Distinct Profiles of Neurocognitive Function in Unmedicated Unipolar Depression and Bipolar II Depression

Distinct Profiles of Neurocognitive Function in Unmedicated Unipolar Depression and Bipolar II Depression Joana V. Taylor Tavares, Luke Clark, Dara M. Cannon, Kristine Erickson, Wayne C. Drevets, and Barbara J. Sahakian Background: Studies have demonstrated neuropsychological deficits across a variety of cognitive domains in depression. Few studies have directly compared depressed subjects with major depressive disorder (MDD) and bipolar disorder (BD), and many are confounded by medication status across subjects. In this study, we compared the performance of unmedicated currently depressed MDD and BD groups on a battery of neuropsychological tests that included measures of risk taking and reflection impulsivity. Methods: Twenty-two MDD, seventeen BDII, and 25 healthy control subjects (HC), matched for age and IQ, were assessed on a battery of neuropsychological tests. Results: The depressed groups showed comparable ratings of depression severity and age of illness onset. The MDD group was impaired on tests of spatial working memory and attentional shifting, sampled less information on a test of reflection impulsivity, and was oversensitive to loss trials on a decision-making test. The BDII subjects were generally intact and did not differ significantly from control subjects on any test. Conclusions: These data indicate differing profiles of cognitive impairment in unmedicated depressed MDD versus BDII subjects. Moderately depressed BDII subjects displayed relatively intact cognitive function, whereas MDD subjects demonstrated a broader range of executive impairments. These cognitive deficits in depression were not attributable to current medication status. Key Words: Bipolar II disorder, major depressive disorder, neuropsychological tests, sensitivity to loss, spatial working memory, unmedicated

C

ognitive symptoms, such as poor concentration and difficulty making decisions, are included in the DSM-IV diagnostic criteria for depression (1) and appear to represent one of the core features of the depressive syndrome with an impact on functional outcome (2,3). Few studies have compared neuropsychological function in the depressed phase between bipolar and unipolar disorders. Whereas Kessing et al. (4) and Sweeney et al. (5) reported similar impairments in subjects with bipolar disorder (BD) and major depressive disorder (MDD) in euthymic and depressed states, respectively, other studies have found worse performance on measures of memory (6) and executive and attentional function (7) in BD (mostly BDI). The diagnosis of BD in DSM-IV distinguishes two syndromes, BDI and BDII, on the basis of the presence of manic versus hypomanic episodes, respectively. In the BDII syndrome, depression is the predominant pathological mood state and also the most persistent. There is an extreme paucity of neuropsychological data on subjects with BDII disorder (8). Impairments have been identified in both euthymic BDII and BDI groups on a number of tests (9) although on tests of executive function and memory, the BDII

From the Departments of Psychiatry (JVTT, BJS), Addenbrooke’s Hospital, University of Cambridge, United Kingdom; National Institute of Mental Health (JVTT, DMC, KE, WCD), National Institutes of Health, Bethesda, Maryland; and Wolfson Brain Imaging Centre (JVTT) and Department of Experimental Psychology (LC), University of Cambridge, United Kingdom. Address reprint requests to Joana V. Taylor Tavares, M.A., Wolfson Brain Imaging Centre, Box 65, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 2QQ, United Kingdom; E-mail: [email protected]. Received April 5, 2007; revised June 19, 2007; accepted June 26, 2007.

0006-3223/07/$32.00 doi:10.1016/j.biopsych.2007.05.034

group performed intermediately between the BDI and HC groups. Martinez-Aran et al. (3) have identified greater impairment associated with a diagnosis of BDI compared with BDII. Comparison of the BDII neuropsychological profile with the pattern of dysfunction in MDD and BDI carries important implications for the diagnostic validity of the BDII syndrome, as well as for treatment. Comparison of the neuropsychological profile of MDD and BD is hampered by medication status. The majority of the neuropsychological studies performed to date have compared medicated depressed subjects with unmedicated control groups. Medication regimes in BD and MDD differ considerably, with selective serotonin reuptake inhibitors typical for MDD, and treatment with mood stabilizers, antipsychotics, or both more usual for BD. It remains unclear whether chronic treatment has a detrimental or beneficial effect— or no measurable effect— on cognitive performance (10 –13). The aims of this study were to compare neuropsychological function during depression in unmedicated groups and to compare directly a group of currently depressed BDII subjects with MDD and healthy control subjects groups. Depression is the predominant mood state in BDII, and the assessment of cognitive performance in MDD and BDII depression can be used to establish whether these pathologic mood states are functionally equivalent. Preliminary evidence has indicated that groups of mostly BDI subjects display greater impairment in executive function than MDD (6,7), and that trait-related impairments during remission are greater in BDI than BDII (3,9). We hypothesized that MDD and BDII patients tested during a depressive episode would both display a significant but similar profile of cognitive impairment compared with nondepressed control subjects.

