Abstract

Several studies have demonstrated impaired performance in inhibition and semantic fluency in the acute phase of illness in patients with recurrent major depression. However, few studies have investigated these functions longitudinally, focusing on how these impairments relate to symptoms over time. The present longitudinal study investigated whether the specific impairment in inhibition and semantic fluency seen in the acute phase of Major Depressive Disorder (MDD) was prolonged or normalized with symptom reduction in a 9-month follow-up. Twenty recurrent major depressive patients and 19 control subjects were included in the study. Inhibition and semantic fluency were investigated using tests from the Delis–Kaplan Executive Function System. The results show that the patient group still had significantly lower scores in inhibition and semantic fluency compared with the control group despite significant symptom reduction. Further, the results show that impaired inhibition in the acute phase was strongly correlated with impaired inhibition in the follow-up, suggesting that the inability to inhibit may represent a trait marker in recurrent MDD.

Introduction

Cognitive impairment in the acute phase of Major Depressive Disorder (MDD) has frequently been documented in the literature during the past decade (for reviews, seeAustin, Mitchell, & Goodwin, 2001; Hammar & Årdal, 2009; Rogers et al., 2004). Further, there has been a growing focus on how the cognitive impairment develops over time and on how it relates to a reduction in depressive symptoms (Hammar & Årdal, 2009). However, longitudinal studies are few and divergent with respect to inclusion criteria and the cognitive domains of interest.

Following the results from a study of cognitive functioning in the acute phase of MDD (Hammar et al., 2011), the present study investigated inhibition and semantic fluency in a longitudinal perspective by following the same patient group over a 9-month period. Hammar and colleagues (2011) tested the cognitive effort hypothesis as postulated in the literature regarding the cognitive profile of MDD patients (Hammar, 2003; Hammar, Lund, & Hugdahl, 2003; Hasher & Zacks, 1979) within the executive function (EF) domain. Several measures of both basic and more effortful cognitive measures were investigated in MDD patients (Hammar et al., 2011). The results from the acute phase did not support the cognitive effort hypothesis in general but, however, demonstrated a specific impairment in the cognitive functions of inhibition and semantic fluency in recurrent MDD. Importantly, the results in the acute phase of illness showed that neither a general psychomotor retardation nor poor mental flexibility could explain the results (Hammar et al., 2011). Further, the results were not correlated with depression severity (Hammar et al., 2011). An important question that arose from the results in the acute phase was whether the observed impairment in inhibition and semantic fluency would be prolonged or would normalize in parallel with symptom reduction.

Although impairment in inhibition in patients with MDD in the acute phase of illness has frequently been reported (Den Hartog, Derix, Van Bemmel, Kremer, & Jolles, 2003; Gohier et al., 2009; Hammar et al., 2011; Markela-Lerenc, Kaiser, Fiedler, Weisbrod, & Mundt, 2006; Stordal et al., 2005), there are only a small number of longitudinal studies which focus on inhibition. Prolonged impairment in inhibition has been reported in patients diagnosed with recurrent MDD in follow-up studies of various time-spans during symptom reduction (Årdal & Hammar, 2010; Biringer et al., 2005; Hammar et al., 2009; Trichard et al., 1995). These studies have followed the same patient and control group in different phases of depression. Moreover, a number of studies report impaired inhibition in remitted MDD patients (Nakano et al., 2008; Paelecke-Habermann, Pohl, & Leplow, 2005; Paradiso, Lamberty, Garvey, & Robinson, 1997; Smith, Muir, & Blackwood, 2006). One study found inhibition to be unimpaired in phases of remission (Merens, Booij, & Van der Does, 2008). In sum, the literature shows that impaired inhibition is a group characteristic associated with the acute phase of MDD. Further, there are indications showing that this impairment might be prolonged despite symptom reduction and recovery. In order to clarify the question of a potential long lasting impairment in inhibition, more longitudinal studies investigating this cognitive function are needed.

