Psychosocial and neurocognitive profiles in depressed patients with major depressive disorder and bipolar disorder

Psychiatry Research 190 (2011) 244–252

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Psychiatry Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s

Psychosocial and neurocognitive profiles in depressed patients with major depressive disorder and bipolar disorder Julie Godard a, b, d,⁎, Simon Grondin b, c, Philippe Baruch a, Martin F. Lafleur a a

Institut universitaire en santé mentale de Québec, Québec, Canada École de Psychologie, Université Laval, Québec, Canada Centre interdisciplinaire de recherche en réadaptation et intégration sociale, Québec, Canada d Centre de réadaptation en déficience physique Le Bouclier, Joliette, Canada b c

a r t i c l e

i n f o

Article history: Received 17 December 2010 Received in revised form 7 June 2011 Accepted 15 June 2011 Keywords: Neuropsychology Cognition Psychosocial functioning Major depressive disorder Bipolar disorder

a b s t r a c t Previous studies have revealed psychosocial and cognitive impairments in patients during depression. The primary aim of this study was to investigate whether patients with major depression (MDD) and bipolar disorder (BD) differ in psychosocial and neurocognitive profiles. A second aim was to examine whether cognitive impairments are homogeneous among depressed patients. Patients with MDD (n = 16) and BD (n = 14) were enrolled during a major depressive episode. About half of them had comorbidities, including personality, substance use, and anxiety disorders. Information was collected about symptomatology and psychosocial functioning, whereas an exhaustive neuropsychological battery was administered to assess cognition. During a depressive episode, MDD and BD patients had global psychosocial dysfunction, characterized by occupational and relational impairments. A cognitive slowing was also observed, as well as deficits related to alertness, spontaneous flexibility, sustained and divided attention. Moreover, severity of depression and cognitive functions were significantly associated with psychosocial functioning. In the case of severe mood disorders, psychosocial and neurocognitive functioning seem similar among MDD and BD patients during a depressive episode. In addition to an altered daily functioning, the neurocognitive profile was heterogeneous with regard to the nature and extent of cognitive deficits. Executive functions, as well as verbal learning and memory, were preserved better than attentional processes. Crown Copyright © 2011 Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction Mood disorders are highly prevalent and constitute a major public health problem. The lifetime prevalence of major depressive disorder (MDD) exceeds 13% of the general population in western countries (Hasin et al., 2005; Alonso and Lépine, 2007), while that of bipolar spectrum disorders (BD) exceeds 8% (Moreno and Andrade, 2005). According to the World Health Organization (WHO, 2004), MDD and BD rank as two of the ten leading causes of disability. MDD is also the first cause of years lost to premature death and disability in developing countries. In addition to high suicidal risk (Ruggero et al., 2007), MDD and BD are often associated with widespread impairments in all domains of functioning. Impaired performance relative to household and work, days missed from work, and work disability are commonly observed during unipolar and bipolar depression (Adler et al., 2006; Simon et al., 2008). The quality of relationships with partners, family ⁎ Corresponding author at: École de psychologie, Université Laval, 2325 rue des Bibliothèques, Sainte-Foy, Québec, Canada, G1V 0A6. Tel.: + 1 418 656 2131; fax: + 1 418 656 3646. E-mail address: [email protected] (J. Godard).

members (Weinstock et al., 2006; Marangell et al., 2009) and friends (Altshuler et al., 2006) is also compromised, along with the frequency of social and leisure activities (Ruggero et al., 2007). These occupational, social and relational dysfunctions reduce the quality of life of depressed patients with MDD (Strine et al., 2009) and BD (Gutiérrez-Rojas et al., 2008). Almost all impairments are comparable among unipolar and bipolar patients during depression (Ruggero et al., 2007) and even worse than those observed among patients with chronic medical illness (Wells and Sherbourne, 1999). Compared to MDD, however, BD is associated with more work disability (Ruggero et al., 2007; Judd et al., 2008). Cognitive deficits seem to explain certain occupational and psychosocial impairments (Jaeger et al., 2006; Martínez-Arán et al., 2007). It is well established that depression is characterized by dysfunction across a range of neuropsychological domains including attention, executive functions, learning and memory (Bearden et al., 2001; Castaneda et al., 2008). The cognitive deficits reported in bipolar depression appear to be the same as those observed in unipolar depression (Quraishi and Frangou, 2002; Marvel and Paradisø, 2004), but they are more severe (Murphy and Sahakian, 2001).

0165-1781/$ – see front matter. Crown Copyright © 2011 Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2011.06.014

