Cognitive functioning in first episode bipolar I disorder patients with and without history of psychosis

Author’s Accepted Manuscript Cognitive functioning in first episode bipolar I disorder patients with and without history of psychosis Chakrabarty Trisha, Alamian Golnoush, Kozicky Jan-Marie, J. Ivan Torres, N. Lakshmi Yatham www.elsevier.com/locate/jad

PII: DOI: Reference:

S0165-0327(17)30505-0 https://doi.org/10.1016/j.jad.2017.10.003 JAD9267

To appear in: Journal of Affective Disorders Received date: 14 March 2017 Revised date: 3 September 2017 Accepted date: 1 October 2017 Cite this article as: Chakrabarty Trisha, Alamian Golnoush, Kozicky Jan-Marie, J. Ivan Torres and N. Lakshmi Yatham, Cognitive functioning in first episode bipolar I disorder patients with and without history of psychosis, Journal of Affective Disorders, https://doi.org/10.1016/j.jad.2017.10.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

COGNITION IN BDI WITH AND WITHOUT PSYCHOSIS

Cognitive functioning in first episode bipolar I disorder patients with and without history of psychosis Chakrabarty Trisha1, Alamian Golnoush2, Kozicky Jan-Marie1, Torres Ivan J.1, Yatham Lakshmi N. 1 1

Department of Psychiatry, University of British Columbia, Vancouver, BC Canada 2255 Wesbrook Mall, Vancouver, BC, Canada V6T 2A1 2 Department of Psychology, University of Montreal, C.P. 6128, Succursale Centre-ville, Montréal, QC, Canada, H3C 3J7

Corresponding Author: Lakshmi N. Yatham, MBBS, FRCPC, MRCPsych(UK) Professor of Psychiatry Department of Psychiatry, University of British Columbia Room 2C7-2255 Wesbrook Mall, Vancouver, BC, Canada V6T 2A1 T: +1 604 822 0562 F: +1 604 822 7922 Email: [email protected] Word count: Abstract 248/250 Paper 4109/5000 Figures: 2 Tables: 3

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COGNITION IN BDI WITH AND WITHOUT PSYCHOSIS

Abstract 248/250 Background: Psychosis in bipolar I disorder (BDI) has been associated with increased cognitive dysfunction, which may relate to poorer functional outcomes. However, it is not known whether cognition differs between BDI patients with (BDP+) or without (BDP-) history of psychosis early in the disease course, or if it is impacted by the presence of mood congruent (MCP) versus incongruent (MIC) psychotic features. We compare cognition between these groups in BDI patients recently recovered from first episode of mania.

Methods: Attention, verbal learning/memory, processing speed and executive functioning were compared between: 1) all BDI patients (n=73) and healthy controls (HC, n=45), 2) BDP+ (n=60) and BDP- (n=13) patients and 3) MCP (n=27) and MIC (n=33) patients. Post-hoc analyses compared all patient groups with HC.

Results: While BDI patients performed worse than HC in all domains, there were no significant differences between BDP+ and BDP-, or MCP and MIC, patients. However, BDP+ and MIC groups demonstrated different patterns of impairment compared to HC then did BDP- or MCP. Executive functioning and cognitive flexibility in particular appeared to be a deficit area in BDP+ patients.

Limitations: This study may have been underpowered to detect differences in direct comparison between BDP+ and BDP- patients.

Conclusion: While replication in larger samples is required, these results suggest that subtle cognitive differences between BDP+ and BDP-, and between MIC and MCP, patients may be present shortly after disease onset. These patient subsets may therefore be of interest in examining early intensive strategies to preserve cognition.

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Keywords: Bipolar Disorder; Affective Disorders, Psychotic; Cognition.

Highlights: 

Cognition in new onset BDI with (BDP+) or without (BDP-) psychosis did not differ.

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BDP+ with (MCP) or without mood incongruent (MIC) psychosis also did not differ.

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However, BDP+ were more impaired compared to HC than was BDP-.

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MIC and MCP also showed different patterns of impairment compared to HC.

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Thus, these patient subgroups may display unique cognitive deficits at illness onset.

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Introduction: Cognitive dysfunction is a core feature of bipolar I disorder (BDI), with deficits in executive functioning, verbal learning and memory detectable in both acutely symptomatic and remitted patients (Martinez-Aran et al., 2004; Torres et al., 2007). These impairments are present at illness onset and may be more correlated with functional outcomes than clinical symptomatology (Daglas et al., 2015; Depp et al., 2012; Lee et al., 2014; Martinez-Aran et al., 2007; Torres et al., 2010). However, while moderate – severe cognitive deficits compared to healthy controls have been consistently replicated on the group level in BDI, there is significant heterogeneity in the degree to which individual patients display these deficits (Bora, 2015). Attempts to characterize the range of cognitive deficits in BDI have found that approximately one third of patients meet criteria for ‘impairment’ (i.e. 1-2 SD below the mean) (Gualtieri and Morgan, 2008; Iverson et al., 2011; Martino et al., 2014), while between 40-70% of patients may not display clinically significant impairment (Szmulewicz AG, 2015). Identifying the clinical features which characterize the cohort of patients displaying greater cognitive dysfunction early in the disease course could help target those who require the most support to achieve full functional recovery. The presence of psychotic features is one such variable that may be related to cognitive functioning. Although the degree to which the clinical course differs between BDI patients with (BDP+) and without (BDP-) psychotic features is unclear, some studies have found an association between psychosis and more frequent mood episodes, increased symptom severity and poorer functional outcomes (Carlson et al., 2012; Coryell et al., 2001; Keck et al., 2003; Van Riel et al., 2008). The two groups may also be neuropathologically distinct, with smaller medial temporal, cingulate and lateral prefrontal volumes seen in BDP+ patients compared to BDP- (Tost et al., 2010; Velakoulis et al., 1999). Previous studies have reported that between 60-90% patients with bipolar disorder have a lifetime history of psychotic symptoms (Dunayevich and Keck, 2000); given the above clinical and neuropathological data, BDP- patients may therefore represent either a less severely affected or pathophysiologically distinct

