Neuropsychological function in unmedicated recurrent brief depression

Journal of Affective Disorders 125 (2010) 155–164

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Journal of Affective Disorders 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 / j a d

Research report

Neuropsychological function in unmedicated recurrent brief depression Stein Andersson a,⁎, Hans Lövdahl a,b,c, Ulrik F. Malt a,c a b c

Dept. of Neuropsychiatry and Psychosomatic Medicine, Division of Clinical Neurosciences, Rikshospitalet University Hospital, Oslo, Norway Department of Psychiatry, Sørlandets sykehus HF-Arendal, Norway Institute of Psychiatry, University of Oslo, Norway

a r t i c l e

i n f o

Article history: Received 23 June 2009 Received in revised form 30 December 2009 Accepted 30 December 2009 Available online 20 January 2010 Keywords: Neuropsychology Recurrent brief depression

a b s t r a c t Background: Recurrent brief depression (RBD) is a mood disorder characterized by mild to severe depressive episodes lasting less than 2 weeks and occurring approximately once a month with complete recovery between episodes. The aim of this study was to describe neuropsychological impairments associated with RBD, relating cognitive performance to clinical features and comorbidity. Methods: Forty-six ICD-10 defined RBD patients (mean age 33.8) and 24 matched controls were assessed on working memory/attention tasks, executive functions, verbal/visual memory, and psychomotor speed. Results: Patients were significantly impaired across all domains of cognition except for verbal learning and non-semantic verbal fluency. Neuropsychological performance was not related to depression severity, duration of depressive episodes, interval duration, psychiatric or somatic comorbidity, or attributable to a general reduction in processing speed or effort. Patients reporting previous major depressive episodes were impaired on one measure of psychomotor speed. Previous episodes of hypomania were not related to neuropsychological performance. Limitations: The relatively high number of self-referrals, high female-to-male ratio in the patient sample, and the relatively high level of education and intellectual capacity among participants may limit the possibility to generalize our results to the RBD population in general. Conclusions: Unmedicated RBD patients demonstrate significant neuropsychological impairment that also may persist into euthymic states. Examining cognitive functions might be equally important in RBD as in major depression with consequences for functional diagnostics and treatment strategies. © 2010 Elsevier B.V. All rights reserved.

1. Introduction Neuropsychological impairment is an essential feature of depression, evident in both the symptomatic phases and remission. Although the degree and nature of neuropsychological deficits varies according to factors such as the type of depressive illness (Porter et al., 2007), medication status (Stein and Strickland, 1998; Gorenstein et al., 2006), early

⁎ Corresponding author. Dept. of Neuropsychiatry and Psychosomatic Medicine, Division of Clinical Neurosciences, Rikshospitalet, N-0027 Oslo, Norway. Tel.: +47 23 07 41 64; fax: +47 23 07 41 70. E-mail address: [email protected] (S. Andersson). 0165-0327/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2009.12.023

versus late-onset depression Naismith et al., 2003), or presence of psychiatric comorbidities such as anxiety disorders (Basso et al., 2007), there seem to be some common core cognitive dysfunctions associated with depression. In an early meta-analysis Veiel (1997) concluded that aspects of executive function are most impaired, while later review papers have suggested that mnemonic, attention, and processing speed dysfunctions are among the most robust findings, in addition to executive dysfunction (Austin et al., 2001; Rogers et al., 2004). Most studies have focused on patients with major depressive disorder (MDD); we are not aware of any studies that have explicitly looked at neurocognitive function in patients with recurring brief episodes of depression.

