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Differentiating Between Comorbidityand Symptom Overlap in ADHD and EarlyOnset Bipolar DisorderAnne H. Udala, Jens Egelandbc, Bjørg Øygardend, Ulrik F. Maltef, HansLövdahlae, Are H. Prippg & Berit Groholtf

a Department of Mental Health, Sörlandet Hospital, Arendal, Norwayb Department of Research, Vestfold Mental Health Care Trust,Tönsberg, Norwayc Institute of Psychology, University of Oslo, Oslo, Norwayd Department of Rehabilitation, Sörlandet Hospital, Arendal, Norwaye Department of Neuropsychiatry and Psychosomatic Medicine, OsloUniversity Hospital–Rikshospitalet, Oslo, Norwayf Institute of Clinical Medicine, University of Oslo, Oslo, Norwayg Biostatistics and Epidemiology Unit, Oslo University Hospital, Oslo,NorwayPublished online: 22 May 2014.

To cite this article: Anne H. Udal, Jens Egeland, Bjørg Øygarden, Ulrik F. Malt, Hans Lövdahl,Are H. Pripp & Berit Groholt (2014) Differentiating Between Comorbidity and Symptom Overlapin ADHD and Early Onset Bipolar Disorder, Developmental Neuropsychology, 39:4, 249-261, DOI:10.1080/87565641.2014.886692

To link to this article: http://dx.doi.org/10.1080/87565641.2014.886692

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DEVELOPMENTAL NEUROPSYCHOLOGY, 39(4), 249–261Copyright © 2014 Taylor & Francis Group, LLCISSN: 8756-5641 print / 1532-6942 onlineDOI: 10.1080/87565641.2014.886692

Differentiating Between Comorbidity and SymptomOverlap in ADHD and Early Onset Bipolar Disorder

Anne H. UdalDepartment of Mental Health, Sörlandet Hospital, Arendal, Norway

Jens EgelandDepartment of Research, Vestfold Mental Health Care Trust, Tönsberg, Norway,

and Institute of Psychology, University of Oslo, Oslo, Norway

Bjørg ØygardenDepartment of Rehabilitation, Sörlandet Hospital, Arendal, Norway

Ulrik F. MaltDepartment of Neuropsychiatry and Psychosomatic Medicine, Oslo University

Hospital–Rikshospitalet, Oslo, Norway, andInstitute of Clinical Medicine, University of Oslo, Oslo, Norway

Hans LövdahlDepartment of Mental Health, Sörlandet Hospital, Arendal, Norway, and

Department of Neuropsychiatry and Psychosomatic Medicine, Oslo UniversityHospital–Rikshospitalet, Oslo, Norway

Are H. PrippBiostatistics and Epidemiology Unit, Oslo University Hospital, Oslo, Norway

Berit GroholtInstitute of Clinical Medicine, University of Oslo, Oslo, Norway

Reported rates of comorbidity between early onset bipolar disorder (BD) and attention deficithyperactivity disorder (ADHD) have a wide range, perhaps due to developmental issues anddifferences in interpretation of overlapping symptoms. We compared questionnaire-based andneuropsychological measures of inattention and impulsivity/hyperactivity, in children/adolescentswith ADHD combined subtype (ADHD-C; n26), concurrent ADHD-C and BD (n15), BD (n25) with

Correspondence should be addressed to Anne H. Udal, M.D., Ph.D., Department of Mental Health, Sörlandet Hospital,Box 783 Stoa, N-4809 Arendal, Norway. E-mail: anne.udal@sshf.no

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Controls (n69). Sub-analyses were performed on BD with and without inattention symptoms. The twoADHD-C groups displayed neuropsychological impairments that were not found in the BD group inspite of subjective and questionnaire-rated inattention. The findings caution against over-diagnosis ofADHD in BD.

