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Lifestyle in adult ADHD

Bron, T.I.

2017

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Bron, T. I. (2017). Lifestyle in adult ADHD: From a Picasso point of view.

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OROS-methylphenidate

IǽGEG]SRWTIGMǻGI\IGYXMZI

JYRGXMSRMRKHIǻGMXWMREHYPXW

[MXL&)-)&VERHSQM^IH

TPEGIFSGSRXVSPPIH

GVSWWSZIVWXYH]

Tannetje I. Bron, Denise Bijlenga, A. Marije Boonstra, Minda Breuk, Willem F.H. Pardoen, Aartjan T.F. Beekman, and J.J. Sandra Kooij

Published in: European Neuropsychopharmacology 2014; 24(4):519-528.

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ABSTRACT

&XXIRXMSRHIǻGMXL]TIVEGXMZMX]HMWSVHIV &)-)MWPMROIHXSMQTEMVIHI\IGYXMZI JYRGXMSRMRK *+8LMWMWXLIǻVWXWXYH]XSSFNIGXMZIP]MRZIWXMKEXIXLIIǺIGXWSJ a long-acting methylphenidate on neurocognitive test performance of adults with ADHD. Twenty-two adults with ADHD participated in a 6-weeks study I\EQMRMRKXLIIǺIGXSJSWQSXMGVIPIEWISVEPW]WXIQQIXL]PTLIRMHEXI 474 mph) on continuous performance tests (CPTs; objective measures), and on the self-reported ADHD rating scale (subjective measure) using a randomized, HSYFPIFPMRH TPEGIFSGSRXVSPPIH GVSWWSZIV HIWMKR 474QTL WMKRMǻGERXP] improved reaction time variability (RTV), commission errors (CE) and d-prime )5EWGSQTEVIHXSFEWIPMRI (SLIRƶWH#FYXHMHRSXEǺIGXLMXVIEGXMSR time (HRT) or omission errors (OE). Compared to placebo, OROS-mph only WMKRMǻGERXP] MRǼYIRGIH 78: SR SRI SJ X[S (58W T! 1MRIEV VIKVIWWMSR EREP]WIW WLS[IH TVIHMGXMZI EFMPMX] SJ QSVI FIRIǻGMEP 474QTL IǺIGXW MR ADHD patients with higher EF severity (RTV: ƌ=0.670, t=2.097, p=.042; omission errors (OE): ƌ=-0.098, t=-4.759, p<.001), and with more severe ADHD symptoms (RTV: F=6.363, p=.019; HRT: F=3.914, p=MHIIǺIGXWVEXIW[IVIWYFWXERXMEPP] FYXRSRWMKRMǻGERXP]KVIEXIVJSV474QTLGSQTEVIHXSTPEGIFS  ZW 

p" 474QTL IǺIGXW MRHMGEXIH 78: EW XLI QSWX WIRWMXMZI TEVEQIXIV

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INTRODUCTION

&XXIRXMSRHIǻGMXL]TIVEGXMZMX]HMWSVHIV &)-)MWGLEVEGXIVM^IHF]EGLMPHLSSH onset and lifelong persistence of symptoms of inattention, hyperactivity and/ or impulsivity [78], and is prevalent in 3.4% of adults [11]. ADHD is thought to be caused by dysregulated catecholaminergic neural circuits, which regulate the amounts of dopamine and epinephrine available in the frontal lobe [79]. Minor GLERKIW MR XLI WYTTP] SJ GEXIGLSPEQMRIW LEZI QEVOIH IǺIGXW SR TVIJVSRXEP cortical balance, which mediates the neural networks of executive functions *+ ?A *+W QEREKI ERH GSRXVSP FILEZMSV IWTIGMEPP] MR XLI IǽGMIRG] SJ goal-directed behavior. Individuals with ADHD have impaired neurocognitive JYRGXMSRWMRXLI*+EVIEWSJ WYWXEMRIHEXXIRXMSRIǺSVXJYPGSRXVSPTVSGIWWMRK WTIIHERHǼYIRG][LIRGSQTEVIHXSXLSWI[MXLSYX&)-)?A&PXLSYKL *+ HIǻGMXW EVI LMKLP] LIXIVSKIRISYW MR&)-) SR E KVSYT PIZIP ERH TVIWIRX in only 40% of patients [16, 17], they are heritable [84] and individually stable SZIVXLIGSYVWISJHIZIPSTQIRX?A8LIVIF]RIYVSGSKRMXMZIHIǻGMXWJYVRMWL accurate and objective descriptions of phenotypes for psychiatric disorders [84], which are almost directly linked to behavior in ADHD [86]. The severity of *+HIǻGMXWLEWIZIRFIIRPMROIHXS&)-)WIZIVMX]?A

