Course of neurocognitive function in first treatment bipolar I disorder: One-year follow-up study

Author’s Accepted Manuscript Course of neurocognitive function in first treatment bipolar I disorder: One-year follow-up study Christine Demmo, Trine Vik Lagerberg, Sofie R Aminoff, Tone Hellvin, Levi R. Kvitland, Beathe Haatveit, Carmen Simonsen, Ole A Andreassen, Ingrid Melle, Torill Ueland www.elsevier.com/locate/psychres

PII: DOI: Reference:

S0165-1781(16)31276-8 http://dx.doi.org/10.1016/j.psychres.2016.12.048 PSY10184

To appear in: Psychiatry Research Received date: 2 August 2016 Revised date: 9 November 2016 Accepted date: 29 December 2016 Cite this article as: Christine Demmo, Trine Vik Lagerberg, Sofie R Aminoff, Tone Hellvin, Levi R. Kvitland, Beathe Haatveit, Carmen Simonsen, Ole A Andreassen, Ingrid Melle and Torill Ueland, Course of neurocognitive function in first treatment bipolar I disorder: One-year follow-up study, Psychiatry Research, http://dx.doi.org/10.1016/j.psychres.2016.12.048 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.

Course of neurocognitive function in first treatment bipolar I disorder: One-year follow-up study Christine Demmoa,b*, Trine Vik Lagerberga, Sofie R Aminoffa, c, Tone Hellvina, Levi R. Kvitlanda, Beathe Haatveita, Carmen Simonsena, Ole A Andreassena, Ingrid Mellea, Torill Uelanda, b aNORMENT

KG Jebsen Centre for Psychosis Research, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Norway bDepartment

of Psychology, University of Oslo, Norway

cDepartment

of Specialized Inpatient Treatment, Division of Mental Health Services, Akershus University Hospital,

Norway Corresponding author: Licensed Psychologist/Cand.Psychol Christine Demmo Division of Mental Health and Addiction Oslo University Hospital Ullevål, Kirkeveien 166 TOP – Psychosis Research Unit, Building 49 P.O. Box 4956 Nydalen, 0424 Oslo, Norway. Fax: +47 23 02 73 33. E-mail: [email protected]

Abstract Neurocognitive impairment has been found to be a marked feature in bipolar disorder (BD), also in the early phase of the illness. The longitudinal course of neurocognitive functioning, however, remains sparsely investigated. The aims of the study were to investigate the course of neurocognitive function in BD I, and to what degree neurocognitive change or stability is observed also on the individual level. Forty-two patients and 153 comparable healthy controls were assessed at baseline and one-year follow-up. Compared to the healthy control (HC) group BD I patients perform significantly poorer at both baseline and follow-up across all neurocognitive domains and on most neurocognitive subtests. Neurocognitive impairment remained stable for most patients from baseline to follow-up, both on a group level and when investigating individual trajectories, indicative of a relatively stable course of neurocognitive functioning in the early phase of BD I. Keywords BD I disorder; first treatment; longitudinal ; neurocognitive impairment; reliable change; manic episodes; psychosis

1

1. Introduction Neurocognitive impairment has been found to be a marked feature in bipolar disorder (BD), also in the early phase of the illness (Bora and Pantelis, 2015; Demmo et al., 2016; Hellvin et al., 2012; Lee et al., 2014; Martino et al., 2015). However, very few studies have investigated the longitudinal course of neurocognitive functioning in this group, and whether these impairments are stable, progressive or improve over time remains unclear. A meta-analysis of the longitudinal course of neurocognition in BD type I and II, found that performance remained stable over a mean follow-up period of 4.62 years, with no patientcontrol differences in change over time (Samame et al., 2014). Similar findings were reported in a recent five-year follow-up study (Santos et al., 2014). Both of these studies conclude that their findings are more indicative of a neurodevelopmental than a degenerative process underlying neurocognitive impairments in BD. However, as both reports included samples of multi-episode BD patients, it remains difficult to draw firm conclusions regarding the course of neurocognitive functioning during the early years of the illness. Early phase patients are essential to investigate in this regard, as this phase has the potential to provide clearer knowledge regarding the trajectory and etiology of the illness. Following these patients over time from an early phase could provide a better understanding of whether there are some time periods that are more crucial in terms of change and potential contributing factors. To our knowledge, so far only two previous studies of early phase BD I samples have examined the longitudinal course of neurocognitive functioning. Torres et al. found that BD I patients showed selective improvements in processing speed and executive functioning reaching the level of the HC group one year after their first manic episode, while remaining consistently impaired on the other investigated domains (Torres et al., 2014). Further, a recent study from Daglas et al., investigating a mixed sample of first episode mania (FEM) patients found no evidence of change at the domain level over a one-year follow-up period, although some 2