Dramatically variable rates of concurrent attention deficit hyperactivity disorder (ADHD) andearly onset bipolar disorder (BD) have been reported in the literature, with comorbidities rang-ing from 0% to 98% (Youngstrom, Arnold, & Frazier, 2010). ADHD and the manic episodes ofBD overlap regarding symptoms of distractibility, restlessness, talkativeness, and loss of socialinhibition. Diagnostic criteria must be applied in a developmentally sensitive way, and countingcommon symptoms towards more than one diagnosis may create false comorbidity. Subjectiveinattention is a nonspecific symptom of child psychiatric disorders and should be carefully inter-preted as comorbid ADHD in the context of BD. On the other hand, the lack of formal recognitionof mood symptoms in ADHD may lead to misdiagnosis of ADHD as the broader spectrum BD,especially with the diagnostic construct “Juvenile BD” including chronic irritability rather thandistinct episodes (Towbin, Axelson, Leibenluft, & Birmaher, 2013).

The symptom overlap between ADHD and BD illustrates the validity problems stemming fromthe descriptive approach in psychiatry. Common pathophysiology have been suggested (Hegerl,Himmerich, Engmann, & Hensch, 2010), but functional magnetic resonance imaging (fMRI)studies have shown similar performance associated with different brain activation patterns inthe ADHD and BD (Passarotti, Sweeney, & Pavuluri, 2010). Also longitudinal-, family-, andtreatment studies studies suggests that the diagnostic categories of BD and ADHD are unre-lated (Duffy, 2012; Kent & Craddock, 2003; Skirrow, Hosang, Farmer, & Asherson, 2012).Treatment studies stresses the importance of accurate delineation of ADHD and BD, includ-ing negative effects of receiving the incorrect medication (Atmaca, Ozler, Topuz, & Goldstein,2009; Mosholder, Gelperin, Hammad, Phelan, & Johann-Liang, 2009), and functional impairmentassociated with delay of appropriate treatment (Leboyer & Kupfer, 2010; Shaw et al., 2012).

The common behavioral manifestations of impulsivity in ADHD and BD may originate fromrelated, but different, neural mechanisms. Prefrontal brain regions sub-serving affect regulationand cognitive control undergo substantial development during childhood and adolescence, anddevelopmental disturbances in prefrontal white matter circuits are probably implicated in bothADHD and BD, though widespread across multiple white matter tracts in ADHD (Marsh, Gerber,& Peterson, 2008; Pavuluri et al., 2009).

There is a discrepancy between the expanding knowledge from brain imaging, and the clin-ical based procedures of ADHD and BD diagnosis. ADHD-specific questionnaires are showndiscriminate ADHD from mixed clinical samples, but their ability to differentiate ADHD fromBD is less compelling (Rucklidge, 2006; Szomlaiski et al., 2009). There are no definitiveneuropsychological tests neither for ADHD or BD. However, high reaction time variability isa robust phenomenon in ADHD (Epstein et al., 2011) but not in pediatric BD (Rucklidge, 2006),whereas memory appears more impaired in BD than in ADHD (Torralva et al., 2010)—despiteforgetfulness being among the criteria of ADHD-C.

In this study we explore questionnaire-based and neuropsychological measures of attentiondeficit, impulsivity and hyperactivity in children and adolescent fulfilling the DSM-IV criteria(American Psychiatric Association, 2000) of ADHD-C with and without comorbid BD, and

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ADHD VS. BIPOLAR: COMORBIDITY OR SYMPTOM OVERLAP 251

of BD (with and without inattention symptoms). We hypothesized that: (1) ADHD symptomquestionnaire scores are elevated in both ADHD-C and BD. (2) ADHD-C, with and without BD,have neuropsychological attentional impairments that are not found in the BD only group in spiteof subjective attention deficit.