Stimulant medications such as methylphenidate are the pharmacological treatment of choice for ADHD [61]. In clinical practice among adults, QIXL]PTLIRMHEXI TVITEVEXMSRW [MXL E PSRKEGXMRK VIPIEWI TVSǻPI SWQSXMG release oral system; OROS-mph) are preferred over immediate-release methylphenidate (IR-mph), primarily because of the longer duration of action ?A.VVIWTIGXMZISJXLIX]TISJVIPIEWITVSǻPI&)-)TEXMIRXWLEZIHMǽGYPXMIW IZEPYEXMRKXLIQIXL]PTLIRMHEXIIǽGEG]SR&)-)W]QTXSQWHYVMRKERHEJXIV treatment [89]. Largely depending on subjective patient reports may therefore LMRHIVVIPMEFPIXMXVEXMSRSJQIHMGEXMSRERHUYERXMǻGEXMSRSJGPMRMGEPMQTVSZIQIRX using objective measures is needed.

very low IR-mph doses [95], or investigated a limited range of CPT parameters ?A &W ]IX RIYVSGSKRMXMZI VIWIEVGL WXYH]MRK XLI IǺIGXW SJ PSRKEGXMRK methylphenidate in an adult population with ADHD has not been conducted, RSVLEZIWTIGMǻG(58TEVEQIXIVWFIIRPMROIHXSXLI&)-)IRHSTLIRSX]TI 8LMWWXYH]MWXLIǻVWXXSMRZIWXMKEXIXLIIǽGEG]SJ474QTLSRWTIGMǻG*+ HIǻGMXW EQSRK EHYPXW [MXL &)-) +VSQ .7QTL VIWYPXW ERH WXYHMIW EQSRK GLMPHVIR[MXL&)-)474QTLMWI\TIGXIHXSEQIPMSVEXI*+HIǻGMXWMREHYPXW [MXL&)-)ERHXSWLS[ZEVMEFPIIǽGEG]VIWYPXWJSVWTIGMǻG(58TEVEQIXIVW [20, 91, 94]. Hereby, we aim at (1) extending the current understanding of using WTIGMǻG SFNIGXMZI (58 TEVEQIXIVW EW MRHMGEXSVW SJ XLI RIYVSTW]GLSPSKMGEP underpinnings of the ADHD endophenotype; and (2) evaluating CPTs as an instrument for monitoring OROS-mph titration in adult ADHD patients.

EXPERIMENTAL PROCEDURES

Study design

+MKYVI  TVIWIRXW XLI ǼS[GLEVX SJ XLMW [IIOW VERHSQM^IH HSYFPI FPMRH placebo-controlled, cross-over trial. Simple randomization was applied for medication order as well as for CPT order, without any restrictions for equality of group sizes.

Participants

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Randomized for CPT test order (n=14) Cross-over to OROS-mph (n=12)  Cross-over to placebo (n=12)  Randomized for CPT test order (n=13)

Discontinued treatment (n=2): side effects OROS-mph (n=1), non-compliance treatment (n=1)

Analysed (n=10)



Allocated to placebo first (n=13)

Discontinued treatment (n=1): administrative error

Allocated to OROS-mph first (n=14)

Analysed (n=12)  ŽŽ‘ …ƒ –‹ ‘ ͕ Screening visit (n=27) SCID, informed consent

Randomized for medication order (n=27)  ”‘ ŽŽ ‡ – Randomized to C-CPT – TOVA test order (n=7) Randomized to TOVA – C-CPT test order (n=6) Randomized to C-CPT – TOVA test order (n=8) Randomized to TOVA – C-CPT test order (n=6)

Week 1: Baseline (n=27) – CPTs, ADHD symptoms, side effects

 ŽŽ‘ …ƒ –‹‘  ͖

Week 2: Lead-in dose 36 mg (n=27) – ADHD symptoms, adherence, side effects

Week 3: Test dose 72 mg (n=24) – CPTs, ADHD symptoms, adherence, side effects

Week 4: Wash-out (no medication; n=24) – ADHD symptoms, side effects

Week 5: Lead-in dose 36 mg (n=24) – ADHD symptoms, adherence, side effects

Week 6: Test dose 72 mg (n=22) – CPTs, ADHD symptoms, adherence, side effects Discontinued treatment (n=2): side effects

OROS-mph ” ‡ƒ – ‡ –’ ‡” ‹‘ † ͕ ” ‡ƒ – ‡ –’ ‡” ‹‘ † ͖

FIGURE 1. Flowchart of the 6-weeks procedure and randomizations of our double-blind, placebo-controlled cross-over study, with every subject receiving both treatments.