fluctuations where evident at the sub-test level (Daglas et al., 2015). Thus the findings from the few existing longitudinal studies of neurocognitive functioning in the early phase of BD I remain inconclusive. In addition to providing important clues regarding the etiology of cognitive impairment in BD I, a clarification of this issue could also have implications for treatment. The current study explores the course of neurocognitive functioning by using a prospective, longitudinal design and focusing on the early phase of BD type I. To avoid misinterpreting natural fluctuations in performance over time as either decline or improvement we have included a comparable HC group. Further, to investigate whether group level results are reflected also at the individual level, i.e. in individual subjects, we calculate reliable change indices (RCI). More specifically the aims of the present study were to: 1. Investigate the development of neurocognitive functioning in BD I over the first year of treatment compared to a HC group. 2. Investigate to what degree neurocognitive change or stability is observed also on the individual level in BD I.

Based on previous findings we hypothesize that neurocognitive impairment in BD I will be relatively stable from baseline to one-year follow-up on a group level, but with some variation on the individual level.

2. Methods 2.1. Participants As part of an ongoing larger study on psychotic disorders, the Thematically Organized Psychosis (TOP) Study, 79 first treatment (FT) BD I patients were recruited consecutively from both inpatient and outpatient psychiatric units from the major hospitals in the Oslo (Norway) area. FT was defined as giving informed consent to participate within 12 months following the 3

start of first adequate treatment for either a manic or mixed episode (with or without psychotic symptoms). Patients were not considered to be FT patients if they previously on any occasion (before the starting point of the index treatment) had been treated with antipsychotic or mood stabilizing medication, for (a) more than 12 weeks or (b) if symptomatic remission was achieved before the twelve weeks. Patients who had experienced previously untreated self-remitting manic or mixed episodes were also included (n = 12). The participants in the HC group were randomly selected from statistical records from the same catchment area as the patient group and contacted by letter inviting them to participate. All participants received a complete description of the study prior to giving written informed consent, and the study was approved by the Regional Committee for Medical Research Ethics and the Norwegian Data Inspectorate. Exclusion criteria for all participants were history of moderate/severe head injury, neurological disorder, unstable or uncontrolled medical condition that could interfere with brain function, IQ below 70, and age outside the range 18-65 years. Participants were also required to have Norwegian (or other Scandinavian language) as their first language or have attended their compulsory schooling in Norway. In addition healthy controls were excluded if they or a first degree relative had a lifetime history of a severe psychiatric disorder, or if they presented with a substance use disorder within the last six months prior to inclusion. Baseline demographic and clinical variables of the patients and healthy controls completing both time points are presented in Table 1. No demographic differences were found between the patients and the HC group except for a minor, but significant, difference in years of education. 2.2. Clinical assessment Clinical assessments were carried out by trained clinical psychologists and psychiatrists, and diagnoses were based on information obtained with the Structured Clinical Interview for DSMIV axis I disorders (SCID-1) (Rush et al., 2000) and available medical records. All patients met the DSM-IV criteria for BD I. Good inter-rater reliability has previously been reported from the 4

TOP Study with an overall kappa score of 0.77 (95% CI: 0.60-0.949) (Ringen et al., 2008). At both time points current manic symptoms were assessed using the Young Mania Rating Scale (YMRS) (Young et al., 1978) and depressive symptoms with the Inventory of Depressive Symptoms - Clinician Rated (IDS-C) (Rush et al., 1996). Positive psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) while current global symptom and functioning level was assessed using the Global Assessment Functioning Scale (GAF-Symptom and GAF-Function) split version (Pedersen et al., 2007). Patients were considered to have a history of psychosis if they met criteria for any SCIDverified psychotic symptoms (lifetime). Lifetime alcohol or drug use disorders were diagnosed using the E-module of the SCID-1 and the severity of alcohol and drug use the last year was assessed with AUDIT and DUDIT respectively (Lange et al., 2014). 2.3. Neurocognitive assessment Neurocognitive assessment at baseline and follow-up was carried out by psychologists trained in standardized neuropsychological testing. The battery consisted of tests previously found to be sensitive to neurocognitive dysfunction in patients with severe mental disorders (Simonsen et al., 2008) and also included assessment of adequate test effort (Delis et al., 2004). Except for measures of premorbid and current IQ (Sundet and Vaskinn, 2008) only assessed at baseline, the neurocognitive battery was identical at both time points. The tests were divided into four domains; verbal learning and memory, executive functioning, processing speed and attention and working memory. Verbal learning and memory was assessed with the Logical Memory test, from the Wechsler Memory Scale (WMS-III) (Wechsler, 2007) and California Verbal Learning Task (CVLT-II) (Delis et al., 2004). Executive functioning was assessed with the Verbal Fluency Test (VF) and Color Word Interference Test (CW) (third and fourth trial) from the Delis Kaplan Executive Function System (D-KEFS) (Delis et al., 2005). Processing Speed was assessed with the Digit Symbol Coding (DS-C) from the Wechsler Adult Intelligence Scale (WAIS-III) 5

