Journal of Affective Disorders 166 (2014) 297–306

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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad

Review

Neurocognitive impairments among youth with pediatric bipolar disorder: A systematic review of neuropsychological research Álvaro Frías a,b,n, Cárol Palma a,b, Núria Farriols a,b a b

FPCEE Blanquerna, University of Ramon-Llull, Císter street 34, Barcelona 08022, Spain Department of Psychiatry, Hospital of Mataró, Cirera street s/n, Mataró 08304, Spain

art ic l e i nf o

a b s t r a c t

Article history: Received 11 February 2014 Received in revised form 18 May 2014 Accepted 19 May 2014 Available online 27 May 2014

Background: Pediatric bipolar disorder (PBD) has emerged as a field of research in which neuropsychological studies are continuously providing new empirical findings. Despite this, a comprehensive framework for neurocognitive impairments is still lacking, and most of the evidence remains unconnected. We addressed this question through a systematic review of neuropsychological research, with the aim of elucidating the main issues concerning this topic. Method: A comprehensive search of databases (PubMed, PsycINFO) was performed. Published manuscripts between 1990 and January 2014 were identified. Overall, 124 studies fulfilled inclusion criteria. Methodological differences between studies required a descriptive review of findings. Results: Evidence indicates that verbal/visual-spatial memory, processing speed, working memory, and social cognition are neurocognitive domains impaired in PBD youth. Furthermore, these deficits are greater among those who suffer acute affective symptoms, PBD type I, and/or attention deficit hyperactivity disorder (ADHD) comorbidity. In addition, several neurocognitive deficits imply certain changes in prefrontal cortex activity and are somewhat associated with psychosocial and academic disabilities. Strikingly, these deficits are consistently similar to those encountered in ADHD as well as severe mood dysregulation (SMD). Besides, some neurocognitive impairments appear before the onset of the illness and tend to maintain stable across adolescence. Finally, any therapy has not yet demonstrated to be effective on diminishing these neurocognitive impairments. Limitations: More prolonged follow-up studies aimed at delineating the course of treatment and the response to it are warranted. Conclusions: Despite noteworthy research on the neurocognitive profile of PBD, our knowledge is still lagging behind evidence from adult counterparts. & 2014 Elsevier B.V. All rights reserved.

Keywords: Pediatric bipolar disorder Neurocognitive impairments neuropsychological research

Contents 1. 2.

3.

n

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 Method. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 2.1. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 2.2. Selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 2.3. Data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 2.4. Method of analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 3.1. Neuropsychological domains impaired in PBD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 3.1.1. Attention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 3.1.2. Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 3.1.3. Processing speed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 3.1.4. Executive functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 3.1.5. Social cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300

Corresponding author. E-mail address: [email protected] (Á. Frías).

http://dx.doi.org/10.1016/j.jad.2014.05.025 0165-0327/& 2014 Elsevier B.V. All rights reserved.

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3.2.

Modulating variables related to neuropsychological impairments among youth with PBD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 3.2.1. Psychopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 3.2.2. Types of PBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 3.2.3. ADHD comorbidity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 3.2.4. Stimulus valence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 3.2.5. Medication status. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 3.3. Clinical correlates related to neuropsychological impairments among youth with PBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 3.3.1. Neurobiological correlates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 3.3.2. Functional correlates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 3.4. Specificity of neuropsychological impairments in PBD compared to other childhood mental disorders . . . . . . . . . . . . . . . . . . . . . . . . . 302 3.4.1. PBD vs. ADHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 3.4.2. PBD vs. SMD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 3.5. Course of neuropsychological impairments in PBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 3.5.1. Onset of neurocognitive impairments among youth with PBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 3.5.2. Evolution of neurocognitive impairments across adolescence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 3.6. Treatment of neuropsychological impairments in PBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 4. Discussion and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 4.1. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 4.2. Limitations and directions for future research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304

1. Introduction Pediatric bipolar disorder (PBD) is a mental disorder affecting roughly 2% of youth less than 18-years-old (Merikangas et al., 2011; Van Meter et al., 2011). Likewise, for 55–60% of adults with bipolar disorder (ABD), the pathology begins in childhood and adolescence (Perlis et al., 2004), frequently exhibiting subthreshold forms of the disorder (Shaw et al., 2005; Youngstrom et al., 2005). The persistence of this psychopathology into early adulthood leads to high levels of morbidity and disability (Birmaher et al., 2009; Wozniak et al., 2011), greatly hampering both academic achievements and psychosocial development (Goldstein et al., 2009). Despite growing and conclusive evidence concerning psychopathology, course, and treatment in PBD (Goldstein and Birmaher, 2012; Torrent et al., 2012; Peruzzolo et al., 2013), a comprehensive framework specifically focused on neurocognitive impairments among PBD youth is still lacking. Accordingly, unlike adult counterparts, the profusion of neurocognitive PBD findings remains disseminated and apparently unconnected (Savitz et al., 2005; Manove and Levy, 2010). This lack of systematicity hinders the progress toward delineating current knowledge and best practice. To date, this is the first systematic review aimed at parsing the main neurocognitive characteristics among PBD youth. Particularly, we sought to elucidate six issues, namely: (i) Which neurocognitive domains are impaired? (ii) Which modulating variables affect findings on these neurocognitive impairments? (iii) Which clinical correlates are related to these neurocognitive impairments? (iv) How specific are these neurocognitive impairments compared to those encountered in other childhood mental disorders? (v) Which is the evolution of these neurocognitive impairments? (vi) What interventions have already been proven effective on treating these neurocognitive impairments?

