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17.5.1 Pharmacological interventions in children and young people Comparisons Included in this Clinical Question () vs. Antidepressant () vs. (Continued on Effective Atomoxetine + vs. Placebo Placebo dose) vs. Atomoxetine (Decreased Atomoxetine alone dose) BIEDERMAN1989 KRATOCHVIL2005 DONNELLY1986 NEWCORN2006 SPENCER2002C

Atomoxetine vs. Placebo vs. Placebo + Clonidine vs. Placebo /Dexamphetamine vs. ALLEN2005 CASAT1987 KURLAN2002 Placebo + BOHNSTEDT2005 CONNERS1996B Methylphenidate/Dexamphetamine BROWN2006 HAZELL2003 KELSEY2004 MICHELSON2001 MICHELSON2002 MICHELSON2004 SPENCER2002A SPENCER2002B WEISS2005 WERNICKE2004A

Dexmethylphenidate vs. Placebo Methylphenidate + Clonidine vs. Methylphenidate + vs. Methylphenidate + Thioridazine vs. Placebo Methylphenidate Placebo WIGAL2004 KURLAN2002 GITTELMANKLEIN1976A GITTELMANKLEIN1976A

Methylphenidate + Thioridazine vs. Methylphenidate 0.3mg/kg vs. Methylphenidate 0.3mg/kg vs. Methylphenidate 0.4mg/kg vs. Thioridazine Methylphenidate 0.5mg/kg Methylphenidate 0.7mg/kg Methylphenidate 0.8mg/kg GITTELMANKLEIN1976A KUPIETZ1988 KUPIETZ1988 IALONGO1994

Methylphenidate 0.7mg/kg vs. Methylphenidate vs. Bupropion Methylphenidate vs. Clonidine Methylphenidate vs. Methylphenidate 0.5mg/kg BARRICKMAN1995 KURLAN2002 KUPIETZ1988 WIGAL2004

Methylphenidate vs. CONNERS1980 Methylphenidate vs. Placebo Methylphenidate vs. Thioridazine vs. Placebo vs. Placebo BUTTER1983 GITTELMANKLEIN1976A BIEDERMAN2005 SHYTLE2002 CONNERS1980 BIEDERMAN2006B FINDLING2006 GREENHILL2006A GITTELMANKLEIN1976A RUGINO2003 GREENHILL2002 SWANSON2006 GREENHILL2006 IALONGO1994 KOLLINS2006 KUPIETZ1988 KURLAN2002 LERER1977 PLISZKA2000 WIGAL2004 WILENS2006A WOLRAICH2001

Pemoline vs. Placebo (+ Placebo) vs. Placebo Sustained-release methylphenidate vs. TCAs vs. Clonidine Immediate-release methylphenidate CONNERS1980 SINGER1995 WOLRAICH2001

TCAs vs. Placebo Thioridazine vs. Placebo SINGER1995 GITTELMANKLEIN1976A

Characteristics of Included Studies Methods Participants Outcomes Interventions Notes ALLEN2005 Study Type: RCT n= 148 Data Used Group 1N= 76 Research from Lilly ADHDRS Inattentive (Change from BL: Research Laboratories Study Description: Comorbidity (Specific: Tic Age: Mean 11 Range 7-17 Atomoxetine. Mean dose 1.33mg/kg/day - means, SDs) Disorder, & non-specific). Sex: 131 males 17 females INITIAL WASHOUT:10-18 day(screening) Sample consisted of 'Children' and ADHDRS Total (Change from Baseline: DOSE: 3wk titration phase- 'Adolescents' (percentages not reported). Diagnosis: means, SDs) began:0.5mg/kg/day,titrated to 30% Chronic Motor Tic Disorder by YGTSS >5, ADHDRS Hyper/Impuls.(Change from BL: 1.0mg/kg/day at end of wk 1, then titrated Type of Analysis: ITT (P's:prov.data @ BL & 1 K-SADS-PL & Clinical Interview means, SDs) up/down (final range 0.5-1.5 mg/kg/day, post-BL assessment) Data Not Used max daily dose 110mg) ADMIN:Daily as divided dose (morning & Blindness: Double blind 22% Oppositional defiant disorder by DSM-IV Yale Global Tic Severity Scale (YGTSS) - late afternoon) Duration (days): Mean 140 outcome not relevant Group 2N= 72 3% ADHD Hyperactive/Impulsive subtype by CGI-ADHD/Psych-S - outcome not relevant Setting: Recruited from 14 sites in USA, DSM-IV, K-SADS-PL, ADHDRS-IV-Parent-Inv CGI-Tic/Neuro-S - outcome not relevant Placebo - INITIAL WASHOUT:10-18 day primarily hospitals and clinics. ADMIN:Daily as divided dose(morning & Tic Symptom Self Report (TSSR) - outcome late afternoon) Notes: Randomisation carried out by a not relevant 36% ADHD Inattentive subtype by DSM-IV, K- NB.: No mention of form/appearance of computerised Interactive Voice Response SADS-PL, ADHDRS-IV-Parent-Inv CGI-Overall-S - outcome not relevant either Placebo or Atomoxetine - assume System. Notes: TAKEN AT:Baseline & Endpoint (Not tablet form, identical?? Info on Screening Process: 10-18 day 7% Major , GAD, or OCD by DSM-IV clear when assesments were made between screening and washout period - physical exam, these times) vital sign measurements, medical history etc. LOST TO F.U.: ATX 2/76, PLB 1/72 (Not incl.in 79% Tourette's Syndrome by YGTSS >5, K- 166 patients entered screening, 148 randomly ITT analysis) SADS-PL & Clinical Interview assisgned, 145 provided data at baseline and at least one postbaseline assesment. 61% ADHD Combined subtype by DSM-IV, K- SADS-PL, ADHDRS-IV-Parent-Inv 18% Chronic Vocal Tic Disorder by YGTSS >5, K-SADS-PL & Clinical Interview