(Wechsler, 2003) while Attention and Working Memory (WM) was measured using the Digit Span (DS), Forward and Backward, also from WAIS-III (Wechsler, 2003). For a more detailed description of the different tests see Demmo et al. (Demmo et al., 2016). 2.4. Statistical analyses All analyses were conducted using the Statistical Package for the Social Sciences version 22 (SPSS Inc, Chicago, IL, USA). Mixed between-within subjects analysis of variance (mixed ANOVA) was used to investigate differences between groups over time, both at the domain level and at the sub-test level, with the neurocognitive domains and subtests entered as dependent variables, group membership entered as the independent variable, and the two time points entered as the repeated variable. Neurocognitive performance across domains was determined by calculating z-scores for each individual sub-test and then using the mean in a given domain. Patients’ raw scores on the various sub-tests were transformed to z-scores by subtracting the average control mean from the patient mean, which then was divided by the control standard deviation (SD). Independent T-tests were used to compare group differences in age, education, premorbid IQ and current IQ, while chi-square analysis compared differences in the group’s test effort. For the patient group paired-samples t-tests were used to assess changes in distributed clinical variables, and Wilcoxon matched pairs was used for the non-normally distributed clinical variables. For dichotomous variables the McNemar’s test was used. The same appropriate tests were used to compare patient completers and noncompleters on baseline demographic and clinical variables where appropriate. RCI was calculated to investigate individual changes including adjustment for practice effects (RCI PE). RCI is an index used to evaluate whether individual changes in test scores are reliable and was calculated using the following formula: ((T2 – T1) – (M2 - M1)) / SEDIverson with T2 and T1 being the discrepancy between test and retest scores, and measurable practice effects the discrepancy between the means (M2 - M1) at baseline and follow-up in the HC group. The 6

resulted practice adjusted discrepancy score is the numerator in the formula with the standard error of difference (SEDIverson) being the denominator with both the variability of the testretest scores taken into consideration: SEDIverson = √((S1√(1-r12)) 2+ (S2√(1-r12)) 2. A neurocognitive global decline score for each participant was calculated based on the twelve possible outcome variables. See Haatveit et al. (Haatveit et al., 2015) for further details. 3. Results 3.1. Demographic and clinical variables Demographic and clinical characteristics for the BD I and HC groups are presented in Table 1. No demographic differences were found between the groups except for a minor difference in education (less than a year). One participant from the HC group had a borderline score of 14 on the measure of adequate test effort, but was included as there were no other indications of less optimal performance. Of the 79 BD I patients included at baseline, a total of 42 patients fully completed reassessment at one-year follow-up including both clinical and neurocognitive data. Thirty-two patients had no data at follow-up due to the following: 18 dropped out of the study, 5 were unreachable, 6 declined to participate at the one-year follow-up but are eligible to be contacted for future follow-up assessments, 2 had died and 1 had moved out of the country. Additionally, 5 patients with clinical interviews at one-year follow-up for various reasons did not complete the neuropsychological testing. Completers did not differ from non-completers on any of the demographic or clinical variables apart from the experience of a psychotic episode (lifetime) with 85.7% of the completers vs. 62.2 % of the non-completers ever having had a psychotic episode (x2 = 4.59, p = 0.03, phi = 0.27). Clinical characteristics of the completers for both time points are presented in Table 2. 3.2. Longitudinal course of neurocognitive functioning 3.2.1. Neurocognitive domains 7

