It is now accepted that bipolar disorder (BD) is associated with

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1 Trait-Related Decision-Making Impairment in the Three Phases of Bipolar Disorder Marc Adida, Fabrice Jollant, Luke Clark, Nathalie Besnier, Sébastien Guillaume, Arthur Kaladjian, Pascale Mazzola-Pomietto, Régine Jeanningros, Guy M. Goodwin, Jean-Michel Azorin, and Philippe Courtet Background: In bipolar disorder (BD), little is known about how deficits in neurocognitive functions such as decision-making are related to phase of illness. We predicted that manic, depressed, and euthymic bipolar patients (BPs) would display impaired decision-making, and we tested whether clinical characteristics could predict patients decision-making performance. Methods: Subjects (N 317; age range: years) including 167 BPs (45 manic and 32 depressed inpatients, and 90 euthymic outpatients) and 150 age-, IQ-, and gender-matched healthy control (HC) participants, were included within three university psychiatric hospitals using a cross-sectional design. The relationship between predictor variables and decision-making was assessed by one-step multivariate analysis. The main outcome measures were overall decision-making ability on the Iowa Gambling Task (IGT) and an index of sensitivity to punishment frequency. Results: Manic, depressed, and euthymic BPs selected significantly more cards from the risky decks than HCs (p.001, p.01, and p.05, respectively), with no significant differences between the three BD groups. However, like HCs, BPs preferred decks that yielded infrequent penalties over those yielding frequent penalties. In multivariate analysis, decision-making impairment was significantly (p.001) predicted by low level of education, high depressive scores, family history of BD, use of benzodiazepines, and nonuse of serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants. Conclusions: BPs have a trait-related impairment in decision-making that does not vary across illness phase. However, some subtle differences between the BD groups in the individual deck analyses may point to subtle state influences on reinforcement mechanisms, in addition to a more fundamental trait impairment in risk-sensitive decision making. Key Words: Bipolar disorder, decision making, depression, euthymia, mania, neurocognition From the Mediterranean Institute of Cognitive Neurosciences (MA, NB, PM-P, RJ, J-MA), Department of Pharmacology and Neuropsychology of Emotions Related to Risk Taking and Reward, National Research Scientific Centre, and Department of Psychiatry (MA, NB, J-MA), Sainte-Marguerite Hospital, Mediterranean University, Marseille, France; Mental Health University Institute Douglas (FJ) and McGill Group for Suicide Studies, McGill University, Montréal, Canada; Department of Experimental Psychology (LC), University of Cambridge, Cambridge, United Kingdom; University Montpellier I (SG, PC), Emergency Department (SG, PC) of Academic Hospital Montpellier, and National Institute of Health and Medical Research U888 (SG, PC), Montpellier, France; University Department of Psychiatry (GMG), Warneford Hospital, Oxford, United Kingdom; and Centre Hospitalier Régional Universitaire Hôpital R. Debré (AK), Reims, France. Address correspondence to Marc Adida, M.D., Ph.D., Sainte-Marguerite Hospital, Department of Psychiatry, Mediterranean University, 270 Bd de Sainte-Marguerite, Marseille, France; marc.adida@aphm.fr. Received Apr 22, 2010; revised Jan 12, 2011; accepted Jan 13, /$36.00 doi: /j.biopsych It is now accepted that bipolar disorder (BD) is associated with substantial alterations in neuropsychologic function. Whereas early studies focused on attentional, mnemonic, and executive domains, recent studies have highlighted the link between simple tests of risky decision-making and the manic phase of the illness (1,2). Although trait-related cognitive impairments have been reported in BD patients (BPs) (3,4), the nature and extent of decisionmaking dysfunction across the phases of the illness remain unclear. Some studies have shown that patients have impaired decisionmaking in both the manic (1,2, 5 7) and depressed (8) states, whereas others have reported conflicting results in patients in remission (9 13). It is also likely that other illness variables, such as number of episodes, severity of acute symptoms, type of medication, and family history of BD have an impact on decision-making cognition. To our knowledge, Yechiam et al. (13) are the only group that has used the same task to assess decision-making in both the acute and remitted state of BD. However, their study was limited by small group sizes and lack of power. Decision-making occurs when the individual has to select between multiple options associated with uncertain consequences. Laboratory tasks have been devised to assess competency in realworld decision-making and dissect some of cognitive processes involved. This study used the Iowa Gambling Task (IGT), a clinically sensitive tool that emulates real-world financial decision-making. Each choice leads to monetary gains or losses. Differences in IGT performance are seen in individuals with neuropsychiatric disorders characterized