Medical-ethical approval has been obtained (METiGG; #7208; CCMO; #NL16911.097.07). Public trial registration #ISRCTN52392534.

Treatment

An independent pharmaceutical company manufactured the visually identical over-encapsulated tablets containing either mph or placebo. OROS-mph treatment was initiated with a once daily dose of 36 mg and continued with an increment of 36 mg after 7 days, resulting in a total once daily dose of 72 mg for all patients in weeks 3 and 6. Standard titration rules for children proclaim increments of 18 mg per 7 days, but titration with 36 mg at once is clinically well XSPIVEXIHMREHYPXTEXMIRXW8LMWWXYH]IZEPYEXIHXLIIǺIGXSJQK474QTL following Newcorn et al. [100]. All subjects took the study medication at 8 AM for optimal methylphenidate plasma concentrations during the CPT task, which was conducted at 9:30 AM [101]. Medication was administered at visits 1, 2, 4 and  +MKYVI&HZIVWIQIHMGEXMSRIǺIGXW[IVIWGSVIHSRXLIMHI*ǺIGXW7EXMRK GEPI?AGSQTVMWMRKXLITVIWIRGISJXLIQSWXGSQQSRWMHIIǺIGXWSJ methylphenidate according to the European Medicines Agency’s summary of product characteristics [103]. Adherence to medication intake was tracked using the Adherence Questionnaire [104].

Outcomes

Objective response

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each. Both CPTs have a high internal consistency (rǸWYǽGMIRXXIWXVIXIWX reliability for the parameters that were analyzed in this study (rǸJSV((58 

rǸJSV84:&ERHKSSHWIRWMXMZMX]XSWXMQYPERXIǽGEG]?A

Five parameters resulting from the C-CPT as well as the TOVA were analyzed at baseline, after 72 mg of placebo medication and after 72 mg of OROS-mph: hit reaction time (HRT), reaction time variability (RTV), commission errors (CEs), omission errors (OEs), and d-prime (DP). The HRT represents the average duration in milliseconds between target and correct response. Both low and high HRT are clinically relevant: very fast responses indicate impulsivity and very slow responses indicate inattention. The RTV measures the variability of the mean correct response times. Lower RTV indicates more consistent reaction times. CEs are made when the subject fails to inhibit a response to a non-target. High CE rates indicate impulsivity. OEs occur when the subject did not respond to a target. A high OE rate indicates inattention and/or low vigilance. The parameter )5VIǼIGXWXLIWYFNIGXƶWHMWGVMQMREXMZIEFMPMX]FIX[IIRXEVKIXWERHRSRXEVKIXW (i.e., the CEs:OEs ratio) with lower scores indicating worse results.

For EF severity, we compared our data to norm data as listed in the C-CPT and TOVA manuals, resulting in standardized test scores (i.e., a t -score) per parameter. The C-CPT normative non-clinical sample comprised 1 920 individuals from the general population of whom 47% was male and ages ranged from 6 to 55+ years old [105]. The TOVA norm sample was recruited from colleges and adult community settings, and contained 250 individuals of whom 31% was male and ages ranged from 20 to 80+ years old [106]. Both normative samples were free of individuals with any central nervous system disorders or injuries.

Subjective response

Statistical analysis

CPT performance after medication

8LI TVIZEPIRGI SJ *+ HIǻGMXW [EW WXYHMIH F] GEPGYPEXMRK XLI TVSTSVXMSRW SJ XLI WEQTPI I\GIIHMRK XLI GPMRMGEP RSVQEXMZI GYXSǺW SR XLI ǻZI ((58 ERH TOVA parameters (HRT, RTV, CE, OE, and DP) at baseline (i.e., t>54 for C-CPT parameters, and t!JSV84:&TEVEQIXIVW?A2IHMGEXMSRIǽGEG][EW XIWXIHF]GEPGYPEXMRKXLIHMǺIVIRGIWMRVE[XIWXWGSVIWFIX[IIRGSRHMXMSRW MI baseline vs. placebo, baseline vs. OROS-mph, and placebo vs. OROS-mph), [LMGL [I HIǻRIH EW XLI HIPXE WGSVIW 5EMVIH WEQTPIW t-tests were used to compare the mean delta scores. Despite of randomization, cwe checked for QIHMGEXMSR SVHIV ERH (58 XIWX SVHIV IǺIGXW F] TIVJSVQMRK TEMVIHWEQTPIW

t-tests.