included indexing terms (e.g. MeSH) and free texts: [(cognition OR cognitive impairment) AND (youth OR pediatric OR child OR adolescent) AND (bipolar disorder)]. 2.2. Selection criteria Inclusion criteria included youth: (i) diagnosed with bipolar disorder type I (BDI), bipolar disorder type II (BD II), or bipolar disorder not otherwise specified (BD NOS) according to DSM-IV-TR criteria (American Psychiatric Association (APA), 2000); (ii) aged 6–18 years-old; (iii) assessed with neuropsychological tests, among other instruments. Thus, 124 manuscripts fulfilled inclusion criteria. Thirteen of them were partial revisions. The remainder were original papers. 2.3. Data extraction For any manuscript, the following variables were recorded: (i) neurocognitive domain assessed; (ii) neuropsychological test used; (iii) influence of modulating variables; (iv) comparative group employed; (v) clinical correlates measured; (vi) data from follow-up assessment and treatment. 2.4. Method of analysis There was remarkable heterogeneity among selected studies concerning outcome measures and assessment instruments. For these reasons, we present a descriptive review of the studies instead of a meta-analysis.

3. Results 3.1. Neuropsychological domains impaired in PBD

2. Method 2.1. Search strategy A literature search was carried out through PsycINFO and PubMed databases from 1990 to January 2014. Terms employed

The first goal of our review was to determine which neuropsychological domains were impaired in PBD compared to healthy control (HC) youth. Main findings related to this issue concern attention (selective/sustained attention), memory (verbal/visualspatial memory), processing speed, executive functions (working

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Table 1 Overview of main neuropsychological findings in PBD. Neurocognitive domain

Authors

Neuropsychological task

Main finding (PBD vs. HC)

Selective attention

Robertson et al. (2003) Rich et al. (2005b) Brotman et al. (2007) Whitney et al. (2012) Robertson et al. (2003) DelBello et al. (2004) McClure et al. (2005b) Doyle et al. (2005) Karakurt et al. (2013)

FD WISC-III Posner attention task Dot-probe task Dot-probe task CPT CPT CPT CPT CPT

No significant differences No significant differences No signficant differences No significant differences No significant differences No significant differences No significant differences Lower performance in PBD Lower performance in PBD

Verbal memory

McClure et al. (2005a) Doyle et al. (2009) Pavuluri et al. (2009) Jacobs et al. (2011) Udal et al. (2012)

CVLT CVLT WMS Affective story task CVLT

Lower Lower Lower Lower Lower

performance performance performance performance performance

in in in in in

PBD PBD PBD PBD PBD

Visual-spatial memory

Dickstein et al. (2004) McClure et al. (2005a) Doyle et al. (2009) Lera-Miguel et al. (2011)

CANTAB Rey complex figure Rey complex figure Rey complex figure

Lower Lower Lower Lower

performance performance performance performance

in in in in

PBD PBD PBD PBD

Processing speed

Doyle et al. (2005) Doyle et al. (2009) Passarotti et al. (2010a) Pavuluri et al. (2010c) Pavuluri et al. (2011) Wegbreit et al. (2011) Karakurt et al. (2013) Passarotti et al. (2013) Doyle et al. (2005) Bearden et al. (2007) Doyle et al. (2009) Passarotti et al. (2010a) Passarotti et al. (2010b) Lera-Miguel et al. (2011) Schenkel et al. (2012a) Karakurt et al. (2013)

Stroop task Stroop task Stroop task Synonym matching task Synonym matching task Synonym matching task Stroop task Synonym matching task Stroop task Delayed response task Stroop task Stroop task ANMT Stroop task ANMT Stroop task

Lower Lower Lower Lower Lower Lower Lower Lower Lower Lower Lower Lower Lower Lower Lower Lower

performance performance performance performance performance performance performance performance performance performance performance performance performance performance performance performance

in in in in in in in in in in in in in in in in

PBD PBD PBD PBD PBD PBD PBD PBD PBD PBD PBD PBD PBD PBD PBD PBD

Cognitive flexibility

Robertson et al. (2003) Dickstein et al. (2004) Gorrindo et al. (2005) McClure et al. (2005b) Dickstein et al. (2007) Nelson et al. (2007) Rau et al. (2008) Doyle et al. (2009) Dickstein et al. (2010) Adleman et al. (2011) Biederman et al. (2011) Lera-Miguel et al. (2011) Kim et al. (2012) Karakurt et al. (2013)