J. Godard et al. / Psychiatry Research 190 (2011) 244–252

Neuropsychological deficits in attention have been demonstrated with regard to alertness (McIntosh et al., 2005; Pardo et al., 2006), information processing speed (Tsourtos et al., 2002; Burdick et al., 2009), vigilance and sustained attention (Porter et al., 2003; Depp et al., 2007), as well as selective (Politis et al., 2004; Burdick et al., 2009) and divided (Lemelin and Baruch, 1998) attention. In addition to learning and memory impairments (Martínez-Arán et al., 2004; Bearden et al., 2006), executive dysfunction has also been reported with respect to inhibition (Gohier et al., 2009; Swann et al., 2009), working memory (Christopher and MacDonald, 2005; Glahn et al., 2006) and cognitive flexibility (Martínez-Arán et al., 2004; Depp et al., 2007; Gohier et al., 2009). However, other studies have revealed good performance on measures of attention (Pardo et al., 2006), executive functions (Airaksinen et al., 2004; Rund et al., 2006), and learning and memory (Wang et al., 2006). While it is commonly accepted that cognitive impairment is associated with MDD and BD, attempts to specify neurocognitive profile in unipolar and bipolar depressions have not been conclusive. According to various studies, neurocognitive functioning is characterized by generalized (Depp et al., 2007) or specific (Rund et al., 2006; Barrett et al., 2009) deficits. Currently, little is known about the nature and extent of the psychosocial and cognitive deficits observed in depressed patients with MDD and BD. The disparity in findings may be explained by differences across studies with regard to the selection of participants. Indeed, age range, severity and length of illness, presence of psychosis, comorbidities and medications may influence psychosocial and neurocognitive functioning. Moreover, variability in study design and methodology also contributes to the inconsistency of results. Cross-sectional design, small test batteries of varied composition and small sample sizes in many studies complicate the comparison of results and limit the generalization of conclusions. The first aim of the present study was to characterize the psychosocial and neurocognitive profiles of patients with MDD and BD during major depressive episodes. We therefore examined the nature and extent of impairments and compared the profiles of the patient groups. With regard to psychosocial functioning, we hypothesized that depressed patients with BD would have relational and social impairments similar to those with MDD, but poorer occupational functioning. It was also predicted that the two patient groups would have similar neurocognitive profiles, involving some deficits on measures of attention, executive functions, learning and memory. Heterogeneity in neurocognitive functioning was anticipated as well. The second aim was to investigate relationships between clinical variables, psychosocial functioning, and neuropsychological performance. We hypothesized that cognitive impairments, among MDD and BD patients, would be related to longer periods of illness, more severe depression and poorer psychosocial functioning. 2. Methods 2.1. Subjects Thirty patients were included in the study. They were recruited at the mood disorders clinic of the Institut universitaire en santé mentale de Québec or were referred to us by Quebec City professionals. Based on the Mini International Neuropsychiatric Interview (MINI; Sheehan et al., 2002), 16 patients met the criteria for a DSM-IV-TR diagnosis of major depressive disorder (MDD: three men, 13 women), eight met the criteria for a DSM-IV-TR diagnosis of bipolar I disorder (BDI: four men, four women) and six met the criteria for a DSM-IV-TR diagnosis of bipolar II disorder (BDII: three men, three women). All patients were recruited during a depressive episode. Nine patients (five MDD, four BD) were unmedicated at the time of testing, while medicated patients were taking unaltered dosages over the two preceding weeks. Four patients were receiving antidepressants and 14 mood stabilizers. As additional medication, nine patients were taking benzodiazepines and six neuroleptics (see Table 1). Some patients had co-morbid psychiatric disorders, which are detailed in Table 2. Exclusion criteria were: co-morbid psychotic disorder, history of moderate or severe head injury, neurological disorder, mental retardation, history of learning disabilities, and age outside the range of 18–65 years. The control group consisted of 30 subjects who did not have an actual depressive episode or a history of psychiatric illness. The patients and healthy controls were matched by age and years of education.

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Table 1 Medications at time of testing of MDD and BD patients.

Antidepressants Fluoxetine Trazodone Tranylcypromine Mood stabilizers Lithium Divalproex Lamotrigine Topiramate Anxiolytics Lorazepam Clonazepam Flurazepam Temazepam Neuroleptics Risperidone Quetiapine Olanzapine

MDD group n (%)

BD group n (%)

1 (6) 2 (13) 1 (6)

0 (0) 0 (0) 0 (0)

0 (0) 0 (0) 4 (25) 0 (0)

4 (29) 4 (29) 2 (14) 1 (7)

1 (6) 2 (13) 2 (13) 2 (13)

0 (0) 0 (0) 0 (0) 2 (14)

1 (6) 0 (0) 2 (13)

1 (7) 1 (7) 1 (7)

Healthy controls completed only CogitEx II tasks. The study was approved by the relevant ethical committees and all patients provided written informed consent.

2.2. Clinical assessment In addition to MINI, all patients were evaluated with the 29-item Hamilton Depression Rating Scale (HDRS-29; Hamilton, 1960), the Montgomery-Åsberg

Table 2 Demographic and clinical characteristics of patients with major depressive disorder (MDD) and bipolar disorder (BD) (values are expressed as mean or frequency, standard deviation is shown in parenthesis).

Demographic characteristics Age Education (years) Characteristics of the illness Age at onset Duration of illness (years) Duration of actual episode (months) Number of episodes Depressive episodes Total episodes Suicide attempts Hospitalizations Psychotic symptoms Actual (number of patients) Past (number of patients) Medications, n (%) Antidepressants Mood stabilizers Benzodiazepines Neuroleptics Co-morbid disorders Anxiety disorders Eating disorders ADHD Somatoform disorders Substance disorders Personality disorders Instruments HDRS-29 score MADRS score BDI-II score YMRS score BAI score ⁎ p b 0.05. ⁎⁎ p b 0.01.