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minority. Differences between these two groups may also extend to neuropsychological functioning. A meta-analysis of studies comparing neurocognitive performance in acutely ill and remitted BDP- and BDP+ patients found significant impairment in the latter group, particularly in the domains of processing speed, verbal memory, verbal learning, working memory and planning (Bora et al., 2010). These impairments have been found in euthymic patients, and previous studies have found the neuropsychological profiles of BDP+ patients to be more similar to patients with primary psychotic disorders than they are to BDP- (Bora et al., 2007; Martinez-Aran et al., 2008; Simonsen et al., 2011). However, most of these studies have only examined patients with long duration of illness, raising the possibility that detected differences may be confounded by the more severe clinical course and long term medication effects of BDP+ patients (Palsson et al., 2013). A recent study which examined BDI patients within 12 months of initiating treatment, one third of whom had experienced previous untreated manic episodes, found no correlation between history of previous psychotic episodes and current neuropsychological functioning (Demmo et al., 2016). This would suggest that BDP+ patients do not display significant early cognitive dysfunction, but such results require replication in other first episode BDP+ populations. Furthermore, effect sizes for neuropsychological differences between BDP+ and BDPhave been modest (Bora et al., 2010). It has been suggested that certain subsets of BDP+ patients, such as those with family history of primary psychotic disorder, display more severe deficits, and pooling all BDP+ patients into a single group may obscure these more pronounced impairments (Bora, 2015; Iverson et al., 2011). The nature of psychotic content in BDP+, such as the presence of mood incongruent (MIC) vs. mood congruent (MCP) features, may also help delineate such phenotypically distinct subtypes. Although the clinical relevance of this distinction remains unclear, evidence suggests that MIC is associated with incomplete interepisode recovery, decreased medication responsiveness and higher rates of suicide compared to MCP BDP+ (Association, 2013; Gaudiano et al., 2007; Marneros et al., 2009; Miklowitz, 1992; Strakowski et al., 2000).

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There is also evidence of partial overlap in susceptibility genes between schizophrenia and MIC, and MIC BDP+ has been associated with more prominent volumetric changes in medial temporal, dorsolateral/ventrolateral prefrontal and cingulate cortices compared to healthy subjects and other BDI patients (Goes et al., 2008; Goes et al., 2007; Tost et al., 2010). Investigation of the potential neuropsychological differences between these two groups, however, has been limited. To our knowledge there has been only one comparison of cognition in MIC vs. MCP patients, conducted as a secondary analysis, which found no significant differences (Bora et al., 2007). To investigate differences in cognitive functioning between bipolar I disorder (BDI) patients with (BDP+) and without (BDP-) history of psychosis, and to control for clinical variables such as illness severity, duration and long term medication effects, we compare the neuropsychological profiles of BDP+ and BDP- patients who have recently recovered from their first episode of mania. To our knowledge this is the first neuropsychological analysis of exclusively first episode BDP+ and BDP- patients, and will help clarify whether there are indeed differential early impairments between the two groups. We also compare performance between BDP+ patients with mood congruent (MCP) and mood incongruent (MIC) psychotic features, to determine whether the two sub-groups have distinct neurocognitive signatures at disease onset. Methods: Participants The data for this analysis comes from the Systematic Treatment Optimization Program for Early Mania [STOP-EM] Program which enrolled patients meeting DSM-IV TR criteria for BDI within 3 months of their first manic episode (Association, 2000). Patients were recruited from UBC Hospital (UBCH) and affiliated sites, as well as community referrals from physicians. The University of British Columbia (UBC) Clinical Research Ethics Board approved all study procedures, and written informed consent was obtained from all participants prior to enrollment. A complete description of the study

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protocol for the larger longitudinal study has been detailed elsewhere (Yatham et al., 2009a). Briefly, board-certified psychiatrists assessed patients using clinical and Mini International Neuropsychiatric Interview (M.I.N.I.) (Sheehan et al., 1998). Patients were required to be 17 – 35 years old, and had experienced their first manic or mixed episode in the 3 months prior to enrollment. We did not exclude patients with comorbidities or substance abuse in order to capture the full range of patients seen in clinical practice. Exclusion criteria included history of neurological disorder (e.g. seizure disorder or severe traumatic brain injury) and poor command of English. All patients received treatment from psychiatrists with expertise in the management of mood disorders according to CANMAT clinical practice guidelines (Yatham et al., 2009b). Mood state in 73 patients was assessed with the 29-item Hamilton Depression Rating Scale (HDRS) (Hamilton 1960) as well as the Young Mania Rating Scale (YMRS) (Hamilton, 1960; Young et al., 1978). Mood rating scales were administered within a mean of 8.7 days (standard deviation 2.0 days) of neuropsychological assessment, with all subjects tested within 30 days. Additional demographic and clinical information was obtained as per the STOP-EM protocol and included medication status and duration, history of substance abuse, number of previous depressive episodes, duration illness and comorbid psychiatric conditions (Yatham et al., 2009a). Antipsychotic dosing was standardized using chlorpromazine equivalents (Woods, 2003). Presence of past psychosis was determined by the information collected by the M.I.N.I. as well as chart review. Psychotic features were defined as the presence of delusions or hallucinations at any time during the manic episode as per DSM-IV TR criteria (Association, 2000). DSM-IV-TR criteria was also used to determine mood congruence: mood-congruent psychotic features were defined as those where the content of delusions/hallucinations was consistent with manic themes (e.g. grandiosity), and moodincongruent as delusions/hallucinations in which the content was inconsistent with manic themes, or was a mixture of mood-incongruent and congruent themes. 45 healthy subjects matched for age, sex, and premorbid IQ were recruited through word

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of mouth and advertisements at UBCH and affiliated sites. Healthy subjects were assessed with the M.I.N.I., and subjects with personal or family history of Axis I psychiatric disorder in first or second-degree relatives were excluded.

Neuropsychological Testing All neuropsychological tests were administered in a quiet testing room following standard procedures as part of a 2-3 hour cognitive battery. The following domains were assessed: 1) sustained attention, by the Cambridge Neuropsychological Test Automated Battery (CANTAB) Rapid Visual Information Processing task (RVIP) discriminability score (Robbins et al., 1994), 2) verbal learning, by the overall level of correct recall from trials 1-5 of the California Verbal Learning Test -II (CVLT 1-5T) (Delis et al., 2000), 3) verbal memory, by the long delayed free recall measure (LDFR) of the CVLT-II (Delis et al., 2000), 4) processing speed, by the Controlled Oral World Association (COWA) test for phonemic fluency (Benton and Hamsher, 1976), the Trail Making Test Part A (TMTA) (Reitan and Wolfson, 1993), Stroop Color (Stroop-C) and Stroop Word (Stroop-W) scores (Golden, 1978), and 5) executive functioning, by the Trail Making Test Part B (TMT-B) (Reitan and Wolfson, 1993), Stroop interference score (Stroop-Int) (Golden, 1978), and total number of errors in the CANTAB Intra-dimensional/Extra-dimensional Set Shift test (IED) (Robbins et al., 1994). Premorbid intellectual functioning was assessed with the North American Adult Reading Test Full Scale IQ (NAART FSIQ) (Blair and Spreen, 1989). Statistical Analysis Statistical analyses were run with SPSS 22.0. All data is reported as means and SD, with median values reported for non-parametric tests. Significant demographic differences between healthy controls (HC), BDP-, and BDP+ patients were assessed using ANOVA or independent samples t-test for continuous, and chi-squared tests for categorical, variables. BDP+ patients were further subdivided into those patients with mood