by problems in impulse control and emotional regulation (14 17). Functional imaging (17,18) and brain lesion studies have implicated distributed neural circuitry in supporting successful decision-making on the IGT, including the ventromedial (ventromedial prefrontal cortex [VMPFC]) (19) and ventrolateral prefrontal cortex (20), and amygdala (21), areas that have been associated with BD (22). On the basis of these findings, we predict that decision-making is impaired in the acute phases but also in remission of BD. The IGT results were further analyzed in relation to sociodemographic and clinical variables in BD patients. Methods and Materials Participants The study population comprised 167 BPS (98 women and 69 men; age range: years) and 150 healthy volunteers (75 women and 75 men; age range: years; see power analysis in Section 1 of Supplement 1). Diagnostic assessment of the patients BIOL PSYCHIATRY 2011;70: Society of Biological Psychiatry

2 358 BIOL PSYCHIATRY 2011;70: M. Adida et al. was initially performed by an experienced psychiatrist and was confirmed using the Structural Clinical Interview for DSM-IV (23). Exclusion criteria included a history of head injury or neurologic disease. All subjects had normal thyroid function. No patient had received electroconvulsive therapy or had a history of substance abuse within the previous 6 months. Control subjects had no psychiatric history, no first-degree relatives with BD, and were not taking any drugs that might affect cognition. The study was approved by the local ethics committees. After complete description of the study to the subjects, written informed consent was obtained. Manic Group Forty-five inpatients suffering from mania were included (30 from Marseille University Department of Psychiatry and 15 from Oxford University Department of Psychiatry). All patients met the DSM-IV criteria for bipolar I disorder, manic episode, with a score greater than 12 on the Young Mania Rating Scale (YMRS) (24) and less than 7 on the Hamilton Depression Rating Scale (HDRS, 17 items) (25). The manic group comprised 22 women and 23 men (age range: years). Thirty-two of the 45 patients were receiving antipsychotic drugs at the time of testing. No patients were receiving D 2 -agonist antipsychotics. Fifteen patients were receiving typical antipsychotics. Seventeen patients were receiving the atypical antipsychotics risperidone (n 1), clozapine (n 1), and olanzapine (n 15). Fourteen of these patients were also receiving lithium, valproate, carbamazepine, or a combination of these drugs. Eleven patients were receiving lithium, valproate, carbamazepine, or a combination of these drugs without a neuroleptic. Twentythree patients were receiving a benzodiazepine, typically diazepam or lorazepam. Depressed Group Thirty-two inpatients suffering from bipolar depression were included (16 from Marseille University Department of Psychiatry and 16 from Montpellier University Department of Psychiatry). All patients met the DSM-IV criteria for bipolar I disorder, depressed episode, with a score of greater than 12 on the HDRS) (25) and less than 7 on the YMRS (24). The depressed group comprised 18 women and 14 men (age range: years). Sixteen of the 32 patients were receiving antipsychotic drugs at the time of testing. No patients were receiving typical antipsychotics. Sixteen patients were receiving the atypical antipsychotics aripiprazole (n 3), olanzapine (n 7), risperidone (n 4), amisulpride (n 1), and clozapine (n 1). Fourteen were also receiving lithium, valproate, carbamazepine, or a combination of these drugs. Thirteen patients were receiving lithium, valproate, carbamazepine, or a combination of these drugs without a neuroleptic. Sixteen patients were receiving lithium, valproate, carbamazepine, or a combination of these drugs with an antidepressant. Sixteen patients were receiving a benzodiazepine. Euthymic Group Ninety bipolar patients in clinical remission were included (60 from Montpellier University Department of Psychiatry and 30 from Oxford University Department of Psychiatry). All patients were euthymic at the time of testing, as defined by a score of less than 8 on the HDRS (25) and less than 8 on the YMRS (24), and met the DSM-IV criteria for bipolar I disorder, euthymic state. The euthymic group comprised 58 women and 32 men (age range: years). Fiftytwo of the 90 patients were receiving lithium, valproate, carbamazepine, or a combination of these drugs. Twenty-two patients were also receiving antipsychotics. Six patients were receiving typical antipsychotics. Seventeen patients were receiving the atypical antipsychotics aripiprazole (n 1), risperidone (n 5), and olanzapine (n 11). Thirty patients were receiving lithium, valproate, carbamazepine, or a combination of these drugs without an antipsychotic. Thirty-eight patients were receiving lithium, valproate, carbamazepine, or a combination of these drugs with an antidepressant. Twenty-three patients were receiving a benzodiazepine. Control Group One hundred fifty healthy volunteers were recruited as control subjects by advertisements in the three communities (15 from Marseille, 30 from Oxford, and 105 from Montpellier). Control