MDD group (n = 16)

BD group (n = 14)

49.5 13.8

(12.3) (3.9)

45.4 14.6

38.1 11.3 22.7

(14.0) (12.6) (22.1)

2.2 2.2 0.9 2.5

(1.7) (1.7) (0.9) (2.6)

Tests χ2/t

p

(9.1) (3.6)

t = 1.03 t = − 0.60

0.310 0.551

34.1 11.6 11.1

(10.2) (9.4) (19.5)

t = 0.89 t = − 0.08 t = 1.30

0.380 0.939 0.206

2.5 4.6 0.4 2.9

(1.6) (2.5) (0.9) (2.8)

t = − 0.92 t = − 3.12 t = 1.49 t = − 0.37

0.364 0.004⁎⁎ 0.147 0.718

1

1

χ2 = 0.54

0.586

3

5

χ2 = 2.68

0.157

χ2 = 4.04 χ2 = 6.47 χ2 = 3.09 χ2 = 0.03

0.103 0.026⁎ 0.118 1.000

χ2 = 0.11 χ2 = 0.91 χ2 = 1.18 χ2 = 0.91 χ2 = 5.59 χ2 = 0.05

1.000 1.000 0.467 1.000 0.031⁎ 1.000

t = 0.50 t = 1.35 t = − 0.26 t = − 1.35 t = 0.14

0.622 0.188 0.794 0.189 0.887

4 4 7 3

(25) (25) (44) (19)

3 1 0 1 1 6 31.2 28.5 33.6 1.0 22.4

0 10 2 3

(0) (71) (14) (21)

2 0 1 0 6 5 (5.1) (8.6) (12.9) (1.3) (14.2)

29.9 24.9 34.7 2.3 21.7

(8.5) (5.7) (10.8) (3.6) (13.3)

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Depression Rating Scale (MADRS; Montgomery and Åsberg, 1979) and the Young Mania Rating Scale (YMRS; Young et al., 1978). Furthermore, patients completed the Beck Depression Inventory (BDI-II; Beck et al., 1996) and the Beck Anxiety Inventory (BAI; Beck and Steer, 1990). Information was also collected about medical and psychiatric illness. 2.3. Psychosocial assessment Psychosocial functioning was assessed with the Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool (LIFE-RIFT; Leon et al., 1999). This scale assessed overall psychosocial functioning and comprised the Work, Interpersonal relationships, Life satisfaction and Recreation subscales. These subscales were added together to obtain a single score ranging from 4 (no impairment, high functioning) to 20 (severe impairment). For the Work and Relationships subscales, the ratings for the worst work and relationships categories were employed in the LIFE-RIFT calculation. 2.4. Neuropsychological assessment Patients completed an extensive neuropsychological battery to assess attention, executive functions, verbal learning and memory, and visual functions. Selected tests focused on cognitive functions that have been shown to be frequently associated with dysfunction in major depressive disorder and bipolar disorder. These tests are briefly summarized below, as detailed descriptions are available elsewhere. 2.4.1. Attention Attentional measures included the Continuous Performance Test (CPT-II; Conners, 2000), D-KEFS (Color-Word Interference: Delis et al., 2001) and CogitEx II (Simple Reaction Time Test, Divided Attention Test, Conditional Reaction Time Test, and Choice Reaction Time Test: Laplante and Baruch, 1999). The CogitEx II is a battery of computerized cognitive tasks. The Simple Reaction Time Test consists in pressing a button as quickly as possible when a circle on a screen turns white. The Divided Attention Test involves the same task, in addition to simultaneous counting aloud. The Conditional Reaction Time Test requires subjects to rapidly press a button when a circle on a screen turns green and to refrain from pressing the button when the circle turns red. In the Choice Reaction Time Test, three circles are presented on a screen and one of them turns white. Subjects must quickly press the button corresponding to the target. 2.4.2. Executive functions Measures of executive function comprised the D-KEFS (Verbal Fluency Test, Design Fluency Test, Tower Test, Twenty Questions Test: Delis et al., 2001) and CogitEx II (Sequential Memorization Test: Laplante and Baruch, 1999). In the Sequential Memorization Test, arrows (↑,↓) are presented one by one. The task consists in identifying the direction of the next-to-last arrow by pressing the button corresponding to that position. 2.4.3. Verbal learning and memory The California Verbal Learning Test (CVLT-II; Delis et al., 2000) was used to test verbal learning and memory. 2.4.4. Visual functions The Block Design (WASI: Chen et al., 1999) was used to assess visual functions. A licensed psychologist (J.G.) clinically examined all patients and administered neuropsychological tests. The total procedure was done in two, 2-hour sessions, with breaks to avoid fatigue. 2.5. Statistical analyses 2.5.1. Demographic and clinical characteristics MDD and BD groups were compared on demographic and clinical variables by using independent sample t-tests and chi-squared tests, as appropriate. 2.5.2. Psychosocial functioning Psychosocial variables were compared across the groups by means of multivariate analysis of variance (MANOVA). If the main effect was significant, univariate analysis of variance (ANOVA) was performed for each psychosocial domain. The proportion of patients with significant psychosocial impairment was calculated. Patients were considered to have impairment if their scores were at or above 3 by psychosocial domain and at or above 13 in all. Chi-square analyses were used to compare the percentage of impaired patients in the MDD and BD groups. 2.5.3. Neuropsychological functioning Performance on CogitEx II tasks was compared across MDD patients, BD patients, and healthy controls by means of multivariate analysis of variance means of MANOVA. If the main effect was significant, ANOVAs were performed, followed by a Tukey Honestly Significant Difference (HSD) post-hoc comparison. To indicate the magnitude of differences between groups, effect sizes (Cohen's d) were computed for pairwise differences between MDD, BD and healthy control groups (μ2 − μ1/σpooled). The raw scores of all neuropsychological tests were converted into Z-scores on the basis of the standardized normative data or the data for the control group (CogitEx II). The Z-scores