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congruent (MCP) and mood incongruent (MIC) features, and demographic comparison between these two groups was conducted using the same procedure. Raw scores for all neuropsychological measures were converted to standardized z or T scores based on normative, demographically matched reference groups obtained from the manuals of the various neuropsychological tests. Normality of test results was confirmed by visual inspection of histograms and by the Shapiro-Wilk’s test. Logarithmic transformations for skewed TMT-A and TMT-B scores were successfully applied and subsequently used for hypothesis testing; LDFR, IED, RVIP scores could not be transformed into a normal distribution. As previous studies have indicated that the neurocognitive signature of BDP+ may be characterized by task rather than domain specific impairment, we chose to compare performance on individual tests rather than aggregate domain scores (Bora et al., 2010). MANOVA for normally distributed test scores was conducted to assess for overall differences in neuropsychological performance between all groups (i.e HC, MCP, MIC and BDP-). Significant MANOVA results were then followed with planned Helmert contrasts comparing: 1) healthy control subjects vs. all bipolar patient subjects (HC vs. BDP), 2) bipolar patients with no psychosis versus patients with history of psychosis (BDP- vs. BDP+) and 3) patients with history of mood congruent psychotic features vs. mood incongruent features (MCP vs. MIC BDP+). Levene’s test was used to assess homogeneity of variances. For non-parametric data, Kruskal-Wallis test was used to detect overall differences between groups, with follow up Mann-Whitney U test for significant results using the three planned contrasts described above. A Bonferroni correction was applied for Mann-Whitney U tests; the level of significance was set at 0.006 (i.e. 0.05/9). For parametric data, Cohen’s d effect sizes with 95% confidence intervals were calculated using means and standard deviations. As Cohen’s d is sensitive to violations of assumptions of normality (Fritz et al., 2012; Onwuegbuzie, 2002), standardized difference for non-parametric measures were calculated based on methods described by

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Newcombe (2006) (Newcombe, 2006a). First, a standard effect size for the MannWhitney U test was calculated using the formula U/nanb, where U is the Mann-Whitney U statistic, na is the sample size of group A and nb the sample size for group B; this value was then converted to Cohen’s d with 95% confidence interval, using a modified HanleyMcNeil approach (Newcombe, 2006; Ruscio, 2008). For parametric data, secondary analyses between patient groups controlling for the effect of residual mood symptoms, premorbid IQ and pertinent clinical variables were conducted by adding the following covariates: 1) YMRS and HDRS scores, 2) NAART FSIQ, 3) number of previous depressive episodes, 4) illness duration (defined as time from index mood episode) and 5) substance use. Antipsychotic doses in chlorpromazine equivalents, and presence of lithium or valproic acid, were also added as covariates. Assumption of homogeneity of regression slopes was tested for all covariates. Additional exploratory analysis consisted of post-hoc pairwise comparisons of all patient groups (BDP+, BDP-, MIC and MCP) with HC. Post-hoc Hochberg’s GT2 test following significant MANOVA was used for normally distributed cognitive measures. Mann-Whitney U tests were used for non-parametric data, with significance level set to 0.004 (i.e. 0.05/12). Cohen's d effect sizes, with 95% CIs, for differences between each patient groups and HC were calculated as described above. Results Demographic Comparison All groups were matched in terms of age, years of education, gender distribution and premorbid IQ. Amongst the patient groups, there was no significant difference in YMRS and HDRS scores, number of previous depressive episodes, and duration of illness. Patient groups also did not differ in the use of mood stabilizer or antipsychotic medications (Table 1). A significantly higher percentage of BDP+ patients had a lifetime history of THC use compared to BDP-.

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Planned contrasts There was a statistically significant difference in overall performance in parametric neuropsychological measures between the four groups [F(21, 327) = 2.384, p=0.001]. Follow up planned contrasts showed significant differences between HC and BDP groups in CVLT 1-5T, COWA, TMT-A, and TMT-B scores (Table 2). Similarly, KruskalWallis tests for overall group differences for non-parametric measures RVIP [H(3) = 10.456, p=0.015], LDFR [H(3) = 11.580, p=0.009] and IED [H(3) = 16.091, p=0.001] were significant. Post-hoc Mann-Whitney U tests showed significant differences again between HC and BDP groups in these three measures, after correcting for multiple comparisons (Table 2). Effect sizes for differences between HC and BDP were moderate - large. BDP+ vs. BDP-, and MIC vs. MCP, contrasts showed no significant differences, although difference in IED scores between BDP+ and BDP- were significant before correction for multiple comparisons (p=0.04 uncorrected). Similarly, the effect size for this measure was moderate (0.70), and the confidence interval did not cross zero. Effect of residual mood symptoms, premorbid IQ, medication status and THC use Adding YMRS and HDRS scores, or NAART FSIQ scores, as covariates did not affect the primary results. There remained a significant difference in performance in the CVLT 1-5T, COWA, TMT-A, and TMT-B scores between HC and BDP groups, but no significant difference between BDP+ vs. BDP- or MIC vs. MCP groups. Similarly, other clinical variables such as number of previous depressive episodes, duration of illness, any substance use, mood stabilizer use or antipsychotic dosing had no impact on the results. The addition of THC use, which was more prevalent in the BDP+ compared to BDPsubjects, as a covariate did not affect the results. Post-hoc exploratory analysis In post-hoc pairwise comparisons of HC, BDP- and BDP+ groups, BDP- was impaired in the COWA test compared to HC at trend level significance. However, BDP+ patients scored significantly lower than HC in RVIP, CVLT 1-5T, LDFR, TMT-A, TMT-B, and