METHODS

Participants

Inclusion diagnoses (1) ADHD combined type (ADHD-C; DSM-IV 314). We included ADHD-C only because data supporting the validity of the other subtypes of ADHD is scarce (Woo &Rey, 2005). (2) BD, defined as BD-1 (DSM-IV 296-7: at least one manic or mixed episode);BD-2 (DSM-IV 296.89 both hypomanic and major depressive episodes), and BD-NOS (DSM-IV 296.80 manic/mixed/hypomanic episodes that are too short to meet the DSM-IV durationcriterion). BD-NOS was defined as “Elated mood plus a minimum of 3 associated DSM-I Vmanic symptoms, along with a change in the level of functioning, duration of a minimum of4 hours a day, at least 4 cumulative lifetime days. . . .” This definition of BD-NOS appears to beon a diagnostic continuum with BD-1 and BD-2 in youths (Towbin et al., 2013). Sub-analyseswere performed on BD with and without more than six inattention symptoms, hereafter namedthe “BD-inattentive” and the “BD-rest” subgroups, respectively. (3) Concurrent ADHD-C andBD (ADHD-C+BD).

Exclusion criteria were mental retardation according to DSM-IV and sequel to brain injury.Clinical diagnoses were obtained from the Schedule for Affective Disorders and

Schizophrenia for School-Age Children–Present and Lifetime Version (KSADS–PL) (Kaufmanet al., 1997). Participants and caregivers were interviewed separately by an experienced psychia-trist. KSADS–PL is a semi-structured clinical interview including a broad anamnesis (surveyingdevelopmental history, lifetime trauma, heredity, academic and social function), and a diag-nostic interview where probes and objective criteria are provided to rate individual symptoms.Excellent-to-good validity and reliability are reported (Kaufman et al., 1997). The taped inter-views, supplied with a short medical history, were validated by a child psychiatrist. Inter-rateragreement (kappa) was 1 on BD and 0.87 on ADHD-C. Further information was obtained fromschools, through a teacher’s oral and written evaluation of the student. The final diagnosis wasbased on the KSADS–PL interview and all available clinical information, in discussion with themain researcher and an experienced child psychiatrist.

Lifetime comorbidities and symptoms were also recorded from the KSADS–PL.All clinical participants completed an IQ-test: the Wechsler Intelligence Scale for Children

(Wechsler, 1991) or Adults (from age 16) (Wechsler, 1997).Clinical participants were recruited from a general out-patient child and adolescent psychiatry

unit in a rural and socioeconomic homogenous district of Norway, over a period of 5 years.Whenever BD was suspected, the patient was evaluated for further assessment (n249); of these,55 participants were included in the study (25 BD, 15 ADHD-C+BD, 15 ADHD-C). In addition,11 remitted patients with ADHD-C only were selected to optimize the age and gender match. Theremaining assessed patients did not meet the inclusion criteria (n182), met the exclusion criteria(n5), or did not wish to participate (n6).

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Controls were recruited from three secondary schools and one junior high school. TheControls had no known learning problem, psychiatric disorders, medication, organic brain dis-ease, or history of head injury. In Controls, IQ was estimated from the scaled scores of theWechsler Intelligence Scale’s subtests Picture Completion and Similarities. The correlationsbetween Picture Completion and Perceptual Organization was r = 0.78 (p < .001) and betweenSimilarities and Verbal Comprehension r = 0.85 (p < .001). This is so high that estimated IQ(IQe) was considered to be a reliable short form of General Ability Index.

Ethics. The study was conducted in accordance with the Helsinki DeclarationIncluded sample. One-hundred and thirty-five participants between 6 and 18 years were

included in the study; (1) ADHD-C: n26, mean years = 12.7 (SD = 3.7), mean IQe = 97.8(SD = 12.3), 12 females. (2) BD n25 (10 BD-1, 7 BD-2, 8 BD-NOS), mean years = 13.7 (SD =3.7), mean IQe = 99.6 (SD = 8.9) 14 females. The BD-inattentive subgroup (n10) was older thanthe other groups, mean age = 15.8 (SD=5.7), included 8 females and the most participants withBD-1 (n6). (3) ADHD-C+BD: n15 (2 BD-1, 3 BD-2, 10 BD-NOS), mean years = 13.5 (SD =3.5), mean IQe = 101.3 (SD = 11.3), 7 females. (4) Controls: n69, mean years =12.3 (SD = 1.9),mean IQe = 99.9 (SD =104), 38 females. There were no significant differences in age, genderand IQe between the Controls and the clinical groups. All participants were Caucasian.