Methods and Materials Participants Subjects aged 18 to 59 years provided written informed consent as approved by the National Institute of Mental Health BIOL PSYCHIATRY 2007;62:917–924 © 2007 Society of Biological Psychiatry

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Table 1. Demographic and Clinical Measures Used and Results from Healthy Control and Depressed Groups. Data Shown are Means with Standard Errors of the Mean in Parentheses What Scale Measures and Reference N F:M Age IQ WASI Age of onset of depression (yr) Years since onset of depression Weeks off medication HSE total MADRS YMRS HAM-A

RSQ CA Total BIS-11 Total

HC 25

Estimates full-scale IQ (14)

Socio-economic status (15) Depression severity (16); 7–19 mild, 20–34 moderate, ⬎35 severe Manic symptoms, (17), ⬍13 normal range Symptoms of anxiety (18); 14–17 mild, 18–24 moderate, 25–30 moderate to severe Ruminative thoughts (19) Physical and social anhedonia (20, 21) Impulsivity (22)

MDD 22

18:7 34.8 (1.76) 118 (2.07) NA NA NA 49.8 (1.38) .16 (.16)

17:5 38.6 (1.72) 114 (1.61) 19.5 (8.56) 18.8 (1.98) 153 (54.7) 49.5 (1.63) 25.5 (1.56)a

.08 (.08)

4.57 (.62)a

.12 (.12)

16.0 (1.51)a

14.2 (.82) 8.40 (1.24) 65.1 (1.96)

BD

F

P

2.18 1.56

.12 .22

.15

.86 ⬍.001

17 12:5 32.6 (2.68) 112 (3.91) 17.0 (1.69) 15.6 (2.72) 226 (71.6) 48.3 (3.30) 24.1 (2.36)a

108 20.8

⬍.001

16.6 (1.80)a

63.6

⬍.001

30.2 (1.06)a 28.8 (3.67)a

26.7 (1.22)a 21.0 (5.42)a

79.1 21.7

⬍.001 ⬍.001

69.0 (2.35)

70.7 (2.04)

5.06 (1.09)a

1.76

.18

Data is missing for one MDD subject on all the scales except the HSES social measure (two) and the BIS (none missing). Data is missing for one BD subject for the RSQ and BIS, for two subjects for the HSES social and the Chapman Anhedonia Scales and for three subjects for the RSQ. BD, bipolar disorder; BIS, Barratt Impulsiveness Scale version 11 to assess impulsivity; CA, Chapman Social and Physical Anhedonia Scales; F, female; HAM-A, Hamilton Anxiety Rating Scale; HC, Healthy controls; HSES, Hollingshead and Redlich’s scale of socioeconomic status; IQ—WASI, Intelligence Quotient—Wechsler Abbreviated Scale of Intelligence; M, male; MADRS, Montgomery-Åsberg Depression Rating Scale; MDD, major depressive disorder; RSQ, Response to Situations Questionnaire; YMRS, Young Mania Rating Scale. a denotes p ⱕ .05 versus HC.

Internal Review Board and were recruited through the National Institutes of Health Clinical Center. Diagnoses were established according to DSM-IV criteria (1) in a clinical interview conducted by a psychiatrist. Subjects were excluded if they met DSM-IV criteria for alcohol or substance abuse within 1 year before screening or had ever met criteria for dependence, had a history of neurological disease, a clinically significant head injury, current pregnancy, a full-scale IQ below 85, or had received psychotropic medications within 3 weeks of testing (8 weeks for fluoxetine). Depressed subjects were seen at least weekly by a health care professional, and if a subject developed clinically serious exacerbation of his or her clinical condition, procedures were in place for withdrawal from the study and more intensive management or inpatient hospitalization. BD Group Seventeen currently depressed subjects who met criteria for BDII were included. One subject had a diagnosis of comorbid obsessive– compulsive disorder (OCD) and a history of attentiondeficit/hyperactivity disorder (ADHD), one subject had a comorbid diagnosis of posttraumatic stress disorder (PTSD), one subject had a social anxiety disorder, one subject had comorbid diagnoses of OCD and panic disorder (PD), and one subject had a sleep disorder. MDD Group Twenty-two currently depressed subjects who met criteria for recurrent MDD took part in the study. Two subjects had a comorbid diagnosis of PD, one of whom was also diagnosed with PTSD. Another subject had a diagnosis of PTSD. Two subjects had a history of ADHD. www.sobp.org/journal