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IED tests (Table 3). Effect sizes of BDP- and BDP+ compared to HC are shown in Figure 1 and are of small – moderate magnitude, with the exception of CVLT1-5T and IED scores in BDP+ (0.81 and 0.83, respectively). IED effect sizes also showed the largest degree of separation between BDP- and BDP+ groups. The addition of covariates listed above to these pairwise comparisons did not affect the results. MIC patients were significantly impaired in RVIP, TMT-A and TMT-B compared to HC. MCP patients differed from HC in RVIP scores before correcting for multiple comparisons, but did not significantly differ in TMT-A or TMT-B. Both groups had significantly lower scores on CVLT 1-5T, with MCP patients being additionally impaired in LDFR; MIC patients significantly differed from HC before Bonferroni correction in this measure. Differences in COWA scores between healthy controls and MCP was at trend level significance. Effect sizes are shown in Figure 2, and with the exception of IED scores and CVLT 1-5T scores for both groups, were of small – moderate magnitude. There also appeared to be little separation in effect sizes between the two groups in most cognitive measures, with the exception of verbal learning and memory. In these domains, MCP patients differed from HC with large effect sizes, while effect sizes were moderate for MIC. Discussion Cognitive functioning in bipolar I disorder, independent of traditionally defined symptomatology, impacts patients’ ability to regain their full premorbid functional capacity (Martinez-Aran et al., 2007). Previous studies have found cognitive deficits to be already present in first episode BDI patients (Lee et al., 2014), and we here examined subsets of newly diagnosed BDI patients defined by the presence (BDP+) or absence (BDP-) of psychosis in their first manic episode, and by the mood congruence (MCP) and mood incongruence (MIC) of psychotic features. The aim was to determine whether the presence and nature of psychotic features could help define cohorts of patients with more prominent cognitive deficits early in the disease course. As expected from previous reports (Daglas et al., 2015), we found that BDI patients as a

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whole demonstrated broad deficits in attention, processing speed, verbal learning, verbal memory and executive functioning compared to healthy subjects, with moderate – large effect sizes (Table 2). Direct comparison between BDP+ and BDP- patients showed no statistically significant difference in neuropsychological performance between the two groups; however, BDP+ patients scored lower than BDP- patients on the IED task before correcting for multiple comparisons, with a moderate effect size. The two groups additionally demonstrated a differential degree of impairment in post-hoc comparisons with healthy controls, with BDP+ patients scoring significantly lower in tests of attention, processing speed, verbal learning/memory and some executive functioning measures, and BDP- patients only differing from controls in measures of attention at trend level significance. There was additionally a large degree of separation in effect sizes in BDP+ vs. HC compared to BDP- vs. HC in IED scores. The addition of residual mood symptoms, medication and THC use as covariates also did not impact the results. Two possibilities are suggested by these results. The first is that BDP+ and BDPpatients do not differ in cognitive functioning at illness onset, supported by the lack of statistically significant differences in direct comparison of these two groups. This would also be consistent with previous studies examining patients with affective psychosis in early phases of illness. Although this is, to our knowledge, the first comparison of BDP+ and BDP- patients in a sample of exclusively first episode patients, a recent study of neuropsychological functioning in BDI patients tested within 12 months of initiating treatment found no association between history of psychosis and neuropsychological functioning (Demmo et al., 2016). These findings would indicate that patients without psychotic features at illness onset do not represent a completely neurodevelopmentally distinct cohort, and the more severe cognitive deficits seen in multiple episode BDP+ patients only become apparent as the illness progresses (Bora et al., 2010). Studies examining whether BDI patients as a whole display progressive cognitive decline have yielded mixed results, but negative associations between cognition and number of mood episodes, as well as progressive decreases in subgenual anterior cingulate volumes, have been reported in BDP+ patients (Goodwin et al., 2008; Koo et al., 2008; Lewandowski et al., 2011; Robinson and Ferrier, 2006; Samame et al., 2014; Zubieta et al., 2001). It is

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therefore possible that BDP+ patients may display a more degenerative course compared to BDP- with regards to neuropsychological functioning. Further longitudinal analysis comparing the two groups is required to establish if this is the case, and if so, whether such differences are mediated by long term medication effects, more frequent mood episodes, or a distinct pathophysiology underlying psychotic and non-psychotic subtypes. Determining whether modifiable factors, such as type of medication treatment and number of episodes, are responsible for worsening cognition in BDP+ patients would additionally suggest therapeutic strategies which could help preserve cognitive functioning in this subgroup. It is also possible that differences are not detected in first episode cohorts due to the problem of diagnostic shift, as patients currently classified as BDP- may develop psychotic symptoms later on. Again, longitudinal follow up to determine the stability of the initial BDP-/BDP+ classification is required. However, the differences in IED scores between BDP+ and BDP- patients, which were significant before correcting for multiple comparisons, and the degree of separation in effect sizes when comparing each patient group to healthy controls in this measure, suggest the second possibility that modest differences do indeed exist between BDP+ and BDP- at illness onset, but require larger sample sizes to detect. Given the more prominent differences in IED scores between BDP+ and BDP- patients, measures of executive functioning and cognitive flexibility may be an especial area of interest. This is in line with a previous study comparing first episode affective patients (encompassing both major depressive disorder and BDI) with and without history of psychosis; this analysis found that patients with psychosis had impairments in cognitive flexibility compared to healthy controls which were not seen in patients without psychosis (Albus et al., 1996). Notably, executive dysfunction has been found to be already established in first episode schizophrenia, and is seen as a core feature of this disorder (Keshavan et al., 2005; Niemi et al., 2003). BDP+ patients, therefore, may have similar deficits early in the disease course, indicating shared features with primary psychotic disorders. Within the BDP+ group, MCP and MIC patients displayed different patterns of performance compared to healthy controls, but again no significant differences in direct

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comparison between the two groups. While both were significantly impaired in verbal learning and IED tasks, MIC scored significantly lower in attention (RVIP), processing speed (TMT-A) and other executive functioning tasks (TMT-B). In contrast, MCP patients appeared to have more specific impairments compared to controls in verbal memory. Interestingly, a large epidemiological study of first episode psychosis found more generalized cognitive deficits in patients with schizophrenia, and more focused impairments in verbal memory in BDI patients (Zanelli et al., 2010). Thus, the pattern of impairment in MIC patients here may be qualitatively more similar to that seen in first episode schizophrenia, while the more restricted deficits in verbal ability of MCP patients may be more specific to BDI. This would seem to support the hypothesis that MIC BDI is pathologically related to primary psychotic disorders; however, the differences in effect sizes between MIC and MCP patients and healthy controls are small, rendering the clinical significance of these findings unclear (Figure 2). Again, it may be the case that MIC and MCP patients follow different trajectories of illness and thus require time to develop more prominent differences in cognition. It has been suggested that BDI patients with a family history of schizophrenia are more likely to display deteriorating cognition; as mood incongruent psychosis has been found to have some genetic overlap with schizophrenia, it is possible that MIC patients may display more deficits later in the illness course (Bora, 2015). Our results suggest that while there do not appear to be substantial differences between first episode BDP+ and BDP- patients, or between MIC and MCP BDP+ patients, subtle distinctions may exist between these groups at illness onset. Compared to healthy controls, BDP+ and MIC patients showed different patterns of impairment compared to BDP- and MCP patients, respectively. In addition, cognitive flexibility and executive functioning appeared to be particularly affected in BDP+ patients. However, there are caveats and limitations to the interpretation of these results. The lack of significant difference between BDP- and HC patients may have been due to the small BDP- sample being underpowered to detect a difference; this relates to the broader observation that the magnitude of differences in many domains between each patient group were small. Thus, replication in larger samples is needed to ensure adequate power, and the degree to which