subjects had no psychiatric or neurological history, no first-degree relatives with BD, and were not taking any drugs that might affect cognition. Procedure Patients mood was formally assessed using the YMRS and HDRS. Level of education and National Adult Reading Test (NART) (26) were used indirectly to assess premorbid intelligence level in the four groups (Table 1). NART Z scores were defined as the Z standardization scores of NART and fnart (French language adaptation of the NART) (27) scores, for English and French participants, respectively. Descriptive data for the 30 manic patients from Marseille, 15 manic and 30 euthymic patients from Oxford, and 60 euthymic patients from Montpellier have been published previously (1,5,12,14). Iowa Gambling Task The computerized version of the IGT (19) was used in which the participant plays for a pretend monetary reward. The participant is required to make a series of 100 choices from four decks of cards, labeled A, B, C, and D. Each card choice results in a monetary win, but occasional choices also result in monetary loss, and the four decks differ in the profile of wins and losses. At the start of the task, the participant has no information about the four decks and must learn to choose advantageously based on trial-by-trial feedback. Penalties begin after 15 picks of cards. Decks A and B are associated with high immediate wins ($100/ choice) but occasionally larger penalties that result in a net loss over time. Decks C and D are associated with smaller immediate wins ($50/choice) but lower long-term losses, such that participants accumulate gradual profit from choosing these decks. Decks B and D provide low-frequency but high-magnitude penalties (with a ratio of total wins to total losses higher in deck D than in deck B, whereas decks A and C provide high-frequency but lowmagnitude penalties (with a ratio of total wins to total losses higher in deck C than deck A). Thus, profitability of the decks (C D vs. A B) is orthogonalized from punishment frequency/magnitude (B D vs. A C). Statistical Analysis Choices in the IGT were analyzed for individual decks A, B, C, and D (Section 2 of Supplement 1), over five blocks of 20 trials (Figure 1) and over 100 picks of cards (Figure 2), and classified as advantageous ( safe ) for decks C and D and disadvantageous ( risky ) for decks A and B. The overall net score or decision-making ability is the difference between the total number of advantageous and disadvantageous choices. Net scores were calculated for each block of 20 trials (Figure 1), for the first 40 and the last 60 trials (Figure 3, Section 3 of Supplement 1). Data were also analyzed in terms of sensitivity to punishment frequency by calculating a difference score [(B D)

3 M. Adida et al. BIOL PSYCHIATRY 2011;70: Table 1. Demographic and Clinical Characteristics of Manic, Depressed, and Euthymic Bipolar Patients, and Healthy Control Subjects Manic (n 45) Depressed (n 32) Euthymic (n 90) Control (n 150) Analysis Characteristic Mean SD Mean SD Mean SD Mean SD F df p Age (years) , Level of Education (years) , NART (Z score) a , Number of Manic Episodes Number of Depressive Episodes Age at Onset of Bipolar Disorder (Years) YMRS Score HDRS Score N % N % N % N % 2 df p , Sex , Male Female Medication Antipsychotic (D1/D2/D3/D4/ D5 Ki values) b,c D2 Antagonist , Typical: Haloperidol (83/2/12/ , /147) Atypical , Risperidone (60/4.9/12.2/ , /16) Amisulpride ( 10 4 /1.3/2.4/ , ) Clozapine (189/431/646/39/ , ) Olanzapine (58/72/63/17.1/ , ) D 2 Agonist Aripiprazole (387/0.95/4.9/ , / 10 3 ) Lithium , Anticonvulsant , Antidepressant , SSRI , SNRI , Tricyclic , Other AD , Benzodiazepine , Anticholinergic , AD, antidepressant; D 2, dopamine receptor subtype 2; HDRS, Hamilton Depression Rating Scale; K i, inhibitor dissociation constant; NART, National Adult Reading Test; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor; Euthymic; YMRS, Young Mania Rating Scale. a NART score assesses premorbid IQ. NART Z scores were defined as the Z standardization scores of NART and fnart (French language adaptation of the NART) scores, for English and French participants, respectively. b The D j -inhibitor constant K i of an antipsychotic is the concentration of that antipsychotic needed to inhibit D j receptor (j 1 5). K i values are reported in nanomolar units. Classically, the potency of an antipsychotic is indicated by the D 2 K i. The higher is the K i, the lower is the potency. An antipsychotic is said to be D 2 specific when D 2 K i is higher than D 1,D 3,D 4, and D 5 K i. For example, we may infer from the values between brackets, that amisulpride is D 2 - and D 3 -specific. c K i values determined by the National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program. K i values selected were those listed as NIMH Psychoactive Drug Screening Program (PDSP) assay certified data, determined from assays using the cloned human receptors with drug of interest as test ligands. For K i values for which PDSP certified assay data were not listed, the average K i value from assay data compiled on the PDSP website using the cloned human receptors with drug of interest as the test ligand was used.