Comorbidity and state. Anxiety disorders (generalized anxiety, panic disorder, separationanxiety, social phobia, other phobia, obsessive-compulsive disorder) were revealed in 6 ADHD-C participants, 10 ADHD-C+BD participants, and 14 BD participants (5 BD-inattentive,9 BD-rest). PTSD was revealed in 3 ADHD-C participants, 5 ADHD-C+BD participants, and3 BD participants (all BD-rest). Behavior problems (conduct disorders, tempers tantrums) werereported in 14 ADHD-C participants, 12 ADHD-C+BD participants, and 17 BD participants(5 BD-inattentive, 12 BD-rest). Lifetime psychotic symptoms were reported in 4 ADHD-C+BDparticipants and 9 BD participants (6 BD-inattentive, 3 BD-rest). The ADHD-C group includedsignificantly less participants with anxiety disorders and lifetime psychotic symptoms, other-wise there were no significant differences between the groups. The neuropsychologist reportedmood symptoms according to the following “scale”: (1) No mood symptoms, (2) A few moodsymptoms, and (3) Considerable mood symptoms. “Considerable” hypomanic symptoms dur-ing assessment were reported in 2 participants (both ADHD-C+BD), otherwise only “a fewmood symptoms” were reported: Hypomanic symptoms were reported in 3 BD subjects (all BD-inattentive). “A few depressive symptoms” were reported in 1 ADHD-C participant and 5 BDparticipants (2 BD-inattentive, 3 BD-rest).

Because increased cortisol may be associated with variability in response time in ADHD (Lee,Shin, & Stein, 2010), serum cortisol was measured the morning of the test day in the clini-cal sample. S-cortisol above normal reference range was revealed in 2 ADHD-C participants,1 ADHD-C+BD participant, and 6 BD participants (2 BD-inattentive. 4 BD-rest). However, meanserum cortisol was not raised in any group and there were no significant differences between thegroups.

Medication was delayed until after the diagnostic and neuropsychological assessments wereaccomplished, if possible. Only 5 BD patients were diagnosed and treated with mood-stabilizerbefore they were referred to the study (lamotrigine n2, lithium n1, valproate n1, valproate +aripiprazole n1). Medication was continued in these patients, but not taken on the morning beforethe neuropsychological assessment. Other medication was discontinued (methylphenidate n5) fora minimum of 5 times the elimination half-life before testing.

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ADHD VS. BIPOLAR: COMORBIDITY OR SYMPTOM OVERLAP 253

Assessment Procedure

ADHD-symptom questionnaires (rated by parents and teachers, respectively). TheADHD rating scale–IV (Barkley, 1990; DuPaul, 1998) consists of checklists with 9 attentiondeficit and 9 hyperactivity/impulsivity items graded from 0 to 3 and linked to the DSM-IV criteriafor ADHD-C. Adequate psychometric properties for the screening and assessment of ADHD arereported (Barkley, 1990; DuPaul, 1998; Szomlaiski et al., 2009), but these studies do not explorethe diagnostic validity for ADHD versus BD.

The Achenbach scales (Achenbach, 2010) include 120 behavioral items rated on a three-stepscale from 0 to 2. These are grouped in problem areas and converted to T-scores relative to popu-lation norms. Adequate diagnostic performance of the Attention Problems scale for the screeningof ADHD is reported (Lampert, Polanczyk, Tramontina, Mardini, & Rohde, 2004).