WCST CANTAB Reversal learning task Change task Reversal learning task Change task Decision making task WCST Reversal learning task Reversal learning task WCST WCST Change task WCST

No significant differences Lower performance in PBD Lower performance in PBD Lower performance in PBD Lower performance in PBD No significant differences No significant differences Lower performance in PBD No significant differences Lower performance in PBD Lower performance in PBD Lower performance in PBD No significant differences Lower performance in PBD

Response inhibition

Robertson et al. (2003) McClure et al. (2005b) Rich et al. (2005a) Rich et al. (2005b) Leibenluft et al. (2007) Mueller et al. (2010) Passarotti et al. (2010c) Singh et al. (2010) Deveney et al. (2012b) Pavuluri et al. (2012) Diler et al. (2013b)

CPT CPT Lottery startle incentives Posner task contingency Stop signal task Pro-antisaccade task Task with stop cues Go-nogo task Stop signal task Block design task Go-nogo task

No significant differences No significant differences No significant differences Lower performance in PBD No significant differences Lower performance in PBD Lower performance in PBD No significant differences No significant differences No significant differences No significant differences

Social cognition

McClure et al. (2003) McClure et al. (2005b) Guyer et al. (2007) Schenkel et al. (2007) Brotman et al. (2008a) Brotman et al. (2008b) Rich et al. (2008) Schenkel et al. (2008) Deveney et al. (2012a) Schenkel et al. (2012a) Kim et al. (2013)

DANVA DANVA DANVA Chicago-PEAT DANVA EEMT EEMT Hinting task DANVA Chicago-PEAT Facial affect set task

Lower Lower Lower Lower Lower Lower Lower Lower Lower Lower Lower

Sustained attention

Working memory

performance performance performance performance performance performance performance performance performance performance performance

in in in in in in in in in in in

PBD PBD PBD PBD PBD PBD PBD PBD PBD PBD PBD

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Table 1 (continued ) Neurocognitive domain

Authors

Neuropsychological task

Main finding (PBD vs. HC)

Schenkel et al. (2013) Seymour et al. (2013) Shankman et al. (2013)

MET DANVA Chicago-PEAT

Lower performance in PBD Lower performance in PBD Lower performance in PBD

ANMT, Affective N-back Memory Task; CANTAB, Cambridge Neuropsychological Test Automated Battery; Chicago-PEAT, Chicago Pediatric Emotional Acuity Task; CPT, Continuous Performance Test; CVLT, California Verbal Learning Test; DANVA, Diagnostic Analysis of Nonverbal Accuracy scale; EEMT, Emotional Expression Multimorph Task; FD-WISC, Freedom from Distractibility index of the Wechsler Intelligence Scale for Children—Third Edition; HC, healthy controls; MET, revised Mind in the Eyes Task; PBD, pediatric bipolar disorder; WCST, Wisconsin Card Sorting Test; WMS, Wechsler Memory Scale.

memory, cognitive flexibility, response inhibition), and social cognition domains (see Table 1). 3.1.1. Attention Concerning neuropsychological studies of selective attention in PBD, the research finds no significant differences between PBD and HC as measured by the freedom from distractibility (FD) composite index of the Wechsler Intelligence Scale for Children—Third Edition (WISC-III) (Robertson et al., 2003), the Posner attention task (Rich et al, 2005b), and the dot-probe task (Brotman et al., 2007; Whitney et al., 2012). Regarding neuropsychological inquiries into potential sustained attention impairment among youth with PBD, some studies find no significant differences between PBD and HC as ascertained by the Continuous Performance Test (CPT) (Robertson et al., 2003; DelBello et al., 2004; McClure et al., 2005b). Conversely, other researches have found significant lower performance on the CPT in PBD (Doyle et al., 2005; Karakurt et al., 2013). 3.1.2. Memory With respect to verbal memory impairment among subjects with PBD, most of the research stresses that these patients exhibit worse verbal memory compared to HC. This deficit has been measured by the California Verbal Learning Test (CVLT) (McClure et al., 2005a; Doyle et al., 2009; Udal et al., 2012), the Wechsler Memory Scale (WMS) (Pavuluri et al., 2009), and the affective story task (Jacobs et al., 2011). Similarly, research aimed at delineating possible visual-spatial memory impairments among PBD youth agrees that these subjects perform more poorly than HC in this neurocognitive domain as assessed either with the Rey–Osterreith Complex Figure (McClure et al., 2005a,; Doyle et al., 2009; Lera-Miguel et al., 2011) or the Cambridge Neuropsychological Test Automated Battery (CANTAB) (Dickstein et al., 2004). 3.1.3. Processing speed Concerning processing speed, most studies report greater impairment among PBD youth than HC subjects (Udal et al., 2013). This result has been obtained using the affective/color-word Stroop task (Doyle et al., 2005, 2009; Passarotti et al., 2010a; Karakurt et al., 2013), and the affective/synonym matching task (Pavuluri et al., 2010c, 2011; Wegbreit et al., 2011; Passarotti et al., 2013). 3.1.4. Executive functions With regard to potential working memory disability among youth with PBD, there is a research consensus indicating that subjects with PBD display worse working memory relative to HC youth (Shear et al., 2002; Biederman et al., 2011). This finding has been obtained using the affective/color-word Stroop task (Doyle et al., 2005, 2009; Passarotti et al., 2010a; Lera-Miguel et al., 2011; Karakurt et al., 2013), the Affective N-back Memory Task (ANMT) (Passarotti et al., 2010b; Schenkel et al., 2012a), and the spatial delayed response task (Bearden et al., 2007).