Exclusions: Weight<20 kg, or >80kg; Children's Yale-Brown Obsessive Compulsive Scale (C-YBOCS) >15, or diagnosis of OCD severe enough to require ; Children's Depression Rating Scale-Revised (CDRS-R) >40, or diagnosis of depression severe enough to require medication; history of bipolar disorder/psychosis; seizure disorder; current use of any psychotropic medication other than study . Notes: YGTSS= Yale Global Tic Severity Scale ADHDRS-IV-Parent:Inv = Attention deficit/hyperactivity disorder Rating Scale-IV-Parent Version: Investigator administered and scored (NB. Needed to be >1.5 SDs above age and sex norm) Baseline: Mean (SD) YGTSS = 22 (8) (mild to moderate level of tic severity) NB: ATX group:significantly greater impairment in their mean ADHDRS-IV-Parent:Inv total and hyperactivity sub- scale scores (Change scores extracted).

ADHDRS Total Mean (SD): ATX: 38.9 (9.1); PLB: 35.0 (9.5)

ADHDRS Inattentive: ATX: 21.6 (4.1); PLB: 20.5 (5.0)

ADHDRS Hyperactive/Implusive: ATX: 17.2 (6.8) PLB: 14.6 (7.2) Results from this paper: Internal validity: 1.1 Well covered 1.2 Well covered 1.3 Well covered 1.4 Well covered 1.5 Adequately addressed 1.6 Adequately addressed 1.7 Well covered 1.8 ATX 65% (49/76), PLB 72% (52/72) 1.9 Well covered 1.10 Not addressed

Overall assessment of the study: 2.1: 1+ BARRICKMAN1995 Study Type: RCT crossover n= 15 Data Used Group 1N= 9 Funding: NR IOWA-Conners Abb.Teacher Rating Study Description: Comorbidity (Non-specific: Age: Range 7-17 Methylphenidate. Mean dose 0.8 +/- 0.1 Scale(mean change) CD, ODD, developmental learning disorders). Sex: 12 males 3 females mg/kg/day - WASHOUT: 14days Sample consisted of 'Children' and Data Not Used DOSE: Wk1 0.4mg/kg/day; Wk2-3 titrated 'Adolescents' (percentages not reported). Diagnosis: WISC-R - Baseline only; not relevant outcome to 0.7+/-0.2mg/kg/day-fixed wks4-6. 100% ADHD by DSM-III-R K-SADS-E - Baseline only ADMIN: 3 Type of Analysis: Completer capsules/day(morn,noon,4pm)[MPH Conner's Continous Performance Test - active morn & noon, & active 4pm if Blindness: Double blind Baseline only; not relevant outcome Exclusions: IQ<70; any other Axis I, II, or III diagnoses required]. Duration (days): Mean 42 (screened with Schedule for Affectiveness Disorders and Children's Manifest Anxiety Scale - Baseline for School-Age Children-Epidemiologic only; not relevant outcome Setting: Outpatient clinic; USA. Version (K-SADS-E); any seizure history; eating disorders; Clinical Global Impression Scale (NIMH) - Notes: RANDOMISATION: No detail; only current use of MOAI Baseline only 'randomised'. NB. Assume equal n's Children's Depression Inventory - Baseline randomised to each group. Baseline: Several scales (Iowa-Conners, CGI, Children's only; not relevant outcome NB. Duration is to point of crossover only Depression Inventory, Revised Children's Manifest Anxiety Matching Familiar Figures Task - Baseline Group 2N= 9 Scale, etc.) administered at baseline, but baseline scores only; not relevant outcome Info on Screening Process: Consecutive Bupropion. Mean dose 2.6 +/- 0.5 not reported. recruitment of p's willing to participate. No Rey Auditory-Verbal Learning Test - Baseline mg/kg/day - WASHOUT: 14days information reported re. No's only; not relevant outcome DOSE: Wk1 1.5mg/kg/day; Wk2 screened/excluded/turn-down trial. IOWA-Conners Abb.Parent Rating Scale - no 2.0mg/kg/day; 3wk titrated to 3.3+/- NB. 18 p's randomised into trial, paper only pre-cross-over data 1.2mg/kg/day-fixed wks4-6. reported demographics for n=15 (reported Notes: TAKEN AT: All outcomes taken at ADMIN: 3 here). baseline; at endpoint: only history, physical capsules/day(morn,noon,4pm)[BUP examinations and Conners scales repeated. active morn & 4pm, & active noon if LOST TO FOLLOW-UP: 3/18 (unknown required]. allocation); completer analysis.

Results from this paper: Internal validity 1.1 Well covered 1.2 Not reported adequately 1.3 Not reported adequately 1.4 Well covered 1.5 Not reported- crossover trial 1.6 Adequately assessed 1.7 Adequately assessed 1.8 17% from whole sample (3/18 dropped out at some point, unclear whether this before crossover or after) 1.9 Poorly addressed 1.10 Not applicable