Neuropsychological assessments. The Conner’s Continuous Performance Test-2 (CPT)(Conners, 2000). Task: To indicate when a letter other than X appears on a computer screen.Letters appear at unequal intervals presented in 6 blocks, facilitating estimates as a functionof interstimulus interval and also performance over time. Measures: Based on a factor analy-sis, 6 standard scores were operationalized as 4 factors: (1) Focused attention: omissions andreaction time variability (RTSE) (2) Vigilance: More RTSE when longer interstimulus inter-vals (RTSE ISI), (3) Sustained attention: More RTSE as the test progresses (RTSE BC), and(4) Hyperactivity/ Impulsivity: commissions and fast RT.

The Children’s Auditory-Verbal Learning Test-2 (Talley, 1993). Task: An orally presented listword list is presented over several learning trials, followed by delayed recognition test. Measure:Word correctly recognized.

Statistical Analyses

Sample size and power calculations were performed using the package “pwr” from the R projectfor statistical computing (www.r-project.org). All other statistical analyses were performed usingSPSS software for Windows, v. 16 (SPSS Inc., Chicago, II). Two-sided alpha levels of p <

.05 were considered statistically significant. Pair-wise post-hoc analyses were performed withsequential Bonferroni adjustments . Because the risk of making Type II errors increases dra-matically in smaller samples and as the number of regressors increases, we report significantdifferences both before and after Sequential Bonferroni adjustment. Because the distribution ofsome of the dependent variables was skewed, differences between the study groups were analyzedusing generalized linear models that allow models to be fitted to data that follow probability dis-tributions other than a normal distribution, have a lesser requirement for equality or constancy ofvariances compared with traditional linear models, and allows covariate analyses. Age and gen-der, as well as estimated IQ, were entered as covariates in the main analyses. Based on estimatedmarginal means and corresponding standard errors from the generalized linear models, effect sizewas expressed as Cohen’s d = � estimated marginal mean/ pooled standard deviation (d = 0.2:small-, d = 0.5 medium-, d = 0.8: large effect size) (Cohen, 1988).

Because state and medication were illness-specific, the effect of these were not entered ascovariates in the main analyses, but added as covariates in the exploratory analyses.

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RESULTS

Figure 1 illustrates the scores on ADHD-symptom questionnaires and Figure 2 illustrates scoreson neuropsychological tests (effect sizes as compared to Controls; i.e., z-scores). The p-valuesmarked with ∗ were significant also after Bonferroni adjustment. The overall pattern was that allclinical groups demonstrated high scores on ADHD symptom questionnaires, whereas only theADHD-C and ADHD-C+BD groups were impaired on tests of attention deficit. In the BD onlygroup, there were no significant differences between those with attention deficit symptoms andthose without (the BD-inattentive and BD-rest subgroups).

ADHD-Symptom Questionnaires

All clinical groups demonstrated significantly increased parent- and teacher rated ADHD symp-toms as compared to Controls, on all seven rating scales (all p-values below .001, all z-valuesabove 1.4).

FIGURE 1 ADHD symptom questionnaires. Note. Effect sizes as com-pared to Controls (z-scores). Based on generalized linear models adjustedfor age, gender, and IQ. BD = Bipolar Disorder. ∗p < .05 after SequentialBonferroni adjustment. H = Home; S = School; ADHDrs = ADHD rat-ing scale-IV; CBCL = Child Behavior Check List, Attention Problems;TRF = Teacher Report form, Attention Problems.

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ADHD VS. BIPOLAR: COMORBIDITY OR SYMPTOM OVERLAP 255

FIGURE 2 Neuropsychological measures of ADHD symptoms. Note.Effect sizes as compared to Controls (z-scores). Based on generalized lin-ear models adjusted for age, gender, and IQ. BD = Bipolar Disorder. ∗p <

.05 after Sequential Bonferroni adjustment. CPT = Conners’ ContinousPerformance test; CAVLT = Children’s Verbal Test-II; RT = Reactiontime; SE = Standard Error; ISI = Interstimulus interval; BC = Blockchange.