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such small differences translate into clinically or functionally meaningful distinctions between groups is questionable. Lastly, further longitudinal analyses to determine how cognitive functioning may evolve over time in these groups would be useful to place these results in context. If there is indeed a more pronounced decline in cognitive functioning in BDP+ or MIC patients over time, the absence of large deficits in these patients in the first episode compared to other BDI subgroups would suggest that an early focus on neuroprotective strategies in these patients might allow for an overall preservation of functioning (Goodwin et al., 2008).

Role of the funding source: This research was supported by an unrestricted grant from AstraZeneca Canada.

Acknowledgements: None

Declaration of Interest: Dr. Yatham has been a member of advisory board, received research grants, and been a speaker for Astrazeneca, Janssen, Lilly, GSK, Bristol Myers Squibb, Novartis, Servier, and Pfizer. Ivan J. Torres has served as a consultant for Lundbek Canada. Golnoush Alamian, Jan-Marie Kozicky and Trisha Chakrabarty report no disclaimers. Contributors: Trisha Chakrabarty conducted data analysis and was the main manuscript author. Golnoush Alamian and Jan-Marie Kozicky assisted with data preparation. Ivan Torres assisted with preparation of the manuscript. Lakshmi Yatham was the studies’ principal investigator.

References Albus, M., Hubmann, W., Wahlheim, C., Sobizack, N., Franz, U., Mohr, F., 1996. Contrasts in neuropsychological test profile between patients with first-episode schizophrenia and first-episode affective disorders. Acta Psychiatr. Scand. 94, 87-93. Association, A.P., 2000. Diagnostic and statistical manual of mental disorders (4th ed., text rev.). American Psychiatric Association, Washington, DC. Association, A.P., 2013. Diagnostic and statistical manual of mental disorders (5th ed.). American Psychiatric Publishing, Arlington. VA.

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Benton, A.L., Hamsher, K., 1976. Multilingual Aphasia Examination manual. University of Iowa, Iowa City. Blair, J.R., Spreen, O., 1989. Predicting premorbid IQ: a revision of the National Adult Reading Test. Clinical Neuropsychology 3, 129-136. Bora, E., 2015. Developmental trajectory of cognitive impairment in bipolar disorder: comparison with schizophrenia. Eur. Neuropsychopharmacol. 25, 158-168. Bora, E., Vahip, S., Akdeniz, F., Gonul, A.S., Eryavuz, A., Ogut, M., Alkan, M., 2007. The effect of previous psychotic mood episodes on cognitive impairment in euthymic bipolar patients. Bipolar Disord. 9, 468-477. Bora, E., Yucel, M., Pantelis, C., 2010. Neurocognitive markers of psychosis in bipolar disorder: a meta-analytic study. J. Affect. Disord. 127, 1-9. Carlson, G.A., Kotov, R., Chang, S.W., Ruggero, C., Bromet, E.J., 2012. Early determinants of four-year clinical outcomes in bipolar disorder with psychosis. Bipolar Disord. 14, 19-30. Coryell, W., Leon, A.C., Turvey, C., Akiskal, H.S., Mueller, T., Endicott, J., 2001. The significance of psychotic features in manic episodes: a report from the NIMH collaborative study. J. Affect. Disord. 67, 79-88. Daglas, R., Yucel, M., Cotton, S., Allott, K., Hetrick, S., Berk, M., 2015. Cognitive impairment in first-episode mania: a systematic review of the evidence in the acute and remission phases of the illness. Int. J. Bipolar Disord. 3, 9. Delis, D.C., Kramer, J.H., Kaplan, E., Ober, B.A., 2000. California Verbal Learning Test - Second Edition. Adult version. Manual. Psychological Corporation, San Antonio, TX. Demmo, C., Lagerberg, T.V., Aminoff, S.R., Hellvin, T., Kvitland, L.R., Simonsen, C., Andreassen, O.A., Melle, I., Ueland, T., 2016. History of psychosis and previous episodes as potential explanatory factors for neurocognitive impairment in first-treatment bipolar I disorder. Bipolar Disord. 18, 136-147. Depp, C.A., Mausbach, B.T., Harmell, A.L., Savla, G.N., Bowie, C.R., Harvey, P.D., Patterson, T.L., 2012. Meta-analysis of the association between cognitive abilities and everyday functioning in bipolar disorder. Bipolar Disord. 14, 217-226. Dunayevich, E., Keck, P.E., Jr., 2000. Prevalence and description of psychotic features in bipolar mania. Curr. Psychiatry Rep. 2, 286-290. Fritz, C.O., Morris, P.E., Richler, J.J., 2012. Effect size estimates: current use, calculations, and interpretation. J. Exp. Psychol. Gen. 141, 2-18. Gaudiano, B.A., Uebelacker, L.A., Miller, I.W., 2007. Course of illness in psychotic mania: is mood incongruence important? J. Nerv. Ment. Dis. 195, 226-232.