FÚåĻƒĞĀϱƒĞŇĻƐ±ĻÚƐŤŹåÚĞσĞƽåƐƽ±ĮƣåƐŇüƐ{‰ƐŤ±Ź±ķåƒåŹž

;I XIWXIH [LMGL (58 TEVEQIXIV W MRHMGEXIH 474QTL IǽGEG] FIWX +MVWX GPMRMGEPP]VIPIZERX474QTLIǺIGXWSRWTIGMǻG(58TEVEQIXIVW[IVIMHIRXMǻIH by calculating Cohen’s d IǺIGX WM^IW QIER (58 HIPXE WGSVI HMZMHIH F] XLI estimated standard deviation of the delta score). However, for clinical purposes [I[IVI TEVXMGYPEVP] MRXIVIWXIH MR XLI TVIHMGXMZIZEPYI SJ 474QTL IǺIGXW on neuropsychological test performance. We therefore investigated whether *+WIZIVMX]MQTEGXIHXLIQIHMGEXMSRIǽGEG]SR(58HIPXEWGSVIWYWMRKPMRIEV VIKVIWWMSR QSHIPW *+ WIZIVMX] [EW HIǻRIH EW XLI TEXMIRXƶW WXERHEVHM^IH CPT test score (tWGSVI EX FEWIPMRI +SV TEVEQIXIVW WLS[MRK WMKRMǻGERX ?QIHMGEXMSR*+WIZIVMX]AMRXIVEGXMSRWEQIHMERWTPMXSR*+WIZIVMX]WXVEXMǻIH XLIWEQTPIMRXSTEXMIRXW[MXLGPMRMGEP*+HIǻGMXW MIt-score below the median; EF_clinicalERHTEXMIRXW[MXLSYXGPMRMGEP*+HIǻGMXW MIt-score above the median; EF_non-clinical). Then, linear regression models were repeated using the dichotomized *+WIZIVMX]MRSVHIVXSHIXIVQMRIEQSHIVEXMSRIǺIGX+MREPP][IMRZIWXMKEXIH [LIXLIV LIXIVSKIRIMX] SJ *+ MQTEGXIH 474QTL IǺIGXW *+ LIXIVSKIRIMX] [EWHIǻRIHEWXLIRYQFIVSJGPMRMGEPP]HIǻGMIRX*+EVIEWEXFEWIPMRI8LVII GEXIKSVMIWSJ*+LIXIVSKIRIMX][IVIMHIRXMǻIHMRSYVWEQTPITEXMIRXW[MXLSYX

ER]*+HIǻGMXW *+)_noneTEXMIRXWLEZMRK*+HIǻGMXWSRSRISVX[STEVEQIXIVW

(EFD_fewERHTEXMIRXWLEZMRK*+HIǻGMXWSRXLVIISVQSVITEVEQIXIVW *+)_multiple).

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Objective vs. subjective measures

;IEREP]^IHXLIWYFNIGXMZIIǽGEG]SJ474QTLERHER]VIPEXMSRWLMTFIX[IIR SFNIGXMZIERHWYFNIGXMZIQIEWYVIWSJQIHMGEXMSRIǺIGXW+MVWXVEXIWSJGLERKI on the ADHD-RS Total Score (i.e., the ADHD-RS delta scores) between baseline, placebo and OROS-mph were studied. Second, we correlated the placebo vs. OROS-mph CPT delta scores with the ADHD-RS delta score, using Pearson’s GSVVIPEXMSR GSIǽGMIRX r. Then, the impact of ADHD severity (i.e., baseline &)-)78SXEPGSVIEWEQSHIVEXSVSJQIHMGEXMSRIǺIGXWSR(58XIWXWGSVIW was investigated, using linear regression models. Again, for CPT parameters WLS[MRKWMKRMǻGERXMRXIVEGXMSRIǺIGXWEQIHMERWTPMXHMZMHIHXLIWEQTPIMRXS

patients with mild ADHD symptoms (i.e., scoring below the median; ADHD_mild)

and patients with severe ADHD symptoms (i.e., scoring above the median; ADHD_severe), whereupon separate linear regression models were performed per ADHD group.