Overall assessment of the study 2.1: 1+ BIEDERMAN1989 Study Type: RCT n= 62 Data Used Group 1N= 31 Funding: Supported in part AE: Decreased appetite (dichotomous data) by grants from Merrell-Dow Study Description: Comorbidity: 'Non-specific' Age: Range 6-17 Placebo - WASHOUT: see excl.'s AE: Abdominal pain (dichotomous data) DOSE/ADMIN: Increased to nearest Pharmaceutical Company; comorbidity. Sex: 58 males 4 females Charlupski Foundation; Sample: 67% 'Children'; 33% 'Adolescents'. AE: Loss of >=5% body weight (dichot data) conveniant no.of pills(identical DSI)to USPHS (NIMH) award and Diagnosis: yield dose >=0.5mg/kg by wk3 & resulted Type of Analysis: ? (P's who completed >=3wks Leaving the Study Early due to Adverse Event grants. 37% Conduct disorder by Unspecified diagnostic indose<=5.6mg/kg given in 2 portions of trial). AE: Dry mouth (/eyes/nose) (dichotomous tool daily. data) Blindness: Double blind NB.Dose in 16/31 maximal dose lowered AE: Trouble sleeping (dichotomous data) or increased more slowly- due to AE's Duration (days): Mean 42 48% Oppositional disorder by Unspecified diagnostic tool CGI-I rating =1 or 2 (very/much improved; Group 2N= 31 dichot) Setting: Boston, US. P's drawn from Desipramine hydrochloride - WASHOUT: AE: Somnolence/daytime consecutive outpatient referrals. 29% Anxiety disorder by Unspecified diagnostic see excl.'s tiredness(dichotomous data) DOSE/ADMIN: Increased to nearest Notes: Randomisation: computer generated list. tool AE: Headache (dichotomous data) conveniant no.of pills to yield dose Info on Screening Process: 73 initially >=0.5mg/kg by wk3 & resulted 76% Learning difficulties by Unspecified AE: Dizziness (dichotomous data) considered for study, all enrolled. NB. N=62 are indose<=5.6mg/kg given in 2 portions diagnostic tool AE: 'Risk of any AE' (dichotomous data) p's who completed at least 3 wks of trial, daily. allocation/data not reported for p's who did not Data Not Used NB.Dose in 22/31 maximal dose lowered complete protocol (n=11). 100% ADDH by DSM-III & >=15 on CPRS- Clinicians Global Impression -Severity (% or increased more slowly- due to AE's Abrev.(Parent or teacher) change) - ?? Need to calculate mean change from % change? 24% Major depression by Unspecified diagnostic Conners Continous Performance Test - not tool relevant outcome Conners Abbrev. Teacher Questionnaire (% Exclusions: IQ < 70; autism, psychosis, other medical or change) - ?? Need to calculate mean change neurological disorder; abnormal results of psychiatric and from % change? medical evaluations (ie. Routine lab tests, ECG). All meds Conners Abbrev. Parent Questionnaire (% were discontinued for at least 1 week before entering the change) - ?? Need to calculate mean change protocol. from % change? Notes: Diagnostic Interview for Children & Adolescents, Parent version (DICA-P) used. Leaving the Study Early for Any Reason - no NB. 2/73 diagnosed ADD without hyperactivity- allocation data (allocation of d/o's not reported) NR, or-represented in n=62 ITT sample? NB.69% sample Children's Depression Inventory - not relevant had prior trtment with no benefit/intolerable AEs. outcome Baseline: Clinicians Global Severity (mean (SEM)): PAL (Paired Associate Learning Task) - not DSI gp: 5.2(0.1); PLB gp: 5.1(0.1) relevant outcome Conners Abbreviated Questionnaire-Parent (mean (SEM)): Notes: OUTCOMES TAKEN AT:CPRS - weekly; DSI gp: 21.8(0.7); PLB gp: 22.8(0.8) CTRS - baseline & endpoint; CGI - weekly; CPT Conners Abbreviated Questionnaire-Teacher (mean & PALT & CDI - baseline & endpoint. AE's (SEM)): assessed systematically weekly with Subjective DSI gp: 18.5(1.2); PLB gp: 17.3(1.3) Treatment-Emergent Symptoms scale (STESS).

Results from this paper: Internal validity 1.1 Well covered 1.2 Adequately addressed 1.3 Not reported adequately 1.4 Well covered 1.5 Adequately addressed 1.6 Adequately addressed 1.7 Well covered 1.8 Unknown (allocation of completers reported only). Total sample dropout = 15% (11/73). 1.9 Poorly addressed (allocation of all p's randomised not reported, and different n's reported for each scale and time point) 1.10 Not applicable