In addition to the impairment in inhibition found in the acute phase of illness in the present patient group, the results also showed impaired semantic fluency (Hammar et al., 2011). Previous studies have reported semantic fluency to be impaired in MDD during the acute phase of illness (Calev, Nigal, & Chazan, 1989; Fossati, Amar, Raox, Ergis, & Allilare, 1999; Fossati, Guillaume, Ergis, & Alular, 2003; Grant, Thase, & Sweeney, 2001; Ravnkilde et al., 2002; Trichard et al., 1995) and in a long-term perspective (Biringer et al., 2005; Nakano et al., 2008; Neu et al., 2005; Reischies & Neu, 2000). Others have found intact semantic fluency in the acute phase of MDD (Austin et al., 1999). Trichard and colleagues (1995) found that semantic fluency to be impaired in the acute phase of MDD. However, this impairment normalized with symptom reduction. In sum, the literature points to an association between depression and impairment in semantic fluency, both in the acute phase and with symptom reduction. Together, inhibition and semantic fluency might be of particular interest in characterizing cognitive difficulties in MDD. Such an interpretation is confirmed in a study by Biringer and colleagues (2005). Investigating executive functioning in MDD patients, they found a long-lasting impairment in inhibition and verbal fluency in a 2-year follow-up study, whereas other measures of executive functioning were normalized.

The aim of the present longitudinal study was to investigate whether the impaired performance in inhibition and semantic fluency in the acute phase of MDD is prolonged or normalizes with symptom reduction in a 9-month follow-up. In accordance with the few longitudinal studies focusing on these cognitive functions, we hypothesized that the patient group would still show impairment in inhibition and semantic fluency during symptom reduction in a 9-month follow-up compared with the healthy control group. And further, for the patient group, we expected that the patients would show a consistent within subject performance from the acute phase to the follow-up assessment, suggesting an individual stability of performance from initial testing to follow-up.

Method

All patients were tested on two occasions: once in the acute phase (T1) and once at the 9-month follow-up (T2). At T1, 24 patients (18 women and 6 men) meeting the DSM-IV criteria (American Psychiatric Association, 2000) for a unipolar recurrent MDD diagnosis, using MINI-International Psychiatric Structural Interview (Leiknes, Leganger, Malt, & Malt, 1999), were included in the study (Hammar et al., 2011). Severity of depression was assessed using two structural rating scales: the Hamilton Depression Rating Scale (HDRS; Hamilton, 1960) and the Montgomery Åsberg Depression Rating Scale (MADRS; Montgomery & Åsberg, 1979). Vision and hearing were normal or corrected to normal.

Inclusion criteria were a minimum of two previous episodes of MDD, and a minimum score of 20 on MADRS and a minimum of 18 on HDRS, indicating a moderate to severe depression. Mean number of hospitalizations was reported by the patients at T1 to be 2.41, with a standard deviation of 1.60, and the mean number of weeks in hospital was reported to be 9.0, with a standard deviation of 15.15. All patients informed that they were prescribed antidepressant medication. The majority of patients were prescribed newer antidepressant medication (selective serotonin reuptake inhibitor, SSRI), except for four patients who used tricyclic antidepressants (TCA). Patients were recruited from the Department of Affective Disorders at Haukeland University Hospital. Patients with a history of known brain damage, alcohol and/or substance abuse and/or psychosis, or if they had been treated with electroconvulsive therapy were excluded from the study.

At T1, a control group consisting of twenty-four healthy subjects (18 women and 6 men) was individually matched to the patient group on age and years of education (within a ±2-year limit). Exclusion criteria for the control group were a history of brain damage, any mental disorder and/or alcohol and/or substance abuse. The control group were asked at inclusion and excluded from the study, if they reported a history of depressive symptoms or other mental illness. The control subjects were recruited among friends and family of the employees of the Department of Biological and Medical Psychology, University of Bergen, and among employees in the healthcare sector.

All patients went through the diagnostic assessment at both T1 and T2. At T2, the mean score on MADRS and HDRS showed a symptom reduction, indicating a level of mild depression (see Table 1 for clinical and demographic variables at T2). For the neuropsychological assessment, data from four patients and five control subjects were not included at T2 due to dropout. For one patient, the only cognitive test administered at T2 was the Color-Word Interference Test. This patient was not able to complete testing due to anxiety and depressive symptoms. At T2, three of the patients used TCA. The remainder of the patients included at T2 was prescribed SSRIs at the time of testing.

Table 1.