were then grouped by cognitive domain: attention, executive functions, verbal learning and memory, as well as visual functions. Each cognitive domain included specific functions for which composite Z-scores were calculated. These composite Z-scores were used in Pearson correlations. A MANOVA was conducted to compare neuropsychological performance between MDD and BD groups. We did not control for age and education in comparisons of cognitive functions since these variables were already corrected for age and education via normative data or control group. As many of the tests used in this study are naturally correlated, this procedure was considered superior to a Bonferroni inequality correction that would tend to increase type II error. If the main effect was significant, group differences were tested in a univariate ANOVA for each cognitive function. In order to assess the proportion of patients with significant cognitive impairment, a cut-off score of 2 S.D. below the mean of normative data or control group was used as a threshold. Because IQ was not considered as covariate in the analysis, this conservative threshold was determined in order to ensure that there is a real cognitive deficit. Patients were then considered to have cognitive impairment in a given function if at least one variable of this function had a Z-score below 2 S.D. This criterion was established because some cognitive functions were assessed only by one variable. Chi-square analyses were used to compare the percentage of impaired patients in the MDD and BD groups. Pearson correlation coefficients were calculated to analyze relationships between clinical, neuropsychological and psychosocial variables. To account for the multiple comparisons, we set the alpha at 0.01. All the tests were two-tailed. This preliminary analysis was exploratory. Data analyses were performed using the SPSS 11.0 statistical package.

3. Results 3.1. Clinical assessment The clinical and demographic features of the MDD and BD patients are shown in Table 2. Bipolar patients were significantly more likely to be receiving mood stabilizers (t (28) = 6.47, p = 0.026). No difference was found between groups with respect to age (t (28) = 1.03, p = 0.310) and years of education (t (28)= −0.60, p = 0.551). With regard to comorbid disorders, only substance disorders were more frequent among bipolar patients (χ2 (1) = 5.59, p = 0.031). Moreover, MDD and BD patients did not differ significantly with respect to age at onset (t (28) = 0.89, p = 0.380), duration of illness (t (28) = −0.08, p = 0.939) or actual episode (t (28) = 1.30, p = 0.206), number of hospitalizations (t (28) = −0.37, p = 0.718) and suicide attempts (t (28) = 1.49, p = 0.147). Whereas the number of previous depressive episodes was comparable between groups (t (28) = − 0.92, p = 0.364), bipolar patients had more affective episodes (t (28) = −3.12, p = 0.004). Finally, no difference was found in the HDRS (t (28) = 0.50, p = 0.622), MADRS (t (28)= 1.35, p = 0.188), BDI-II (t (28) = −0.26, p = 0.794), YMRS (t (28)= −1.35, p = 0.189) and BAI (t (28) = 0.14, p = 0.887) scores. 3.2. Psychosocial assessment The psychosocial assessment results and the percentage of impaired patients per psychosocial domain are shown in Table 3. The MANOVA was not significant (F (11, 18) = 0.57, p = 0.829), indicating no difference in psychosocial functioning between groups. On average, MDD and BD patients presented mild to moderate deficits concerning interpersonal relationships with their spouse, children, other relatives, and friends. They were moderately to severely dysfunctional with regard to work, recreational activities and life satisfaction. In sum, psychosocial functioning was globally altered during depressive episodes for all patients. While more than half of patients had relational difficulties, all patients had occupational impairments. Chi-square analyses revealed no difference in the proportion of MDD and BD patients with significant impairments in each psychosocial domain. 3.3. Neuropsychological assessment The MANOVA comparing performance on CogitEx II tasks was significant (F (12,106) = 2.32, p = 0.011), with significant ANOVA differences on all variables except for the Sequential Memorization

J. Godard et al. / Psychiatry Research 190 (2011) 244–252 Table 3 Psychosocial functioning of patients with major depressive disorder (MDD) and bipolar disorder (BD) (values are expressed as mean or frequency, standard deviation is shown in parenthesis).

Work Employment Housework Interpersonal relationships Spouse Children Other relatives Friends Life satisfaction Recreation Total

MDD group (n = 16)

BD group (n = 14)

Scores

Scores

Percentage impaireda

Percentage impaireda

4.6 (0.8) 4.4 (0.7)

100 100

4.8 (0.5) 4.0 (0.9)

100 92

3.2 (1.2) 3.0 (1.4) 3.6 (1.3)

83 75 81

3.0 (1.1) 3.6 (1.6) 3.5 (1.3)

50 71 71

3.4 (1.5) 4.0 (0.8) 4.0 (0.7) 17.1 (1.9)

86 94 100 100

3.6 (1.4) 4.1 (0.7) 4.0 (0.9) 17.4 (2.0)

71 100 93 100

Psychosocial domains (Work, Relationships, Life satisfaction, Recreation) of Life-Rift: 1 = very good; 2 = good; 3 = fair; 4 = poor; 5 = very poor. Total: sum of these domains ranging from 4 (no impairment, high functioning) to 20 (severe impairment). a Percent impaired refers to percent of patients scoring at or above 3 by psychosocial domain and scoring at or above 13 on total.