SPSS 18.0 (Chicago, IL) was used for data analysis. An ƋPIZIPSJǷ X[SWMHIH

MRHMGEXIHWXEXMWXMGEPWMKRMǻGERGI.RXIVEGXMSRIǺIGXW[IVIWMKRMǻGERXEXERƋ-level

SJǷ X[SWMHIH

RESULTS

Baseline general characteristics

A total of 27 individuals participated in the study1_{, of whom n=5 dropped out}

(see Figure 1). We found no selection bias between participants and dropouts regarding sex, age, or baseline ADHD severity (p>.100). Table 1 presents the baseline general characteristics of subjects who completed the study. Side IǺIGXW[IVIVITSVXIHF]XIRWYFNIGXW  [LMPIYWMRKTPEGIFS.VVMXEFMPMX] R"   ERHMRWSQRME R"  [IVIXLIQSWXVITSVXIHWMHIIǺIGXW474QTL WMHIIǺIGXW[IVITVIZEPIRXMR SJXLIWYFNIGXW R"[LSQSWXP]VITSVXIH decreased appetite (n=9; 41%), a dry mouth (n=7; 32%), weight loss (n=5; 23%), headaches (n=5; 23%), and nervousness (n=5; 23%). Although substantially more WMHIIǺIGXW[IVIVITSVXIHMRXLI474QTLKVSYTXLIWMHIIǺIGXVEXIW[IVI

RSX WMKRMǻGERXP] HMǺIVIRX FIX[IIR 474QTL ERH TPEGIFS =EXIWơ2_=3.45,

p"FYXXLIX]TIWSJWMHIIǺIGXWHMH8LVIIWYFNIGXWHMWGSRXMRYIHXVIEXQIRX

HYIXS474QTLWMHIIǺIGXW[LMPIWMHIIǺIGXWSRTPEGIFS[IVIRSVIEWSRXS stop study participation.

TABLE 1. Baseline general characteristics of the total group of adults with ADHD, N=22

Characteristics Total group N=22 Sex: female, n (%) 5 (22.7) Age, M (SD) 30.5 (7.4) Vocational status:

Lower vocational training, n (%) Higher secondary school, n (%) Pre-university education, n (%) Higher professional school, n (%) University, n (%) 1 (4.5) 11 (50.0) 3 (13.6) 4 (18.2) 3 (13.6) ADHD severity (ADHD-RS Total Score) *, M (SD) 30.2 (6.3) Psychiatric history, n (%), of which:

Mood disorder, n (%) Anxiety disorder, n (%)

Substance abuse disorder, n (%) Eating disorder, n (%) 17 (77.3) 11 (50.0) 3 (13.6) 9 (40.7) 1 (4.5)

Note. N=total sample size; n=group size; %=percentage of total group; M=mean; SD=standard deviation; ADHD-RS=ADHD-Rating Scale.

* ADHD-RS Total Score ranges from 0 to 54 points.

*+HIǻGMXWMREHYPXW[MXL&)-)

&XFEWIPMRI SJXLIWYFNIGXWVITSVXIH*+HIǻGMXWSRER]SJXLIǻZI(58

TEVEQIXIVW SJ IMXLIV (58 TIGMǻG VEXIW SJ *+_clinical for the C-CPT parameters

were: HRT (n=9; 41%), RTV (n=5; 23%), CEs (n=12; 55%), OEs (n=2; 9%) and DP (n = 9; 41%). On the TOVA parameters these were: HRT (n=6; 27%), RTV (n=13; 59%), CEs (n=6; 27%), OEs (n=9; 41%), and DP (n=9; 41%).

4FNIGXMZIIǽGEG]SJ474QTL

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Despite of randomization, we found an unexpected medication order IǺIGX [LIVI WYFNIGXW VIGIMZMRK 474QTL ǻVWX WLS[IH WMKRMǻGERXP] QSVI improvement on C-CPT and TOVA OE (p=.005 and p=.043 respectively), CE (p=.017 and p=.038 respectively), and C-CPT DP (p=&(58SVHIVIǺIGX[EW EPWS JSYRH MRHMGEXMRK E PIEVRMRK IǺIGX XLI WIGSRH (58 XIWX WLS[IH FIXXIV test scores, irrespective of the type of CPT test performed (C-CPT RTV: p=.020; C-CPT CE: p=.003; and TOVA DP: p=-S[IZIV(58SVHIVIǺIGXW[IVISRP] observed in the OROS-mph group, not in the placebo group.