Clinical and demographic variables for the patient group and the control group at T2

 T2
 
 Patient group, N = 20
 
Control group, N = 19
 
 M SD M SD 
Age 38.85 11.46 38.15 10.84 
Years of education 12.45 2.21 12.85 2.32 
IQ at T1a 105.58 10.86 110.5 7.97 
MADRS scoreb 14.65 6.04 c c 
HDRS scoreb 11.75 4.61 c c 
 T2
 
 Patient group, N = 20
 
Control group, N = 19
 
 M SD M SD 
Age 38.85 11.46 38.15 10.84 
Years of education 12.45 2.21 12.85 2.32 
IQ at T1a 105.58 10.86 110.5 7.97 
MADRS scoreb 14.65 6.04 c c 
HDRS scoreb 11.75 4.61 c c 

Notes: MADRS = Montgomery Åsberg Depression Rating Scale; HDRS = Hamilton Depression Rating Scale.

aThere was no significant difference between groups on total IQ as measured by WASI at T1.

bPatients were screened at testing.

cHealthy control group, no history of mental illness.

Procedure

At T2, the Color-Word Interference Test and the Verbal Fluency Test from Delis–Kaplan Executive Function System (D-KEFS) were administered. Informed consent was obtained from all participants at T1. The study was performed in accordance with the Helsinki Declaration of the World Medical Association Assembly. The Regional Committee for Medical Research Ethics and The Norwegian Data Inspectorate approved the study.

Neuropsychological Assessment

The D-KEFS Color-Word Interference Test contains the four following conditions: (1) Color Naming (C), (2) Word Reading (W), (3) Inhibition (the classic Stroop condition) (CW), and (4) Inhibition/Switching (IS). In Conditions 1 and 2 successively, basic cognitive skills such as naming of color patches and reading of words are measured. In Condition 3, the subject is asked to inhibit reading the colored words but to name the incongruent ink color the words are written in, and thereby to inhibit the automatic response of reading. In Condition 4, the subject is asked to inhibit reading the colored words but to name the incongruent ink color the words are written in, except reading the colored words when the words are presented within a frame. In Condition 4, the ability to inhibit an automatic response of reading and the ability to shift mental set (mental flexibility) are measured. For the D-KEFS Color-Word Interference Tests, an internal consistency value between 0.72 to 0.82 (combined color naming and word reading composite score) are reported for the age group between 20 and 49. Test–retest reliability statistics for all ages are reported to be 0.76 for Condition 1, 0.62 for Condition 2, 0.75 for Condition 3, and 0.65 for Condition 4 (Delis, Kaplan, & Kramer, 2001b).

The D-KEFS Verbal Fluency Test includes three conditions: (1) Letter Fluency (F, A, and S), where the subjects are to name phonemically lexical items beginning with F, A, or S within a 60-s time limit for each trial, (2) Category Fluency (animals and boys' names), where the subjects are to say as many boys' names and animals as possible within a 60-s time limit for each trial, (3) Category Switching (fruit and furniture), where the subjects are to switch successively between categories, naming fruits and furniture, within a 60-s time limit. All three conditions measure cognitive skills such as vocabular knowledge, spelling ability, and basic attention. For the specific conditions, cognitive functions that are measured are systematic retrieval of phonemically similar lexical items (FAS, Condition 1), rapid retrieval of multiple words from a semantic category (Category Fluency, Condition 2), and set shifting (Category Switching, Condition 3). For the D-KEFS Verbal Fluency Test internal consistency values for the age groups 20–49 are reported to be between 0.77 and 0.90 for Condition 1, between 0.61 and 0.76 for Condition 2, between 0.43 and 0.68 for Condition 3, and between 0.59 and 0.72 for an additional score obtained in Condition 3 (the total switching accuracy). Test–retest reliability statistics for all ages are reported to be 0.80 for Condition 1, 0.79 for Condition 2, 0.52 for Condition 3, and also for Condition 3, test–retest reliability statistics are given for total switching accuracy to be 0.36 (Delis et al., 2001b).

The D-KEFS further provides an investigation of contrast scaled scores for each test to investigate more thoroughly impaired performance in the different conditions of the test. Each contrast measure is derived by subtracting the completion-time scaled score for one-component tasks, such as naming colors or reading words, from the completion-time scaled score for one of the EF tasks, such as Condition 3 (Inhibition) and Condition 4 (Inhibition/Switching). A new scaled score is then derived from the scaled score difference, which can give information about how to interpret an impaired score. The contrast scaled scores have a mean of 10, and a standard deviation of 3. A contrast scaled score between 8 and 12 reflects an equivalent level of performance on the EF task and on the component task. A contrast scaled score of 13 or higher reflects a better performance on the EF task relative to the component task and a contrast scaled score of 7 or lower indicates worse performance on the EF task. The D-KEFS also provides the opportunity to pursue error analysis for the different conditions (Delis, Kaplan, & Kramer, 2001a).