There was a main effect of group for verbal learning and memory (F 1, 192 = 4.47, p = 0.04, partial eta squared = 0.02), executive functioning (F 1, 190 = 22.05, p = <0 .001, partial eta squared = 0.10), processing speed (F 1, 192 = 21.59, p = <0.001, partial eta squared = 0.10) but not attention and working memory (F 1, 193 = 3.06, p = 0.08, partial eta squared = 0.02) (Figure 1). There were no differences between patients with and without previously untreated self-remitting manic or mixed episodes. 3.2.2. Neurocognitive subtests Scores for all sub-tests at baseline and follow-up are presented in Table 3. The mixed ANOVA showed that the BD I group performed significantly poorer than the HC group at both time points on all sub-tests except CVLT-II delayed recall, Logical Memory (immediate and delayed recall) and Digit Span forward. There was a significant time effect for CVLT learning and delayed recall, Logical Memory immediate and delayed recall, C-W interference and setshifting and DS-C. There was a significant group by time interaction for CVLT delayed recall (Wilks Lambda = 0 .98, F 1, 192 = 4.76, p = 0.030, partial eta squared = 0.024) and verbal fluency phonetic (Wilks Lambda = .98, F 1, 192 = 4.90, p = 0.028, partial eta squared = 0.03). 3.2.3. Reliable Change Index RCIPE was estimated by calculating the standard deviation at baseline and follow-up for both the BD I group and the HC group as well as the correlation between the two assessments points for all the subtests for the HC group. Standard deviations are presented in Table 3., and the correlations were as following: CVLT-II learning 0.69 and delayed recall 0.53; logical memory immediate recall 0.56 and delayed recall 0.58; verbal fluency phonetic 0.70, semantic 0.53 and set-shifting 0.40; C-W interference 0.78 and set-shifting 0.65; DS-C 0.80; digit span forward 0.39 and backward 0.46. All correlations from baseline to follow-up were significant with mostly large values (on nine out of the twelve sub-tests). This is indicative of high reliability implying consistency of change within each group (Haatveit et al., 2015). The 8

individual sub-test scores are counted and divided into stable, declining or improving according to a cutoff point of 1.645 (Table 4.). In the verbal learning and memory domain, the HC group show a range in stability scores varying from 88-93% compared to 69-81% in the BD I group. In the executive functioning domain the stability scores of the HC group vary from 8994% compared to 71-91% in the BD I group. In processing speed 90% of the HC group and 91% of the patients remained stable, while in the attention and working memory the stability scores of the HC group vary from 88-97% compared to 86-91% in the BD I group. A higher percentage of the BD I group compared to the HC group showed improvement in all verbal learning and memory sub-tests, with an improvement range varying from 12-17% in the BD I group compared to 2-7% in the HC group. This was also the case for one executive functioning sub-test (C-W interference), with 26% of the BD I patients improving compared to 5% of the HC group and one subtest from the attention and working memory domain (digit span backward), with 10% versus 2% favoring BD I. Furthermore, a higher percentage in the BD I group showed a selective decline compared to the HC group in CVLT-II learning (14% of the BD I group vs. 5% of the HC group) from the verbal learning and memory domain, and verbal fluency phonetic (14% of the BD I group vs. 4% in the HC group) and set-shifting (12% of the BD I group vs. 3% in the HC group) from the executive functioning domain. Chi square test of independence (Fisher`s Exact Probability Test) showed significant associations between group affiliation and CVLT-II delayed recall (2(1,194) = 8.66, p = 0.004), logical memory delayed recall (2(1,195) = 6.68, p = 0.008), C-W interference (2(1,193) = 13.89, p = < .001) and digit span backward (2(1,195) = 3.48, p = 0.04). As only a few patients scored lower on several subtests (one patient had a global decline score of 5, four patients had a score of 3, five patients had a score of 2), no global pattern of decline can be assumed. 4. Discussion

9

The main finding of the present study is that neurocognitive functioning in a group of BD I patients remains stable for most patients over the first year of treatment both on a group level and when investigating individual trajectories based on RCI. Compared to the HC group, BD I patients perform significantly poorer at both baseline and follow-up across all neurocognitive domains and on most neurocognitive subtests. These results are in accordance with previous work from our group investigating both first treatment (Hellvin et al., 2012) and multiepisode (Simonsen et al., 2011) patients. On the domain level the BD I group and the HC group showed the same pattern of change and there were no significant group by time interactions. Both groups over all remained stable from entering the study to follow-up, and the differences in neurocognitive performance observed at baseline thus remained. However, although the HC group performed better than the BD I group in the verbal learning and memory domain at both time points, a main group effect was observed only on the CVLT-learning sub-test. This implies that the poorer performance in the verbal learning and memory domain observed in the BD I group is mainly explained by poorer learning On the sub-test level, some changes were, however, observed with a change over time found for seven of the twelve sub-tests. An improvement was observed for all the sub-tests in the verbal learning and memory domain, however, for CVLT-II delayed recall, the improvement was seen only in the BD I group. The remaining time effects were found in two sub-tests (C-W interference and set shifting) in the executive functioning domain in addition to processing speed (DS-C), with no time by group interactions. The only additional time by group interaction was in phonetic verbal fluency, where the BD I group showed a small decline and the HC group improved (no time effect). The degree of stability observed on a group level in the current study was also reflected on the individual level. By using RCI we were able to investigate individual trajectories, showing 10