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Although still conceptually controversial, recurrent brief depression (RBD) was included in the most recent classification of mental and behavioral disorders (ICD-10 F38.1) by the World Health Organization in 1992 (WHO, 1993). These diagnostic criteria for RBD were based primarily on work from the Zürich epidemiological studies performed by Jules Angst and co-workers, who described a mood disorder characterized by intermittent major depressive episodes lasting less than 14 days (Angst and Dobler-Mikola, 1985; Angst, 1990). The ICD-10 F 38.1 criteria state that the recurring depressive episodes should have occurred about once a month over the past year with a duration of less than 2 weeks, typically 2– 3 days, and with complete recovery between episodes. Furthermore, depressive episodes should fulfill the symptomatic criteria for mild, moderate, or severe depressive episodes and should not be synchronous with the menstrual cycle in women. Using these criteria, different community-based studies of RBD have presented lifetime prevalence estimates ranging from 2.6 to 10.0% and a lifetime prevalence of 5.0–8.2% (Altamura et al., 1995; Carta et al., 2003; Maier et al., 1994a, b). In WHO funded studies on psychological disorders in primary care, a 1-year prevalence of 3.7–9.9% was reported (Maier et al., 1994a; Weiller et al., 1994). The DSM-IV only provides provisional criteria for intermittent depressive episodes of less than 14 days, but these criteria limit RBD to patients who have never experienced a major depressive or hypomanic episode (APA, 2000). It has been suggested that RBD may be a bipolar spectrum disorder. A significant portion of RBD patients experience brief episodes of hypomania (Angst et al., 2003). Recently, our group has, in a partly overlapping sample included in accordance with the ICD-10 diagnostic criteria, described the phenomenology of RBD patients (Lövdahl et al., 2009). Brief episodes of hypomania were reported in 47% of the RBD patients. Moreover, evidence of hypomanic episodes in RBD may be a marker of severity; these patients had significantly more extensive psychiatric comorbidity in terms of panic disorders and general anxiety disorder. However, hypomanic RBD patients did not differ from those without hypomania in regard to other clinical features, including the amount and nature of typical or atypical depressive symptoms, age of symptom onset, and the mean length of depressive episodes and symptom-free phases. This study is part of a larger collaboration studying the phenomenology and neurobiology of RBD. The main purpose of the study is to describe the neuropsychological profile of patients with RBD and test whether their cognitive performances are significantly impaired compared to matched controls. We hypothesize that, similar to what is found in MDD, RBD is associated with significant impairment in attention, memory, executive function, and processing speed, and that the magnitude of neuropsychological impairment is sufficient to interfere with daily life activities. Also, a substantial portion of RBD patients have experienced episodes of hypomania (Lövdahl et al., 2009). If the presence of additional brief hypomanic episodes is a marker of severity in RBD, one would expect RBD patients with a history of hypomania to show additional neuropsychological deterioration compared to those without hypomania. Neuropsychological performances are dependent upon behavioral responses and, as such, are sensitive to motivational states and effort, variables that may be seriously

disturbed in depression. The notion that cognitive deficits in depression are basically a result of reduced effort, the socalled effort hypothesis, states that performances on effortful tasks are disproportionately impaired compared to performances on automatic tasks (Roy-Byrne et al., 1986; Hartlage et al., 1993; Hammar et al., 2003). The cognitive speed hypothesis states that reduced cognitive function in depression is a product of a generalized cognitive slowness affecting all aspects of cognitive performance (Den Hartog et al., 2003). We predict that neurocognitive impairment in RBD patients is not a result of general cognitive slowing, but we expect that deficits in memory, executive function, and working memory/attention will persist after controlling for speed of information processing. 2. Methods 2.1. Patient inclusion, diagnostic procedures, and comorbidity Forty-six patients (32 females) with a mean age of 33.8 years and fulfilling the ICD-10 F38.1 research criteria for RBD were included in the study. A total of 124 individuals were assessed as potential participants, a majority of these individuals (65%) were self-referred after reading about the project in the media; the rest were referred by local general practitioners or psychiatrists. Patients with a current diagnosis of major depressive episode, dysthymia, personality disorder cluster A and B, or a history of severe mental disorders with psychosis or neurological diagnosis were excluded. After a preclinical screening interview, patients included in the study were examined by a senior psychiatrist. An abbreviated version of The Stanley Foundation Network Entry Questionnaire (aNEQ) was given to collect demographic, patient's case history, and supplementary information (Suppes et al., 2001). Axis I diagnoses and psychiatric comorbidities were assessed by the MINI-neuropsychiatric interview (MINI and MINI-plus) and DSM-IV criteria version 5.0 (Sheehan et al., 1998), revealing disorders such as panic disorder, agoraphobia, social phobia, generalized anxiety disorder, post-traumatic stress disorder, obsessive–compulsive disorder, isolated phobia, alcohol abuse and dependence, drug abuse and dependence, psychotic symptomatology, somatization disorder, somatoform pain disorder, hypochondria, body dysmorphic disorder, anorexia nervosa, bulimia, and premenstrual dysphoric disorder. The magnitude of depression symptoms at the time of assessment were measured by the Montgomery and Asberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 1979). Hypomanic symptoms were assessed by addressing all items for hypomania/mania listed in MINI. All patients were taken off medication for one week prior to the neuropsychological examination. Medication cessation was only confirmed by patient's report. Twenty-five of the patients had not used any psychoactive medication prior to the study. Of the remaining 21 patients that ever had used psychoactive medication 6 patients had used SSRI as monotherapy; 3 patients had used lamotrigine as monotherapy; 5 patients had used combined SSRI and lamotrigine; 2 patients had used an anxiolytic; 3 patients had used combined SSRI and anxiolytic; 1 patient had used combined lamotrigine and anxiolytic; and 1 patient had used combined SSRI, lamotrigine and anxiolytic. In