Data Scoring and Analyses

A repeated-measures analysis of variance (ANOVA) was conducted to assess the performance of the patient group and control group across two time points (T1 and T2). For the Color-Word Interference Test, the basic design was a 2 × 2 × 4 factorial design with Group (depressed patients and control subjects) × Test occasion (Test 1 and Test 2) × condition (C, W, CW, and IS). Data used were raw scores, that is, seconds to complete the different conditions. For the Verbal Fluency Test, the basic design was a 2 × 2 × 3 factorial design with Group (depressed patients and control subjects) × Test occasion (Test 1 and Test 2) × condition (FAS, Category fluency and Category switching). Data used were raw scores, that is, number of words produced within the time limit specified for each condition.

A one-way between-groups ANOVA was further conducted to assess the differences between the two groups on each condition at T2. In the Inhibition condition, and in the Category Fluency condition, the assumption of homogeneity of variance was violated. The robust test of equality of means, Brown–Forsythe test, is therefore reported for these conditions. To further examine the performance for the patient group on the different conditions at T2, mean contrast scaled scores were computed for the Color-Word Interference Test in order to interpret an impaired score. Data used were the sum of contrast scaled scores provided for each individual by the D-KEFS, divided by the number of patients. Error analysis was conducted using independent samples t-tests comparing the two groups on the proportion of errors made in the different conditions. A paired sample t-test was conducted to assess the difference in depression severity in the patient group between T1 and T2. Further, partial correlations were conducted to explore the relationship between scores on the Inhibition condition and the Category (semantic) Fluency condition at T1 and T2, while controlling for depression severity measured at both test occasions.

Results

There was a statistically significant decrease in depression severity scores measured by HDRS from T1 (M = 23.00, SD = 4.71) to T2 (M = 11.75, SD = 4.61), t(19) = 7.208, p < .0005 (two tailed). The mean decrease in HDRS was 11.25 with a 95% confidence interval ranging from 7.983 to 14.517.

There was a statistically significant decrease in depression severity scores measured by MADRS from T1 (M = 26.60, SD = 5.14) to T2 (M = 14.65, SD = 6.04), t(19) = 5.535, p < .0005 (two tailed). The mean decrease in MADRS was 11.95 with a 95% confidence interval ranging from 7.432 to 16.468.

Color-Word Interference Test

There was a significant main effect of group: F(1, 37) = 8.176, p = .007, partial η2 = 0.18, showing a significant difference between groups in test scores across the time period from T1 to T2. There was a main effect for the condition, Wilks' λ = 0.06, F(3, 35) = 186.32, p = .000, partial η2 = 0.94, showing that the scores in the four conditions differ significantly. There was a main effect of time: Wilks' λ = 0.88, F(1, 37) = 5.142, p = .029, partial η2 = 0.12, showing that the scores in the two groups change from T1 to T2.

The two-way interaction of time and group was not significant, showing that there is no significant difference in the effect of time on scores from T1 to T2. Further, the two-way interaction between group and condition, the two-way interaction of time and condition, and the three-way interaction between time, condition, and group were not significant, showing that the groups did not change significantly in scores on the different conditions from T1 to T2 (Fig. 1).

Fig. 1.

Mean scores for the four conditions in the Color Word Interference Test for the patient group and control group at initial tesing (T1) and at follow-up assessment (T2). Asterisks denote the significant differences between the groups at both T1 and T2.

Fig. 1.

Mean scores for the four conditions in the Color Word Interference Test for the patient group and control group at initial tesing (T1) and at follow-up assessment (T2). Asterisks denote the significant differences between the groups at both T1 and T2.

The results showed that the patient group used significantly more time to complete Condition 1 (Color Naming), Condition 3 (Inhibition), and Condition 4 (Inhibition/Switching) compared with the control group at T2. There were no significant differences between the two groups on Condition 2 (Word Reading; Table 2 and Fig. 1).

Table 2.