Test and commissions on the Conditional Reaction Time Test (Table 4). Post hoc comparisons also revealed that the MDD and BD patients had significantly poorer performance than the healthy control group on all attentional variables. Analysis of the effect sizes indicated large to huge differences between the MDD or BD group and the control group on almost all variables. The mean effect size for differences between the MDD and control groups was 0.98 (S.D. = 0.37), and 1.16 (S.D. = 0.53) for differences between the BD and control groups. Main effect size for differences between the MDD and BD groups was negligible (mean = 0.08, S.D. = 0.06). Table 5 contains the results of neuropsychological assessment. The MANOVA did not reveal significant differences between groups (F (28,1) = 5.12, p = 0.338). On average, only information processing speed was significantly impaired in MDD and BD patients according to standardized norms or the healthy control group. The average percentage of MDD patients and BD patients scoring more than 2 S.D. below the mean of normative data or the control group is presented in Table 5 and Fig. 1. The majority of patients showed attentional (69% MDD, 71% BD) and executive (56% MDD, 71%

247

BD) impairments. Some patients presented verbal learning and memory deficits (38% MDD, 36% BD), while none had visual function impairments. The most frequently impaired cognitive functions were alertness, information processing speed, sustained and divided attention, and spontaneous flexibility. The most rarely impaired cognitive functions were updating in working memory, planning and storage in verbal memory. The abstraction and visual functions were preserved in MDD and BD patients. Chi-square analyses revealed no difference in the proportion of MDD and BD patients with significant impairments in each cognitive function. Concerning neurocognitive profiles of the MDD and BD patients enrolled in this study, most of them (44% MDD, 57% BD) presented deficits in more than one cognitive domain for attention, executive functions and verbal learning and memory. However, some patients manifested only attentional (25% MDD, 14% BD) or executive (13% MDD, 21% BD) impairments, while few had no cognitive deficits (19% MDD, 7% BD). 3.4. Correlations between variables No relationship was found between history of illness and clinical, psychosocial or neuropsychological variables. While BDI-II scores were significantly correlated to information processing speed (r = −0.531, p = 0.003), MADRS scores were significantly associated with life satisfaction (r = − 0.724, p b 0.001), recreation (r = − 0.532, p = 0.002) and global psychosocial functioning (r = − 0.634, p b 0.001). With regard to psychosocial and neuropsychological functioning, some correlations were significant. Maximum work was related to attention (Alertness: r = −0.495, p = 0.005), executive functions (Spontaneous flexibility: r = −0.486, p = 0.006) and verbal memory (Retrieval: r = − 0.490, p = 0.006). Relationships with children were also associated with attention (Information processing speed: r = −0.557, p = 0.001; Sustained attention: r = −0.575, p = 0.001) and executive functions (Updating: r = − 0.471, p = 0.009). Whereas life satisfaction was correlated to verbal learning (Encoding: r = − 0.528, p = 0.003), global psychosocial functioning was related to executive functions (Updating: r = − 0.470, p = 0.009) and verbal learning (Encoding: r = − 0.545, p = 0.002). 4. Discussion To our knowledge, this is one of the rare studies to carry out an exhaustive assessment concerning both psychosocial and neurocognitive

Table 4 Comparison of raw scores on tasks of CogitEx II among groups (values are expressed as mean, standard deviation is shown in parenthesis).

Attention Alertness Simple RT Test (ms) Information processing speed Choice RT Test (ms) Conditional RT Test (ms) Divided attention Divided Attention Test (ms) Divided Attention Test (errors) Executive functions Inhibition Conditional RT Test (commissions) Updating Sequential memorization (good responses) ⁎⁎ p b 0.01. ⁎⁎⁎ p b 0.001.

MDD group

BD group

Healthy controls

ANOVAs

(n = 16)

(n = 14)

(n = 30)

d.f. (2.57)

Post-hoc comparisons

MDD–control

Effect sizes (Cohen's d) BD–control

MDD–BD

495.4 (342.5)

532.6 (232.0)

324.1 (106.7)

F = 5.56⁎⁎

MDD = BD N Control

0.80

1.36

0.13

970.2 (463.8) 656.5 (225.7)

956.6 (276.9) 646.8 (174.8)

619.5 (143.4) 462.5 (84.1)

F = 10.53⁎⁎⁎ F = 11.25⁎⁎⁎

MDD = BD N Control MDD = BD N Control

1.22 1.34

1.77 1.57

0.04 0.05

815.6 (414.2) 3.9 (3.6)

755.9 (333.0) 3.4 (4.1)

504.7 (166.3) 1.2 (2.0)

F = 7.26⁎⁎ F = 5.27⁎⁎

MDD = BD N Control MDD = BD N Control

1.15 1.06

1.11 0.83

0.16 0.12

2.3 (2.1)