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addition, 1 patient had tried lithium, and 1 patient had tried a neuroleptic drug. In both of these cases medication had been ceased more than one year prior to inclusion. Only SSRI and lamotrigine were used close up to the time of inclusion corresponding to the time of the clinical interview. 2.2. Healthy controls Twenty-four subjects (16 females) with a mean age of 34.2 years were randomly selected from the general population register of Oslo and served as controls. The controls were matched for gender, age, and educational level and screened for neurological and psychiatric disorders before being included in the study. The controls underwent a full psychiatric examination similar to that of the included patients. 2.3. Neuropsychological assessment All patients and controls were assessed by a neuropsychological test battery composed to cover the different aspects of cognition empirically known to be affected in patients with affective disorders, emphasizing different aspects of executive function, learning and memory, attention, and psychomotor speed. In addition, tests to estimate general verbal and nonverbal intellectual capacity were included. i) Executive functions: The Verbal Fluency Test is a nonsemantic word generation test requiring subjects to produce words starting with F, A, and S at 1-minute intervals (Benton, 1976). The Tower Test from the Delis–Kaplan Executive Test System (D-KEFS) is a test measuring strategy and planning in problem-solving (Delis et al., 2001). The Stroop Color–Word Interference Test is a measure of cognitive control and conflict monitoring that requires subjects to inhibit an automatic response set. (Stroop, 1935). ii) Verbal and visual memory: From the California Verbal Learning Test (CVLT-II) we report learning (total of acquisition trials 1–5), long delay free recall, and recognition scores (Delis et al., 2000). For visual memory, we report the 30-minute delayed recall from the Rey–Osterreith Complex Figure Test (Corwin and Bylsma, 1993). iii) Attention/working memory: In the Paced Auditory Serial Addition Test (PASAT), subjects add one digit numbers presented every 3 s, requiring processing speed, attention, and working memory capacity (Gronwall, 1977). The Letter–Number Span Test is a working memory test in which subjects are randomly presented with numbers and letters and immediately asked to recall the numbers in ascending order and letters in alphabetical order (Gold et al., 1997). iv) Processing speed: The Digit Symbol Test from the Wechsler Adult Intelligence Scale — Revised (WAIS-R) requires subjects to substitute numbers with symbols, measuring processing speed (Wechsler, 1981). The color naming and word reading conditions from the Stroop test were also included as information processing speed tests. v) Estimated IQ: The subtests Vocabulary and Matrices from the Wechsler Abbreviated scale of Intelligence (WASI) were used to estimate current IQ (Wechsler, 1999).

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All tests were administered during one session in a fixed order by the same examinee (SA). 2.4. Statistical analyses The Statistical Package for the Social Sciences (SPSS for Windows, version 15.0, SPSS Inc., Chicago, IL, USA) was used for all statistical analyses. Group statistics were done using analysis of variance (ANOVA). Effect size is expressed as Cohen's d, defined as the difference of the means over the pooled standard deviation; 0.2 is indicative of a small, 0.5 a medium, and 0.8 a large effect size. When comparing subgroups of RBD patients to controls, one-way ANOVA with the Tukey post hoc procedure was used. Because neuropsychological test scores are highly intercorrelated no tests were performed to control for Type I error across the multiple tests. Pearson's product moment correlation analysis was used to explore associations between clinical psychiatric features and neuropsychological performance. To test the effects of processing speed/effort, the Digit Symbol subtest was entered as a covariate in a series of univariate ANOVAs with the neuropsychological domain score as the dependent variable and patients/controls as the factor variable. 3. Results 3.1. Patient characteristics The RBD group and controls were comparable with respect to age, level of education, gender composition, and general intelligence as estimated by the Matrices and Vocabulary subtests of the WASI (Table 1). As expected, there was a significant difference in the MADRS score at the time of neuropsychological assessment difference between patients and controls. The mean duration of depressive episodes was 3.4 days with a mean interval of 16.5 days between episodes. The mean age of symptom onset was 20.4 years. Also, as shown in Table 1, a majority of the patients had MADRS score in the non-clinical range at the time of neuropsychological testing. Previous major depression episode (MDE) was identified in 41% of the patients. However, no patients had experienced more than one MDE meaning that the single MDE was superimposed on their chronic RBD condition. Forty-four percent reported one or more brief episode of hypomania. However, none of the patients were hypomanic at the time of assessment. Anxiety disorders were most frequent among comorbid psychiatric disorders, while tension headache, migraine, and previous minor head concussion represented the most frequent somatic comorbidities. 3.2. Neuropsychological performance in RBD versus controls The one-way ANOVA of neuropsychological raw scores shows that RBD patients had significantly reduced performances on a majority of the administered neuropsychological tests compared to healthy controls (Table 2). The differences in favor of healthy controls are most evident and consistent on tests in the cognitive domain of working memory, which consisted of the Letter–Number Span Test (F = 11.99, p = .001) and PASAT (F=4.98, p=.03) with effect sizes (Cohen's d) of 0.87 and 0.58, respectively. On tests measuring aspects of executive