Parameter sensitivity

+SVFSXL(58WXLIPEVKIWXFEWIPMRIZW474QTLIǺIGXWM^IW[IVIJSYRHSR the parameters RTV, CEs, and DP (all between d=0.49–0.74; see Table 2). When GSVVIGXIH JSV TPEGIFS IǺIGX WM^IW SJ 474QTL[IVI XLI WXVSRKIWX JSV XLI parameter DP (C-CPT and TOVA both d=0.40).

+SV XLI ((58 HIPXE WGSVIW E WMKRMǻGERX PMRIEV VIPEXMSR FIX[IIR QIHMGEXMSR condition and EF severity was found for the parameters RTV (F=6.297, p=.001,

R2_{=.326), DP (F=2.937, p=.045, R}2_{=.184), OE (F=90.859, p<.001, R}2_{=.875), and CE}

(F=3.367, p=.028, R2_{=.206), but not for HRT (F=0.526, p=.667, R}2_{=.039). A main}

IǺIGX[EWJSYRHJSVQIHMGEXMSRGSRHMXMSRSRXLITEVEQIXIV((584* ƌ=4.421,

t=3.928, p< 2SVISZIV *+ WIZIVMX] QSHIVEXIH 474QTL IǺIGXW SR XLI

parameters C-CPT RTV (ƌ=-0.184, t=-2.277, p=.028), and C-CPT OE (ƌ=-0.098,

t=-4.759, p<MRHMGEXMRKXLEXWYFNIGXW[MXLGPMRMGEP*+HIǻGMXWTVSǻXIHQSVI

JVSQ474QTLXLERHMHWYFNIGXW[MXLRSRGPMRMGEP*+HIǻGMXW

+SV XLI 84:& HIPXE WGSVIW XLI PMRIEV VIKVIWWMSR QSHIPW [IVI WMKRMǻGERX JSV

the parameters RTV (F=7.827, p<.001, R2_{=.370), HRT (F=3.278, p=.031, R}2_=.197),

OE (F=6.298, p=.001, R2_{=.321), and CE (F=3.742, p=.018, R}2_{=.219), but not for DP}

(F=2.376, p=.084, R2"2EMRIǺIGXWJSVQIHMGEXMSRGSRHMXMSR[IVIJSYRHSR

TOVA RTV (ƌ=-68.366, t=-2.562, p=.014) and HRT (ƌ=-154.066, t=-2.028, p=.049).

+YVXLIVQSVIQIHMGEXMSRGSRHMXMSRWMKRMǻGERXP]MRXIVEGXIH[MXL*+WIZIVMX]SR

the parameter TOVA RTV (ƌ=0.670, t=2.097, p= [LMGL EJXIV WXVEXMǻGEXMSR

VIWYPXIH MR WMKRMǻGERXP] QSVI JEZSVEFPI VIWYPXW JSV 474QTL MR XLI *+_clinical

group (F=4.638; ƌ=-27.727; t=-2.154; p=.044).

.RWYQQEV]XLIQER]RIEVWMKRMǻGERXXVIRHW[IJSYRHMRI\TIGXIHHMVIGXMSRW MQTPMGEXIETPEYWMFPIEWWSGMEXMSRFIX[IIR474QTLIǺIGXWERHXLIWIZIVMX]

SJ*+HIǻGMXWQEMRP]JSVXLIEXXIRXMSRVIPEXIHTEVEQIXIVW78:ERH4* 72_=0.320

or higher on both CPTs). None of the hyperactivity/impulsivity parameters WMKRMǻGERXP]PMROIH474QTLIǺIGXXS*+WIZIVMX]ERHTVSTSVXMSRWSJHIGPEVIH

Heterogeneity of EF

Subdivision of our subjects into groups of EF heterogeneity on the C-CPT led to

GPEWWMǻGEXMSRSJR"WYFNIGXWMRXLI*+)_none, n=14 subjects in the EFD_few, and n=4

subjects in the EFD_multiple group. For the TOVA, these were EFD_none=6, EFD_few=8,

and EFD_multiple" VIWTIGXMZIP] 8LI KVSYTW SJ *+ LIXIVSKIRIMX] SRP] HMǺIVIH

on the parameter C-CPT OE (H(2)=8.940, p" [LIVI WMKRMǻGERXP] QSVI

improvement on OROS-mph was found for the EFD_multiple group as compared

to the EFD_none group (U=6.500, p=.009; r=-0.65) and the EFD_few group (U=36.500,

p=.009; r=-0.43). Figure 2 presents the mean delta scores for the groups of EF

heterogeneity separately, on the sensitive parameters HRT, RTV, and OE.