2.1 (1.8)

1.9 (1.5)

F = 0.25

0.22

0.13

0.09

20.1 (4.5)

20.1 (4.3)

21.6 (4.8)

F = 0.76

0.32

0.32

0

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J. Godard et al. / Psychiatry Research 190 (2011) 244–252

Table 5 Neuropsychological performances (Z-Scores) and percentage of patients with cognitive impairment (values are expressed as mean or frequency, standard deviation is shown in parenthesis). MDD group (n = 16) Z-scores Attention Alertness CPT-II: hit RT CPT-II: hit RT SE CogitEx II: Simple RT Test (RT) Information processing speed CogitEx II: Choice RT Test (RT) CogitEx II: Conditional RT Test (RT) Sustained attention CPT-II: omissions CPT-II: hit RT block change CPT-II: hit RT SE block change Divided attention CogitEx II: Divided Attention Test (RT) CogitEx II: Divided Attention Test (errors) Executive functions Inhibition CogitEx II: Conditional RT Test (commissions) C-W interference : inhibition vs color C-W interference : inhibition (errors) Reactive flexibility C-W interference : inhibition/switching vs inhibition Design fluency : switching vs (filled + empty) Verbal fluency : category switching vs category Spontaneous flexibility Verbal fluency: letter fluency Verbal fluency: category fluency Design fluency : combined filled dots + empty dots Updating CogitEx II: Sequential Memorization Test Planning Tower: move accuracy ratio Tower: total achievement Abstraction Twenty Questions : initial abstraction Twenty Questions : total weighted achievement Verbal learning and memory Encoding CVLT-II: trials 1–5 total Retrieval CVLT-II: short delayfree recall CVLT-II: short delay cued recall CVLT-II: long delay free recall CVLT-II: long delay cued recall Storage CVLT-II: total recognition discriminality Visual functions Analysis/synthesis WASI: block design a

BD group (n = 14) Percentage impaireda

Z-scores

27

50 − 0.03 (1.7) − 0.85 (1.3) − 1.95 (2.2)

0.70 (1.6) − 0.99 (1.8) − 1.61 (3.2) 69 − 2.45 (3.2) − 2.31 (2.7)

64 − 2.35 (1.9) − 2.19 (2.1)

38 − 1.45 (2.9) − 1.09 (1.3) − 0.54 (1.3)

29 − 0.74 (1.8) − 0.16 (0.9) − 0.74 (1.0)

50 − 1.87 (2.5) − 1.34 (1.8)

36 − 1.51 (2.0) − 1.12 (2.0)

25 − 0.46 (1.3) − 0.44 (1.1) − 0.33 (1.1)

14 − 0.25 (1.2) 0.33 (0.7) − 0.28 (1.0)

19

29 − 0.69 (1.4) − 0.07 (0.7) 0.33 (0.6)

0.33 (1.6) 0.13 (0.9) 0.29 (0.9) 25 − 0.90 (0.6) − 0.90 (0.6) − 0.25 (1.0)

43 − 0.83 (1.1) − 1.22 (1.4) − 0.60 (0.7)

0 − 0.31 (0.9)

7 − 0.31 (0.9)

6 0.40 (1.1) − 0.73 (0.9)

0 0.31 (0.6) − 0.26 (0.7)

0 − 0.06 (1.0) 0.25 (0.6)

0 − 0.45 (0.5) 0.02 (0.8)

6 − 0.72 (1.1)

29 − 0.87 (1.5)

38 − 0.81 − 0.69 − 0.81 − 0.78

21 − 0.93 − 1.00 − 0.82 − 0.64

(1.3) (1.5) (1.7) (1.3)

(1.3) (1.1) (1.3) (1.1)

19 − 0.38 (1.3)

0 0.00 (0.9)

0 − 0.27 (0.6)

Percentage impaireda

0 − 0.34 (0.7)

Percentage impaired refers to percent of patients scoring at or below 2 standard deviations by cognitive function according to standardized norms or healthy controls (CogitEx II).

functioning during a moderate to severe depressive episode in MDD and BD patients and to compare the profiles between groups. The results demonstrated an important psychosocial dysfunction and attentional disturbances among MDD and BD patients. 4.1. Psychosocial functioning As hypothesized, psychosocial functioning was globally impaired for all patients during major depressive episodes. Moderate to severe impairments in their work and home functioning roles were observed, as well as mild to moderate impairments in relationships. Patients not only neglected housework, as was expected, but also performed poorly at work or presented work disability. Their involvement in recreational activities or hobbies was also limited and they derived little enjoyment from such activities. Their relations with family members and friends were characterized by conflicts or limited contacts. Consequently, patients were very dissatisfied in most areas

and derived little pleasure from life. These results are consistent with those of previous studies reporting a loss of efficiency at work, absenteeism or work disability (Adler et al., 2006; Altshuler et al., 2006; Gardner et al., 2006; Simon et al., 2008; Marangell et al., 2009), as well as interpersonal difficulties (Judd et al., 2000; Altshuler et al., 2006; Marangell et al., 2009) and altered quality of life and well-being (Kuehner and Buerger, 2005; Gutiérrez-Rojas et al., 2008; Strine et al., 2009), during a major depressive episode. As anticipated, depressed patients with BD had relational and social impairments similar to those with MDD. However, in contrast to our hypothesis and the results of previous studies, BD patients did not have poorer occupational functioning than MDD patients. This contradiction of previous research could be explained by the fact that the bipolar patients included in that research generally had more severe illness than the unipolar patients. Indeed, the unipolar and bipolar patients involved in the present study had a similar severity of depression and history of illness. All patients were moderately to