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Table 1 Demographic characteristics, clinical psychiatric features, and comorbidities. RBD (N = 46)

Controls (N = 24)

Demographics Female/male ratio Age (year), mean (SD) Education (years), mean (SD) Estimated IQ (WASI), mean (SD)

32/14 33.8 (7.68) 14.1 (2.36) 115.0 (10.33)

16/8 34.2 (7.57) 15.0 (2.28) 116.2 (8.80)

Clinical psychiatric features MADRS score at time of assessment, mean (SD) MADRS score 0–11, n (%) MADRS score 11–19, n (%) MADRS score N20, n (%) Previous major depressive episode, n (%) Duration of depressive episodes (days), mean (SD) Interval between depressive episodes (days), mean (SD) Previous hypomania, n (%) Age at symptom onset, mean (SD)

10.6 (8.79) 26 (56) 11 (24) 9 (20) 19 (41) 3.4 (2.26) 16.5 (7.99) 20 (44) 20.4 (6.51)

0.5 (1.18)

Psychiatric and somatic comorbidities Panic disorder, n (%) a GAD, n (%) a Specific phobias, n (%) a Social phobia, n (%) a OCD, n (%) a PTSD, n (%) a Alcohol abuse, n (%) a Substance abuse, n (%) a Migraine, n (%) b Tension headache, n (%) b Epilepsy, n (%) b Previous minor head concussion, n (%) b

22 (47.8) 16 (34.8) 8 (17.4) 13 (28.3) 9 (19.6) 4 (8.7) 4 (9) 1 (2) 17 (37) 24 (52) 1 (2) 24 (52)

F/chi-square 0.06 0.04 2.53 0.21

31.53

p ns ns ns ns

b.001

GAD = general anxiety disorder, OCD = obsessive compulsive disorder, PTSD = post-traumatic stress disorder. a MINI version 5.0. b aNEQ.

functions, healthy controls performed significantly better compared to RBD patients on the Tower Test (F=7.45, p=.008) and Stroop C–W interference test (F=5.06, p=.03) with effect sizes in the medium to high range (0.73 for the Tower Test and 0.60 for Stroop interference test). Also, on various aspects of verbal and visual memory, controls performed significantly above patients on CVLT delayed recall (F=4.78, p=.03, Cohen's d=0.55), CVLT recognition (F=5.39, p=.02, Cohen's d=0.72), and delayed recall of the Rey–Osterreith figure (F=7.76, p=.007, Cohen's d=0.76). There was no significant difference for the acquisition part of the CVLT (trials 1–5). Only on one measure included in the domain of processing speed, the Digit Symbol Test, controls performed significantly better than RBD patients (F=5.05, p=.03, Cohen's d=0.56), whereas the color naming condition of the Stroop test reached borderline significance (F=3.97, p=.05, Cohen's d=0.52). In addition to CVLT acquisition, only the Stroop reading condition and verbal fluency test (FAS) did not reach significant difference between the groups.

3.3. Neuropsychological performance related to clinical features and comorbidity Among the RBD patients, there were no significant correlations between any neuropsychological test result and the degree of depression as measured by MADRS. As shown in Table 1, 41% of the RBD patients had experienced previous major depressive episodes. Only the Digit Symbol Test

measuring processing speed differed significantly, showing that patients with a history of previous major depressive episodes performed worse (F = 5.11, p = .03); otherwise, there were no significant differences in any neuropsychological test results between RBD patients with or without previous major depressive episodes. Depression severity at the time of assessment, as measured by MADRS scores, was not significantly correlated to any neuropsychological measure, and there were not any significant group differences between patients with MADRS scores above or below 11, used as an index of no ongoing depression versus a state of mild to more severe depression. Moreover, the length of depressive episodes or symptom-free intervals was not significantly related to any of the neuropsychological measures in RBD patients. There were no significant differences in the performances on any test between patients with or without a history of panic disorder, generalized anxiety disorder, specific phobia, or social phobia. There also was not any significant difference if the patient group was dichotomized according to whether they had one or more comorbid anxiety disorder. In Table 3 ANOVAs with Tukey post hoc tests comparing RBD subgroups with and without history of hypomania (RBDH and RBD-O) and control group are presented. There were no significant differences in neuropsychological performance between the two RBD subgroups. Significant differences between controls and RBD-H patients were only obtained for the Letter–Number Span Test (Table 3). However, one or more episodes of hypomania were reported by 44% of the

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Table 2 Neuropsychological test results for patients with recurrent brief depression (RBD) and healthy controls. RBD (N = 46)