that for the vast majority of BD I patients neurocognitive performance remained stable from baseline to follow-up. The improvement in verbal memory observed on a sub-test level was further supported by a significant association between group affiliation and degree of improvement on two of the memory sub-tests. As RCI controls for practice effects this supports the notion that the improvements found on a sub-test level in verbal memory in the main analyses are not due to practice effects. Thus, although there is overall stability in both groups, some fluctuations in both directions are present in the BD I group with selective improvements on the individual level for some of the sub-tests. No pattern of either global decline or improvement, with many participants showing change in several subtests, was however found. Our findings of stability in neurocognitive functioning in the early phase of BD I are in accordance with results from studies of more chronic samples (Samame et al., 2014; Santos et al., 2014), where neurocognitive impairment has been found to be stable over longer periods. This is also the case when comparing our findings with the two existing studies of early phase samples. However, some minor variations between the studies are evident and warrant mentioning. As in the current study, Daglas et al. found no evidence of change in any neurocognitive domains (Daglas et al., 2015). Also in accordance with the present study, Torres et al. found their BD I group to show stable but impaired neurocognitive performance compared to the HC group at one-year follow-up in working memory, attention, verbal and non-verbal memory (Torres et al., 2014). The latter study did, however, find selective improvements in the BD I group in the domains of executive functioning and processing speed compared to the HC group. This is in contrast to both the current study and the Daglas et al. study, as well as the studies of chronic samples, showing stable performance in all domains. There are also some small variations between the studies at the sub-test level. The Daglas study for instance found improvements on a measure of immediate memory in addition to a 11

measure of processing speed, while the current study found improved delayed memory. As the Torres study does not report findings on a sub-test level, in depth interpretation of these minor sub-test findings remain difficult. The existing discrepancies between the three studies could be due to methodological variations in the study samples as well as in the sub-tests used to measure neurocognitive performance.

4.2. Strengths and limitations The current study has several strengths. It is one of the few existing longitudinal studies investigating neurocognitive trajectories in FT BD I including a HC group. By using the RCI method, the current study also controls for measurement error and practice effects and investigates individual as well as group level trajectories. Limitations of the study include a high attrition rate that could increase the risk for drop out bias. However, completers and noncompleters were comparable on all baseline demographic, clinical and neurocognitive factors, except for the prevalence of psychosis, where a higher percentage of the completers had experienced a psychotic episode. There was however no difference in neurocognitive performance between completers and non-completers at baseline, an indication that a history of psychosis does not influence neurocognitive functioning (Demmo et al., 2016). Nevertheless, the specific implications of lifetime psychosis on the longitudinal course of neurocognitive functioning in the early phase of BD I remain inconclusive and should be further investigated in future research. The overall lack of differences between completers and non-completers is in accordance with other findings (Samame et al., 2014), and is supportive of the generalizability of the results. Finally, optimally a standardized test battery such as the MATRICS Consensus Cognitive Battery (MCCB) (Nuechterlein et al., 2008) should have been used. This would enable comparison across studies. However, the current study was initiated prior to the release of the MCCB battery. 12

4.3. Conclusion Our results are indicative of a relatively stable course of neurocognitive functioning in the early phase of BD I. Only a minority of patients present with greater decline or improvement compared to healthy participants over a one-year follow-up period. Thus, our findings are in accordance with results from both longitudinal studies of more chronic BD patients and findings from the other available longitudinal studies investigating neurocognitive trajectories in FT BD I. This stability could indicate that the pathophysiology of neurocognitive impairment is more related to a neurodevelopmental than to a degenerative process. This interpretation is also supported by our previous report (Demmo et al., 2016) where neurocognitive impairments in this FT BD I sample were not explained by number of previous untreated affective episodes, apart from indications of an association between number of previous untreated manic episodes and executive functioning. As neurocognitive impairments are present in the early stage of BD I, and remain impaired after one year in treatment, they should be a treatment target. In terms of implications for future research, some minor discrepancies in terms of indications of different selective improvements in the FT BD I group are evident and need further investigation. To enable comparison across studies the use of standardized cognitive batteries should be emphasized.

The authors of this paper have no conflicts of interest

Acknowledgements The study was funded by grants from the Research Council of Norway (#181831, 147787/320, #67153/V50) and the South-Eastern Norway Regional Health Authority (#2010-074, #2006258).