Concerning cognitive flexibility within PBD youth, there is disagreement between collected studies. Particularly, discrepancies in the research are not accounted for by neuropsychological tests used. Thus, there are evidences highlighting no significant differences between both PBD and HC youth as measured by the reversal learning task (Dickstein et al., 2010), the decision making task (Rau et al., 2008), the change task (Nelson et al., 2007; Kim et al., 2012), and the Wisconsin Card Sorting Test (WCST) (Robertson et al., 2003). Likewise, other neuropsychological studies have shown less cognitive flexibility in PBD youth as ascertained by the reversal learning task (Gorrindo et al., 2005; Dickstein et al., 2007; Adleman et al., 2011), the change task (McClure et al., 2005b), the CANTAB (Dickstein et al., 2004), and the WCST (Doyle et al., 2009; Biederman et al., 2011; Lera-Miguel et al., 2011; Karakurt et al., 2013). In addition, response inhibition has emerged as a main neuropsychological target connected to trait impulsivity among subjects with PBD (Passarotti and Pavuluri, 2011). To date, findings from these studies are not conclusive. On the one hand, there are several studies that have found no significant differences between PBD and HC youth as measured by the CPT (Robertson et al., 2003; McClure et al., 2005b), the go-nogo task (Singh et al., 2010; Diler et al., 2013b), the stop signal task (Leibenluft et al., 2007; Deveney et al., 2012b), the block design task (Pavuluri et al., 2012), and the lottery startle paradigm with incentives (Rich et al., 2005a). On the other hand, the remaining studies have shown worse response inhibition among PBD than HC youth as assessed with the affective Posner task with contingencies (Rich et al., 2005b), the mixed pro-antisaccade task with monetary incentives (Mueller et al., 2010), and the response inhibition task with stop cues (Passarotti et al., 2010c). 3.1.5. Social cognition Social cognition studies, albeit incipient, have already provided further evidences regarding neuropsychological impairments in PBD youth. Accordingly, all the inquiries point out worse facial emotion labelling in PBD relative to HC youth as ascertained by the Chicago Pediatric Emotional Acuity Task (Chicago-PEAT) (Schenkel et al., 2007, 2012a; Shankman et al., 2013), the Diagnostic Analysis of Nonverbal Accuracy scale (DANVA) (McClure et al., 2003; McClure et al., 2005b; Guyer et al., 2007; Brotman et al., 2008a; Deveney et al., 2012a; Seymour et al., 2013), the revised Mind in the Eyes Task (MET) (Schenkel et al., 2013), the emotional expression multimorph task (Brotman et al., 2008b; Rich et al., 2008), the hinting task (Schenkel et al., 2008), and the picture of facial affect set task (Kim et al., 2013). 3.2. Modulating variables related to neuropsychological impairments among youth with PBD The next objective of our review was to establish the extent to which the main findings described above may be modulated by confounding variables. To determine their potential effect, results arising from psychopathology, types of PBD, ADHD comorbidity, stimulus valence, and medication status are arranged separately.

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3.2.1. Psychopathology Regarding current mood symptomatology as a modulating variable for neurocognitive findings among youth with PBD, there are divergences concerning neuropsychological domains targeted. For instance, post hoc analyses within PBD samples tend to underline no effects from mood state as measured by rating scales on attention (Dickstein et al., 2004), visual-spatial memory (Dickstein et al., 2004), executive functions (Dickstein et al., 2004; Bearden et al., 2007; Rau et al., 2008; Dickstein et al., 2010; Mueller et al., 2010; Biederman et al., 2011), and social cognition as well (Schenkel et al., 2012a, 2012b). Similarly, comparative studies among acutely ill vs. clinically stabilized (euthymic) youth also show no significant differences between both PBD groups on these neurocognitive domains (DelBello et al., 2004; Pavuluri et al., 2006a, 2006b; Schenkel et al., 2007). Conversely, some studies point out that depressed mood state accounts for the observed findings on verbal memory (McClure et al., 2005a, 2005b), either impairing recall of details (Jacobs et al., 2011) or diminishing retrieval of positive valence stimulus (Whitney et al., 2012). Likewise, some research aimed at addressing processing speed as measured by the affective/synonym matching task reveal that manic symptoms correlate negatively with accuracy for negative words (Passarotti et al., 2013) as well as with reaction time for positive words (Wegbreit et al., 2011). Concerning prior psychotic symptoms among youth with PBD, post hoc analyses have revealed that those with a previous history of psychotic symptoms are more impaired on executive functions (Udal et al., 2013) and verbal memory (Udal et al., 2012).