Performance on the CWIT and the VFT for the patient group (N = 20) and the control group (N = 19) at T2

Test Measure Patient group
 
Control group
 
Statistics
 
  M SD M SD Sig. Eta Sq. 
CWIT 
 Color naming STC 33.95 7.85 29.42 4.70  
 Word reading STC 26.55 13.71 21.31 2.89 p = .112 .067 
 Inhibition STC 58.50 18.83 48.95 7.95  
 Inhibition/Switching STC 65.45 19.12 52.16 10.06  
VFT 
 Letter Fluency NWP 44.95 9.46 46.84 17.02 p = .674 .005 
 Category Fluency NWP 42.00 5.90 49.95 8.92  
 Category Switching NWP 14.11 1.66 15.42 2.39 p = .056 .097 
Test Measure Patient group
 
Control group
 
Statistics
 
  M SD M SD Sig. Eta Sq. 
CWIT 
 Color naming STC 33.95 7.85 29.42 4.70  
 Word reading STC 26.55 13.71 21.31 2.89 p = .112 .067 
 Inhibition STC 58.50 18.83 48.95 7.95  
 Inhibition/Switching STC 65.45 19.12 52.16 10.06  
VFT 
 Letter Fluency NWP 44.95 9.46 46.84 17.02 p = .674 .005 
 Category Fluency NWP 42.00 5.90 49.95 8.92  
 Category Switching NWP 14.11 1.66 15.42 2.39 p = .056 .097 

Notes: See text for statistical analysis. CWIT = Color Word Interference Test; VFT = Verbal Fluency Test; STC = Seconds To Complete;

NWP = Number of Words Produced.

*Significant at p < .05.

In Condition 1, Color Naming (C), the patient group used significantly more time to complete the trial (M = 33.95, SD = 7.85) compared with the control group (M = 29.42, SD = 4.70) at T2, F(1, 37) = 4.711, p = .036, partial η2 = 0.11 (Table 2).

In Condition 3, Inhibition (CW), the patient group used significantly more time to complete the trial (M = 58.50, SD = 18.83) compared with the control group (M = 48.95, SD = 7.94), at T2, F(1, 37) = 4.332, p = .047, partial η2 = 0.10 (Table 2).

In Condition 4, Inhibition/Switching (IS), the patient group used significantly more time to complete the trial (M = 65.45, SD = 19.12) compared with the control group (M = 52.16, SD = 10.06) at T2, F(1, 37) = 7.267, p = .011, partial η2 = 0.16 (Table 2).

The computation of a mean contrast scaled score for the patient group when the performance on the Color Naming condition had been factored out from the Inhibition condition showed a mean contrast scaled score of 11.8, indicating that the patient group had an equivalent level of impaired performance on the Inhibition condition relative to the Color Naming condition. The impaired performance on color naming can therefore not explain the impaired performance on the Inhibition condition.

The computation of a mean contrast scaled score for the patient group when the performance on the Inhibition condition had been factored out from the Inhibition/Switching condition showed a mean contrast scaled score of 10.0, indicating that the patient group shows an equivalent level of impaired performance on the Inhibition/Switching condition relative to the Inhibition condition. These results indicate that the patient group is equally impaired under both conditions.

The patient group (M = 1.50, SD = 1.61) made significantly more total errors compared with the control group (M = 0.21, SD = 0.54) at T2 on Condition 4, Inhibition/Switching (IS), t(23,38) = 3.398, p = .002.

There was no significant difference between the patient group and the control group on total errors made on Condition 1, Color Naming (C), or Condition 3, Inhibition (CW).

Verbal Fluency Test

There was a significant main effect of group, F(1, 36) = 4.58, p = .039, partial η2 = 0.11, showing a significant difference between groups in test scores across the time period from T1 to T2. There was a main effect for the condition, Wilks' λ = 0.039, F(2, 35) = 430.88, p = .000, partial η2 = 0.96, showing that the scores in the three conditions differ significantly. The two-way interaction between time and condition was significant, Wilks' λ = 0.724, F(2, 35) = 6.65, p = .004, partial η2 = 0.27, showing that time had a significant effect on scores in the different conditions. The two-way interaction between group and condition was also significant, Wilks' λ = 0.717, F(2, 35) = 6.90, p = .003, partial η2 = 0.28, showing that the group performance changed significantly on one or more conditions from T1 to T2.