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MDD BD IP Su S s t. A D tt. iv . In Att. hi bi tio Re n ac t. Sp fl. on t. f U pd l. at Pl ing an A nin bs g tra ct En ion co di Re ng tri ev a St l or ag e V is u al

le rtn es s

80 60 40 20 0 A

% impaired patients

J. Godard et al. / Psychiatry Research 190 (2011) 244–252

Cognitive functions Fig. 1. Percentage of impaired patients in each cognitive function. Information processing speed (IPS), Sustained attention (sust. att.), Divided attention (div. att.), Reactive flexibility (react. fl.), Spontaneous flexibility (spont. fl.), Major depressive disorder (MDD), Bipolar disorder (BD).

severely depressed and had a chronic or recurrent evolution. It is possible therefore that severity of depression and history of illness could have a greater impact on occupational functioning than the diagnosis itself. 4.2. Neuropsychological functioning The present study clarified the nature and extent of cognitive deficits during a moderate to severe depressive episode and compared profiles among MDD and BD patients. The neurocognitive profile observed in the MDD and BD patients was characterized by heterogeneity regarding the nature and extent of cognitive deficits. Some patients had adequate neurocognitive functioning, while most of them had different cognitive deficits. This is consistent with the few studies carried out among MDD (Rund et al., 2006) and BD patients (Summers et al., 2006; Martino et al., 2008; Simonsen et al., 2008) and suggests that the neurocognitive profiles associated with mood disorders are heterogeneous, regardless of the phase of the illness. Despite a heterogeneous neurocognitive profile, generalized slowing appears to be a significant aspect of information processing speed in depression. According to the models proposed by Cerella (1985) and Cerella and Hale (1994), information processing is divided into two components, one sensorimotor and the other cognitive. On the one hand, sensorimotor speed plays an important role in easier tasks, and is particularly involved in motor response selection and execution. On the other hand, cognitive speed plays a significant role in complex tasks, and is involved in the cognitive processing steps required to make an accurate decision. Compared to healthy controls, MDD and BD depressed patients manifested an important slowing of both sensorimotor and cognitive processes, as assessed by timed tasks. These results may be interpreted in light of the model of diversity in speeded information processing, developed by Myerson et al. (2003), in which information processing is represented by a series of generic computational steps. Although an individual's processing steps may vary in duration, they are assumed to be correlated with each other. In other words, individuals tend to perform on all of these steps relatively slowly or rapidly, reflecting the existence of a general cognitive speed factor. Consistent with previous studies (Janer et al., 1992; White et al., 1997), MDD and BD depressed patients were slower than healthy controls across a variety of information-processing tasks. Taken together, these results strongly support the hypothesis of a global slowing of sensorimotor and cognitive processes during unipolar and bipolar depression. The data presented in this research suggest that basic cognitive processes are frequently altered in MDD and BD depressed patients. In fact, 70% of patients enrolled in this study manifested attentional dysfunction. Considering all cognitive functions, the most frequently impaired functions were alertness, information processing speed, sustained and divided attention, and spontaneous flexibility. In addition to exhibiting slowed cognitive processes, depressed patients were less able to mobilize their attentional resources, deal with multiple sources of information and carry out simultaneous tasks.

They also had difficulty in generating strategies or solutions in order to resolve problems. These results are along the lines of those of previous studies reporting difficulties related to the regulation of attentional activation (McIntosh et al., 2005; Pardo et al., 2006), maintenance of attention (Porter et al., 2003; Depp et al., 2007), and spontaneous flexibility (Martínez-Arán et al., 2004; Rund et al., 2006; Depp et al., 2007). During a depressive episode, complex cognitive functions, such as abstraction and planning, seem relatively preserved. In our study, many of the patients inhibited adequately distractors and irrelevant elements and updated information in working memory. In the context of problem solving, they also shifted strategies, if necessary. When episodic memory was altered, encoding and retrieval processes were most often concerned. Compared with normative data, some patients showed a deficit in learning trials and free recall. Many studies have also concluded that verbal learning and memory are altered (Martínez-Arán et al., 2004; Bearden et al., 2006) during a major depressive episode. Taking into account that encoding and retrieval processes are closely related to processing speed, the central executive component of working memory, and inhibition processes (Van der Linden et al., 1999), it is not surprising that patients with memory deficits also demonstrated attentional or executive deficits. An underlying executive dysfunction could affect the effective organization of material memorization (Elderkin-Thompson et al., 2007) and limit the quantity of encoded elements. In this case, retrieval difficulties would be due to an information availability problem in long-term memory, because of the absence of specific memory traces. Executive deficits could also affect generation of cues and reduce the quantity of retrieved information (Fossati et al., 2002). There would thus be an access problem with regard to information in long-term memory. Although the majority of patients showed deficits affecting more than one cognitive domain, some of them presented fairly well preserved cognitive functioning. These ones had adequate functioning, while others had specific attentional or executive deficits. Previous research has also suggested that attentional (Pardo et al., 2006), executive (Airaksinen et al., 2004; Rund et al., 2006) and mnesic (Wang et al., 2006) capacities are preserved in some depressed patients. Contrary to previous research, this study suggests that executive functions, as well as verbal learning and memory, were better preserved than attentional processes during unipolar and bipolar depression. It is possible that executive (Harvey et al., 2004; Summers et al., 2006; Depp et al., 2007) and mnesic (Martínez-Arán et al., 2004; Bearden et al., 2006) deficits observed in several studies may mainly reflect an impairment in attentional processes. It would be essential to exhaustively evaluate neurocognitive functioning during depression in order to clarify the nature of cognitive deficits. Moreover, the range of methods used and the diversity of the characteristics of the patients involved may partly explain the contradictory results obtained in studies on the cognitive abilities of depressed patients. It is also possible that the results simply reflect the presence of heterogeneous