3.2.2. Types of PBD There are various comparative studies aimed at delineating distinctive neurocognitive profiles for types of PBD (PBD type I vs. PBD type II). All of them obtained results indicating that PBD I youth perform more poorly than PBD II on neuropsychological tests related to sustained attention (Schenkel et al., 2012a, 2012b), verbal memory (Glahn et al., 2005), executive functions (Schenkel et al., 2012b), and social cognition (Schenkel et al., 2013).

3.2.3. ADHD comorbidity Meta-analyses of PBD studies have found an average of 62% also meeting criteria for ADHD (Youngstrom et al., 2010). There is a flourishing literature on the question of whether ADHD comorbidity impacts the neurocognitive profile of PBD youth. First, both post hoc analyses and comparative studies (PBD þADHD vs. PBD alone) have failed to obtain effects from ADHD comorbidity on processing speed among youth with PBD (Doyle et al., 2005; Mattis et al., 2011; Passarotti et al., 2013; Udal et al., 2013). Similar results have been found on sustained attention (DelBello et al., 2004; Adler et al., 2005; Doyle et al., 2005). With regard to executive functions, results are mixed using these types of methodology, either indicating no significant differences (DelBello et al., 2004; Dickstein et al., 2004; Doyle et al., 2005; McClure et al., 2005a, 2005b; Rau et al., 2008; Udal et al., 2013) or more impaired executive functions among youth with ADHD comorbidity (Pavuluri et al., 2006a, 2006b; Rucklidge, 2006). Regarding social cognition, findings are not conclusive, identifying either no differences (McClure et al., 2005a, 2005b) or higher impairment among PBD youth with ADHD comorbidity (Schenkel et al., 2007). Finally, studies focused on verbal memory tend to show effects from ADHD comorbidity on this domain, mainly greater impairment within this subset of PBD patients (McClure et al., 2005a, 2005b; Rucklidge, 2006).

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3.2.4. Stimulus valence According to neuroimaging and behavioural studies, the role of emotion processing on cognitive function among PBD youth has gained increasing recognition over the last few years (Pavuluri et al., 2008). These findings have encouraged neuropsychological research aimed at delineating neurocognitive deficits related to stimulus valence used on neuropsychological tests (Rosen and Rich, 2010; Yang et al., 2013). Regarding verbal memory, negative (vs. positive) words material has been found to interfere with recall among PBD youth compared to HC (Jacobs et al., 2011), except for self-referent adjectives (Whitney et al., 2012). Similarly, processing speed as measured by a synonym matching task showed a greater disruptive effect of emotional (vs. neutral) words in PBD relative to HC, especially for negative ones (Passarotti et al., 2013). Conversely, in other studies there were no significant differences between PBD and HC adolescents based on stimulus valence as measured by the affective color matching task (Pavuluri et al., 2010a, 2010b, 2010c, 2011). Concerning working memory, no significant differences have been obtained between PBD and HC on stimulus (faces/words) valence as assessed with the ANMT (Schenkel et al., 2012a) and the emotional Stroop task (Passarotti et al., 2010a). Regarding response inhibition, results are mixed. On the one hand, PBD subjects who performed a Posner attention task with contingencies showed no decreased reaction time after punishment (vs. reward) feedback relative to HC (Rich et al., 2005a). On the other hand, there was no significant interaction effect group x contingency valence in a sample of PBD and HC youth who carried out a mixed pro-antisaccade task with monetary incentives (Mueller et al., 2010). Finally, group  (facial) emotion interactions have tended not to be significant on social cognition as assessed with the DANVA (Deveney et al., 2012a), the PEAT (Schenkel et al., 2007, 2012a), the Cognitive and Emotional Perspective Taking Task (CEPTT) (Schenkel et al., 2013), the Emotion Recognition test (ER-40) (Shankman et al., 2013), and the Emotional Expression Multimorph Task (Brotman et al., 2008b; Rich et al., 2008). Conversely, one piece of research has found more identification errors on happy (vs. sad, angry or fearful) children's faces among PBD than HC youth as measured by the DANVA (Seymour et al., 2013). Likewise, another study showed greater social cognition impairment on the positive and negative conditions (vs. neutral) of the affective story task in PBD subjects compared to HC youth (Schenkel et al., 2008). 3.2.5. Medication status Despite a plethora of evidence concerning the effects of psychotropic medications on neurocognitive functions, there are few studies of their impact on neurocognitive impairments among youth with PBD (Wingo et al., 2009; Torrent et al., 2013b; Dias et al., 2012). Regarding sustained attention, post hoc analyses do not evidence differences between medicated vs. unmedicated PBD subjects when compared to HC (DelBello et al., 2004). Similar results have been found in comparative studies (medicated vs. unmedicated PBD patients) on verbal/visual-spatial memory and executive functions (Pavuluri et al., 2006a, 2006b; Dickstein et al., 2010). Furthermore, social cognition research has also obtained no significant differences between either condition using post hoc analyses (Deveney et al., 2012a, 2012b) as well as comparative studies (Schenkel et al., 2007). Finally, post hoc analyses underline poorer performance on processing speed among PBD youth using (vs. not using) antipsychotic medications (Bearden et al., 2007). 3.3. Clinical correlates related to neuropsychological impairments among youth with PBD The next goal of our review was to determine main clinical correlates related to neuropsychological impairments. Hence,