There was no significant main effect of time, and the two-way interaction of time and group was not significant, showing that there is no significant effect of time on the difference between the groups. Further, the three-way interaction between time, condition, and group was not significant, showing that the difference in scores between groups did not change significantly from T1 to T2 (Fig. 2).

Fig. 2.

Mean scores for the three conditions in the Verbal Fluency Test for the patient group and control group at initial tesing (T1) and at follow-up assessment (T2). Asterisks denote the significant differences between the groups at both T1 and T2.

Fig. 2.

Mean scores for the three conditions in the Verbal Fluency Test for the patient group and control group at initial tesing (T1) and at follow-up assessment (T2). Asterisks denote the significant differences between the groups at both T1 and T2.

The results show that the patient group (M = 42.00, SD = 5.89) produced significantly fewer words in a 2-min time limit compared with the control group (M = 49.95, SD = 8.92) in the Category Fluency condition at T2, F(1, 31,207) = 10.49, p = .003, partial η2 = 0.23. There were no significant differences between the patient group and the control group on performance in the Letter Fluency condition and the Category Switching condition (Table 2 and Fig. 2).

There was no significant difference between the patient group and the control group on total errors made on Condition 2, Category Fluency.

There was a significant positive partial correlation between scores on the Inhibition condition at T1 and scores on the Inhibition condition at T2, while controlling for depression severity measured by MADRS at both T1 and T2, r = .612, n = 20, p < .003. Impaired performance in the acute phase (T1) was associated with impaired performance in symptom reduction (T2). An inspection of the zero-order correlation (r = .724) suggested that controlling for depression severity had a small effect on the strength on the relationship between these two variables. There was no significant partial correlation between scores on the Category Fluency condition at T1 and scores on the Category Fluency condition at T2. Controlling for depression severity measured by MADRS at both T1 and T2 did not have any effect on this relationship.

Four of the patients from T1 did not meet for the second test at T2. A descriptive investigation of the variables describing these four patients showed that these patients did not differ in terms of years of education, but they showed a higher mean age and mean MADRS score and slightly poorer test performance on the cognitive tests at T1 compared with the patients included at T2 (Table 3).

Table 3.

Education, age, HDRS, MADRS, and scores on Conditions 1, 3, and 4 in the CWIT, and scores on Condition 2 in the verbal fluency test at T1 for 20 patients included at T2, and four patients not included at T2 due to dropout

 Mean scores at T1 for 20: patients included at T2
 
Mean scores at T1 for four patients: not included at T2
 
 M SD M SD 
Years of education 12.40 2.01 12.50 1.0 
Age 37.90 11.67 39.0 11.77 
HDRS 23 4.71 19.25 0.96 
MADRS 26.60 5.14 29.50 5.44 
Color naming, Condition1 35.35 8.08 35.0 5.94 
Inhibition, Condition 3 62.1 14.77 62.75 27.58 
Inhibition/switching, Condition 4 68.1 15.62 69.25 25.32 
category fluency, Condition 2 40.1 9.5 44.0 7.79 
 Mean scores at T1 for 20: patients included at T2
 
Mean scores at T1 for four patients: not included at T2
 
 M SD M SD 
Years of education 12.40 2.01 12.50 1.0 
Age 37.90 11.67 39.0 11.77 
HDRS 23 4.71 19.25 0.96 
MADRS 26.60 5.14 29.50 5.44 
Color naming, Condition1 35.35 8.08 35.0 5.94 
Inhibition, Condition 3 62.1 14.77 62.75 27.58 
Inhibition/switching, Condition 4 68.1 15.62 69.25 25.32 
category fluency, Condition 2 40.1 9.5 44.0 7.79 

Notes: MADRS = Montgomery Åsberg Depression Rating Scale; HDRS = Hamilton Depression Rating Scale.

Discussion

The results from the present study support the hypothesis that the patient group performs significantly worse compared with the healthy control group in inhibition and semantic fluency despite symptom reduction. The results show that the two groups' performances do not change markedly from initial testing to the follow-up assessment. Further, the results show that for the ability to inhibit, impaired performance in the acute phase was correlated with impaired performance in the follow-up assessment, indicating that the patients that performed worse in the acute phase also performed worse at follow-up. An inspection of the zero-order correlation showed that depression severity did not have an impact on this relationship. However, this pattern of within patient performance was not found for performance in semantic fluency.

