morbid psychiat-

ric disorders, nor any medical, neurological, or developmental

conditions that could affect cognition (e.g., attention deficit

hyperactivity disorder, brain injury, mild cognitive impairment,

chronic pain). The investigation was carried out in accordance

with the Declaration of Helsinki, and informed consent was

obtained from all subjects.

Assessments

The assessments were performed using the following instru-

ments: 1) the 7-item Hamilton Rating Scale for Depression

Y. KANEDA

(HAM-D7; McIntyre et al., 2005) to determine the severity of

depression and remission status; full remission was defined as a

score of 3 or less, partial remission (mild depression) as a score

of 10 or less on the HAM-D7, and 2) the Brief Assessment of

Cognition in Schizophrenia (BACS; Keefe et al., 2004) Digit

Sequencing Task (DST) to assess verbal WM (the patients were

presented with clusters of numbers in random order of increas-

ing length, and asked to recount these numbers in the right or-

der, from lowest to highest, to the investigator). The BACS

DST has been validated in normal control subjects (Keefe et al.,

2004). The DST scores in each depression group were normal-

ized for the respective age- and sex-matched control groups

(data available on request). Functional outcome (productivity),

including the ability to go to work, do household chores, go to

school and so on, was assessed by the author based on inter-

views with patients and their partners/parents/children, and was

graded on a 0 - 3 scale: 0 = non-impaired, 1 = mildly impaired,

2 = moderately impaired, 3 = severely impaired. The clinical

assessments were performed on two occasions: 1) on the day of

entry and 2) after approximately 12 weeks (a mean period of

90.6 days, SD = 14.2).

Analyses

The JMI software (Version 8.0. 1) for Macintosh was used to

perform the analyses. For numerical variables, the t-test for

independent group comparisons was used to compare differ-

ences in variables between the two groups. The clinical assess-

ment scores were compared between the two assessments by re-

peated-measure analysis of variance (ANOVA). Pearson’s cor-

relation was used to examine the relationships between two

numerical variables. A logistic regression model with forward

selection criteria was used to predict functional outcomes using

functional outcome as a dependent variable and depressive and

verbal WM scores as independent variables. The level of sig-

nificance was set at p < .05.

Results

The demographic characteristics at baseline are presented in

Table 1. At baseline, eight of the 22 patients (36%) were taking

paroxetine, and two were taking sulpiride. In addition, 12 of the

22 patients (55%) were taking benzodiazepines. At the time of

the second assessment, all patients were receiving treatment

with paroxetine (mean dose, 28.8 mg), and one patient was tak-

ing sulpiride in addition to paroxetine. Fourteen of the 22 pa-

tients (64%) were being treated with benzodiazepines (mean

dose, 4.7 mg).

At the second assessment conducted after 12 weeks, accord-

ing to symptom severity scores, nine of the 22 patients (41%)

with a current episode of MDD were in full remission. In addi-

tion, normalization of work function was seen in eight patients

of these nine patients (89%).

A significant decrease in HAM-D7 scores from 11.0 ± 3.8 to

5.5 ± 4.9 (p < .0001) was observed during the 12-week study

period. In addition, DST scores (z-score) increased significantly

during the same period (from –1.1 ± 1.1 to –.7 ± 1.4, p < .05).

At baseline, functional outcomes were correlated signifi-

cantly with HAM-D7 scores (r = .56, p < .01), but not DST

scores, whereas at 12 weeks, functional outcomes correlated

significantly with both DST (r = –.46, p < .05) and HAM-D7 (r

= .72, p < .001) scores. When looking only at patients in full or

partial remission (mild depression), functional outcome corre-

lated more strongly with DST (r = –.74, p < .001) than with

HAM-D7 (r = .51, p < .05) scores.

There was no significant relation between DST and HAM-

D7 scoresat either baseline or at 12 weeks.

According to multiple regressi on analysis with a forward step-

wise procedure, the DST scores at baseline contributed more

strongly to the prediction of functional outcome at 12 weeks (F

= 1.9, df = 1, p = .19) than did HAM-D7 scores (F = .1, df = 1,

p = .74). On the other hand, HAM-D7 scores at baseline contri-

buted more strongly to the prediction of HAM-D7 scores at 12

weeks (F = 4.8, df = 1, p < .05) than did DST scores (F = 1.2, df

= 1, p = .29).

Discussion

The findings of this study suggest a correlation between a

verbal WM deficit associated with MDD and post-treatment

functional outcome. When looking at only patients in full or

partial remission (mild depression), the correlation was more

apparent. These ﬁndings are consistent with those of a previous

cross-sectional study carried out by the author (Kaneda, 2009a).