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main results regarding neurobiological and functional correlates using regression and correlation analysis are described below. 3.3.1. Neurobiological correlates Neurobiological findings among subjects with PBD can be widely consulted elsewhere (Frazier et al., 2005; Wegbreit and Pavuluri, 2012). Here we are concerned solely with functional magnetic resonance imaging (fMRI) studies of certain between-group neurocognitive differences between HC and PBD youth. Thus, it is possible to link the observed neurocognitive impairments to neural mechanisms underlying these deficits. To date, fMRI researches have merely provided neurobiological evidence regarding executive function deficits among PBD patients relative to HC subjects. First, working memory impairment within PBD youth has been accompanied by either increased or decreased activation in the dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC), depending on the stimulus valence employed (Passarotti et al., 2010a, 2010b). Regarding cognitive flexibility deficits observed in patients with PBD, an fMRI study found hypoactivation in the caudate among PBD subjects compared to HC youth (Adleman et al., 2011). With respect to response inhibition impairments among PBD youth, research has provided blurred results, either enhanced right DLPFC activation (Singh et al., 2010) or diminished activation in the left VLPFC and in the right anterior cingulate cortex (ACC) (Passarotti et al., 2010c). Besides, other fMRI researches on processing speed deficits among PBD youth showed mixed results compared to HC adolescents, either decreased (Wegbreit et al., 2011) or greater activation in DLPFC and VLPFC (Pavuluri et al., 2010a, 2010b, 2010c). 3.3.2. Functional correlates Results from researches on functional correlates related to neurocognitive deficits among youth with PBD comprise both academic and psychosocial domains. Concerning academic achievements, most studies tend to show worse performance among PBD than HC youth on mathematics and reading/writing measurements as assessed mainly with the Wide-Range Achievement Test (WRAT) (Lagace et al., 2003; Henin et al., 2007; Biederman et al., 2011). Particularly, math difficulties have been associated with attentional disabilities (Pavuluri et al., 2006a, 2006b) as well as executive impairments (Biederman et al., 2011). Concerning psychosocial correlates, PBD patients show greater psychosocial impairment than HC subjects as measured by the longitudinal interval follow-up evaluation (LIFE), the index of peer relations (IPR), and the social adjustment inventory for children and adolescents (SAICA) (Rich et al., 2008; Biederman et al., 2011; Schenkel et al., 2013). Specially, psychosocial impairments have been associated with social cognition deficits (Rich et al., 2008; Schenkel et al., 2013) rather than executive disabilities (Biederman et al., 2011). 3.4. Specificity of neuropsychological impairments in PBD compared to other childhood mental disorders The next purpose of our review was to determine how specific were neuropsychological impairments evidenced in PBD youth. In order to address this concern, main findings from comparative studies between PBD vs. attention deficit hyperactivity disorder (ADHD) as well as PBD vs. severe mood dysregulation (SMD) are displayed. 3.4.1. PBD vs. ADHD A burgeoning research field has emerged focusing on neuropsychological differences between PBD and ADHD youth. Due to overlapping symptomatology between the disorders (Luckenbaugh et al.,