4 360 BIOL PSYCHIATRY 2011;70: M. Adida et al. Figure 1. Number of cards selected in individual deck A, B, C, and D and decision-making ability on the Iowa Gambling Task (IGT), in the manic, depressed, and euthymic bipolar patients (BPs), and healthy controls (HCs), graphed as a function of trial block. a,b (A) In HCs, the number of cards selected changed significantly over the course of the task in deck A (one-way analysis of variance [ANOVA] for repeated measures F 18.17, df 4, p.001), deck B (one-way ANOVA for repeated measures F 7.40, df 4, p.001), deck C (one-way ANOVA for repeated measures F 10.95, df 4, p.001), and D (one-way ANOVA for repeated measures F 4.77, df 4, p.01). (B) In euthymic BPs, the number of cards selected changed significantly over the course of the task in deck A (one-way ANOVA for repeated measures F 3.42, df 4, p.05), deck B (one-way ANOVA for repeated measures F 7.57, df 4, p.001), deck C (one-way ANOVA for repeated measures F 6.94, df 4, p.001), and deck D (one-way ANOVA for repeated measures F 13.69, df 4, p.001). (C) In manic BPs, the number of cards selected changed significantly over the course of the task in deck C (one-way ANOVA for repeated measures F 2.46, df 4, p.05) but not in deck A (one-way ANOVA for repeated measures F 1.70, df 4, p.15), deck B (one-way ANOVA for repeated measures F 1.19, df 4, p.32), and deck D (one-way ANOVA for repeated measures F 1.31, df 4, p.27). (D) In depressed BPs, the number of cards selected changed significantly over the course of the task in deck D (one-way ANOVA for repeated measures F 4.00, df 4, p.01) but not in deck A (one-way ANOVA for repeated measures F 2.08, df 4, p.16), deck B (one-way ANOVA for repeated measures F 2.50, df 4, p.06), and deck C (one-way ANOVA for repeated measures F.27, df 4, p.6). (E) Net scores changed significantly over the course of the task in the HCs (one-way ANOVA for repeated measures F 38.3, df 4, p.001) but not in the manic (one-way ANOVA for repeated measures F 4.8, df 4, p.24), depressed (one-way ANOVA for repeated measures F 3.1, df 4, p.13), and euthymic BPs (one-way ANOVA for repeated measures F 1.4, df 4, p.06). a Choices in the IGT were analyzed for each individual deck A, B, C, and D over 100 picks of cards and for each block of 20 trials and classified as disadvantageous for decks A and B (the risky decks are associated with high immediate wins but occasionally larger penalties that result in a net loss over time) and as advantageous for decks C and D (the safe decks are associated with smaller immediate wins but negligible long-term losses that results in gradual profit). B and D are decks with low-frequency/high-magnitude penalties, and A and C are decks with high-frequency/low-magnitude penalties. Penalties begin after 10 picks of cards. b *p.05, **p.01, and ***p.001. (A C)], where a positive score indicates a preference for lowfrequency/high-magnitude penalties and a negative score a preference for high-frequency/low-magnitude penalties. The difference score [(B D) (A C)] were calculated for the first 40 and the last 60 trials (Figure 4, Section 3 of Supplement 1). The demographic, clinical, and cognitive variables were normally distributed (as assessed by the Kolmogorov Smirnov test and visual inspection) and were analyzed with parametric statistical tests with a threshold of p.05 (two-tailed). Age, level of education, and NART Z score for the manic, depressed, and euthymic patients and for control subjects were compared by one-way ANOVA, while gender and medication received were compared using chi-squared tests. Individual deck (Section 2 of Supplement 1) and IGT summary measures were analyzed using analysis of variance (ANOVA) with group (manic, depressed, euthymic, control) as a between-subjects factor and block (1 20, 21 40, 41 60, 61 80, and ) as a within-subjects factor. Sensitivity to punishment frequency scores were also compared with the value zero using single sample t tests. Post hoc Tukey tests of honestly significant differences (HSD) were performed to determine significant group differences and to control for Type I error (28). Univariate analysis with Pearson s correlations was performed to test for associations between IGT net score for the 165 bipolar patients and demographic and clinical variables (gender, age, level of education, NART Z score, number of manic episodes, number of depressive episodes, total number of admissions, age at onset, family history of BD, HDRS score, YMRS score, alcohol misuse history, drug misuse history, suicide attempt history, use of selective serotonin reuptake inhibitor (SSRI) antidepressant, use of serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant, use of tricyclic antidepressant, use of other antidepressant, use of aripiprazole, use of haloperidol, use of olanzapine, use of clozapine, use of amisulpride, use of risperidone, use of anticonvulsant, use of lithium, use of anticholinergic, and use of benzodiazepine). A threshold of p.2 (29) was set to select variables for multivariate regression analysis. One-step multivariate linear regression analysis was then carried out to determine how much of the variation in IGT net score for bipolar patients could be explained and which demographic and clinical variables might predict variations in decisionmaking ability in BPs. Results Demographic and Clinical Characteristics The demographic and clinical characteristics of the manic, depressed, euthymic, and control groups are shown in Table 1. There was no significant between-group difference with respect to age, level of education, NART Z score, and sex ratio. For manic patients, mean YMRS score was and mean HDRS score was Nine patients were experiencing a first episode of mania, and 22 had a manic episode with psychotic features. The manic group had experienced an average of manic episodes (range: 1 12) and depressive episodes (range: 0 9), with a mean age at onset of years (range: 15 38). For depressed patients, mean YMRS score was and mean HDRS score was The depressed group had experienced an average of manic episodes (range: 1 10) and depressive episodes (range: 0 13), with a mean age at onset of years (range: 15 45). For euthymic patients, mean YMRS score was and mean HDRS score was The euthymic group had experienced an average of manic episodes (range: 0 9) and depressive episodes (range: 1 9), with a mean age at onset of years (range: 16 45).