Controls (N = 24)

F (df = 1)

p

ES (Cohen's d)

Mean (SD)

Mean (SD)

Attention/working memory PASAT a Letter–Number Span (n = 68)

47.9 (8.20) 14.9 (2.36)

52.0 (5.61) 16.9 (2.21)

4.98 11.99

.03 .001

− 0.58 − 0.87

Psychomotor speed Digit Symbol Stroop C–W, color naming (n = 69) Stroop C–W, word reading (n = 69)

58.2 (8.98) 24.5 (3.95) 15.6 (2.50)

63.3 (9.15) 22.7 (2.91) 15.2 (2.44)

5.05 3.97 0.85

.03 .05 ns

− 0.56 0.52 0.16

Verbal memory CVLT-II, 1–5 learning b CVLT-II, long delay free recall CVLT-II, long delay recognition

57.0 (10.59) 13.2 (2.44) 15.0 (1.25)

61.0 (7.81) 14.3 (1.40) 15.7 (0.56)

2.72 4.78 5.39

ns .03 .02

− 0.43 − 0.55 − 0.72

Visual memory ROCFT, delayed recall c

20.7 (6.99)

25.0 (3.90)

7.76

.007

− 0.76

Executive function Tower Test (n = 68) Stroop C–W interference (n = 69) Verbal fluency (FAS)

18.3 (3.92) 43.9 (10.29) 45.1 (11.49)

21.0 (3.50) 38.6 (7.01) 48.8 (10.22)

7.45 5.06 1.75

.008 .03 ns

− 0.73 0.60 − 0.34

ES = effect size. a Paced Auditory Serial Addition Test. b California Verbal Learning Test II. c Rey Osterreith Complex Figure Test.

patients; for all other test results that reached significance only RBD-O were significantly different from normal controls according to post hoc analyses. There were no significant differences in neuropsychological test scores among patients reporting or not reporting

migraines or previous minor head concussion. When excluding patients with migraines from the between-group analyses all significant differences reported in Table 2, except the Tower Test, are kept. When excluding previous minor concussion (excluding 52% of the patient sample) significant

Table 3 Neuropsychological test results for RBD patients with (RBD-H) and without (RBD-O) hypomania and healthy controls (CON). RBD-O (N = 26)

RBD-H (N = 20)

Controls (N = 24)

Mean (SD)

Mean (SD)

Mean (SD)

Attention/working memory PASAT a Letter–Number Span (n = 68)

48.0 (8.30) 15.1 (2.03)

47.7 (8.27) 14.6 (2.74)

52.0 (5.61) 16.9 (2.21)

2.45 6.24

.092 .003

Psychomotor speed Digit Symbol Stroop C–W, color naming (n = 69) Stroop C–W, word reading (n = 69)

57.6 (10.21) 25.6 (4.23) 15.9 (2.71)

59.1 (7.25) 23.1 (3.09) 15.1 (2.15)

63.3 (9.15) 22.7 (2.91) 15.2 (2.44)

2.65 4.84 0.87

.078 .011 .423

Verbal memory CVLT-II, 1–5 learning b CVLT-II, long delay free recall CVLT-II, long delay recognition

57.5 (8.68) 13.3 (2.25) 15.2 (1.34)

56.2 (12.86) 13.0 (2.71) 14.9 (1.12)

61.0 (7.81) 14.3 (1.40) 15.7 (0.56)

1.45 2.45 3.00

.242 .094 .056

Visual memory ROCFT, delayed recall c

19.8 (7.73)

21.8 (5.92)

25.0 (3.90)

4.45

.015

Executive function Tower Test (n = 68) Stroop C–W interference (n = 69) Verbal fluency (FAS)

17.7 (3.96) 45.6 (11.54) 45.1 (10.59)

19.2 (3.82) 41.5 (7.95) 45.1 (12.85)

21.0 (3.50) 38.6 (7.01) 48.8 (10.22)

4.54 3.69 0.86

.014 .030 .428

a b c

Paced Auditory Serial Addition Test. California Verbal Learning Test II. Rey Osterreith Complex Figure Test.