COGNITION IN BDI WITH AND WITHOUT PSYCHOSIS

18

Goes, F.S., Sanders, L.L., Potash, J.B., 2008. The genetics of psychotic bipolar disorder. Curr. Psychiatry Rep. 10, 178-189. Goes, F.S., Zandi, P.P., Miao, K., McMahon, F.J., Steele, J., Willour, V.L., Mackinnon, D.F., Mondimore, F.M., Schweizer, B., Nurnberger, J.I., Jr., Rice, J.P., Scheftner, W., Coryell, W., Berrettini, W.H., Kelsoe, J.R., Byerley, W., Murphy, D.L., Gershon, E.S., Bipolar Disorder Phenome, G., Depaulo, J.R., Jr., McInnis, M.G., Potash, J.B., 2007. Mood-incongruent psychotic features in bipolar disorder: familial aggregation and suggestive linkage to 2p11-q14 and 13q21-33. Am. J. Psychiatry 164, 236-247. Golden, J.C., 1978. Stroop Color and Word Test. Stoelting, Chicago, IL. Goodwin, G.M., Martinez-Aran, A., Glahn, D.C., Vieta, E., 2008. Cognitive impairment in bipolar disorder: neurodevelopment or neurodegeneration? An ECNP expert meeting report. Eur. Neuropsychopharmacol. 18, 787-793. Gualtieri, C.T., Morgan, D.W., 2008. The frequency of cognitive impairment in patients with anxiety, depression, and bipolar disorder: an unaccounted source of variance in clinical trials. J. Clin. Psychiatry 69, 1122-1130. Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56-62. Iverson, G.L., Brooks, B.L., Langenecker, S.A., Young, A.H., 2011. Identifying a cognitive impairment subgroup in adults with mood disorders. J. Affect. Disord. 132, 360-367. Keck, P.E., Jr., McElroy, S.L., Havens, J.R., Altshuler, L.L., Nolen, W.A., Frye, M.A., Suppes, T., Denicoff, K.D., Kupka, R., Leverich, G.S., Rush, A.J., Post, R.M., 2003. Psychosis in bipolar disorder: phenomenology and impact on morbidity and course of illness. Compr. Psychiatry 44, 263-269. Keshavan, M.S., Diwadkar, V.A., Montrose, D.M., Rajarethinam, R., Sweeney, J.A., 2005. Premorbid indicators and risk for schizophrenia: a selective review and update. Schizophr. Res. 79, 45-57. Koo, M.S., Levitt, J.J., Salisbury, D.F., Nakamura, M., Shenton, M.E., McCarley, R.W., 2008. A cross-sectional and longitudinal magnetic resonance imaging study of cingulate gyrus gray matter volume abnormalities in first-episode schizophrenia and first-episode affective psychosis. Arch. Gen. Psychiatry 65, 746-760. Lee, R.S., Hermens, D.F., Scott, J., Redoblado-Hodge, M.A., Naismith, S.L., Lagopoulos, J., Griffiths, K.R., Porter, M.A., Hickie, I.B., 2014. A meta-analysis of neuropsychological functioning in first-episode bipolar disorders. J. Psychiatr. Res. 57, 111.

COGNITION IN BDI WITH AND WITHOUT PSYCHOSIS

19

Lewandowski, K.E., Cohen, B.M., Ongur, D., 2011. Evolution of neuropsychological dysfunction during the course of schizophrenia and bipolar disorder. Psychol. Med. 41, 225-241. Marneros, A., Rottig, S., Rottig, D., Tscharntke, A., Brieger, P., 2009. Bipolar I disorder with mood-incongruent psychotic symptoms: a comparative longitudinal study. Eur. Arch. Psychiatry Clin. Neurosci. 259, 131-136. Martinez-Aran, A., Torrent, C., Tabares-Seisdedos, R., Salamero, M., Daban, C., Balanza-Martinez, V., Sanchez-Moreno, J., Manuel Goikolea, J., Benabarre, A., Colom, F., Vieta, E., 2008. Neurocognitive impairment in bipolar patients with and without history of psychosis. J. Clin. Psychiatry 69, 233-239. Martinez-Aran, A., Vieta, E., Reinares, M., Colom, F., Torrent, C., Sanchez-Moreno, J., Benabarre, A., Goikolea, J.M., Comes, M., Salamero, M., 2004. Cognitive function across manic or hypomanic, depressed, and euthymic states in bipolar disorder. Am. J. Psychiatry 161, 262-270. Martinez-Aran, A., Vieta, E., Torrent, C., Sanchez-Moreno, J., Goikolea, J.M., Salamero, M., Malhi, G.S., Gonzalez-Pinto, A., Daban, C., Alvarez-Grandi, S., Fountoulakis, K., Kaprinis, G., Tabares-Seisdedos, R., Ayuso-Mateos, J.L., 2007. Functional outcome in bipolar disorder: the role of clinical and cognitive factors. Bipolar Disord. 9, 103-113. Martino, D.J., Strejilevich, S.A., Marengo, E., Ibanez, A., Scapola, M., Igoa, A., 2014. Toward the identification of neurocognitive subtypes in euthymic patients with bipolar disorder. J. Affect. Disord. 167, 118-124. Miklowitz, D.J., 1992. Longitudinal outcome and medication noncompliance among manic patients with and without mood-incongruent psychotic features. J. Nerv. Ment. Dis. 180, 703-711. Newcombe, R.G., 2006. Confidence intervals for an effect size measure based on the Mann-Whitney statistic. Part 2: asymptotic methods and evaluation. Stat. Med. 25, 559573. Niemi, L.T., Suvisaari, J.M., Tuulio-Henriksson, A., Lonnqvist, J.K., 2003. Childhood developmental abnormalities in schizophrenia: evidence from high-risk studies. Schizophr. Res. 60, 239-258. Onwuegbuzie, A.J., 2002. Common methodological, analytical, and interpretational errors in published educational studies: An analysis of the 1998 volume of the British Journal of Educational Psychology. Educational Research Quarterly 26. Palsson, E., Figueras, C., Johansson, A.G., Ekman, C.J., Hultman, B., Ostlind, J., Landen, M., 2013. Neurocognitive function in bipolar disorder: a comparison between bipolar I and II disorder and matched controls. BMC Psychiatry 13, 165.