13

We thank our collaborators in the NORMENT KG Jebsen Centre for psychosis research, and all participants taking part in the study. References Bora, E., Pantelis, C., 2015. Meta-Analysis of Neurocognitive Impairment in First-Episode BD: Compared to First-Episode Schizophrenia and Healthy Controls. Schizophr. Bull. 41 (5), 1095-1104. Daglas, R., Allott, K., Yucel, M., Pantelis, C., Macneil, C.A., Berk, M., Cotton, S.M., 2015. The trajectory of cognitive functioning following first episode mania: A 12-month follow-up study. Aust N Z J Psychiatry. Delis, D.C., Kaplan, E., Kramer, J.H., 2005. Delis-Kaplan Executive Function System (D-KEFS). Norwegian Manual. Pearson Assessment, Stockholm. Delis, D.C., Kramer, J.H., Kaplan, E., Ober, B.A., 2004. California Verbal Learning Test, Second Edition (CVLTII). Norwegian Manual Supplement. Pearson Assessment, Stockholm. 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 (2), 136-147. Haatveit, B., Vaskinn, A., Sundet, K.S., Jensen, J., Andreassen, O.A., Melle, I., Ueland, T., 2015. Stability of executive functioning in first episode psychosis: one year follow up study. Psychiatry Res. 228 (3), 475--481. Hellvin, T., Sundet, K., Simonsen, C., Aminoff, S.R., Lagerberg, T.V., Andreassen, O.A., Melle, I., 2012. Neurocognitive functioning in patients recently diagnosed with bipolar disorder. Bipolar Disord. 14 (3), 227-238. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13 (2), 261-276. Lange, E.H., Nesvag, R., Ringen, P.A., Hartberg, C.B., Haukvik, U.K., Andreassen, O.A., Melle, I., Agartz, I., 2014. One year follow-up of alcohol and illicit substance use in first-episode psychosis: does gender matter? Compr. Psychiatry 55 (2), 274-282. 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, 1-11. Martino, D.J., Samame, C., Ibanez, A., Strejilevich, S.A., 2015. Neurocognitive functioning in the premorbid stage and in the first episode of bipolar disorder: a systematic review. Psychiatry Res. 226 (1), 23-30. Nuechterlein, K.H., Green, M.F., Kern, R.S., Baade, L.E., Barch, D.M., Cohen, J.D., Essock, S., Fenton, W.S., Frese, F.J., 3rd, Gold, J.M., Goldberg, T., Heaton, R.K., Keefe, R.S., Kraemer, H., Mesholam-Gately, R., Seidman, L.J., Stover, E., Weinberger, D.R., Young, A.S., Zalcman, S., Marder, S.R., 2008. The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity. Am J Psychiatry 165 (2), 203-213. Pedersen, G., Hagtvet, K.A., Karterud, S., 2007. Generalizability studies of the Global Assessment of Functioning-Split version. Compr. Psychiatry 48 (1), 88-94. Ringen, P.A., Lagerberg, T.V., Birkenaes, A.B., 2008. Differences in prevalence and patterns of substance use in schizophrenia and bipolar disorder. Psychol. Med. 38, 1241-1249. Rush, A.J., Gullion, C.M., Basco, M.R., Jarrett, R.B., Trivedi, M.H., 1996. The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol. Med. 26 (3), 477-486. Rush, A.J., Pincus, H.A., First, M.B., al., e., 2000. Psychiatric Measures. American Association, Washington. 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. Santos, J.L., Aparicio, A., Bagney, A., Sanchez-Morla, E.M., Rodriguez-Jimenez, R., Mateo, J., Jimenez-Arriero, M.A., 2014. A five-year follow-up study of neurocognitive functioning in bipolar disorder. Bipolar Disord. 16 (7), 722-731.

14

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 (1), 73-83. Simonsen, C., Sundet, K., Vaskinn, A., Birkenaes, A.B., Engh, J.A., Hansen, C.F., Jonsdottir, H., Ringen, P.A., Opjordsmoen, S., Friis, S., Andreassen, O.A., 2008. Neurocognitive profiles in bipolar I and bipolar II disorder: differences in pattern and magnitude of dysfunction. Bipolar. Disord. 10 (2), 245-255. Sundet, K., Vaskinn, A., 2008. Estimating premorbid IQ (in Norwegian with English abstract). J Norwegian Psychological Ass. 45, 1108-1115. Torres, I.J., Kozicky, J., Popuri, S., Bond, D.J., Honer, W.G., Lam, R.W., Yatham, L.N., 2014. 12-month longitudinal cognitive functioning in patients recently diagnosed with bipolar disorder. Bipolar Disord. 16 (2), 159-171. Wechsler, D., 2003. Wechslers Adult Intelligence Scale - Third Edition (WAIS-III). Norwegian Manual. Pearson Assessment, Stockholm. Wechsler, D., 2007. Wechsler Memory Scale, Third Edition (WMS-III). Norwegian Manual. Pearson Assessment, Stockholm. 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. Figure 1 "Longitudinal course of neurocognitive functioning across domains". Abbreviations should be as follows: "Note: Differences in neurocognitive performance across domains was determined by calculating z-scores for each individual test and then using the mean in a given domain; SD demonstrated by bars".