Healthy Control Group Twenty-five healthy subjects with no history of psychiatric disorder and no first-degree relatives with a mood disorder were recruited. Clinical and Psychological Rating Scales A battery of clinical and self-rating scales was administered to assess severity of clinical symptoms, anhedonia and impulsivity. These scales are summarized in Table 1. Cognitive Test Battery Subjects were tested on a comprehensive neuropsychological test battery from the Cambridge Neuropsychological Test Automated Battery (CANTAB; http://www.camcog.com) administered on a PC computer with responses registered via touchsensitive screen or response key. Descriptions of CANTAB tests are presented in Table 2, and more detailed information on the more recent Cambridge Gamble Task (CGT) and Information Sampling Task (IST) is presented later in the paragraphs that follow. The CGT was designed to assess quality of decision-making and risk-taking preferences (26). Subjects are presented with a display of 10 boxes, colored red or blue. They are instructed that the computer has hidden a token inside one of the boxes. The ratio of red:blue boxes varies across trials from 6:4, 7:3, 8:2 to 9:1. On each trial, the subjects must first decide whether the token is hidden in a red or blue box and must then stake a percentage of their current points total on their red or blue choice. After betting, the location of the token is revealed, and the bet is added or deducted from the total score as appropriate. Bets are presented in an ascending condition (in which the initial bet is low and increases over time) and a descending condition, to enable

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J.V. Taylor Tavares et al. Table 2. Summary of Neuropsychological Tests Test Pattern Recognition Memory (PRM) Spatial Recognition Memory (SRM) Spatial Span (SSP)

Simultaneous and Delayed Matching to Sample (SMTS & DMTS)

Spatial Working Memory (SWM)

Intra-Dimensional ExtraDimensional Set Shifting (IDED)

Description

References

A two-choice test of abstract visual pattern recognition memory. A two-choice forced discrimination paradigm testing spatial recognition memory. A test of a subject’s recall of the order in which a series of boxes are highlighted on screen.

(23)

Proportion correct

(23)

Proportion correct

(23)

This is four-choice test of both simultaneous and delayed matching to sample of abstract patterns. In the simultaneous condition four choice patterns (the target and three distractors) appear below the central presentation of the sample. In the delay conditions the sample does not remain on screen and there is a delay of 0, 4, or 12 seconds before the four choice stimuli are presented. SWM is a self-ordered search test which assesses spatial working memory and strategy performance. Subjects are required to ‘search through’ boxes on a screen to find a blue token. Subjects are instructed that once they find a token under a particular box they will not find another token under that box on a particular trial. ‘Between search errors’ occur when a subject opens a box in which they have already found a blue token. Strategy is measured by the extent to which a repetitive search pattern is used and can be estimated from adding together the number of search sequences starting with the same box. A high strategy score represents a low use of strategy. IDED is a test of visual discrimination learning which assesses the ability to selectively attend to and shift between a number of stimulus dimensions, including shape and colour. The test has nine stages which progress from a simple discrimination of two shapes (SD) to a compound discrimination (CD) between two pink shapes and two white lines through to an intra-dimensional shift (ID) which requires subjects to maintain their response to shapes rather than lines and finally to an extradimensional shift (ED) which requires a subject to shift their attention to the lines. The subject progresses to a subsequent stage by making six consecutive correct responses within 50 trials.