Kitagawa & Koyama (2009) have also suggested a relationship

between functional outcomes and neurocognitive functions in

depression. In their review, Kennedy et al. (2007) suggested

that residual symptoms after remission of depression may lead

to enduring psychosocial impairment, as many subtle neurocog-

nitive deficits. While the findings of this study do not under-

score the importance of clinical remission from depression, a

defined objective outcome indicated by a quantifiable score

with a depressive symptom measurement tool, symptomatic full

remission should always be the primary goal of treatment, since

it is the optimal outcome for patients with depression (McIntyre

et al., 2005). However, the present findings do suggest that en-

hancement of verbal WM function, e.g., via cognitive rehabili-

tation, may facilitate normalization of functioning which is an

important component of remission (Zimmerman et al., 2006).

In terms of predictive factors, previous studies have de-

scribed the value of neurocognitive functions for predicting

symptomatic improvement, mainly in geriatric patients with

depression (Marcos et al., 2005). However, in this study,

HAM-D7 scores were found to be more important for predict-

ing symptomatic improvement than DST scores used to assess

verbal WM, a finding well in line with that reported by Biringer

et al. (2007), who showed that neurocognitive function at base-

line did not predict amelioration of depressive symptoms over

time in young adults. The present results, however, suggest

verbal WM to be more important for predicting functional out-

Table 1.

Demographic Data.

N (F/M) Age (yr.) Education (yr.) Age at onset (y r. )Antidepressa n t dose (mg/d)a Benzodiazepines dose (mg/d)b

22 (9/13) 37.9 (13.3) 12.5 (2.9) 36.8 (13.0) 7.7 (13.3) 2.0 (3.2)

Note: Data are expressed as mea ns (SD); aParoxetine equivalent; bDiazepam equivalent.

Y. KANEDA

comes than depressive symptoms. Therefore, in order to obtain

a better functional outcome, it may be important to place more

emphasis on pretreatment verbal WM than depressive symp-

toms.

The findings of this study also suggest again that MDD-as-

sociated deficits in verbal WM exist both in acute depression

and after the treatment of depression. These ﬁndings are con-

sistent with those of previous studies conducted by the author

(Kaneda, 2009b) and by Nebes et al. (2003), who found that

verbal WM dysfunction persisted in older depressed patients

even after their mood disorder had responded to antidepressant

medications. The observations made herein may be explained

by an impairment of WM/central executive functions in MDD,

as suggested by Rose & Ebmeier (2006), since executive func-

tion impairment is considered to be, at least to some degree,

trait-related (Porter et al., 2003).

Regarding the effects of antidepressant medications on cog-

nitive function, a significant increase in DST scores was ob-

served during 12-week treatment with paroxetine in the present

study. Although a potential effect which would be maximized

by testing twice within 5 days (Keefe et al., 2004), cannot be

completely ruled out, paroxetine is suggested to possibly im-

prove cognitive function in depressed subjects. Antidepressant

medications may also have some negative effects on cognitive

function (Gorenstein et al., 2006, Hindmarch, 2009). Cassano et

al. (2002), in their double-blind, randomized, parallel-group,

multicenter study comparing paroxetine and fluoxetine treat-

ment for 1 year, found that improvement, rather than deteriora-

tion, was observed in most of the tested cognitive functions. It

has been speculated that paroxetine may have indirect effects

which improve cognitive function via amelioration of depres-

sion, and that this could outweigh the mildly toxic effects of

paroxetine (Hindmarch, 2009).

A limitation of this study is that the possible influence of

benzodiazepines (Stewart, 2005) on verbal WM function could

not be completely ruled out. Another limitation of this study is

that patients with full and partial remission (mild depression)

were analyzed together, mainly because there were few patients

with full remission. Also, a longer observation may be needed

to allow sufficient recovery of verbal WM function. Therefore,

a further long-term study of patients showing remission of de-

pression, who are no longer taking medication, might be neces-

sary to confirm the present results.

Acknowledgements

This work was supported in part by grants from Daido Life

Welfare Foundation (2009), the Japanese Association of Neuro-

Psychiatric Clinics (Ken TANAKA Memorial Grant, 2008),

and the Charitable Trust Kimi IMAI Memorial Stress Associ-

ated Diseases Research Aid Fund (2009, 2010). This study was

presented in part at the 20th Annual Meeting of the Japanese

Society of Clinical Neuropsychopharmacology, held jointly with

the 40th Annual Meeting of the Japanese Society of Neuropsy-

chopharmacology, in Sendai, Japan, and 164th Annual Meeting

of the American Psychiatric Association in Honolulu, USA.

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