Table 1. Baseline demographics and clinical characteristics for participants completing assessments at both time points 1. BD I n 42

2. HC group n

Independent T-test/Chi-Square/ANOVA

153

analysis/Mann-Whitney U t/x2/F/U

P

Post

hoc Demographics Gender, male (%)

20 (47.6)

81 (52.9)

x2 = 0.2

0.662

Age (SD)

30.0 (9.6)

30.7 (7.3)

t = -0.4

0.665

Education

13.6 (2.1)

14.3 (2.1)

t = -2.0

0.050

NART IQa

111.2 (6.6)

113.2 (5.0)

t = -1.7

0.096

WASIb

110.6 (12.2)

113.9 (9.3)

t = -1.9

Functional level

15

1<2

GAF-Fc

49.6 (10.0)

GAF-Sc

56.9 (12.6)

Illness course History of psychosis n (%)

37 (88.1)

Age at onsetd

27.4 (9.9)

Duration of treatment, Md

0 (0-1)

(min-max)e Medication Antipsychotic n (%)

26 (61.9)

Antidepressive n (%)

12 (28.6)

Lithium, n (%)

8 (19.0)

Antiepileptics, n (%)

10 (23.8)

Lifetime substance use disorder Alcohol use disorder n (%)

9 (21.4)

Substance use disorder n

7 (16.7)

(%) Note: Means (SD) are reported unless otherwise specified. aNART IQ, Estimate of premorbid IQ, measured by the National Adult Reading Test; number of missing scores = 4 bWASI = Wechsler Abbreviated Scale of Intelligence; cGAF = Global Assessment of Functioning; GAF-S = Global Assessment of Functioning-symptom score; GAF-F = Global Assessment of Functioning-function score; number of missing scores = 2 dAge at onset manic or mixed episode eDuration of treatment = Duration of adequate treatment for manic or mixed episode

Table 2. Patient clinical variables at baseline and follow-up Baseline n 42

Follow-up n 42

10.0 (3.8)

8.8 (2.5)

t = 2.0

0.065

12.5 (6-22)

10 (4-17)

-2.6

0.009

2.0 (0-5)

1.0 (0-4)

-1.4

0.155

dGAF-S d

56.9 (12.6)

66.6 (13.7)

t = -4.2

<0.001

base
dGAF-F d

49.6 (10.0)

62.6 (16.6)

t = -5.1

<0.001

base
aPANSS

bIDS,

positive total

Md (25 th -75 th) c

cYMRS,

Md (25 th -75 th)

Medication

16

base>post

Antipsychotic n (%)

26 (61.9)

20 (47.60)

0.210

Antidepressive n (%)

12 (28.6)

11 (26.2)

1.00

Lithium, n (%)

8 (19.0)

11 (26.2)

0.549

Antiepileptic, n (%)

10 (23.8)

14 (33.3)

0.424

Substance use eAUDIT

score

10.4 (7.8)

7.2 (6.7)

t = 2.9

0.007

fDUDIT

score

4.3 (8.0)

2.5 (6.8)

t = 1.6

0.112

base>post

aPANSS

= Positive and Negative Syndrome Scale; = Inventory of Depressive Symptomatology; number of missing scores = 2 (baseline), 3 (follow-up. cYMRS = Young Mania Rating Scale; dGAF = Global Assessment of Functioning; GAF-S = Global Assessment of Functioning-symptom score; GAF-F = Global Assessment of Functioning-function score; number of missing scores = 2 eAUDIT = Alcohol Use Identification Test; number of missing scores = 6 fDUDIT = Drug Use Identification Test; number of missing scores = 6 bIDS

Table 3. Neurocognitive performance at baseline vs. follow-up at one year BD I

Baseline

HC

F values

Follow-up

Baseline

Follow-up

Time

Time x group

Group

Verbal learning and memory CVLT-II Learning

54.9 (12.4)

60.4 (10.8)

58.2 (9.2)

63.0 (9.0)

45.3***

0.2

3.9*

Delayed recall

12.4 (3.4)

13.7 (2.2)

13.5 (2.2)

13.8 (2.6)

12.7***

4.8*

2.3

Logical memory (WMS-III) Immediate recall

24.4 (7.2)

27.3 (6.4)

26.4 (5.8)

28.2 (5.2)

22.8***

1.4

2.6

Delayed recall

21.4 (7.9)

25.4 (7.0)

23.8 (6.0)

26.5 (5.8)