(24)

Span length (longest sequence recalled) Total Errors Proportion correct Response latency (msec)

risk-preference behavior to be distinguished from delay aversion or impulsivity: impulsive subjects would bet low in the ascend condition but high in the descend condition, whereas risk-taking subjects would bet high in both conditions. The IST is designed to assess reflection impulsivity (27). On each trial, subjects are presented with a 5 ⫻ 5 matrix of gray boxes. When a subject selects a box from the matrix, one of two colors is revealed. Subjects must decide which box color lies in the majority in the matrix. After it is opened, a box stays uncovered for the remainder of the trial to minimize working memory demands. Subjects are instructed that they can open as many boxes as they wish before making a decision. After a decision, the colors of all squares are revealed and subjects receive feedback indicating points won or lost. There are two task conditions of 10 trials each: Fixed Win (FW) and Descending Win (DW). In the FW condition subjects win or lose 100 points irrespective of the number of boxes opened. In the DW condi-

(23)

Measures

Between search errors (returning to search in a box where a token has previously found)

Strategy

(25)

Total errors Total stages passed

tion, the number of points available decreases (by 10) for each box opened, from a maximum of 250. If wrong, they lose 100 points irrespective of boxes opened. Data Analysis Analyses were carried out using Statistical Package for Social Sciences V11.0.1 (SPSS, Chicago, Illinois). t tests, univariate or repeated-measures analysis of variance (ANOVA), were used as appropriate for the analysis. When significant overall group differences were found, Bonferroni tests were used to assess the significance of specific contrasts between groups. The significance threshold was set at p ⱕ .05. To stabilize variance or reduce skew, the following data were transformed (28): DMTS proportion correct, SWM between-search error, CGT proportion selected most likely outcome and latency, and the number of incorrect judgments on the IST. When data could not be transformed to meet the assumptions of normality, nonparametric www.sobp.org/journal

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Table 3. Summary of Test Results Test PRM SRM SSP Delayed MTS SWM IDED CGT

IST Fixed Reward Decreasing Reward

HC

MDD

BD

Proportion correct Proportion correct Spatial span length Proportion correct—all delays Latency correct (msec)—all delays Total between-search errors Strategy score Stages completed Total errors Mean bet Proportion selected most likely outcome Mean latency (msec) Quality of decision-making after a win Quality of decision-making after a loss

.924 (.02) .846 (.031) 6.75 (.30) .885 (.022) 3601 (163) 15.9 (3.81) 29.5 (1.18) 8.76 (.14) 13.9 (2.13) 54.0 (3.33) .950 (.02) 2107 (236) .944 (.020) .956 (.020)

.927 (.014) .753 (.02) 6.05 (.35) .833 (.018) 3336 (197) 38.1 (5.11)a 34.4 (1.39)a 8.17 (.98) 21.6 (3.00) 57.7 (2.52) .935 (.02) 2329 (360) .949 (.023) .898 (.020)b

.869 (.024) .806 (.03) 6.19 (.33) .849 (.030) 3869 (448) 25.6 (4.80) 33.2 (1.40) 8.87 (.52) 16.5 (2.40) 51.3 (2.86) .969 (.01) 2085 (236) .954 (.018) .982 (.019)

␹2 ⫽ 5.02, p ⫽ .081 F ⫽ 2.87, p ⫽ .065 ␹2 ⫽ 3.26, p ⫽ .195 F ⫽ 2.8, p ⫽ .07 F ⫽ 1.00, p ⫽ .383 F ⫽ 8.11, p ⫽ .001 F ⫽ 4.29, p ⫽ .018 2i ⫽ 7.14, p ⫽ .028 F ⫽ 2.54, p ⫽ .089 F ⫽ .482, p ⫽ .621 F ⫽ .313, p ⫽ .732 F ⫽ .917, p ⫽ .406 F ⫽ .094, p ⫽ .911 F ⫽ 3.08, p ⫽ .055

Boxes opened Incorrect judgments Boxes opened Incorrect judgments

15.53 (1.01) .84 (.20) 9.48 (.73) 2.08 (.24)

11.58 (1.10)a 2.09 (.35)a 8.85 (.92) 2.45 (.28)

14.82 (1.36) 1.53 (.040) 9.75 (.86) 2.29 (.38)

F ⫽ 3.53, p ⫽ .035 F ⫽ 4.72, p ⫽ .012 F ⫽ .29, p ⫽ .749 F ⫽ .084, p ⫽ .920

Values shown for each variable are the mean and standard errors of the mean for each group. Data is missing for two subjects from each group on the PRM and DMTS; 2 HC, 3 MDD and 1 BD on SRM; 1 HC, 2 MDD and 1 BD on SSP and SWM; 4 HC, 4 MDD and 2 BD subjects on the IDED and 4HC, 4 MD and 3 BD on the CGT due to problems with data collection. BD, bipolar disorder; CGT, Cambridge Gamble Test; DMTS, delayed matching to sample; HC, Healthy control; IDED, intra-dimensional, extra-dimensional attention shifting; IST, information sampling test; MDD, major depressive disorder; MTS, matching to sample; PRM, pattern recognition memory; SRM, spatial recognition memory; SSP, spatial span; SWM, spatial working memory. a denotes p ⱕ .05 versus HC. b denotes p ⱕ .05 versus BD.