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neurocognitive profiles among BD and MDD patients during depression. Further research should target the causes of this neuropsychological functioning heterogeneity and clarify the occupational, social and relational impacts. 4.3. Relations between variables Contrary to the initial hypothesis, history of illness was not associated with neuropsychological and psychosocial functioning. Previous research had suggested that longer length of illness, chronicity and recurrence of affective episodes were associated with psychosocial functioning impairments (Rytsälä et al., 2006, 2007) or poorer cognitive performance (Fossati et al., 2004). The absence of significant correlations in this study is related perhaps to the relative homogeneity of the history of patients' illness, characterized by chronicity of symptoms and recurrence of affective episodes. However, greater severity of depression was associated with slower cognitive processing. A meta-analysis conducted by McDermott and Ebmeier (2009) also concluded to a relationship between the severity of depression and information processing speed. In agreement with the literature, poorer psychosocial functioning was associated with cognitive deficits (Wingo et al., 2009) and greater severity of depression (Pope et al., 2007; Chung et al., 2009). Therefore, during a major depressive episode, attentional, executive and mnesic deficits alter work functioning, interpersonal relationships and social activities. The heterogeneity of the neurocognitive profiles of depressed BD and MDD patients could explain the variability of the psychosocial functioning frequently observed.

be exclusively explained by medication effects, we cannot definitively rule out the possibility of treatment effects on neurocognitive functioning. Although an exhaustive neuropsychological battery was selected for this study, only one task assessed working memory. Future research is needed to investigate all components of working memory and to consider the contribution of these processes to other cognitive functions. Moreover, IQ was not considered as covariate in the analysis. Because of these limitations, the data should be interpreted with caution. Further studies involving larger samples are required to confirm our results concerning neurocognitive profiles among MDD and BD patients during depression. 4.6. Conclusion In the case of severe and complex mood disorders, psychosocial and neurocognitive functioning seem similar among MDD and BD patients during a depressive episode. All patients had global psychosocial dysfunction, characterized by occupational, relational and social impairments. The neurocognitive profile was heterogeneous with regard to the nature and extent of cognitive deficits. Some patients had adequate neurocognitive functioning, while others had different cognitive deficits. Attentional processes were frequently altered. A cognitive slowing was observed, as well as deficits related to alertness, sustained and divided attention, and spontaneous flexibility. Executive functions and verbal learning and memory were preserved better than attentional processes. Acknowledgments

4.4. Clinical implications The fact that the psychosocial functioning and neurocognitive profile were comparable among the MDD and BD patients enrolled in the present study suggests that severe and complex mood disorders refer to a similar clinical reality during a depressive episode. Beyond a certain level of depressive severity, the history of illness and psychiatric comorbidities seem more important than the diagnosis itself to determine the functional and cognitive impacts of depression. The clinical, functional and cognitive prognoses depend on the severity of the mood disorders. Consequently, an exhaustive assessment about symptomatology, daily functioning, and cognitive capacities appears essential in order to identify deficits related to depression and to propose appropriate interventions. These interventions must aim the achievement of complete remission and restrict depressive impacts. 4.5. Limitations Our results must be interpreted with caution in view of several methodological limitations. Indeed, the generalizability of the results is limited by certain factors. As all patients were severely depressed and treated in a specialized service, the findings cannot be generalized to larger community samples. Moreover, the absence of control groups for some tests also restricts some findings, and it would be premature at this point to conclude that cognitive impairments can be attributed exclusively to depression. It should also be noted that we did not control for the possible effects of medication on test performance. Psychotropic medications may tend to adversely affect some cognitive functions, most notably alertness and information processing speed. However, there is no consensus about the effect of medication on cognition. Literature reviews suggest that antidepressants, mood stabilizers, anxiolytics, and neuroleptics could be associated with varying effects on neurocognitive functioning, involving improvements or impairments (Stein and Strickland, 1998; MacQueen and Young, 2003; Pachet and Wisniewski, 2003). Whereas cognitive dysfunction does not appear to

This study was supported in part by grants from Janssen-Ortho. However, JanssenOrtho had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. All authors designed the study and wrote the protocol. Julie Godard managed the literature searches and undertook the statistical analysis. She also wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript. We especially thank Marie-Eve Roussel for her assistance with the statistical analyses.

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