Overall assessment of the study 2.1: 1+ BIEDERMAN2005 Study Type: RCT n= 248 Data Used Group 1N= 84 Funding: Sponsored by ADHD-RS-IV Home Inattention (mean change Cephalon, Inc. Study Description: Comorbidity: NR Age: Mean 10 Range 6-17 Placebo - WASHOUT: see 'exclusions' ADHD-RS-IV Home Total (mean change) Sample: 'children' & 'adolescents', %'s NR. Sex: 177 males 71 females DOSE: As for MOD: Individually AE: Colds/allergies/infections (dichotomous titrated(based on tolerability & efficacy) on Type of Analysis: ITT(p's:took >=1 meds & >=1 Diagnosis: data) schedule: days1-2:85mg(1 tablet); days3- postBL outcome meas.) 2% ADHD Hyperactive/Impulsive subtype by Conners PRS-Revised-Abbrev. (mean change 7: 2 tablets; days8-14: 3 tablets; days15- Blindness: Double blind DSM-IV 21: 4 tablets; day22-end: 5 tablets. AE: Accidental injury (dichotomous data) Admin: Morning, once daily. Duration (days): Mean 63 Leaving the Study Early for Any Reason 59% ADHS Combined subtype by DSM-IV Group 2 N= 164 AE: Rhinitis (dichotomous data) Setting: 24 sites in the USA. No further detail. Modafinil - WASHOUT: see 'exclusions' ADHD-RS-IV Home Hyperact./Impuls. (mean DOSE: individually titrated(based on Notes: Randomisation: code generated by 100% ADHD by DSM-IV change) Cephalon, Inc., and implemented by a central tolerability & efficacy) on schedule: days1 AE: Insomnia/Sleep problems(dichotomous 2:85mg(1 tablet); days3-7:170mg; days8- agency (Phoenix Data systems, PA) 38% ADHD Inattentive subtype by DSM-IV data) 14:255mg; days15-21:340mg; day22- Info on Screening Process: 372 screened with AE: Asthenia (dichotomous data) end:425mg. 28 days of baseline, 124 not enrolled (entry Exclusions: History or current diagnosis of pervasive AE: Abdominal pain (dichotomous data) Admin: Morning, once daily. criteria not met=91; consent withdrawn=13; developmental disorder, schizophrenia, other psychotic AE: Nervousness (dichotomous data) Lost to follow-up=9; other=11). disorders (DSM-IV Axis I); evidence of suicide risk; current AE: Pharyngitis (dichotomous data) psychiatric morbidity requiring pharmacotherapy; other active clinically significant disease; p's for whom ADHD is CGI-I rating =1 or 2 (very/much improved; well managed and satisfied with current ADHD therapy, and dichot) p's who've failed to respond to >=2 courses of stimulant ADHD-RS-IV School Total (mean change) therapy for ADHD (ethical concerns); clinically significant AE: Fever (dichotomous data) drug sensitivity to stimulants; hisory of or substance ADHD-RS-IV School Inattention (mean abuse (DSM-IV); consumption of >250mg per day; change) low absolute neutrophil count; hypo/hypertension; resting heart rate outside of 60-115 bpm; outside of the 5th-95th AE: Headache (dichotomous data) percentile for weight and height (on basis of National Center AE: Aches/pains (dichotomous data) for Health Statistics guidelines); IQ <80 (Weschler Individual AE: Somnolence/daytime Achievement Test-2nd Ed.-Abbreviated); not attending full- tiredness(dichotomous data) time school. NB. Concomitant use of AE: Decreased appetite (dichotomous data) prescription/nonprescription agents with psychotropic AE: Nausea and Vomiting (dichotomous data) properties (incl. ADHD treatments and dietary supplements) ADHD-RS-IV School Hyperact./Impuls. (mean prohobited within 1 week of the baseline visit (within 2 weeks change) for monoamine oxidase inhibitors & SSRIs), and during the study. Leaving the Study Early due to Adverse Event AE: Rash (dichotomous data) Notes: NB. DSM-IV diagnosis via psychiatric/clinical evaluation & Diagnostic Interview Sched.for Children, AE: Cough increased (dichotomous data) 4thEd.; +CGI-S >=4; teacher/investigator rated ADHD-RS- Data Not Used IV School version >1.5 SDs above norms for age & gender. Child Health Questionnaire - no data; not relevant outcome Baseline: NB. BL does not include data from n=2 from PLB gp (who did not receive study-drug, therefore not included CGI - Severity - no data; baseline only in any analysis) Social Skills Rating System - no data; not ADHD-RS-IV total score: Mean (SD) relevant outcome School version: MOD gp 35.8(9.2); PLB gp 35.5(8.9) Notes: TAKEN AT: ADHD-RS's/CGI-I: BL (not Home version: MOD gp 37.7(9.6); PLB gp 36.9(9.1) CGI-I), wks 1,2,3,5,7,9; CPRS/SSRS:BL, wks CGI-S score (%) 3,7,9; CHQ: BL, wk9; AE's-spontaneous reports Moderately ill: MOD gp 44%; PLB gp 52% anytime. Markedly ill: MOD gp 40%; PLB gp 33% LOST to Follow-up:(not included in efficacy ITT Severely ill: MOD gp 15%; PLB gp 15% analysis):MOD 0.6%(1/164);PLB 3.6%(3/84) Among the most extremely ill: MPG gp <1%; PLB gp 0%

Results from this paper: Internal validity: 1.1 Well covered 1.2 Well covered 1.3 Well covered 1.4 Well covered 1.5 Well covered 1.6 Adequately covered 1.7 Well covered 1.8 MOD gp: 41% (67/164); PLB gp: 61%(51/84) 1.9 Well covered 1.10 Not reported adequately