Neuropsychological Assessments

Focused attention (CPT omissions and reaction time variability; RTSE). The ADHD-C and ADHD-C+BD groups were impaired as compared to Controls on both omissions (p =.029, z = 0.52 and p < .001∗, z = 1.33) and RTSE (p < .001∗, z = 0.81 and p < .001∗, z =1.04).

Vigilance (CPT more reaction time variability when longer interstimulus interval; RTSEISI). The ADHD-C and ADHD-C+BD groups were equally impaired as compared to Controlson the vigilance test (z = 0.51 for both groups), but below significant level only for the ADHD-Cgroup (p = .044; not surviving Bonferroni adjustment).

Sustained attention (CPT more reaction time variability as the test progresses; RTSEBC). Only the ADHD-C+BD group reached significant levels of impairment as compared toControls (p = .009∗, z = 0.98).

Hyperactivity (CPT fast RT). No group showed faster reaction time than Controls.Actually, the ADHD-C group demonstrated significantly slower RT than Controls (p = .001∗,z = –0.75).

Impulsivity (CPT commissions). No group demonstrated more commissions thanControls.

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Memory (CAVLT word recognized). This was the only test where the BD and ADHD-C+BD groups were significantly impaired as compared to Controls (p < .001∗; z = –1.31 andp = .010∗; effect size = –0.63), whereas the ADHD-C group was not (p = .224; z = –0.28).

BD With and Without Attention Deficit Symptoms

Subanalyses were performed between the BD group with more than six attention deficit symp-toms (the BD-inattentive subgroup, n10) and the other clinical groups, including the BDparticipants with less inattentive symptoms (the BD-rest subgroup, n15). There were no signif-icant differences between the BD-inattentive and BD-rest subgroups on any neuropsychologicalmeasure (p-values ranging from .419 to .898 on the CPT tests before Bonferrroni adjustment, andonly small effect sizes). On the memory test (CAVLT recognition) there was a large effect sizedifference between the BD subgroups (effect size = 0.86; p = .127).

The BD-inattentive subgroup performed significantly better than the ADHD-C+BD group onthe two CPT measures of Focused attention (omissions: p = .001∗, effect size = 1.36 and RTSE:p = .037, effect size = 0.88); and also on CPT commissions (p = .021, effect size = 0.96).

Exploratory analyses revealed a small effect of mood symptoms on impulsivity (CPT com-missions (F(1,50) = 4.0, p = .050) and a larger effect of lifetime psychosis on memory (CAVLTrecognition: F(1,51) = 7,4, p = .009) Otherwise there were no significant effects of moodsymptoms, medication, cortisol, or comorbidity on the statistical models.

Removing BD–NOS from the sample did not alter the performance of the BD group.

DISCUSSION

Although teacher and parent rated ADHD-symptom questionnaire scores were significantlyelevated in all clinical groups, only the ADHD-C and ADHD-C+BD groups demonstratedimpairments on the neuropsychological tests of attention deficit. Thus, our hypotheses werelargely confirmed: (1) ADHD-symptom questionnaire scores are elevated in both ADHD-C andBD, (2) The ADHD-C and ADHD-C+BD groups have neuropsychological attention impairmentsthat are not found in the BD only group, despite subjective inattention. This may indicate thatattention deficit symptoms in the context of BD represent symptom overlap rather than comorbidADHD, whereas ADHD-C in the context of BD may be similar to ADHD-C that occurs alone.The findings are in line with the expanding knowledge from brain imaging: The common behav-ioral manifestation of ADHD and BD appears to originate from different neural mechanisms:Inattention symptoms in ADHD appears related to reaction time variability (Wahlstedt, 2009),whereas inattention symptoms in pediatric BD may be related to negative emotions (Schenkel,Passarotti, Sweeney, & Pavuluri, 2012). Impulsivity in ADHD is predominantly cognitivelydriven and stems from dorsal frontostriatal dysfunction, whereas in pediatric BD impulsivityis predominantly emotionally driven and stems from ventral frontostriatal circuitry dysfunction(Passarotti & Pavuluri, 2011).