COGNITION IN BDI WITH AND WITHOUT PSYCHOSIS

20

Reitan, R., Wolfson, D., 1993. The Halstead-Reitan Neuropsychological Test Battery: Theory and Clinical Interpretation. Neuropsychology Press, Tucson, AZ. Robbins, T.W., James, M., Owen, A.M., Sahakian, B.J., McInnes, L., Rabbitt, P., 1994. Cambridge Neuropsychological Test Automated Battery (CANTAB): a factor analytic study of a large sample of normal elderly volunteers. Dementia 5, 266-281. Robinson, L.J., Ferrier, I.N., 2006. Evolution of cognitive impairment in bipolar disorder: a systematic review of cross-sectional evidence. Bipolar Disord. 8, 103-116. Ruscio, J., 2008. A probability-based measure of effect size: robustness to base rates and other factors. Psychol. Methods 13, 19-30. Samame, C., Martino, D.J., Strejilevich, S.A., 2014. Longitudinal course of cognitive deficits in bipolar disorder: a meta-analytic study. J. Affect. Disord. 164, 130-138. Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R., Dunbar, G.C., 1998. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry 59 Suppl 20, 2233;quiz 34-57. Simonsen, C., Sundet, K., Vaskinn, A., Birkenaes, A.B., Engh, J.A., Faerden, A., Jonsdottir, H., Ringen, P.A., Opjordsmoen, S., Melle, I., Friis, S., Andreassen, O.A., 2011. Neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders depends on history of psychosis rather than diagnostic group. Schizophr. Bull. 37, 73-83. Strakowski, S.M., Williams, J.R., Sax, K.W., Fleck, D.E., DelBello, M.P., Bourne, M.L., 2000. Is impaired outcome following a first manic episode due to mood-incongruent psychosis? J. Affect. Disord. 61, 87-94. Szmulewicz AG, S.C., Martino D, Strejilevich S, 2015. An updated review on the neuropsychological profile of subjects with bipolar disorder. Archives of Clinical Psychiatry 42, 139-146. Torres, I.J., Boudreau, V.G., Yatham, L.N., 2007. Neuropsychological functioning in euthymic bipolar disorder: a meta-analysis. Acta Psychiatr. Scand. Suppl., 17-26. Torres, I.J., DeFreitas, V.G., DeFreitas, C.M., Kauer-Sant'Anna, M., Bond, D.J., Honer, W.G., Lam, R.W., Yatham, L.N., 2010. Neurocognitive functioning in patients with bipolar I disorder recently recovered from a first manic episode. J. Clin. Psychiatry 71, 1234-1242. Tost, H., Ruf, M., Schmal, C., Schulze, T.G., Knorr, C., Vollmert, C., Bosshenz, K., Ende, G., Meyer-Lindenberg, A., Henn, F.A., Rietschel, M., 2010. Prefrontal-temporal gray matter deficits in bipolar disorder patients with persecutory delusions. J. Affect. Disord. 120, 54-61.

COGNITION IN BDI WITH AND WITHOUT PSYCHOSIS

21

Van Riel, W.G., Vieta, E., Martinez-Aran, A., Haro, J.M., Bertsch, J., Reed, C., Van Os, J., 2008. Chronic mania revisited: factors associated with treatment non-response during prospective follow-up of a large European cohort (EMBLEM). World J. Biol. Psychiatry 9, 313-320. Velakoulis, D., Pantelis, C., McGorry, P.D., Dudgeon, P., Brewer, W., Cook, M., Desmond, P., Bridle, N., Tierney, P., Murrie, V., Singh, B., Copolov, D., 1999. Hippocampal volume in first-episode psychoses and chronic schizophrenia: a highresolution magnetic resonance imaging study. Arch. Gen. Psychiatry 56, 133-141. Woods, S.W., 2003. Chlorpromazine equivalent doses for the newer atypical antipsychotics. J. Clin. Psychiatry 64, 663-667. Yatham, L.N., Kauer-Sant'Anna, M., Bond, D.J., Lam, R.W., Torres, I., 2009a. Course and outcome after the first manic episode in patients with bipolar disorder: prospective 12-month data from the Systematic Treatment Optimization Program For Early Mania project. Can. J. Psychiatry. 54, 105-112. Yatham, L.N., Kennedy, S.H., Schaffer, A., Parikh, S.V., Beaulieu, S., O'Donovan, C., MacQueen, G., McIntyre, R.S., Sharma, V., Ravindran, A., Young, L.T., Young, A.H., Alda, M., Milev, R., Vieta, E., Calabrese, J.R., Berk, M., Ha, K., Kapczinski, F., 2009b. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009. Bipolar Disord. 11, 225255. Young, R.C., Biggs, J.T., Ziegler, V.E., Meyer, D.A., 1978. A rating scale for mania: reliability, validity and sensitivity. Br. J. Psychiatry 133, 429-435. Zanelli, J., Reichenberg, A., Morgan, K., Fearon, P., Kravariti, E., Dazzan, P., Morgan, C., Zanelli, C., Demjaha, A., Jones, P.B., Doody, G.A., Kapur, S., Murray, R.M., 2010. Specific and generalized neuropsychological deficits: a comparison of patients with various first-episode psychosis presentations. Am. J. Psychiatry 167, 78-85. Zubieta, J.K., Huguelet, P., O'Neil, R.L., Giordani, B.J., 2001. Cognitive function in euthymic bipolar I disorder. Psychiatry Res. 102, 9-20.

COGNITION IN BDI WITH AND WITHOUT PSYCHOSIS

22

23

COGNITION IN BDI WITH AND WITHOUT PSYCHOSIS

Table 1: Demographic characteristics of BDI patient and healthy control groups BDP+ BDPHC Statistic/pMCP MIC value Sample size

60

13

45

27

33

Statistic/pvalue

24

COGNITION IN BDI WITH AND WITHOUT PSYCHOSIS

Age Mean(SD)

22.97 (4.84)

20.92 (3.75)

23.38 (5.23)

F(2,115) 1.28/0.28

22.78 (5.06)

23.12 (4.71)

t(58) -0.27/ 0.80

31/29

4/9

21/24

X2(2) 2.19/0.53

15/12

16/17

X2(2) 0.30/0.59

13.57 (2.44)

13.38 (2.40)

14.49 (2.21)

F(2,115) 2.32/0.10

13.52 (2.41)

13.61 (2.51)

t(58) -0.14 /0.89

105.60 (8.07)

108.85 (6.88)

107.71 (6.87)

F(2,115) 1.58/0.21

104.41 (8.71)

106.58 (7.50)

1.05 (1.95) 5.90 (7.06)

2.23 (3.72) 5.85 (4.45)

F(1,71) 2.70/0.11 F(1,71) 0.001/0.98

1.07 (1.96) 6.44 (7.20)

1.03 (1.98) 5.45 (7.02)

t(58) -1.04/ 0.30 t(58) 0.09/0.93 t(58) 0.54/0.59

0.95 (1.32)

1.83 (2.37)

t(67) 1.81/0.23

1.12 (1.27)

0.81 (1.36)

t(55) 0.87/0.39

20.02 (5.37)

18.55 (3.24)

t(68) 0.88/0.38

19.58 (5.76)

20.36 (5.10)

t(57) -0.56/0.58

2.66 (4.13)

2.73 (4.22)

t(67) 0.05/0.96

2.80 (4.51)

2.55 (3.89)

t(56) 0.23/0.82

48%

25%

X2(1) 3.26/0.20

32%

60%

X2(1) 5.45/0.07

38%

13%

29%

45%

12%

33%

8%

15%

31%

51%

50%

52%

38%

44%

42%

45%

77%

75%

81%

72%

Gender (M/F)