Kruskal-Wallis Tests were used. Data are presented as untransformed means. Pearson Correlation Coefficients were used to investigate the contribution of clinical and psychological variables to neuropsychological test performance.

diagnosis [F (2,55) ⫽ 2.800, p ⫽ .070] with the MDD group tending to make more errors than HCs. No significant delay ⫻ diagnosis interaction was found. For latency, there was a main effect of delay [F (2.3,134.2) ⫽ 50.82, p ⬍ .001] with longer latencies for longer delays but no effect of diagnosis.

Results Clinical and Psychological Rating Scales The three groups did not differ significantly with respect to age, sex [␹2(2) ⫽ .877, p ⫽ .195], IQ, or socioeconomic status (15) total score (see Table 1). The two depressed groups did not differ in terms of age of onset of depression [t (36) ⫽ .961, p ⫽ .343], years since onset [t (36) ⫽ .980, p ⫽ .334], and time off medication [t (36) ⫽ ⫺1.17, p ⫽ .248]. There was a significant difference (p ⬍ .05) between groups on a number of scales (see Table 1): as expected, the HC group showed less depression, anxiety, mania, rumination, and anhedonia than the two depressed groups, but the depressed groups did not differ significantly on these measures. Neuropsychological Performance No significant group differences were found on the Pattern Recognition Memory, Spatial Recognition Memory, and Spatial Span tests. Neuropsychological scores are reported in Table 3, and tests revealing significant between-group effects are now described in more detail. Simultaneous and Delayed Matching to Sample Data were analyzed in two mixed-model ANOVAs for the dependent variables proportion correct and latency to respond on correct trials, with delay (simultaneous, short, medium, or long) and diagnosis as within- and between-subjects factors, respectively. For proportion correct, there was a main effect of delay [F (3,165) ⫽ 26.5, p ⬍ .001] and a trend for a main effect of www.sobp.org/journal

Spatial Working Memory (SWM) Results for between-search errors were analyzed using a repeated-measures ANOVA with level of difficulty (four, six, or eight box) as a within-subject factor. There was a main effect of diagnosis [F (2,57) ⫽ 7.81, p ⫽ .001], as well as a significant diagnosis ⫻ level of difficulty interaction [F (4,114) ⫽ 3.46, p ⫽ .011] (see Figure 1). Post hoc tests revealed that MDD subjects made significantly more errors than the BD group at the four-box stage (p ⫽ .041) and more errors than HCs at the six- and eight-box stages (p ⱕ .05). There was a trend for the BD group to make more errors than HCs at the eight-box stage (p ⫽ .063). A one-way ANOVA revealed a main effect of group for strategy score [F (2,57) ⫽ 4.29, p ⫽ .018] with the MDD group having poorer strategy use than the HC group (p ⫽ .021). The BD group did not differ significantly from the MDD (p ⫽ 1.00) or HC (p ⫽ .16) groups. Intra-Dimensional Extra-Dimensional Set Shifting (IDED) All subjects completed at least seven of the nine stages of the test. Two HCs, seven MDD, and one BD subject failed at the Extra-Dimensional Shift (EDS) stage (stage 8), and one HC and one MDD subject failed at the Extra-Dimensional Reversal (EDR) stage (stage 9). Test completion rates were analyzed using a likelihood ratio analysis, which is useful with small cell frequencies (29,30). Groups differed significantly in completion rates at the EDS stage [2i(2) ⫽ 7.14, p ⫽ .028] with a larger percentage of MDD subjects failing at this stage than either HC

J.V. Taylor Tavares et al.

Figure 1. Number of between-search errors made by healthy control (HC), major depressed (MD), and bipolar depressed (BD) subjects, across the four-, six-, and eight-box conditions of the Spatial Working Memory Test. The MDD subjects were significantly impaired at the six- and eight-box stages compared with HC subjects. Error bars represent standard error of the mean.