5 M. Adida et al. BIOL PSYCHIATRY 2011;70: Figure 2. Number of cards selected in individual decks A, B, C and D, and decision-making ability on the Iowa Gambling Task (IGT) in the manic, depressed, and euthymic bipolar patients (BPs) and healthy control subjects (HCs), over 100 picks of cards. a,b,c,d (A) One-way analysis of variance (ANOVA) revealed significant differences in deck A overall score between the four groups [F(3,313) 3.24, p.05], and post hoc Tukey tests of honestly significant differences (HSD) revealed that manic BPs selected significantly more cards from the deck A than did HCs (p.05; effect size [d].48), with no significant differences between depressed BPs and HCs (p.99), euthymic BPs and HCs (p.43), or depressed and euthymic BPs (p.73). (B) One-way ANOVA revealed significant differences in deck B overall score between the four groups [F(3,313) 7.50, p.001] and post hoc Tukey tests of HSD revealed that manic (p.01; d.68), depressed (p.01; D.79), and euthymic (p.05; d.44) BPs selected significantly more cards from the deck B than HCs with no significant differences between manic and depressed (p.94), manic and euthymic (p.58), or depressed and euthymic (p.28) BPs. (C) One-way ANOVA revealed no significant differences in deck C overall score between the four groups [F(3,313) 2.45, p.071]. (D) One-way ANOVA revealed significant differences in deck D overall score between the four groups [F(3,313) 4.42, p.01], and post hoc Tukey tests of HSD revealed that manic BPs selected significantly fewer cards from the deck D than HCs (p.01; effect size d.53) with no significant differences between depressed BPs and HCs (p.40), euthymic BPs and HCs (p.08), or depressed and euthymic (p.99) BPs. One-way ANOVA revealed highly significant differences in decision-making ability between the four groups [F(3,313) 8.1, p.001]. Post hoc Tukey tests of HSD revealed that manic (p.001; effect size d.68), depressed (p.01; d.59), and euthymic (p.05; D.35) BPs selected significantly more cards from the risky decks than HCs with no significant differences between manic and depressed (p.97), manic and euthymic (p.23), or depressed and euthymic (p.62) BPs. a (E) Choices in the IGT were analyzed for each individual deck (A, B, C, and D) over 100 picks of cards and for each block of 20 trials and classified as disadvantageous for decks A and B (the risky decks are associated with high immediate wins but occasionally larger penalties that result in a net loss over time) and as advantageous for decks C and D (the safe decks are associated with smaller immediate wins but negligible long-term losses that results in gradual profit). B and D are decks with low-frequency/high-magnitude penalties, whereas decks A and C are decks with high-frequency/low-magnitude penalties. Penalties begin after 10 picks of cards. b *p.05, **p.01, and ***p.001. c Cohen s d effect size is calculated as the difference between each of the three patient groups and the control group. The value of d is typed at the top of each patient group s histogram. d Budescu (59) reported that for normally distributed populations with heterogeneous variances, substituting for, in the denominator of equation f m /, the square root of the n i -weighted population variance, results in good power approximations. IGT Performance Decision-Making Ability. Net score changed significantly over the course of the task in the healthy control group (one-way ANOVA for repeated measures F 38.3, df 4, p 10 3 ) but not in the manic (F 4.8, df 4, p.24), depressed (F 3.1, df 4, p.13), and euthymic groups (F 1.4, df 4, p.06; Figure 1E) (Figure 1A, 1B, 1C, and 1D, see comments in Section 2 of Supplement 1). When IGT performance was analyzed according to the decisionmaking ability, one-way ANOVA revealed highly significant differences in decision-making ability between the four groups ([F(3,313) 8.1, p.001], and post hoc Tukey tests of HSD revealed that manic (p.001; effect size [d].68), depressed (p.01; d.59), and euthymic (p.05; d.35) BPs selected significantly more cards from the risky decks than healthy control subjects, with no significant differences between manic and depressed (p.97), manic and euthymic (p.23), or depressed and euthymic (p.62) BPs (Figure 2E) (Figure 2A, 2B, 2C and 2D, see comments in Section 2 of Supplement 1). IGT performance was also analyzed according to the decisionmaking ability, over the first 40 picks and over the last 60 picks of cards (Figure 3, see comments in Section 3 of Supplement 1). Sensitivity to Punishment Frequency When IGT performance was analyzed according to sensitivity to punishment frequency, all four groups preferred decks offering low-frequency penalties (B D) over those with high-frequency penalties (A C; t 5.0, p.001; t 6.0, p.001; t 7.5, p.001; and t 7.4, p.001 for manic, depressed, and euthymic BPs and healthy volunteers, respectively), with no significant differences between the four groups [one-way ANOVA F(3,313) 1.5, p.22] (Figure 4A) (Figure 4B and 4C, see comments in Section 3 of Supplement 1). Association Between IGT Performance and Clinical Variables Univariate analysis of sociodemographic and clinical variables was carried out against IGT net score for the 167 BD patients. Gender (females performed worse; r.23, p.01), level of education (r.26, p.001), NART Z score (r.17, p.05), total number of admissions (r.22, p.05), HDRS score (r.25, p.01), YMRS score (r.28, p.01), use of benzodiazepine (r.29, p.001), and family history of BD (r.22, p.05) correlated with IGT net score at p.05 and were subjected to multivariate analysis with age at onset and use of serotonin and norepinephrine reuptake inhibitor antidepressants (SNRIs; p.2). In multivariate analysis, level of education (.26, t 2.79, p.01), HDRS score (.24, t 2.46, p.05), family history of BD (.23, t -2.53, p.05), use of benzodiazepine (.19, t 1.93, p.05), and use of SNRI antidepressant (.21, t 2.29, p.05) were significant predictors of IGT net score in bipolar patients (Table 2). Discussion Impaired decision-making was detected in all three phases of BD. Risk-taking behavior is a diagnostic feature of mania, and depressed patients also exhibit difficulties in decision-making in their daily lives. The translation of these ecological observations to the laboratory is difficult. It is therefore relevant to report that, using an experimental paradigm to detect risky-choice preference, both manic and depressed patients showed lower scores than healthy volunteers. These findings in the acute phases of BD are broadly consistent with previous studies of decision-making deficits assessed with the IGT (1,5 7), with the Cambridge Gamble Task (6 8), and in relation to an increased sensitivity to error during a twochoice prediction task (2). In addition, we report impaired decisionmaking in euthymic patients, which is also in accordance with some