41.6***

1.6

3.5

Phonetic

42.8 (15.6)

41.4 (14.0)

45.7 (10.3)

47.5 (10.4)

0.7

4.9*

5.8*

Semantic

45.3 (10.3)

45.8 (9.8)

49.6 (7.2)

49.5 (8.4)

0.1

0.2

9.5**

Set-Shifting

13.9 (3.1)

13.6 (2.4)

15.1 (2.3)

15.3 (2.7)

0.3

0.7

15.7***

Executive functioning Verbal fluency (D-KEFS)

17

C-W Interference (D-KEFS)a Interference

57.3 (17.5)

52.2 (12.2)

48.6 (10.3)

46.1 (9.2)

22.7***

2.5

17.6***

Set-Shifting

60.9 (14.3)

59.0 (14.6)

54.4 (12.5)

51.5 (11.5)

6.9**

2.9

12.4***

68.2 (15.5)

71.8 (16.0)

78.9 (13.7)

82.8 (13.6)

22.9***

0.0

21.6***

Forward

6.2 (1.6)

6.3 (1.3)

6.3 (1.1)

6.4 (1.4

0.8

0.0

0.3

Backward

4.5 (1.2)

4.7 (1.3)

5.0

5.1 (1.2)

1.8

0.4

6.4*

Processing speed DS-C (WAIS-III) Attention and WM Digit Span (WAIS-III)

(1.2)

Note: CVLT-II = California Verbal Learning Test-revised, number of missing scores for the HC group = 1; WMS-III = Wechsler Memory Scale; D-KEFS = Delis Kaplan Executive Functioning System, number of missing scores for the HC group = 1; C-W Interference = Color-Word Interference, number of missing scores for the HC group = 1-2; WAIS-III = Wechsler Adult Intelligence Scale, number of missing scores for the HC group = 0-1. * P < 0 .05; ** P < 0.01; *** P < 0.001

Table 3. Reliable changes within 90 % CI ± 1.645 Declined n (%)

BD I

Stable n (%)

HC group

BD I

HC group

Improved n (%)

BD I

HC group

Verbal learning and memory CVLT-II Learning (42/152)

6 (14)

8 (5)

29 (69)

133 (88)

7 (17)

10 (7)

Delayed recall (42/152)

2 (5)

7 (5)

34 (79)

142 (93)

6 (14)

3 (2)

Immediate recall (42/153)

3 (7)

5 (3)

34 (81)

139 (91)

5 (12)

9 (6)

Delayed recall (42/153)

3 (7)

5 (3)

32 (76)

142 (93)

7 (17)

6 (4)

Logical memory (WMS-III)

Executive functioning Verbal fluency (D-KEFS)

18

Phonetic (42/152)

6 (14)

6 (4)

36 (86)

142 (93)

0 (0)

3 (2)

Semantic (42/152)

2 (5)

6 (4)

38 (91)

135 (89)

2 (5)

10 (7)

Set-Shifting (42/152)

5 (12)

5 (3)

35 (83)

139 (92)

2 (5)

8 (5)

Interference (42/151)

1 (2)

6 (4)

30 (71)

137 (91)

11 (26)

8 (5)

Set-Shifting (42/152)

3 (7)

6 (4)

38 (91)

143 (94)

1 (2)

3 (2)

2 (5)

9 (6)

38 (91)

137 (90)

2 (5)

6 (4)

Forward (42/153)

2 (5)

1 (1)

38 (91)

149 (97)

2 (5)

3 (2)

Backward (42/153)

2 (5)

15 (10)

36 (86)

135 (88)

4 (10)

3 (2)

C-W Interference (D-KEFS)

Processing speed DS-C (WAIS-III) (42/152) Attention and WM Digit Span (WAIS-III)

Note: CVLT-II = California Verbal Learning Test-revised, number of missing scores for the HC group = 1; WMS-III = Wechsler Memory Scale; D-KEFS = Delis Kaplan Executive Functioning System, number of missing scores for the HC group = 1; C-W Interference = Color-Word Interference, number of missing scores for the HC group = 1-2; WAIS-III = Wechsler Adult Intelligence Scale, number of missing scores for the HC group = 0-1.

Highlights: -

Investigating longitudinal course of neurocognitive impairment in first treatment bipolar I disorder

-

One of the first studies investigating the course of neurocognitive functioning in early phase bipolar I patients, both on a group level as well as on the individual level

-

Bipolar I patients perform poorer than healthy controls at both baseline and at one-year follow up

19

-

Neurocognitive impairment remained stable for most patients

-

Indicate a stable course of neurocognitive functioning in the early phase of the disorder

-

Demonstrates the need for neurocognitive impairment to be a treatment target

20