[2i(1) ⫽ 4.87, p ⫽ .027] or BD subjects [2i(1) ⫽ 5.15, p ⫽ .023] (see Figure 2). Error data were manually adjusted for subjects failing to complete the final stage (all subjects attempted the eighth stage, even if they failed it): the average number of reversal errors for reversal stages completed was applied to the ninth, EDR, stage. The one-way ANOVA for total errors only approached significance [F (2,51) ⫽ 2.54, p ⫽ .089]. Cambridge Gamble Test For each of the three dependent variables, speed of decision making, quality of decision making, and betting behavior (percentage of points risks at different odds), a repeated-measures

Figure 2. Cumulative percentage of subjects failing at stages of the IntraDimensional, Extra-Dimensional Attention Shifting Test for each of the three groups tested: healthy control (HC), major depressed (MD), and bipolar depressed (BD) subjects. Significantly more MD subjects failed at the extradimensional shift stage than HC or BD subjects.

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Figure 3. Quality of decision making in the healthy control (HC), major depressed (MD), and bipolar depressed (BD) groups following a win trial and following a loss trial on the Cambridge Gamble Test. Quality of decision making was impaired in MDD subjects following a loss trial. Error bars represent standard error of the mean.

ANOVA was carried out with condition (ascend or descend) and ratio of colored boxes as within-subject factors. Test order was counterbalanced across subjects. There was a significant main effect of ratio on the amount bet [F (3,150) ⫽ 77.7, p ⬍ .001], the proportion of likely choices [F (1.906,95.29) ⫽ 6.717, p ⫽ .021], and the speed of decision making [F (3,150) ⫽ 7.03, p ⬍ .001]. Subjects were more likely to choose the color in the majority, respond faster, and place a higher bet at the more favorable odds. There was also a significant effect of condition [F (1,50) ⫽ 350.4, p ⬍ .001] on betting behaviour, with higher bets placed in the descend condition. The main effect of group and group interaction terms were not significant on any of the three dependent variables. A further analysis was conducted to compare performance on trials following a win versus a loss. A repeated-measures ANOVA was carried out with win or lose as a within-subjects factor for latency, bets, and quality of decision. For quality of decision, there was a significant win/lose ⫻ diagnosis interaction [F (2,50) ⫽ 3.86, p ⫽ .028]. The quality of decision after a loss was impaired in the MDD group compared with the BD group (p ⫽ .049) (see Figure 3). There was no significant win/lose ⫻ diagnosis interaction for latency or betting behavior. Information Sampling Test A repeated-measures ANOVA was initially carried out for each dependent variable with condition (fixed win [FW] or descending win [DW]) as a within-subject factor and diagnosis and order (FW or DW first) as between-subjects factors. There was no effect of order so this was omitted from the analysis. With the average number of boxes opened as the dependent variable, there was a significant condition ⫻ diagnosis interaction [F (1,61) ⫽ 4.35, p ⫽ .017]. The main effect of condition was significant [F (1,61) ⫽ 86.8, p ⬍ .001], because subjects opened more boxes during the fixed win FW condition than the DW condition. The main effect of diagnosis (p ⫽ .140) was not significant. In a simple effects analysis, we assessed betweengroup differences in the FW and DW conditions separately. Groups differed significantly in the FW condition [F (2,64) ⫽ 3.53, www.sobp.org/journal

922 BIOL PSYCHIATRY 2007;62:917–924

J.V. Taylor Tavares et al. which subject groups were significantly impaired and measures of age of onset of depression, time off medication, MontgomeryÅsberg Depression Rating Scale (MADRS), Response to Situations (RSQ), Chapman Social and Physical Anhedonia Scales (CA), and total on the Barratt Impulsiveness Scale (BIS). For the MDD group, MADRS scores correlated negatively with number of stages completed on the IDED [r (15) ⫽ ⫺.559, p ⫽ .02]. The MDD subjects failing at the EDS stage had a MADRS score on average 8 points higher (28 vs. 21) than those completing all stages. Stages completed also correlated with RSQ [r (15) ⫽ ⫺493, p ⫽ .044]. Finally, oversensitivity to loss on the CGT correlated negatively with CA total [r (15) ⫽ ⫺.661, p ⫽ .004]. These correlations are considered exploratory and were not corrected for multiple comparisons.