6 362 BIOL PSYCHIATRY 2011;70: M. Adida et al. Figure 3. Iowa Gambling Task (IGT) net score, in the manic, depressed, and euthymic bipolar patients (BPs) and healthy control subjects (HCs), over the first 40 and the last 60 picks of cards, a,b,c (A) One-way analysis of variance (ANOVA) revealed no significant differences in IGT net score between the four groups [F(3,313) 1.61, p.18] over the first 40 picks of cards. (B) One-way ANOVA revealed highly significant differences in IGT net score between the four groups [F(3,313) 7.9, p.001] over the last 60 picks of cards. Post hoc Tukey tests of honest significant difference revealed that manic (p.001), depressed (p.05), and euthymic (p.01) BPs selected significantly more cards from the risky decks than HCs with no significant differences between manic and depressed (p.86), manic and euthymic (p.57), or depressed and euthymic (p.99) BPs. a Choices in the IGT were analyzed for each individual deck (A, B, C, and D) over 100 picks of cards and for each block of 20 trials and classified as disadvantageous for decks A and B (the risky decks are associated with high immediate wins but occasionally larger penalties that result in a net loss over time) and as advantageous for decks C and D (the safe decks are associated with smaller immediate wins but negligible long-term losses that results in gradual profit). B and D are decks with low-frequency/high-magnitude penalties, whereas decks A and C are decks with high-frequency/low-magnitude penalties. Penalties begin after 10 picks of cards. b *p.05, **p.01, and ***p.001. c Budescu (59) reported that for normally distributed populations with heterogeneous variances, substituting for, in the denominator of equation f m /, the square root of the n i -weighted population variance, results in good power approximations. previous studies of decision-making deficits assessed with the IGT. Yechiam et al. (13) reported a similar decision-making impairment in 14 euthymic patients assessed with the IGT. Christodoulou et al. (10) reported an IGT score close to 0 in a group of 25 euthymic subjects. These findings suggest that decision-making alterations could be considered as a trait abnormality in BD. The failure of the BD patients to select from the safe decks may reflect a classic myopia for the future (30), that is, the inability to use outcome information to guide an advantageous long-term strategy, acting as a trait marker in BD. However, some subtle differences were observed between the BD groups in the individual deck analyses. First, all groups preferred the two decks that yielded infrequent penalties over those that yielded more frequent penalties. This indicates that bipolar patients appear to be normally sensitive to the impact of losses. Nevertheless, the depressed BD group exhibited a specific punishment-sensitive pattern of choice by selecting more cards in decks with low-frequency penalties (B, D) and fewer cards in decks with high-frequency penalties (A, C) than did other groups; this difference was statistically significant over the last 60 trials of the task. In contrast, manic bipolar patients were less likely to avoid low-magnitude/high-frequency punishments (A, C) and more likely to avoid high-magnitude/low-frequency (B, D), as if they were less sensitive than other bipolar groups to the impact of frequent and small losses. These differences may point to subtle state influences on reinforcement mechanisms that operate during decision-making, over and above a more fundamental trait impairment in risk-sensitive decision-making. This is also the first report of any associations between decisionmaking impairment in BD and clinical variables. Five independent variables were found to be associated with IGT overall score in the regression analysis: high depression ratings, low level of education, use of benzodiazepines, nonuse of SNRIs, and family history of BD. Several additional factors that were associated with IGT performance in the univariate, but not the multivariate, analysis, were probably intercorrelated with one or more of those predictors. Interestingly, a relationship was previously reported in BD between the number of episodes and the severity of depression, which could be explained by the presence of residual symptoms from prior depressive episodes (31). Moreover, women with BD may experience more depressive episodes than men (32). Thus, in our study, high levels of depression (HDRS score) might be correlated with both total number of admissions and gender. In support of this, our group of depressed patients exhibited a greater number of previous depressive episodes and a higher proportion of females in comparison with the manic group. Similarly, the association with level of education is consistent with previous reports of a positive correlation between performance in cognitive and executive function tests and level of education in BD (33). However, its association with decision-making is disputed (34). The association between the use of benzodiazepine and impaired decision-making is consistent with previous reports of these drugs to have an adverse effect on psychomotor ability and memory (35). The positive correlation between the use of SNRI antidepressants and decision-making ability in BD is consistent with the psychopharmacology of SNRI antidepressant action. Although SNRI antidepressants are commonly called dual-action serotonin-norepinephrine agents, they actually have a third action on dopamine in the prefrontal cortex, but not elsewhere in the brain: they enhance dopamine levels and increase dopamine s diffusion radius, probably enhancing the ability of dopamine to regulate cognition (36). Furthermore, a large increase of dopamine release may facilitate learning in corticostriatal systems (37) when salient stimuli occurred. This salience may be produced by unexpected or highmagnitude rewarding or punishing events or by novelty (38,39). Thus, boosting dopamine with SNRIs may improve IGT performance; however, we assume that excessive tonic dopamine might lead to reduced punishment sensitivity.