Further, the results showed that the patient group still had a significantly poorer performance compared with the control group on the Color Naming and Inhibition/Switching condition of the Color-Word Interference Test. However, a calculation of mean contrast scaled scores show that the patient group performed equally poorly under all three conditions; Color Naming, Inhibition and Inhibition/Switching. Further, an interpretation of a general psychomotor retardation, or impairment in mental flexibility, was not supported by the extensive test battery in the acute phase of illness (Hammar et al., 2011). Thus, it is not a likely explanation at the follow-up assessment.

The results in the present study make an important contribution to the scarce existing literature on follow-up studies regarding continuing cognitive impairments in inhibition and semantic fluency in MDD. The results confirm previous findings showing that this subgroup of patients is characterized by impairment in inhibition and semantic fluency, both in the acute phase of illness and with symptom recovery. These findings are important to highlight in that one can interpret the impairment seen in inhibition and semantic fluency to be characteristic for this patient group, maybe representing a vulnerability factor contributing to the prevalence of recurrence. Depressed patients are characterized by rumination of negative thoughts and negative self-evaluation. Further, ruminative thoughts have been associated with vulnerability to the development and recurrence of depression (Nolen-Hoeksema, 2000). These ruminative thoughts are often described by patients to be unintentional and difficult to control. However, little is known about the cognitive processes that control the tendency to ruminate (for review, seeGotlib & Joorman, 2009). Based on findings of impaired inhibition in MDD patients in the literature, Joorman and colleagues (2007) postulate in a review on cognitive inhibition in depression that the inability to inhibit irrelevant stimuli may represent an underlying cognitive impairment which contributes to sustained negative thoughts and rumination. They, and others, argue that inhibition can be understood as a cognitive process which controls the individual's processing of internal and external stimuli (Gohier et al., 2009; Joormann, Yoon, & Zetsche, 2007). The ability to inhibit the processing of irrelevant stimuli reaching attention makes the individual more in control of his or her behavior and emotional responses (for review, seeGotlib & Joorman, 2009). Studies have demonstrated that deficits in inhibition are correlated with sustained processing of negative information and that samples of depressed individuals shows impaired ability to inhibit negative stimuli (for review, seeGotlib & Joorman, 2009). The inability to inhibit unwanted, automatic negative thoughts may therefore represent a vulnerability factor, making the individual more vulnerable for experiencing depressive thoughts and feelings, which again may lead to the development of relapses and recurrences, which has been shown to characterize this patient group. The finding of prolonged inability to inhibit despite symptom reduction in the present study may represent one step in the right direction in gaining more knowledge about the cognitive function of this subgroup of depressive patients.

Further, the impaired performance in the Category (semantic) Fluency condition indicates difficulties in the ability to rapidly generate words from a semantic category. The clinical implication of impaired Category (semantic) Fluency is difficult to understand, but important to pursue further in the light of literature, which reports that MDD patients to be impaired on this cognitive function both in the acute phase of illness and in a long-term perspective. Neu and colleagues (2005) postulate that the ability to perform well on a semantic fluency task demands organized retrieval strategies and word generation. Fossati and colleagues (2003) has argued that performance on this task depends on the integration of semantic knowledge. This may indicate that an impaired performance can be caused by a less integrated semantic network, which leads to disorganized retrieval processes, making it difficult to retrieve words belonging to the same category.

Following these interpretations, together with the impaired inability to inhibit, MDD patients may experience difficulties in inhibiting a dysphoric affect and negative thoughts and to change course, retrieving new, preferable positive thoughts. MDD patients may experience difficulties in expanding the category of positive concepts as alternatives to the negative and in strengthening the association between them. More specific knowledge about how this patient group functions cognitively may contribute to more efficient treatment. Training patients in the ability to inhibit, taking more control of which stimuli to attend to and in addition change course, may reduce sustained negative thoughts and rumination.

When discussing the implications of impaired inhibition and semantic fluency in MDD, it is important to emphasize that the inability to inhibit seems to represent a stable individual deficit across the time period from initial testing to the follow-up assessment for the patient group. The patients showed an individually stable level of performance on this task both in the acute phase of illness and after symptom reduction. This pattern can be interpreted to represent a vulnerability trait for recurrent depression. However, in order to fully understand this relationship, more studies are needed which longitudinally investigates the cognitive function of inhibition in MDD patients, also including patients experiencing their first episode. Following a group of first episode patients will give the opportunity to correlate the prevalence of relapses or recurrence to the ability to inhibit.