Discussion

Figure 4. Performance on the Information Sampling Test in the healthy control (HC), major depressed (MD), and bipolar depressed (BD) groups in terms of the probability of making a correct response [P(correct)] at the point of decision. The P(correct) variable is highly correlated with the number of boxes opened but precisely quantifies the extent of information sampled on a trial-by-trial basis. For example, if the subject opens 20 boxes, these may be distributed 10 yellow and 10 blue [P(yellow) ⫽ .5] or 15 yellow and 5 blue [P(yellow) ⫽ 1.0]. P(correct) is calculated using the following formula: z z P (Correct) ⫽

兺

k⫽A

冉冊 k

2

z

,

where Z ⫽ 25 ⫺ (number of boxes opened) A ⫽ 13 ⫺ (number of boxes of chosen colour) Error bars represent standard error of the mean.

p ⫽ .035], with MDD subjects opening fewer boxes than HCs (p ⫽ .034). There were no between-group differences in the DW condition. Qualitatively similar findings were found in the analysis of the probability of making a correct response at the point of decision (see Figure 4). Inadequate sampling of information is likely to affect the accuracy of the eventual decision, and the number of boxes opened was significantly correlated (p ⬍ .001) with the number of incorrect judgments in the HC [r (23) ⫽ ⫺.686], MDD [r (20) ⫽ ⫺.710] and BD [r (15) ⫽ ⫺.949] groups. Error data were analyzed with a mixed-model ANOVA of condition by diagnosis, which again yielded a significant condition ⫻ diagnosis interaction [F (2,61) ⫽ 3.17, p ⫽ .049]. In a simple effects analysis, there was a significant between-group difference in the FW condition [F (2,61) ⫽ 4.72, p ⫽ .012], but not in the DW condition [F (2,61) ⫽ .084, p ⫽ .920]. In the FW condition, MDD subjects made more incorrect judgments than HCs (p ⫽ .011). There was no group difference in the time taken to uncover boxes in the FW condition [F (2,61) ⫽ .701, p ⫽ .500]. Relationship between Neuropsychological Performance and Clinical Characteristics Correlations were calculated separately for MDD and BD subjects. Correlations were performed between measures on www.sobp.org/journal

The results of this study suggest that unmedicated BDII depressed subjects demonstrate generally intact performance in a wide range of neuropsychological domains including memory function, executive function, and decision making. The MDD group displayed a number of impairments: they had poorer strategy use and made more between-search errors on the test of spatial working memory, they were more likely to fail at the critical EDS stage of the IDED Set Shifting test, they sampled less information on a novel test of “reflection impulsivity,” and they were oversensitive to loss trials on the Cambridge Gamble Test. The differential performance of the BD and MDD groups cannot be readily explained by differences in mood or anxiety symptom severity: the two groups scored similarly on the scales of depressive symptomology, anxiety, and mania. Moreover, the differences cannot be explained by contrasting medication regimes: both subject groups were unmedicated at the time of testing and had been off medication for a comparable length of time. It should be acknowledged, however, that the BDII group (n ⫽ 17) was slightly smaller than the MDD group (n ⫽ 22). It seems unlikely that reduced power may explain the distinct neuropsychological profiles given that on several measures the BD subjects performed more similarly to the HC rather than the MDD subjects (see Figures 2 and 4) and differed significantly from the MDD group in their performance following a loss trial on the CGT, although it should be noted that there was a trend for BD subjects to make more between-search errors at the most difficult eight-box stage of the SWM test. With a sample size of 17 BDII and 25 HCs, we have 80% power to detect a significant difference between the groups at a two-tailed alpha of .05, if the effect size is .88 (Cohen’s d). Such effect sizes have been observed previously for mood disorder groups on tests of cognitive functioning (31,32). The MDD subjects were impaired on two tests of executive function: SWM and IDED. Impairments in SWM have previously been identified in medicated MDD subjects (33) and in the mixed state, but not the depressed state, of BD (5). The MDD subjects were also more likely to fail the IDED test at the EDS stage. Failure at the EDS stage was associated with increased MADRS scores, suggesting that performance may be sensitive to depression severity. However, Clark et al. (34) showed that individuals with remitted MDD display subtle impairments on this measure, indicative of a trait-related disturbance. The SWM strategy and the EDS stage of the IDED test are both closely associated with the integrity of dorsolateral PFC (35–38). The MDD group showed an additional deficit on the IST, which was designed to measure the tendency to leap to a