7 M. Adida et al. BIOL PSYCHIATRY 2011;70: Figure 4. Difference score [(B D) (A C)] on the Iowa Gambling Task (IGT) in the manic, depressed, and euthymic bipolar patients (BPs) and healthy controls (HCs) over 100 picks of cards (sensitivity to punishment frequency), over the first 40, and over the last 60 picks of cards. a,b (A) All four groups preferred decks offering low-frequency/high-magnitude penalties (decks B and D) over those with high-frequency/low-magnitude penalties (decks A and C; t 5.0, p.001; t 6.0, p.001; t 7.5, p.001; and t 7.4, p.001 for manic, depressed, and euthymic BPs and HCs, respectively), with no significant differences between the four groups [one-way analysis of variance (ANOVA) F(3,313) 1.5, p.22]. (B) One-way ANOVA revealed no significant differences in [(B D) - (A C)] score between the four groups [F(3,313).53, p.66] over the first 40 picks of cards. (C) One-way ANOVA revealed a significant difference in [(B D) (A C)] score between the four groups [F(3,313) 2.75, p.05] over the last 60 picks of cards. Post hoc Tukey tests of honest significant difference revealed a significant difference between depressed (p.05) but not manic (p.98) or euthymic (p.99) BPs and HCs, with a significant difference between depressed and euthymic (p.05) but not between manic and depressed (p.19) or between manic and euthymic (p.98) BPs. a Choices in the IGT were analyzed for each individual deck (A, B, C, and D) over 100 picks of cards and for each block of 20 trials and classified as disadvantageous for decks A and B (the risky decks are associated with high immediate wins but occasionally larger penalties that result in a net loss over time) and as advantageous for decks C and D (the safe decks are associated with smaller immediate wins but negligible long-term losses that results in gradual profit). B and D are decks with low-frequency/high-magnitude penalties, whereas decks A and C are decks with high-frequency/low-magnitude penalties. Penalties begin after 10 picks of cards. b * p.05. The association between family history of BD and impaired decision-making observed here also parallels the genetics of mood disorders in which bipolar patients with a family history of BD exhibit enrichment of genetic effects compared with bipolar patients without a family history of BD (40). One target for future research will be to determine whether impaired decision-making impairment might be a candidate endophenotype to BD. This is suggested by Lovallo et al. (41) in alcoholic patients. According to Hasler et al. (42), a dysmodulation of motivation and reward might be a candidate endophenotype to BD. Thus, we would recommend that future studies test for other criteria for the identification of Table 2. Multivariate Linear Regression Analysis of Demographic and Clinical Variables Associated with Decision-Making Ability in Patients with Bipolar Disorder a Analysis Variable t p Constant Sex Level of Education (years) b NART (Z score) c YMRS Score HDRS Score b Total No. Hospital Admissions Age at Onset of BD (years) Familial History of BD b Medication Received SNRI AD b Benzodiazepine b AD, antidepressant; BD, bipolar disorder; HDRS, Hamilton Depression Rating Scale; NART, National Adult Reading Test; SNRI, serotonin and norepinephrine reuptake inhibitor; YMRS, Young Mania Rating Scale. a The significance of the explained amount of variance (R 2 ) was assessed by analysis of variance [F(7,92) 6.37; p.001]. b R 2.41; adjusted R c NART score assesses premorbid IQ. NART Z scores were defined as the Z standardization scores of NART and fnart (French language version) scores, for English and French participants, respectively. endophenotype: heritability, cosegregation with BD within families, and presence in unaffected relatives at a higher rate than in the general population (43). Previous studies on decision-making in patients with psychiatric disorders suggest that age (44), female sex (45), drug misuse (46), and suicide attempt (14) are associated with disadvantageous decision-making. In this study, these variables were not related to IGT performance. Age may be a critical factor in adolescent (47) and in old-age individuals (48) who are not represented in our study. Female sex was associated with a lower IGT net score in bipolar patients and control subjects, but the effect did not survive multivariate analysis. The lack of replication in drug misuse and suicide attempt may be related to a strong effect of BD leading to a ground effect in these patients. Brain lesion studies implicate distributed neural circuitry in supporting successful decision-making on the IGT, including the VMPFC (20,49) and amygdala (21). Several functional imaging studies of manic (22), depressed (22), and euthymic (22) patients have also implicated VMPFC dysfunction. Thus, VMPFC attenuation may represent a trait feature of the disorder (22). In support of this hypothesis, Stanfield et al. (50) reported gray matter deficits in the bilateral VMPFC in 66 bipolar patients in different phases of the disorder. Our findings are consistent with a model of VMPFC abnormalities in mania, bipolar depression, and euthymia, leading