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ADHD-Symptom Questionnaires

The main finding was that all clinical groups consistently differed from Controls on all sevenrating scale measures related to the core symptoms of ADHD. This cautions against theover-diagnosis of ADHD in patients with BD. High rates of questionnaire-based ratings of ADHDsymptoms in children and adolescents with BD without comorbid ADHD, has also been reportedby others (Robertson, Kutcher, & Lagace, 2003; Rucklidge, 2006). This is not surprising, giventhe overlapping of symptoms of distractibility, impulsivity and hyperactivity between ADHD-Cand BD. Symptom checklists do not assess the course of the symptoms, which is necessary todistinguish the episodic presentation of BD from the chronicity of ADHD. Thus, when makinga differential diagnosis between ADHD and BD, one should not rely on cross-sectional symp-tom description, but include a semi-structured interview surveying heredity, lifetime symptoms,developmental history and environmental stress, as well as neurological assessments (Carlson &Meyer, 2006; Udal et al., 2009).

Neuropsychological Assessments

Whereas the rating scales did not different ADHD-C from BD, the neuropsychological testsclearly did. The main finding was that the ADHD-C and ADHD-C+BD groups differed fromControls on CPT’s attention tests, whereas the BD group performed consistently normal on CPTwith no significant differences between those with inattention symptoms and those without (theBD-inattentive and BD-rest subgroups).

ADHD-C With and Without Concurrent BD

Both the ADHD-C and the ADHD-C+BD groups were impaired on the measures of Focusedattention. The most pronounced impairment in both groups was on RT variability (RTSE), consis-tent with the reports of RT variability being the most frequent cognitive impairment in ADHD-Cand also related to and susceptive genes for ADHD-C (Epstein et al., 2011; Kebir & Joober,2011). This may indicate that ADHD-C in the context of BD is similar to ADHD-C that occursalone, and also support the suggestion that comorbidity with ADHD may account for many ofthe neuropsychological deficits reported in early onset BD. This may also be the case whenneuropsychological attention deficit is reported in studies of adults with BD, as these seldomaccount for comorbid ADHD.

However, an unspecific pattern of impaired focused attention is reported in psychiatric dis-orders other than ADHD (Egeland & Kovalik-Gran, 2010). Both ADHD-C groups were alsomoderately impaired as compared to Controls (z = 0.51) on the vigilance test (RTSE ISI), indi-cating a particular problem with upholding attention when stimulus intervals increase. This isthought to be specific to ADHD-C, and often interpreted as a deficit in arousal regulation or tem-poral processing/timing (Kuntsi & Klein, 2012). However, reduced connectivity in dopamine richcircuits connecting prefrontal cortex, striatum, parietal cortex, and cerebellum is important in theneurobiology of ADHD and may affect both arousal and timing processes (Curatolo, D’Agati,& Moavero, 2010). Thus, boosting the dopamine system by energetic or motivational factorsmay modify RT variability in ADHD (Kuntsi, Wood, Van Der Meere, & Asherson, 2009). This

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explain why not all ADHD-C participants exhibited increased RT variability (about 40%, in linewith other studies (Schoechlin & Engel, 2005)).

Despite similar impairments within the domains of Focused attention and Vigilance, therewere also some differences between the two ADHD-C groups. The ADHD-C only group demon-strated slow RT, whereas the ADHD-C+BD group had more problems within the domains ofsustained attention (RTSE BC) and impulsivity (commissions). This is not necessarily indica-tive of ADHD-C in BD being different from ADHD-C that occurs alone, because in our study thecomorbid group comprised the two BD participants with the most manic symptoms. Mania causesa risk-taking and impatient response style (Passarotti, Fitzgerald, Sweeney, & Pavuluri, 2013) thatmay modulate the ADHD-C related slow RT, and lead to more commissions and impaired abilityto sustain attention.