F (df = 2)

p

Tukey post hoc tests

Cohen's d

RBD-O versus CON

RBD-H versus CON

RBD-O,RBD-H b CON

− 0.56 − 0.84

− 0.61 − 0.92

RBD-O b CON = RBD-H

− 0.59 0.80 0.27

− 0.51 0.13 − 0.04

− 0.42 − 0.53 − 0.49

− 0.45 − 0.60 − 0.90

RBD-O b CON = RBD-H

− 0.85

− 0.64

RBD-O b CON = RBD-H RBD-O b CON = RBD-H

− 0.88 0.73 − 0.36

− 0.49 0.39 − 0.32

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differences were maintained for the learning/memory tests, the Tower Test, and the Letter–Number Span test. 3.4. Magnitude of neuropsychological deficit in RBD To explore the clinical significance of neurocognitive deficits in the total RBD sample, and RBD patients with and without hypomania specifically, the proportion of patients performing 1.5 standard deviations below the average of the control group was calculated. The number of RBD patients falling below the clinical cut-off value varied from 13% for the verbal fluency test up to 50% for the visual recall test (Table 4). Calculating the mean percentage of RBD patients with results below 1.5 SD, 25.3% of the patients were clinically impaired across all tests. Chi-square analyses revealed that only the Letter–Number Span Test was significantly different between RBD patients with and without hypomania, with 40% of those with hypomania performing below the 1.5 SD cut-off compared to 13% of those without hypomania (χ2(1) = 4.40, p = .04). 3.5. Neuropsychological performance controlled for information processing speed To test the impact of psychomotor or processing speed as a possible general mediator of cognitive impairment in depression, a multivariate analysis of covariance (MANCOVA) was carried out with the composite domain T-scores as dependent variables, patient/control group as the factor, and the composite T-score of the processing speed domain as the covariate. The analysis showed a significant overall difference in neuropsychological performance between groups when controlling for processing speed (F(4, 60) = 4.17, p = .005). Between-

subject differences in favor of healthy controls were significant for every cognitive domain: working memory (F(1) = 12.26, p = .001), verbal learning and memory (F(1) = 6.27, p = .02), executive functions (F(1) = 5.22, p = .03), and visual memory (F(1) = 7.52, p = .008). 4. Discussion To our knowledge, this is the first study to examine neuropsychological function in patients with RBD, diagnosed according to the ICD-10 (F38.1) criteria. Our main finding is that RBD represents a depressive disorder associated with deficits in working memory, processing speed, verbal and visual memory, and various aspects of executive functions. In the working memory domain, both the PASAT and Letter– Number Span Test were significantly impaired. Two of three tests of processing speed reached significance, and the word reading condition of the Stroop test was not significantly different. Reading is a highly automated function that requires less involvement of higher cognitive functioning. The acquisition part of the California Verbal Learning Test did not differentiate between groups, only the recall and recognition parts. Also, for the recall of newly learned visual information, there was a significant between-group difference. These results may indicate that memory deficits in RBD are mainly associated with the retrieval aspects of memory function, with acquisition being less impaired. Episodic memory is shown to be one of the main cognitive domains vulnerable to the adverse effects of depression (Ilsley et al., 1995; Airaksinen et al., 2004) and has been linked to temporal lobe dysfunction. In patients with unipolar and bipolar recurrent major depression, the number of depressive episodes is associated with verbal memory

Table 4 Patients with clinically significant impairment (performing below 1.5 SD of the control group mean) for the total RBD group and RBD patients with (RBD-H) and without (RBD-O) hypomania. Cut-off score

RBD (n = 46)

RBD-O (n = 26)

RBD-H (n = 20)

Chi-square (χ2, df = 1)

n (%)

n (%)

n (%)

RBD-O versus RBD-H

Attention/working memory PASAT a Letter–Number Span

43.6 13.6

10 (22) 11 (25)

7 (27) 3 (13)

3 (15) 8 (40)

0.95, p = 0.33 4.40, p = 0.04

Psychomotor speed Digit Symbol Stroop C–W, color naming Stroop C–W, word reading

49.6 27.1 18.8

7 (15) 7 (16) 5 (11)

5 (19) 5 (19) 4 (15)

2 (10) 2 (11) 1 (5)

0.75, p = 0.39 0.63, p = 0.43 1.14, p = 0.29

Verbal memory CVLT-II, 1–5 learning b CVLT-II, long delay free recall CVLT-II, long delay recognition

49.3 12.2 14.8

12 (26) 17 (37) 12 (26)

6 (23) 9 (37) 6 (23)

6 (30) 8 (40) 6 (30)

0.28, p = 0.60 0.14, p = 0.71 0.28, p = 0.60

Visual memory ROCFT, delayed recall c

19.1

23 (50)

15 (58)

8 (40)

1.42, p = 0.23

Executive function Tower Test Stroop C–W interference Verbal fluency (FAS)

15.7 49.1 33.4

11 (25) 12 (27) 6 (13)

6 (24) 9 (35) 3 (12)

5 (26) 3 (16) 3 (15)

0.03, p = 0.86 1.99, p = 0.16 0.12, p = 0.73

a b c

Paced Auditory Serial Addition Test. California Verbal Learning Test II. Rey Osterreith Complex Figure Test.