to impaired decision-making. This study has several limitations. First, all bipolar patients were receiving some type of medication. Although univariate analysis was unable to detect any differences between patients who were receiving (71% of manic, 50% of depressed and 24% of euthymic BPs) or not receiving antipsychotic medication, there is a strong case for reinforcement learning performance and decision-making ability to be sensitive to dopaminergic agents (51 53). Thus, comparison of decision-making ability between BD subgroups might be confounded by this point. In addition, we detected differences between BD patients who were receiving or not receiving benzodiazepines. These drugs have been reported to have an adverse effect on psychomotor ability and memory (35) and for anticonvulsants on general cognitive functioning (54), although the importance of

8 364 BIOL PSYCHIATRY 2011;70: M. Adida et al. these effects is disputed (35). Second, we did not use any complementary neuropsychological test with the IGT to characterize BD patients in this study. Fellows et al. (55) showed that deficit in reversal learning was an important mechanism underlying the difficulties in the IGT. Maia et al. (53) reported that IGT might assess not only pure implicit decision-making, on the basis of somatic markers inaccessible to consciousness, but both conscious and nonconscious knowledge. Thus, impaired decision-making in BPs may be associated with defects in reversal learning or explicit memory. From this study, we cannot determine whether deficits reported in BPs are specific abnormalities in decision-making (and what subprocesses may be implicated) or refer to a more global impairment in cognitive control processes. Thus, further research should include additional investigations. Third, the multicenter nature of the study might have introduced potential site differences in clinical characteristics and IGT performance of bipolar and control participants. The only difference detected here between IGT net scores was for the 30 British euthymic subjects compared with the 60 French euthymic patients but was explained by level of education. Fourth, the study did not assess smoking status, which should be considered in further studies. Fifth, there is a strong case for an ecologically valid support for a link between cognitive and psychosocial functioning in BD (56,57). Further research should test for an association between decision-making ability and psychosocial functioning in BD (58). In conclusion, manic, depressed, and euthymic BD patients showed poor performance in a laboratory test (IGT) of decisionmaking. Impaired decision-making was correlated with high depression scores, low level of education, use of benzodiazepines, nonuse of SNRIs, and family history of BD. Thus, the decision-making capacity of patients with BD is modulated by state, education/ IQ, and medication. The observation that trait-related deficits in BD are characterized by an objective failure to weigh costs versus benefit in a simple game is of clinical interest and may represent a future therapeutic target. This work was supported by National Research Scientific Centre (CNRS), Marseille, France; National Institute of Health and Medical Research, Montpellier, France; Academic Hospital (CHU) Lapeyronie, CHU Sainte-Marguerite, and Oxford University. We thank Professors C. Lançon and J. Naudin for their collaboration; Dr. Adéla Ionita and Mrs. Nadia Corréard, Nathalie Viglianese-Salmon, and Sara-Nora Elissalde for their help in assessment; Anderson Loundou from the Public Health Department, University of Marseille, for his help concerning statistics; and Professors A. Bechara and A. Damasio for the use of the Iowa Gambling Task. Philippe Courtet has accepted reimbursement for advice or participation in industry-supported symposia from most pharmaceutical companies with an interest in bipolar disorder or suicide in the past 5 years. Jean-Michel Azorin has accepted reimbursement for advice or participation in industry-supported symposia from most pharmaceutical companies with an interest in bipolar disorder in the past 5 years and holds grants from Lilly and Sanofi-Aventis. Luke Clark is a consultant for Cambridge Cognition. Guy M. Goodwin has accepted reimbursement for advice or participation in industry-supported symposia from most pharmaceutical companies with an interest in bipolar disorder in the past 5 years and holds grants from Sanofi-Aventis for the balance trial and from Servier. Marc Adida received grants from Lilly (Bourse Lilly en Santé Mentale 2008) and Servier (Bourses de l Institut Servier 2008 et 2009) for his postdoctoral years in United Kingdom. Fabrice Jollant, Nathalie Besnier, Sébastien Guillaume, Arthur Kaladjian, Pascale Mazzola-Pomietto, and Régine Jeanningros report no biomedical financial interests or potential conflicts of interest. Supplementary material cited in this article is available online. 1. Adida M, Clark L, Pomietto P, Kaladjian A, Besnier N, Azorin JM, et al. (2008): Lack of insight may predict impaired decision making in manic patients. 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