BD With and Without Attention Deficit Symptoms

Significant memory impairment was evident in the BD and ADHD-C+BD groups, but not inthe ADHD-C group. This support the diagnostic validity of our BD participants, as verbal mem-ory deficit is the most consistent neurocognitive finding in early onset BD (Horn, Roessner, &Holtmann, 2011). There was non-significantly (although large effect sized) more memory deficitin the BD-inattentive than in the BD-rest subgroup. This difference was driven by the more BD-1 subjects with lifetime psychosis in the BD-inattentive subgroup (Udal, Oygarden, Egeland,Malt, & Groholt, 2012).

Our findings of normal performance on CPT despite subjective inattention symptoms are inline with most of the few studies of early onset BD without comorbid ADHD (Robertson et al.,2003; Rucklidge, 2006). In our study, those BD participants with considerable subjective attentiondeficit (the BD-inattentive subgroup) actually performed significantly better than the ADHD-Cand ADHD-C+BD groups on the Focused attention tests (omissions and RTSE). That is, thetests where the ADHD-C and ADHD-C+BD groups were the most impaired. This gives furthersupport to the assumption that attention problems in BD do not necessarily represent the comorbidinattentive subtype of ADHD. Actually, some studies report more RT variability in the inattentivesubtype of ADHD than in ADHD-C.

The subjectively reported ADHD symptoms in our BD group may be explained by other cog-nitive problems than those revealed by CPT, as we did reveal memory impairment in our BDgroups. Subjective attention deficit in BD may also be state dependent, consistent with the mosthypomanic symptoms in our BD-inattentive subgroup and ADHD-C+BD group, and also smalleffect of mood symptoms on CPT performance. Otherwise we did not detect any significanteffect of state, cortisol level, medication, or comorbidity on CPT performance. This may be dueto small sample, or to the fact that most of our participants were euthymic and very few weremedicated.

However, studies of adult BD do report (mostly moderate) neuropsychological attention deficitin BD also in the euthymic phase (Clark & Goodwin, 2004). This may have several reasons.First, adult studies seldom account for comorbid ADHD. Second, the pathophysiology of BDmay implicate a developmental arrest so that cognitive deficits become more prominent with age.Third, attentional deficits in adults with BD may be related to progression of the illness (Robinson& Ferrier, 2006). Acceleration of cycles, cognitive decline, and incremental volume loss indicate

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a neurodegenerative process, mediated by inflammation, oxidative stress, apoptosis, and changesin neurogenesis (Berk et al., 2013).

Strengths, Limitations, and Further Directions

Strengths of our study were that we did account for IQ, as well as the thoroughly diagnosticevaluation and the fact that most of the BD participants were euthymic and not medicated duringassessment. Neither the ADHD-C participants were medicated. Our findings are neverthelesslimited by a small and convenient sample, developmentally insensitive criteria for BD diagnosis,and the heterogeneity of the BD groups. Despite extensive recruitment, the BD sample size wastoo small to make more homogeneous BD groups possible, probably reflecting that this is a rarecondition in child and adolescent psychiatry. However, removing BD-NOS from the sample didnot alter the performance of the BD group, and our definition of pediatric BD-NOS is reported tobe on a diagnostic continuum with BD-1 and BD-2.

In conclusion, if confirmed in a larger sample, our findings indicate that attention deficit symp-toms in BD may be associated with BD mainly and less with the inattentive subtype of ADHD.Still, future studies should include an inattentive subtype of ADHD-group.

Our findings also highlight the impact of comorbid ADHD on neurocognitive functioning inBD. Such deficits in adult BD may also be an effect of illness-related factors. If attention deficitin BD individuals is associated with repeated mood episodes, this has serious implications for theimportance of early detection and treatment of BD. Longitudinal studies are warranted to clarifyif repeated mood episodes do impact the neuropsychological functioning in BD, and if prompttreatment may be neuroprotective and attenuate the neurostructural and neurocognitive changesthat may emerge with chronicity.

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