Overall assessment of the study: 2.1: 1+

NB. Outcomes extracted from graph (therefore may not be exact): Conners PRS-Revised-Abbrev. (mean change, nb. SEM reported on graph, converted to SD using equation SD = SEM x √n). BIEDERMAN2006B Study Type: RCT n= 248 Data Used Group 1N= 50 Funding: Supported by Leaving the Study Early due to Adverse Event Cephalon Inc. Study Description: Assume 'Pure ADHD' Age: Mean 9 Range 6-14 Modafinil 300mg morn only - WASHOUT: AE: Cough (dichotomous data) sample: see exclusions Sex: 185 males 63 females 7-10 day single-blind PLB phase Sample: 'Children' & 'Adolescents' Leaving the Study Early for Any Reason DOSE:100mg/day days 1-3; increased Diagnosis: 100-mg increments every 2 days to max Type of Analysis: ITT AE: Diastolic blood pressure (mm Hg, mean 2% ADHD Hyperactive/Impulsive subtype by change) dose (ie. 300mg by day 6) Blindness: Double blind DSM-IV (psychiatric evaluation & DISC) ADMIN:3 tablets early morn(0700-0800) + AE: Rhinitis (dichotomous data) 2 tabs 4-5hrs later(1100-1300). Each Duration (days): Mean 28 ADHD-RS-IV Home Hyperact./Impuls. (mean tablet=100mg MOD or matched PLB 100% ADHD by DSM-IV (psychiatric evaluation change) Setting: 28 centres in the US. & DISC) Group 2N= 51 AE: Insomnia/Sleep problems(dichotomous Placebo - WASHOUT: 7-10 day single- Notes: Randomisation:Stratified schema based data) blind PLB phase on body weight: Weight <30kg either 20% ADHD Inattentive subtype by DSM-IV AE: Infection (dichotomous data) DOSE:NA - All p's given 5 tablets per day 300mg/day or PLB; >=30kg either (psychiatric evaluation & DISC) AE: Systolic blood pressure (mm Hg, mean ADMIN:3 tablets early morn(0700-0800), 300,400mg/day (2x probability) or PLB. change) 2 tabs 4-5hrs later(1100-1300). Each 77% ADHD Combined subtype by DSM-IV Info on Screening Process: 343 children tablet matched PLB (psychiatric evaluation & DISC) ADHD-RS-IV Home Total (mean change) screened, 248 enrolled and randomised. No AE: Heart rate (bpm, mean change) further detail reported. Exclusions: Weight<5th percentile in standardised growth ADHD-RS-IV School Total (mean change) charts; not attending full-day kindergarten, elementary ADHD-RS-IV School Hyperact./Impuls. (mean Group 3N= 49 school or middle school; having taken stimulant medication change) Modafinil 200mg morn + 100mg in past or satisfactory response to stimulant therapy; IQ<80 AE: Abdominal pain (NOS; dichotomous data) afternoon - WASHOUT: 7-10 day single- (Wechsler Intelligence Scale for Chidlren 3rd Ed.); score<80 Conners DSM-IV Parent vers.(26-item; mean blind PLB phase on screener version of Weschler Individual Achievement change) DOSE:100mg/day days 1-3; increased Test; no parent and weekday teacher available to AE: Decreased appetite (dichotomous data) 100-mg increments every 2 days to max participate; active, clinically significant gastrointestinal, dose (ie. 300mg by day 6) cardiovascular, hepatic, renal, hematologic, neoplastic, CGI-I rating =1 or 2 (very/much improved; ADMIN:3 tablets early morn(0700-0800) + endocrine, neurologic, immunodeficiency, pulmonary, or dichot) 2 tabs 4-5hrs later(1100-1300). Each other major clinically significant disorder or disease; any AE: Headache (dichotomous data) tablet=100mg MOD or matched PLB current psychiatric comorbidity, including but not limited to ADHD-RS-IV School Inattention (mean depression or other mood disorder, anxiety disorder, or Group 4N= 50 change) pervasive mental disorder that required pharmacotherapy; Modafinil 200mg morn + 200mg use of any prescription or non-prescription medication with AE: Fever (dichotomous data) afternoon - WASHOUT: 7-10day sgl-blind psychoactive propertieswithin 1 week of the start of the ADHD-RS-IV Home Inattention (mean change PLB phase washout period; a history or evidence of . Notes: TAKEN AT:Teacher scale taken twice a DOSE:100mg/day days 1-3; increased 100-mg increments every 2 days to Notes: NB. Subtype of ADHD data missing for n=2 day- scores averaged across each week; Parent max(ie.400mg:day 8).NB only p's 77 (31%) had taken stimulants for ADHD within 30 days of scales: weekly throughout trial. AE's weighing>=30kg in this grp. screening, MPH most common spontaneousy reported or identified by clinician a visits (weekly); pulse & BP measured weekly. ADMIN:3 tabs morn(7-8am) + 2 tabs Baseline: NB. All p's required to have clinician-rated CGI- later(11am-1pm). Each tablet=100mg Severity scale score of >=4 (moderately ill or worse). MOD or matched PLB Data grouped by MOD dose (N): 300/0 (50), 200/100 (49), Group 5N= 48 100/200 (48), 200/200 (50), PLB (51) CGI-S, N (%): Modafinil 100mg morn + 200mg Moderately Ill: 17 (34%); 22 (45%); 19 (40%); 24 (48%); 25 afternoon - WASHOUT: 7-10 day single- (49%) blind PLB phase Markedly Ill: 26 (52%); 24 (49%); 24 (50%); 21 (42); 23 DOSE:100mg/day days 1-3; increased (45%) 100-mg increments every 2 days to max Sverely Ill: 7 (14%); 2 (4%); 4 (8%); 5 (10%); 3 (6%) dose (ie. 300mg by day 6) Among Most Extremely Ill: 0 (0%); 1 (2%); 1 (2%); 0 (0%); 0 ADMIN:3 tablets early morn(0700-0800) + (0%) 2 tabs 4-5hrs later(1100-1300). Each tablet=100mg MOD or matched PLB ADHD-RS-IV, mean (SD)- School Version: Total: 27.3 (14.1); 27.7 (13.5); 25.5 (14.1); 23.0 (11.4); 24.5 (13.8) Inattention: 15.0 (7.3); 15.9 (6.8); 15.1 (7.7); 13.7 (6.2); 13.3 (7.1) Hyperactivity-Impulsivity: 12.7 (8.3); 12.0 (7.8); 10.9 (7.7); 9.7 (6.6); 11.6 (7.7) ADHD-RS-IV, mean (SD)- Home Version: Total: 36.5 (10.2); 37.6 (9.4); 36.8 (9.3); 34.0 (10.9); 35.5 (8.9) Inattention: 19.7 (5.0); 20.3 (5.0); 20.3 (4.6); 19.4 (5.9); 19.4 (4.3) Hyperactivity-Impulsivity: 16.8 (6.6); 17.3 (5.7); 16.4 (6.7); 14.6 (6.5); 16.1 (6.2)