J.V. Taylor Tavares et al. decision impulsively, described as “reflection impulsivity” (39). Reduced information sampling in the MDD group occurred in the fixed reward condition, when subjects could attain complete certainty in their decisions without incurring penalties. The HC and BDII groups sampled information until the average probability of being correct was 86% and 84%, respectively, whereas the MDD group tolerated more uncertainty (mean ⫽ 76%). In concordance with this finding, the MDD subjects opened fewer boxes and made more incorrect judgments as a direct result of their inadequate sampling of information. In other words, their impulsive behavior had a direct impact on poorer decision making. The MDD group and the BDII group performed at the level of control subjects on the CGT in terms of their judgment of favorable odds and their betting behavior, consistent with findings in medicated MDD (40). However, deficits in quality and speed of decision making have previously been identified in a medicated depressed group of BDI patients (41). Notably, the MDD subjects were more sensitive to loss on the CGT, resulting in poorer quality of decision making on the subsequent trial. This result is consistent with findings of an oversensitivity to negative feedback in MDD (32,42) and suggests that this extends to unmedicated depressed subjects. In the MDD group, subjects with increased sensitivity to loss also had higher scores of anhedonia, suggesting that an inability to feel pleasure may underlie the oversensitivity to negative feedback. There was an absence of significant impairment on a range of tests. Previous examinations of CANTAB performance in MDD subjects have yielded some heterogeneous findings that appear to depend on age, symptom severity, and medication status. Elliott et al. (33) identified impairments across a range of tests in medicated patients who were more severely depressed (mean MADRS score was nine points higher) and older (mean age 50) than the present group. In a younger MDD sample, Purcell et al. (43) identified a selective deficit in IDED set shifting. Differences across studies may also be due to the effects of medication or BDII versus BDI diagnoses. Although in our study, performance was intact on a range of test measures, some results were suggestive of poorer performance, and larger sample sizes may be necessary to identify more subtle impairments. One of the core findings in our study is that depression in recurrent MDD, but not BDII, is associated with an oversensitivity to negative feedback on loss trials of the CGT. This has implications for treatment focused on targeting cognitive impairment in BD and also for nosological models about the affective spectra. In addition to the historical debate about the categorical or dimensional structure of bipolar and schizophrenic psychoses (44), there is similar controversy about the overlap between the bipolar and unipolar syndromes and the number of distinct points on the bipolar spectrum. Given the comparable levels of overall symptomatology in the two groups, the distinct cognitive profile in MDD and BDII may reflect direct differences in underlying neuropathology associated with the two diagnoses or may arise indirectly from quantitative differences in specific symptom dimensions. For example, there is evidence for a greater prevalence of cognitive and somatic complaints in MDD compared with BD depression (45), with psychomotor retardation characteristic in MDD and psychomotor activation in BDII (46). Psychomotor retardation is predictive of deficits in attention (47) and of a more conservative response bias on tests of verbal memory (48), suggesting that this specific clinical dimension might underlie the broad range of cognitive impairments identified in the MDD but not BDII group.

BIOL PSYCHIATRY 2007;62:917–924 923 In future research, it will be critical to compare directly unmedicated BDI and BDII groups. With respect to our study, a few caveats should be noted. First, although our group sizes were similar to many previous reports, they remained fairly small, and we opted for an exploratory neuropsychological analysis that did not control for multiple comparisons. Second, although depressed subjects were unmedicated at the time of testing, the majority were not drug-naïve, and the effects of treatment may be long lasting. Furthermore, although the depressed groups did not differ significantly in length of time off medication, there was large variability across subjects, and this may reflect differences in illness severity. Moreover, the recruitment of unmedicated patients may introduce a sampling bias that limits generalizability of these findings. In conclusion, the results of this study suggest that moderately depressed unmedicated BDII subjects have generally intact performance on a range of cognitive tests. Even performance on tests of impulsivity and decision making, which have clear relevance to the bipolar manic syndrome, did not reveal substantial impairments. In contrast, the MDD group, although also unmedicated, was impaired compared with HCs on a range of tests, including two measures of executive function sensitive to the integrity of dorsolateral PFC. The MDD group were also significantly more sensitive to negative feedback on the CGT than the BD depressed group. It is likely that these cognitive deficits affect functional outcome, which may have an impact on the ability to perform successfully in a work setting.

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