2009), neuropsychological studies have been postulated as an alternative standpoint for recognizing their boundaries. With the exception of one inquiry (Udal et al., 2012), comparative studies (PBD vs. ADHD) tend to show no significant differences between either group on executive functions such as response inhibition (Rucklidge, 2006; Passarotti et al., 2010c), working memory (McCarthy et al., 2004; Passarotti et al., 2010a, 2010b), and cognitive flexibility (Rucklidge, 2006; Udal et al., 2013). These findings contradict previous researches that had relied on independent studies of both disorders instead of direct comparative studies (Walshaw et al., 2010). Similarly, studies geared at investigating verbal memory differences point out that deficits identified in PBD adolescents resemble those encountered in ADHD youth (Rucklidge, 2006; Udal et al., 2012). Furthermore, researches on social cognition have obtained mixed results as ascertained by the DANVA (Guyer et al., 2007; Seymour et al., 2013). Likewise, comparative studies focused on processing speed have revealed mixed results. Some studies have shown greater impairment either in PBD (Mattis et al., 2011) or in ADHD youth (Rucklidge, 2006). Other studies have obtained no significant differences between the disorders (McCarthy et al., 2004; Passarotti et al., 2010a; Udal et al., 2013). 3.4.2. PBD vs. SMD As SMD (or disruptive mood dysregulation disorder, DMDD) has already obtained nosological recognition in DSM-V (APA, 2013), recent efforts have being aimed at delineating neuropsychological differences relative to PBD (Leibenluft, 2011). First, comparative studies have not shown significant differences between the disorders on social cognition (Guyer et al., 2007; Rich et al., 2008; Deveney et al., 2012a, 2012b; Kim et al., 2013). Second, one study found greater cognitive flexibility impairment among SMD youth than PBD adolescents as measured by the reversal learning task (Adleman et al., 2011), whereas another study showed no differences between the groups as assessed with the decision making task (Rau et al., 2008). Third, SMD youth exhibit reduced selective attention modulated by emotional stimuli as assessed with the emotional interrupt task (Rich et al., 2010). 3.5. Course of neuropsychological impairments in PBD The following section of our review aims to establish the course of neuropsychological impairments in PBD, both the onset and the evolution across adolescence. 3.5.1. Onset of neurocognitive impairments among youth with PBD Studies in adolescents at high-risk (HR) for PBD have comprised youth without a mood disorder and at least one parent and/ or sibling diagnosed as BD (Hauser and Correll, 2013). Within this approach, neuropsychological researches have focused mainly on delineating potential endophenotypes for PBD (Arts et al., 2008; Balanzá et al., 2008; Bora et al., 2009). However, these types of studies can also provide further evidence on the course of neuropsychological impairment, clarifying whether these deficits appear before or during the onset of the illness. Regarding verbal memory, one study found better recall of negative words among HR PBD children than HC youth as assessed with a self-referent encoding task (Gotlib et al., 2005). Similarly, other researches assessing visual-spatial memory showed greater deficit among HR PBD adolescents compared to HC peers (Klimes-Dougan et al., 2006; Doyle et al., 2009). With respect to executive functions results are mixed. On the one hand, comparative studies between HR PBD vs. HC subjects highlight worse performance in the former group (Klimes-Dougan et al., 2006; Doyle et al., 2009; Singh et al., 2009; Roberts et al., 2013). On the other hand, those studies that

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include a third group of PBD youth have found more impaired executive functions in this clinical group as measured by the WCST and the color-word Stroop task (Doyle et al., 2009; Karakurt et al., 2013). Concerning social cognition, one comparative study between HR PBD vs. HC youth demonstrated greater social cognition impairments in the former group as ascertained by the social responsiveness scale (SRS) (Whitney et al., 2013). In addition, those inquiries that included a PBD group did not find any difference between PBD and HR PBD adolescents as assessed with the DANVA (Brotman et al., 2008a, 2008b) and the emotional expression multimorph task (Brotman et al., 2008a, 2008b). 3.5.2. Evolution of neurocognitive impairments across adolescence With regard to the trajectory of neurocognitive impairments across adolescence, there are few follow-up studies targeting this issue. Concerning verbal memory, one study of medicated PBD youth found that negative memory bias was stable over a 1 year follow-up (Whitney et al., 2012). Similarly, another prospective study showed that medicated PBD adolescents showed stable deficits on executive functions, verbal memory and visual-spatial memory over a 3 years follow-up (Pavuluri et al., 2009). 3.6. Treatment of neuropsychological impairments in PBD As a novel research area, our last objective was to summarize tests for potential pro-cognitive medications for PBD, including findings either from open trials (OT) or from randomized controlled trials (RCT). First, no significant interactions of group (PBD vs. HC) by testing time were found on response inhibition after 6 weeks follow-up of either naturalistic treatment (Diler et al., 2013a, 2013b) or risperidone vs. divalproex treatment (Pavuluri et al., 2012). A 14 weeks follow-up of treatment with secondgeneration antipsychotics followed by lamotrigine monotherapy (200 mg/day) yielded similar results (Pavuluri et al., 2011). In an additional OT, a 24-week aripiprazole treatment showed significant improvements in perseverative errors in the WCST among PBD youth (Wang et al., 2012). With regard to working memory, findings are not conclusive, depending on the neuropsychological tests employed. On the one hand, a 14 weeks follow-up treatment with second-generation antipsychotics followed by lamotrigine monotherapy (200 mg/day) found no significant interactions of group by testing time as measured by the affective two-back task (Passarotti et al., 2011). On the other hand, another clinical trial with same follow-up period and treatment showed that PBD adolescents improved significantly on working memory as assessed with the digit span (Pavuluri et al., 2010a, 2010b, 2010c). Concerning processing speed, results have not shown significant interactions of group by testing time after 6-weeks follow-up of either naturalistic treatment (Wegbreit et al., 2011) or risperidone vs. divalproex treatment (Pavuluri et al., 2011). Identical findings have been obtained after 14 weeks follow-up of treatment with second-generation antipsychotics followed by lamotrigine monotherapy (200 mg/day) (Pavuluri et al., 2010a, 2010b, 2010c). It is worth noting that a majority of results described above have been evidenced regardless of symptom severity at post-treatment (Pavuluri et al., 2010a, 2010b, 2010c, 2011, 2012).