CADS-P, mean (SD) t score: Total: 74.3 (9.8); 76.2 (10.6); 75.1 (9.6); 74.1 (11.2); 73.4 (10.9) ADHD Index: 73.0 (8.0); 73.1 (9.3); 73.6 (8.1); 72.6 (9.4); 73.4 (9.2) Inattentive: 72.9 (9.4); 72.6 (10.6); 72.3 (8.9); 71.3 (10.2); 71.5 (10.2) Hyoeractive-Impulsive: 72.8 (12.0); 77.0 (10.9); 74.0 (12.8); 73.3 (12.7); 72.2 (13.5) Results from this paper: Internal Validity 1.1 Well covered 1.2 Adequately addressed 1.3 Not reported adequately 1.4 Well covered 1.5 Adequately addressed 1.6 Well covered 1.7 Well covered 1.8 MOD groups 11% (22/197), comparable n's across dosing groups; PLB group: 6% (3/51) 1.9 Well covered 1.10 Not reported adequately

Overall assessment of study 2.1 1+ BOHNSTEDT2005 Study Type: RCT n= 16 Data Used Group 1N= 6 Funding: Grants from Eli ADHDRS-I (Change from Baseline: mean) Lilly and Company and Study Description: Non-specific comorbidity. Age: Mean 9 Range 8-11 Placebo. Mean dose NA - ADMIN: Notes: TAKEN AT: Baseline, then Weekly (visits Indiana University School of Sample: 'Children' (8-11) Sex: 14 males 2 females Morning 2-7). Medicine. Type of Analysis: ITT Group 2N= 10 Diagnosis: LOST TO F.U.: 0% (all p's completed trial and Atomoxetine. Mean dose NR - Blindness: Double blind 69% Oppositional defiant disorder by Kiddie provided all data) DOSE:Began with 0.8mg/kg/day (3 days), Schedule for Affective Disorders… Duration (days): Mean 49 then increased to 1.2mg/kg/day. Dosing could either be increased by 1.8 Setting: Indiana, US. P's recruited from large 31% ADHD Inattentive subtype by Kiddie mg/kg/day or decreased to 0.8mg/kg/day child psychiatry outpatient clinics. Schedule for Affective Disorders… based on response (Max. 1.8mg/kg/day or 120mg/day). Notes: No details given on randomisation ADMIN:Morning. procedure or allocation concealment. 69% ADHD Combined subtype by Kiddie Schedule for Affective Disorders… Info on Screening Process: 22 screened, 6 excluded because they did not meet study Exclusions: None given. criteria (primarily due to failing to meet diagnostic criteria). Baseline: Not given. Results from this paper: Internal validity:

1.1 Well covered 1.2 Not reported 1.3 Not addressed 1.4 Well covered 1.5 Well covered 1.6 Well covered 1.7 Well covered 1.8 0% 1.9 Well covered 1.10 Not applicable

Overall assessment of the study:

2.1: 1-

NB. Small sample size BROWN2006 Study Type: RCT n= 153 Data Used Group 1 N= 101 Funding: Not reported CPRS-ADHD Index (mean change) Study Description: 'Non-specific' comorbidity: Age: Mean 9 Range 8-12 Atomoxetine. Mean dose 1.32mg/kg (SD "Responders": ADHD-RS-Teacher version Some p's with 'Class 1' or 'Class 2' Sex: 123 males 30 females = 0.30) - WASHOUT: Approximately one comorbidities. (dichot) week Sample: 'Children' & 'Adolescents' Diagnosis: Leaving the Study Early for Any Reason DOSE: Began at 0.8mg/kg/day for 1st 3 33% Oppositional defiant disorder by DSM-IV (K- days; Titrated to max of 1.8mg/kg/day (if Type of Analysis: ITT (LOCF, >=1 dose & 1 "Responders": CPRS-ADHD Index (dichot) SADS-PL: Behavioral Disorders Suppl.) necessary & tolerated), to max 30mg/day. post-BL assessmt) ADHD-RS-Teacher version (mean change) Final 2 weeks-steady dose. Data Not Used ADMIN: Once daily with breakfast, Blindness: Double blind 1% ADHD Hyperactive/Impulsive subtype by "Responders": CHQ-Psychosocial Summary medication identical to PLB Duration (days): Mean 49 DSM-IV (K-SADS-PL: Behavioral Disorders (dichot) - not relevant outcome Suppl.) Leaving the Study Early due to Adverse Setting: 10 sites across the USA. P's recruited Events - no data through primary care clinicians, mental health professionals and by advertisement. Nt N dtil d i ti Info on Screening Process: NR: Only that 153 30% Learning Disorder by DSM-IV (K-SADS-PL: Academic Performance Rating Scale (mean Group 2N= 52 were randomised. Behavioral Disorders Suppl.) change) - not relevant outcome Placebo - WASHOUT: Approximately one CHQ-Psychosocial Summary (mean change) week 100% ADHD by DSM-IV (K-SADS-PL: not relevant outcome DOSE: Began at 0.8mg/kg/day for 1st 3 Behavioral Disorders Suppl.) Notes: TAKEN AT: Clinic visits weekly initially, days; Titrated to max of 1.8mg/kg/day (if then bi-weekly toward end of trial. necessary & tolerated), to max 30mg/day. 27% ADHD Inattentive subtype by DSM-IV (K- NB.'Responders' for any measure = if endpoint t- Final 2 weeks-steady dose. SADS-PL: Behavioral Disorders Suppl.) score was no worse than one standard deviation ADMIN: Once daily with breakfast, below the normative mean for their age and medication identical to ATX gender; CHQ= Child Health Questionnaire 72% ADHD Combined subtype by DSM-IV (K- SADS-PL: Behavioral Disorders Suppl.)