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deficits, an association that could be explained by progressive cerebral dysfunction and anatomical changes (Fossati et al., 2004). Recently, Vasic et al. (2008) reported a reduction in the gray matter volume of the left hippocampal gyrus, cingulate gyrus, and thalamus, and that depression severity is related to hippocampal volume reduction. Executive dysfunction has been identified as another core neurocognitive dysfunction in major depression that persists into remission (Fossati et al., 2002; Rogers et al., 2004), and Withall et al. (2008) found that sub-scores on the Wisconsin Card Sorting Test predict worse social and occupational outcomes in major depressed patients. In our study, three different tests were used to investigate different aspects of executive function: the Tower Test for strategic problemsolving and planning, the Stroop Color–Word Interference Test for response inhibition and conflict monitoring, and the FAS letter fluency for cognitive initiation. The FAS test results did not differ significantly between RBD patients and controls. Interestingly, in a review of cognitive function in euthymic bipolar depression (Robinson et al., 2006), phonemic verbal fluency was, among several other measures of executive function, the test with the lowest effect size. In a study of bipolar II patients, our group recently reported no significant difference in performance on FAS compared to controls (Andersson et al., 2008). Similarly, Torrent et al. (2006) found a significant difference for semantic word fluency (animal naming) but not letter fluency (FAS), and in a meta-analysis of verbal fluency in depression, Henry and Crawford (2005) found semantic fluency deficits to be substantially larger than those of phonemic fluency. Impaired FAS scores have been reported as a more state-dependent neuropsychological measure and have also been shown to predict the fluoxetine response in major depression, with non-responders being most impaired on the FAS test prior to treatment (Taylor et al., 2006). A majority of our RBD patients were not clinically depressed at the time of assessment, 56% had a MADRS score below 11 and only 20% had a score in the moderate to severe range (MADRS N 20). Moreover, there were no significant correlations between the severity of depression and test performance, and there were no differences in neuropsychological results between RBD patients who had experienced previous major depressive episodes and those who had not. Neither the clinical features related to RBD, such as the mean duration of depressive episodes, nor the interval between episodes was related to test performance. Therefore, the neurocognitive impairment in our group of RBD patients seems to reflect basic neurobiological dysfunction. Impairment in the Tower Test and Stroop test suggests a dysfunction of the neural circuitry involving different prefrontal areas. Imaging studies using Tower Test paradigms have reported increased activation in different prefrontal regions, such as the bilateral dorsolateral, right ventrolateral, and left rostrolateral prefrontal cortices, in addition to striatal activation during Tower Test problem-solving (van den Heuvel et al., 2003; Wagner et al., 2006). Although the test paradigms used in functional imaging studies are modified versions of the standardized neuropsychological methods, it might support the hypothesis that impaired Stroop test result is associated with anterior cingulate dysfunction; as this and related tasks involving conflict monitoring have been shown in several

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imaging studies to be associated with activation of the anterior cingulate (Peterson et al., 1999; Carter and van Veen, 2007). In an extensive review of volumetric MRI studies in depression and bipolar disorder, Konarski et al. (2008) reported evidence for regional deficits in the frontal lobe, particularly in the anterior cingulate and orbitofrontal cortex, in subjects with mood disorders. Although cautions must be taken when inferring from neuropsychological test results to localized cerebral dysfunction, changes at the structural level involving prefrontal neural circuits might underlie the observed executive dysfunction in these patients. Our results gave no evidence of additional cognitive impairment in RBD patients with a history of hypomania compared to those without hypomania, and there were no significant differences on any neuropsychological measure between the two groups. An inspection of raw scores in Table 3 shows that RBD patients with hypomania perform slightly more poorly compared to RBD patients without hypomania on all aspects of attention/working memory and verbal memory, whereas test scores for psychomotor speed, visual memory, and executive functions are slightly different and in the opposite direction. However, there were significant differences between RBD patients without hypomania and normal controls on five of 12 cognitive measures, whereas there was only one test that was significantly different between RBD patients with hypomania and controls. Inspecting the effects sizes between controls and the two RBD subgroups show a more differentiated pattern with larger effect sizes for RBD-H versus controls for attention/working memory and verbal memory compared to effects sizes for RBD-O versus controls (Table 3). For tests measuring psychomotor speed, visual memory and executive functions the effect sizes show the opposite pattern. These results do not, however, support the hypothesis that additional hypomania in RBD patients is a marker of severity with respect to cognitive functioning in general. It has been debated whether patients with bipolar and unipolar depression present distinctly different neurocognitive profiles. Studies have presented conflicting findings; for example, Smith et al. (2006) reported increased executive and verbal memory dysfunction in euthymic bipolar patients compared to patients with remitted major depressive disorder. Borkowska and Rybakowski (2001) found significantly greater impairment in bipolar depression compared to major depression across a range of executive functions. In contrast, Taylor Tavares et al. (2007) found impaired attention and executive function in unmedicated patients with unipolar depression compared to unmedicated bipolar depression. In our study of patients with bipolar II disorder using an overlapping neuropsychological test protocol, we reported generally larger effect sizes, ranging from 0.62 to 1.34, than in the present study (Andersson et al., 2008). These findings may indicate that bipolar II is a condition associated with a more severe cognitive impairment compared to RBD. This corresponds to clinical studies which suggest that bipolar II is a more severe disorder than RBD. 4.1. Psychomotor retardation as an explanation of cognitive impairment Speed of information processing could be considered a core element of or a prerequisite for optimal cognitive