4FNIGXMZIZWWYFNIGXMZIIǽGEG]SJ474QTL

+MKYVIWLS[WXLIWYFNIGXMZIIǽGEG]SJ474QTL2SWXWYFNIGXWVITSVXIH MRGVIEWIH&)-)W]QTXSQWEJXIVYWMRKTPEGIFSQIHMGEXMSR[LMGLWMKRMǻGERXP] HMǺIVIHJVSQXLI474QTLGSRHMXMSR[LIVIEPPWYFNIGXWVITSVXIHHIGVIEWIH

ADHD symptoms (68.2% vs. 0.0%; ơ2_{=19.83, p<&PWSWMKRMǻGERXHMǺIVIRGIW}

[IVI JSYRH MR XLI TVSTSVXMSRW SJ WYFNIGXW VITSVXMRK E GPMRMGEPP] WMKRMǻGERX HIGVIEWI SJ&)-) W]QTXSQW MI HIGVIEWI SJ   SV QSVI[LMGL[EW ǻZI

times higher in the OROS-mph condition (45.5% vs. 9.1%; ơ2_{=5.61, p=.018).}

8LIVI [EW E TSSV VIPEXMSRWLMT FIX[IIR SFNIGXMZI ERH WYFNIGXMZI IǽGEG] SJ OROS-mph, except for the parameter TOVA RTV (r=.447, p=.037). Linear relations of medication condition and ADHD severity were found on TOVA RTV (F=4.655,

p=.007, R2_{=.259) and TOVA HRT (F=3.800, p=.017, R}2_{=.222) delta scores. ADHD}

WIZIVMX] WMKRMǻGERXP] MRXIVEGXIH[MXL QIHMGEXMSR GSRHMXMSR SR XLI TEVEQIXIVW TOVA RTV (ƌ=-3.226, t=-2.340, p=.024) and TOVA HRT (ƌ=-5.413, t=-1.875, p=.068). XVEXMǻIHVIKVIWWMSREREP]WIWWLS[IHQSVIJEZSVEFPIVIWYPXWJSV474QTLMR

the ADHD_severe group, on delta scores of TOVA RTV (mean delta score -15.542

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T ABLE 2. Comparisons o f delta sc or es on the r a w C-CPT and T O V A t est r esults be tw

een baseline, plac

ebo and OROS-mph

 FIGURE 2. 2 IERHIPXEWG SV IWSR((58 ERH 84 : & -7 87 8: ERH4*J SV TE XMIR XWLE ZMRKRSJ I[ SV QYPXMTPI*+ HI ǻG MXWE XFEWIPMRI N o

te. Baseline is used as the r

e

fer

enc

e ca

tegory

, the lines illustr

a

te the mean delta sc

or es f or baseline v s. plac

ebo, and base

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Self-reported ADHD symptoms

Change per medication condition

increase 0-15% decrease 15-30% decrease * * 0 4 8 12 16 20 Placebo OROS-mph N u m b e r o f s u b je c ts ( n ) >30% decrease

FIGURE 3. Increases or decreases of self-reported ADHD symptoms as measured with the ADHD-Rating Scale Total score after placebo or 72 mg OROS-mph medication, as compared to baseline.

Note. Baseline is used as the reference category. OROS-mph=osmotic-release methylphenidate. MKRMǻGERXHMǺIVIRGIWFIX[IIRFEWIPMRIERH474QTLEXERƋ-level of .05 or smaller.

DISCUSSION

In this randomized double-blind cross-over placebo-controlled trial, we MRZIWXMKEXIHXLIWIRWMXMZMX]SJWTIGMǻG(58TEVEQIXIVWJSVQIEWYVMRK474QTL IǽGEG] MR SVHIV XS KMZI MRWMKLX MRXS XLI RIYVSTW]GLSPSKMGEP IRHSTLIRSX]TI YRHIVP]MRK XLI GSRWXVYGX SJ &)-) 8S SYV ORS[PIHKI XLMW MW XLI ǻVWX WXYH] XS SFNIGXMZIP] MRZIWXMKEXI XLI IǺIGXW SJ E PSRKEGXMRK QIXL]PTLIRMHEXI SR neurocognitive test performance of adults with ADHD.