Exclusions: Weighed less than 25kg at study entry; documented history of bipolar I or II disorder, or any history of psychosis; had mental retardation; any organic brain disease, or history of any seizure disorder; taking any psychotropic medication; history of alcohol or drug abuse within previous 3 months, significant previous or current medical conditions; unavailabilty of a single primary teacher to provide ratings and reports as required. Notes: NB. All p's at least average intelligence (assessed using Weschler Abbreviated Scales of Intelligence; P's with anxiety &/or depressive disorders were eligible for trial-entry Baseline: Previous Stimulant Use: 59.5% of total sample. ADHDRS-TV Mean(SD): N(ATX)=99, N(PLB)=51 ATX group: 65.6(5.2); PLB group: 64.4(6.3) CPRS-ADHD Index Mean(SD): N(ATX)=99, N(PLB)=51 ATX group: 74.6(8.5); PLB group: 75.2(8.5) Results from this paper: Internal validity; 1.1 Well covered 1.2 Not reported adequately 1.3 Not reported adequately 1.4 Well covered 1.5 Well covered 1.6 Well covered 1.7 Adequately addressed 1.8 ATX group: 16.8% (84/101); PLB group: 7.7% (4/52) 1.9 Poorly addressed (last observation carried forward for the participants who had at least one trial medication dose and those who had at least one post-baseline assessment); Lost to Follow-up (ie. Not included in ITT analysis, according to text: ATX = 2/101; PLB = 1/52; Actually- n's vary for each scale. 1.10 Not reported adequately

Overall assessment of the study; 2.1: 1+ BUTTER1983 Study Type: RCT n= 30 Data Used Group 1N= 10 Funding: Financial support Conners Teacher Rating scale (mean) provided by Scientific Study Description: Assume'Pure Age: Range 6-12 ACTH4-9 analog. Mean dose NR - Development Group, ADHD'(comorbidities NR) Digital pulse volume (mean) - relevant WASHOUT: 1wk, followed by 1wk PLB Sex: all males Organon International B.V., Sample pred.'Children',some'preschoolers'(%'s outcome?? (open label ??) phase. Oss, The Netherlands (also NR). Diagnosis: Skin conductance (mean) - not relevant DOSE: Adjusted for body weight supplied ACTH4-9 analog) NB.trial incl.ACTH4-9analog arm(not relevant 100% ADD with Hyperkinesis by "Clinical outcome??? (0.5mg/kg; range 10-20mg) here). diagnosis" NOS & Conners shortformRS>15 ConnersShortformRS(mean;parent&investiga ADMIN: Single capsule ingested at r rated) 7:30am (assume appearance the same Type of Analysis: ITT (assume no dropouts-not across condititions to maintain blind-NR) reported) Exclusions: IQ <= 85; abnormal perceptual functioning Data Not Used (NOS); hyperkinetic behavior not apparent throughout most Matching Familiar Figures Task - not relevant Blindness: Double blind of the day; untreated hyperkinetic behavior not a severe outcome Duration (days): Mean 7 difficulty at both home and school. Notes: NB. Mean age mean not reported. Setting: Ottawa, Baseline: At end of PLB washout: Mean (SD) PLB gp; MPH Notes: Randomisation: No detail. gp; ACTH gp, resp. If S i P N d il Conners Short form RS: 17.7 (3.7); 17.0(6.3); 21.7(4.0) Notes: TAKEN AT: End of PLB washout phase; Group 2N= 10 Conner Teacher RS: 42.7(14.2); 41.4(18.3); 39.1(17.1) and Endpoint (90mins after medication taken) Methylphenidate. Mean dose NR - LOST to F.U.: Unknown (no n's reported in WASHOUT: 1wk, followed by 1wk PLB results, no d/o's reported either- assume no d/o's (open label ??) phase. DOSE: Adjusted for body weight (0.5mg/kg; range 10-20mg) ADMIN: Single capsule ingested at 7:30am (assume appearance the same across condititions to maintain blind-NR) Group 3N= 10 Placebo. Mean dose NA - WASHOUT: 1wk, followed by 1wk PLB (open label ??) phase. DOSE: Adjusted for body weight (0.5mg/kg; range 10-20mg) ADMIN: Single capsule ingested at 7:30am (assume appearance the same across condititions to maintain blind-NR) Results from this paper: Internal Validity 1.1 Well covered 1.2 Adequately addressed 1.3 Poorly addressed 1.4 Adequately addressed (double-blind only, no further description) 1.5 Adequately addressed 1.6 Poorly addressed (not reported whether were similar in appearance) 1.7 Adequately addressed 1.8 0% (assumed, Not addressed) 1.9 Not addressed 1.10 Not applicable