Surprisingly, the relationship regarding the individual stability of performance from initial testing to the follow-up assessment for the patient group was not found for semantic fluency. There was no correlation between the individual scores in the acute phase and in follow-up. This may indicate that the performance on this test is more dependent on other factors that characterize this patient group and can represent an impairment that is present at different phases in recurrent MDD. The significantly poorer performance seen in semantic fluency at follow-up assessment can therefore not be regarded as a stable trait characterizing this patient group to the same degree as the inability to inhibit. However, at a group level, the patient group still show a poorer performance compared with the control group on this task at follow-up. The performance in semantic fluency should therefore be further investigated in order to clarify the relationship between the development and course of depression and impaired performance in semantic fluency.

Methodological Considerations

The present study has included a relatively small number of subjects, which may affect the power of the tests used to identify differences between the two groups and increases the likelihood of a type II error, thus failing to identify differences between the two groups. However, the inclusion of a well-defined patient group and the inclusion of a control group that have been individually matched to the patient group on age, gender and education strengthen the study. Further, the present study is longitudinal, following the same patient and control groups over time and investigating several measures of cognitive functions in recurrent MDD in the acute phase of illness and following the findings in relation to symptom reduction.

It is important to consider the effect medication can have on cognitive performance. However, in the present study, the majority of patients were prescribed newer antidepressant medication, SSRIs. Three patients were prescribed TCA at follow-up, which have been shown to affect cognitive performance compared with SSRIs (Biringer, Rongve, & Lund, 2009; Peretti, Judge, & Hindmarch, 2000). However, when statistically adjusting for the patients using tricyclic antidepressant in the acute phase of illness, the results did not change (Hammar et al., 2011). Further, an inspection of the mean scores for the three patients prescribed tricyclic antidepressant medication at follow-up did not indicate a notably poorer performance compared with the mean scores on the cognitive tests administered.

The D-KEFS is a relatively new set of tests developed to measure EFs (Delis et al., 2001a) and, to our knowledge, the D-KEFS has not been administered to samples of depressed patients prior to this longitudinal study. As reported in the method section, the internal consistency and test–retest reliability for the switching conditions of both the verbal fluency test and the color-word interference test are moderate to low (Delis et al., 2001b). Further, the validity of the D-KEFS tests has received criticism (Shunk, Davis, & Dean, 2006; Schmidt, 2003). However, researchers find D-KEFS to be a sensitive tool in the assessment of EF deficits in numerous clinical populations (Delis, Kramer, Kaplan, & Holdnack, 2004; Homack, Lee, & Riccio, 2005). The D-KEFS tests which we used in the present study are both adaptations of commonly used clinical neuropsychological tests to assess cognitive function in clinical populations (Årdal & Hammar, 2010; Biringer et al., 2005; Hammar et al., 2009, 2011). Further, the inclusions of a well-matched control group, and the analysis of raw scores when comparing the two groups, represent strengths of the present study that could contribute in overcoming the challenges regarding reliability and validity when using the D-KEFS.

Conclusion

In conclusion, the present longitudinal study shows that a group of recurrent MDD patients has a prolonged impairment in inhibition. Further, there was an individual consistent performance from the acute phase to the follow-up assessment, which may indicate that the inability to inhibit may represent a trait characteristic of individuals experiencing recurrent MDD. The results also show that the patient group still shows impairment in semantic fluency. However, there was no consistent individual performance from the acute phase to the follow-up in semantic fluency, indicating that the performance on this test is dependent on other factors, showing a different pattern across the phases in recurrent MDD. First, our findings contribute to the scarce literature following this patient group longitudinally in order to gain more knowledge about the cognitive profile of MDD patients. Second, the findings in the present study contribute to the growing literature associating depression with impaired ability to inhibit, linking this impairment to the processing of emotional information in MDD. It is therefore important that the implications of these findings are considered in further research and in the treatment and rehabilitation of this patient group.

Funding

Funding for this study was provided by The Research Council of Norway (RCN), Moodnet Research Group, Helse Bergen HF, and the University of Bergen to ÅH. The funding institutions had no other role in the planning, conduction, and analysis of the study and in the decision to submit the paper for publication.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgements

We are grateful to all participating patients and control subjects.

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