.RSYVWXYH] SJEHYPXW[MXL&)-)LEH*+HIǻGMXW[LMGLMWMRPMRI[MXL a prevalence rate of 40% reported earlier in the study of Biederman et al. [17]. 8LIPEVKIZEVMERGIMRXLISGGYVVIRGISJ*+HIǻGMXWLMKLPMKLXWXLILIXIVSKIRIMX] SJ*+HIǻGMXWMRXLMWTEXMIRXKVSYT?AEWXLI*+HIǻGMIRG]LMKLP]HITIRHW on which EF areas are being tested [16, 19]. Subdividing our sample into small KVSYTWSJ*+LIXIVSKIRIMX]MRHMGEXIHXLEXHMZIVWMX]MR*+HIǻGMIRG]QE]EPWS TPE]EVSPIMR474QTLIǽGEG]FYXXLMWRIIHWXSFIMRZIWXMKEXIHMRPEVKIV samples.

474QTL WMKRMǻGERXP] SYXTIVJSVQIH TPEGIFS SR 78: MR SRI SJ X[S (58W ERH [EW RIEVWMKRMǻGERXP] WYTIVMSV SR XLI SXLIV (58 EW [IPP 474QTL IǽGEG] VIWYPXIH MR QIHMYQ XS LMKL IǺIGX WM^IW GSQTEVEFPI XS XLSWI JSYRH for immediate-release methylphenidate (IR-mph) [108]. The variability in reaction times (RTV), commission errors (CEs) due to impulsive reactions, and detectability ratio between targets and non-targets (d-prime; DP) were most WIRWMXMZIJSV474QTLIǽGEG]

Digging one layer deeper, on the neural systems level endophenotypic for &)-)XLITEVEQIXIVW78:-78ERH4*TVIHMGXIH474QTLIǽGEG]8LIWI parameters all aim at measuring the construct of attention [105, 106], and have shown to overlap in prior studies [83, 112]. Of these, RTV was the only parameter relating severity of ADHD behavior to neuropsychology, by showing QSVIFIRIǻGMEP474QTLIǺIGXWJSVWYFNIGXW[MXL[SVWI*+HIǻGMXWERHQSVI ADHD symptoms [87]. In a previous study, subjective ratings and objectively QIEWYVIH*+HIǻGMXW[IVISRP][IEOP]VIPEXIH?AERHPMOIP]XSEWWIWWHMǺIVIRX PIZIPW SJ *+ ?A8LI JEGX XLEX SYV WXYH] HMH ǻRH ER EWWSGMEXMSR IQTLEWM^IW XLEX78:VIǼIGXWEFVSEHYRHIVP]MRKMRHMGEXSVJSVSZIVEPP*+HIǻGMIRG]SRE neuropsychological level as well as a behavioral level.

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when compared to healthy controls [117]. ADHD patients thus appear to posses ƵHYEPHIǻGMXWƶHYVMRKGSKRMXMZIXEWOWQSVIVIWXMRKWXEXIEGXMZEXMSRSRXLISRI hand and less task-related activation on the other hand [20]. As a consequence SJ FSXL HIǻGMXW XLI XEWORIKEXMZI RIX[SVO ERH XLI XEWOTSWMXMZI RIX[SVO constantly compete [116], inducing lapses of inattention, a high RTV and more OEs [20, 118]. Strikingly, RTV and omission errors were also moderately related in the current study (Pearson’s r=.526, p=.012). The facts that methylphenidate treatment normalized DMN deactivation in ADHD children [93] and ameliorated the cognitive-attention network in adults with ADHD [119], may explain why 474QTLQEMRP]MQTVSZIHERHLEHXLILMKLIWXIǺIGXSRXLIEXXIRXMSRVIPEXIH neurocognitive parameters (i.e., RTV and OE) in our study. OROS-mph even led XS GVSWW(58 PIEVRMRK IǺIGXW TSWWMFP] F] IRLERGMRK EXXIRXMSR F] VIHYGMRK XIWXVIPEXIHWXEXIER\MIX]?ASVF]MRHYGMRKE-E[XLSVRIIǺIGXFIGEYWISJ increased environmental awareness [121].

Limitations