4. Discussion and conclusions 4.1. Summary This systematic review has intended to display the main empirical findings and research about neurocognitive impairments among PBD youth. Particularly, we sought to elucidate 6 themes:

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(i) Which neurocognitive domains are impaired? (ii) Which modulating variables affect findings on these neurocognitive impairments? (iii) Which clinical correlates are related to these neurocognitive impairments? (iv) How specific are these neurocognitive impairments compared to those encountered in other childhood mental disorders? (v) Which is the evolution of these neurocognitive impairments? (vi) What interventions have been proven effective on treating these neurocognitive impairments? First, widespread evidence of impairments in verbal/visual-spatial memory, processing speed, working memory and social cognition have been obtained from PBD samples. Second, greater verbal memory impairments are systematically identified in those youth with higher depressive symptoms, history of psychotic symptoms, PBD type I (vs. type II), and ADHD comorbidity. In addition, greater deficits in processing speed are usually encountered in those adolescents with more severe manic symptoms. Furthermore, social cognition impairments are more severe in PBD type I (vs. type II). Conversely, neurocognitive impairments do not appear to be determined by stimulus valence or medication status. Third, both working memory and processing speed deficits imply changes in DLPFC and VLPFC activity. Likewise, social cognition deficits tend to be associated with psychosocial impairments. Fourth, neurocognitive impairments on these domains are consistently similar to those encountered in ADHD as well as SMD youth. Fifth, both social cognition and verbal/visual-spatial memory impairments seem to appear before the onset of PBD. Moreover, verbal/visual-spatial memory deficits tend to maintain stable at mid-term (up to 3 years follow-up). Sixth, to date no psychopharmacological treatment has proved its effectiveness in diminishing these neurocognitive impairments. 4.2. Limitations and directions for future research First, studies focused on verbal fluency are neglected in PBD youth, precluding sound conclusions throughout all executive function domains. Thus, research aimed at delineating potential deficits on verbal fluency is warranted. Second, there is a lack of research comparing PBD and childhood schizophrenia (Nieto and Castellanos, 2011). Accordingly, further studies should establish whether these childhood disorders differ on neurocognitive domains (Arango et al., 2013). Similarly, differences in neurocognitive profiles between PBD and SMD/ADHD remain altogether unclear. The lack of differences raise some questions about diagnostic boundaries between these mental disorders, particularly among pre-puberal patients suffering from unspecified emotional disturbances, somehow classified as PBD-NOS. We postulate that this potential methodological flaw (false-positive diagnosis) can hinder possibilities of getting between-group differences. Thus, the diagnosis of PBD spectrum must be improved using standardized interviews with multiple reporters (Weintraub et al., 2014). Third, longitudinal studies following PBD into adulthood are still lacking (Mora et al., 2013). Therefore, more prolonged followup research must be encouraged in order to verify neurocognitive impairments not limited to childhood or adulthood (Mur et al., 2008; Braw et al., 2013). Fourth, with respect to neurobiological correlates, neuroimaging studies should be undertaken (James et al., 2011). Moreover, ongoing fMRI studies must be advocated in order to provide concurrent validity for neuropsychological test findings. Besides, the role of both DLPFC and VLPFC on working memory and processing speed deficits should be clarified. We hypothesized that working memory tasks require greater cognitive control resources within PBD subjects because of a reduced processing speed ability. Hence, this compensatory mechanism may lead to higher activation of some PFC areas (Hillary et al., 2006). Fifth, unlike adult counterparts, cognitive remediation therapy for PBD has not yet been tested (Bowie et al., 2013;

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Demant et al., 2013; Torrent et al., 2013a, 2013b). Thus, efforts should not only be focused on pro-cognitive medications, but should advance neurocognitive therapy toward an integrative approach. Sixth, there is also a lack of comparative studies between PBD and ABD, which could provide conclusive evidence regarding the extent to which early-onset BD may or may not constitute a more severe manifestation of the illness based on neurocognitive findings (Kyte et al., 2006; Cahill et al., 2007; Joseph et al., 2008; Cahill et al., 2009; Horn et al., 2011). Of particular interest, these forthcoming comparative studies should elucidate whether PBD subjects display fewer executive function deficits than ABD patients as suggested by independent findings (Bellivier, 2012). Finally, next studies must provide accurate data from type and percentage of PBD subjects included as some previous research have pointed out neurocognitive differences depending on this variable (PBD I vs. PBD II). Role of funding source None.

Conflict of interest None.

Acknowledgements None.

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