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functioning, and it is an essential aspect of most neuropsychological methods. According to the cognitive speed hypothesis depressed patients perform significantly more poorly than controls due to a general cognitive slowing (Den Hartog et al., 2003) and this psychomotor retardation might explain impairments in several areas of neuropsychological functioning observed in patients with depression (Cohen et al., 1982; Tancer et al., 1990; Parker et al., 1993). The significant differences between RBD patients and controls with respect to executive functions, memory, and working memory in the present study were all maintained when controlling for processing speed. Therefore, we conclude that the differences in neuropsychological performance in RBD patients reflect genuine impairment of specific neurocognitive function and not merely differences of general psychomotor retardation. However, by inspecting our results we could argue that poor effort contribute to the differences between RBD patients and controls. Performance on effortdemanding tasks such as the PASAT and the Letter–Number Span test differed significantly, while the word reading condition of the Stroop test requiring automatic and welllearned responses did not differ.

condition. The relatively high level of education among the patients might also reflect this aspect. A mean of 14.1 years of education means that the majority of patients had education beyond high school. An estimated IQ of 1 SD above the normative mean further supports the notion of a high functioning sample that might not be representative of the RBD population in general, requiring caution in making generalizations from our findings. The majority of female participants in our sample does not correspond to the near 50/50 gender distribution usually found in epidemiological studies of RBD (Pezawas et al., 2003), making firm conclusions across gender more difficult. Another limiting factor addressing generalization is the number of participants included, requiring caution especially when making conclusions regarding sub-samples. Psychiatric comorbidity is frequent in patients with affective disorders, in our sample a large proportion of the patients also had comorbid migraine and a history of minor head concussion which represents a limitation of the study. Another limitation is the large number of statistical test employed which increase the risk of committing Type I error. 4.4. Conclusion

4.2. Clinical significance The nature and magnitude of neurocognitive deficits in affective disorders may have consequences for psychosocial and vocational functioning, as shown in bipolar disorders across symptomatic phases (Martínez-Arán et al., 2004; Malhi et al., 2007). Moreover, neuropsychological deficits, especially those involving memory, attention, and executive functions, may affect the patient's responsiveness to psychotherapeutic interventions. Looking at the effect sizes, 9 out of 12 were above medium range (N0.50), and a substantial proportion of our RBD patients had test scores below 1.5 SD from the mean of the control group, defining clinically significant impairment. On average, across all test results, over 25% the RBD group belonged to the clinically impaired category, demonstrating that cognitive impairment might represent a major difficulty interfering with many aspects of daily living. Compared to studies in major depression samples, e.g. meta-analyses by Burt et al. (1995), the magnitude of cognitive impairment found in our RBD patients is considerable. The neurobiology and pathophysiology of RBD is unknown, as is the neurocognitive effects of frequent recurrent depressive episodes. It cannot be ruled out that RBD represent a condition associated with substantial neurocognitive impairment with severity level comparable to what is found in patients with major depression. However, our findings emphasize the importance of neuropsychological assessment in order to identify patients who, even in nonsymptomatic phases, have cognitive impairments that have to be taken into consideration when planning their treatment regimen. 4.3. Limitations A substantial portion of the patients participating in this study were self-referred after reading about the project in different media. This could cause a possible bias because of patients being more aware and competent about their

In summary, this study shows that neuropsychological deficits across different cognitive domains are present in unmedicated patients with ICD-10 defined RBD. The majority of patients was euthymic or sub-clinically depressed at the time of assessment and the degree of neuropsychological impairment was not related to depression severity, and there was not any significant difference between RBD patients with or without comorbid anxiety disorder, a history of previous major depressive episodes, or a history of hypomania. Reduced psychomotor speed could not account for the differences in neuropsychological performance, indicating that RBD patients demonstrate specific and genuine neurocognitive impairments similar to other types of depression. Role of funding source This project was partly financed by the Research Council of Norway, Rikshospitalet University Hospital, Sørlandet Hospital, and the South-Eastern Norway Regional Health Authority. These institutions 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. Conflict of interest Dr Lövdahl and Dr. Malt have received speaker's fees for lecturing about RBD at meetings organized by pharmaceutical companies.

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