Years Education Mean(SD) NAART FSIQ Mean(SD) YMRS Mean(SD) HDRS Mean(SD) Number previous depressive episodes Mean(SD) Age of illness onset Mean(SD) Duration of illness Mean(SD) Lifetime history any drug abuse Lifetime THC use Lifetime alcohol use Lithium VPA Antipsychotic

X2(1) 4.08/0.04 X2(1) 5.33/0.07 X2(1) 1.72/0.19 X2(1) 0.14/0.71 X2(1) 0.007/0.94

X2(1) 1.56/0.21 X2(1) 1.94/0.38 X2(1) 0.01/0.91 X2(1) 0.06/0.81 X2(1) 0.62/0.43

Antipsychotic dose (CPZ 93.94 137.95 t(63) 132.34 141.77 t(52) equivalents) (95.53) (150.33) -0.93/0.36 (127.61) (166.04) -0.23/0.82 Mean(SD) Significant results underlined. BDP+, bipolar I patients with psychotic features; BDP-, bipolar I patients with no psychotic features; HC, healthy controls; MCP, bipolar I patients with mood congruent psychotic features; MIC, bipolar I patients with mood incongruent psychotic features; NAART FSIQ, North American Adult Reading Test Full Scale IQ; YMRS, Young Mania Rating Scale; HDRS, Hamilton Depression Rating Scale; VPA, valproic acid; CPZ, chlorpromazine

25

COGNITION IN BDI WITH AND WITHOUT PSYCHOSIS

Table 2. Comparison of neuropsychological performance between healthy control and patient groups BDP Mean (SD) (n=73) -0.47 (0.99) Md: -0.44

HC Mean (SD) (n=45) 0.07 (1.12) Md: 0.34

p value

Cohen’s d (95% CI)

BDP+ Mean (SD) (n=60) -0.53 (0.98) Md: -0.60

BDPMean (SD) (n=13) -0.45 (1.09) Md: -0.41

p value

Cohen’ sd (95% CI) 0.14 (-0.48 – 0.75)

MCP Mean (SD) (n=27) -0.42 (1.03) Md:-0.21

MIC Mean (SD) (n=33) -0.49 (0.95) Md:-0.53

p value

Cohen’s d (95% CI)

0.001 (HC> BDP)

0.65 (0.25 – 1.02)

0.71

0.10 (0.42 – 0.61)

Verbal learning CVLT 1-5 T

50.00 (11.13)

57.91 (9.27)

0.001 (HC> BDP)

0.76 (0.38 1.16)

49.42 (11.45)

52.69 (9.40)

0.32

0.31 (-0.30 0.92)

46.67 (11.15)

50.85 (11.67)

0.18

-0.38 (-0.890.16)

Verbal memory CVLT LDFR

-0.36 (1.22) Md:0.00

0.32 (1.01) Md:0.50

0.002 (HC> BDP)

0.61 (0.210.98)

-0.42 (1.18) Md:0.00

-0.08 (1.37) Md:0.20

0.30

0.33 (-0.29– 0.91)

-0.63 (1.29) Md:-0.50

-0.25 (1.08) Md:0.00

0.28

-0.29 (0.80 0.24)

Processing speed COWA

-0.52 (0.81)

-0.01 (1.18)

0.004 (HC> BDP)

0.50 (0.12 0.88)

-0.48 (0.80)

-0.72 (0.87)

0.42

-0.30 (-0.93 0.35)

-0.62 (0.67)

-0.36 (0.89)

0.27

-0.33 (-0.83 0.22)

Processing speed TMT-A

46.96 (11.51)

53.71 (11.44)

0.005 (HC> BP)

0.59 (0.21 0.97)

46.58 (11.96)

48.69 (9.38)

0.42

0.20 (-0.42 0.81)

47.37 (12.06)

45.94 (12.02)

0.63

0.12 (-0.39 0.64)

Processing speed Stroop-C

43.29 (10.71)

45.76 (10.93)

0.185

0.23 (-0.15 0.60)

43.57 (11.59)

42.00 (5.08)

0.69

-0.18 (-0.78 0.43)

41.07 (11.51)

45.61 (11.43)

0.11

-0.40 (-0.92 0.12)

Processing speed Stroop-W

46.81 (10.23)

50.13 (11.03)

0.177

0.31 (-0.06 0.69)

46.08 (10.78)

50.15 (6.53)

0.19

0.46 (-0.16 – 1.07)

44.11 (10.85)

47.70 (10.61)

0.19

-0.34 (-0.85 0.19)

Executive functioning TMT-B

49.75 (9.99)

56.27 (9.27)

0.002 (HC> BDP)

0.67 (0.26 1.01)

49.32 (10.30)

51.77 (8.49)

0.37

0.25 (-0.31 0.87)

50.85 (8.33)

48.06 (11.64)

0.16

0.27 (-0.25 0.81)

Executive functioning Stroop-Int

55.66 (6.42)

57.67 (8.60)

0.138

0.28 (-0.11 - 0.64)

56.02 (6.34)

54.00 (6.76)

0.36

-0.31 (-0.91 0.31)

56.56 (6.96)

55.58 (5.87)

0.61

0.15 (-0.39 0.63)

Executive functioning IED

-0.39 (1.34) Md:0.10

0.04(1.16) Md:0.39

0.001 (HC> BDP)

0.65 (0.25 – 1.03)

-0.42 (1.26) Md:0.17

-0.28 (1.72) Md:0.42

*0.04

*0.70 (0.03 – 1.30)

-0.25 (1.07) Md:0.17

-0.54 (1.41) Md:0.06

0.84

0.05 (-0.46 – 0.61)

Sustained attention RVIP

0.67

COGNITION IN BDI WITH AND WITHOUT PSYCHOSIS

Significant results are underlined. *Not significant after correcting for multiple comparisons. Median values (Md) are also reported for non-parametric measures. Effect sizes reported as Cohen's d, with 95% confidence interval in brackets. BDP, bipolar I patients; HC, healthy control; BDP+, bipolar I patients with psychotic features; BDP-, bipolar I patients with no psychotic features; MCP, bipolar I patients with mood congruent psychotic features; MIC, bipolar I patients with mood incongruent psychotic features.

Highlights: 

Cognition in new onset BDI with (BDP+) or without (BDP-) psychosis did not differ.



BDP+ with (MCP) or without mood incongruent (MIC) psychosis also did not differ.



However, BDP+ were more impaired compared to HC than was BDP-.



MIC and MCP also showed different patterns of impairment compared to HC.



Thus, these patient subgroups may display unique cognitive deficits at illness onset.

26