Overall assessment of study 2.1 1+ CASAT1987 Study Type: RCT n= 30 Data Used Group 1N= 20 Funding: Supported by a Conners' Teacher Q(39-item)Hyperact. factor grant from the Burroughs- Study Description: Comorbidity: NR Age: Mean 8 Range 6-12 Bupropion - WASHOUT:All p's drug-free (mean) Wellcome Company. Sample: 'Children' and 'Adolescents'(%'s NR) Sex: 25 males 5 females min.14days prior to trial. Conners' Abbrev. Teacher Q (10-item) (mean DOSE: All p's PLB for 1wk (single-blind) Type of Analysis: Completer (continuous data Diagnosis: Conners' Abbrev. Parent Q (10-item) (mean) then 3mg/kg on day 1, escalated to reported only) 3% Conduct disorder by DSM-III CGI - Severity (mean) 6mg/day days 15-28. All PLB again-1wk Blindness: Double blind @ end (s-blind). Conners' Parent Q(93-item) Hyperact. factor ADMIN:'Matching' tablets; given at 7am & Duration (days): Mean 28 100% ADD with Hyperactivity by DSM-III (mean) 7pm daily. Data Not Used Setting: Outpatient children, USA. Group 2N= 10 Exclusions: IQ <70 on WISC-R; history of seizure disorder, Brief Psychiatric Rating Scale for Children - Placebo - WASHOUT:All p's drug-free Notes: Randomisation: No detail. tic disorder, and unstable medical condition, and known not relevant outcome min.14days prior to trial. NB. 1wk single-blind PLB lead in, then 4wks hypersensitivity to psychotropic ; weight <20 Continuous performance test (NOS) - not DOSE: All p's PLB for 1wk (single-blind) randomised(double blind)BUP/PLB, then 1wk kgs; poor physical health; abnormal hematological or clinical relevant outcome then 3mg/kg on day 1, escalated to single-blind PLB. ie.6wks total. lab values, or EEG or EKG; postmenarchal females. Conners' Teacher Q(39-item)Conduct factor 6mg/day days 15-28. All PLB again-1wk Info on Screening Process: Not reported. NB. Notes: Additional diagnostic criteria required for inclusion: (mean) - ?? Unsure if relevant @ end (s-blind). 31 recruited to trial, 1 dropped out prior to Concurence of mean P and T scores of >1.5 on Short term memory test (NOS) - not relevant ADMIN:'Matching' tablets; given at 7am & randomisation (reasons unrelated to trial). Hyperactive factor for teacher questionnaire & >1.5 on outcome 7pm daily. Therefore 30 randomised. Impulsive-hyperactive or Restless-immature factors for Conners' Parent Q(93-item) Restless factor NB. 4/30 previously sucessfully treated with parent questionnaire. (mean) - ?? Unsure if relevant MPH- randomisation resulted in 2 in each arm Baseline: Conners Parent Questionnaire: Mean(SD): Conners' Parent Q(93-item) Conduct factor of trial. 26/30 drug naive. Hyperactivity Factor: BUP gp 1.22(0.48); PLB gp 1.19(0.22) (mean) - ?? Unsure if relevant Restless Factor: BUP gp 1.67(0.60); PLB gp 2.12(0.54) CGI - Improvement (mean) - possibly Conduct Factor: BUP gp 1.31(0.51); PLB gp 1.53(0.49) usable??? Scored 'backwards'

Conners PQ-Abbrev.: Mean(SD): BUP gp: 17.47(6.47); PLB gp: 21.33(5.61) Notes: TAKEN AT: CGI, BPRSC: Baseline & Conners Teacher Questionnaire: Mean(SD): weekly by study physician; CT/PQ's: baseline & Hyperactivity Factor: BUP gp 1.81(0.48); PLB gp 1.88(0.34) weekly; CPT & STMT: at start & end of active Conduct Factor: BUP gp 1.29(0.67); PLB gp 1.23(0.81) drug trial. Lost to Follow-Up: 10% (1/10) PLB gp; 5% (1/20 Conners TQ-Abbrev.: Mean(SD): BUP gp (not included in analysis). BUP gp: 19.93(4.62); PLB gp: 20.67(7.87)

CGI-Severity: Mean(SD): BUP gp: 5.26(0.56); PLB5.67(0.50)

Results from this paper: Internal validity: 1.1 Well covered 1.2 Not reported adequately 1.3 Not reported adequately 1.4 Well covered 1.5 Adequately addressed 1.6 Adequately addressed 1.7 Well covered 1.8 PLB gp: 10% (1/10); BUP gp: 5% (1/20) 1.9 Poorly addressed 1.10 Not applicable

Overall assessment of the study: 2.1 + CONNERS1980 Study Type: RCT n= 60 Data Used Group 1N= 21 Grant received from Abbott AE: Negativism (dichotomous data) laboratories. Study Description: 'Hyperkinetic Disorder only' Age: Mean 7 Range 6-11 Placebo - ADMIN: All tablets looked AE: Enuresis (dichotomous data) sample, NB: 81% of sample considered to Sex: 57 males 3 females identical. Patients received 2 doses per display learning 'problems' (NOS) in school. AE: Nausea (dichotomous data) day Sample: 'Children' Diagnosis: AE: Nervousness (dichotomous data) Group 2N= 19 100% Hyperkinetic disorder by "Physician Type of Analysis: Completer (N's vary for each AE: Grouchy(dichotomous data) Pemoline. Mean dose 2.25mg/kg/day Diagnosed" (NOS) outcome reported) Conners Teacher Q (Hyperactivity subscale; (60.4 mg/day) - DOSE:Started @ mean) 37.5mg/day, increased each wk (by this Blindness: Double blind Exclusions: WISC IQ <80, unstable family, obsessive, Conners Parent Q (Impulsivity subscale; mea amount); to max 112.5mg/day (stabilised Duration (days): Mean 56 compulsive or phobic behaviour; abnormal laboratory values @ max dose btwn wks 4-8). (relative to the established pediatric norms); Current medical AE: Insomnia/Sleep problems(dichotomous ADMIN:In 18.75mg tablets (identical to Followup: final clinical rating made 2 illness or medical history that contraindicates prescribed data) MPH & PLB), taken: morning (+afternoon weeks`after medication stopped drug therapy; Receiving within the 6 months AE: Stuttering (dichotomous data) dose of PLB to maintain blind, ie. to Setting: 'Majority from middle class homes, prior to recruitment; demonstable or suspected need for AE: Moodiness (dichotomous data) match MPH admin). antiseizure medications; any concurrent therapy referable to relatively stable Boston suburbs'. 'Good AE: Palpitations (dichotomous data) Group 3N= 20 environmental and educational milieu'. chronic illness; Visual/auditory acuity insufficient for normal learning process (ie. 20/50 acuity in one eye for inclusion; Conners Teacher Q (Conduct problem Methylphenidate. Mean dose Notes: Eight week double blind comparison btn bilateral hearing loss >20dB = exclusion) subscale; mean) 0.82mg/kg/day (22mg/day) - DOSE: PEM, MPH and PLB. No details of AE: Irritability/Agitation (dichotomous data) Started at 10mg/day; increased in 5mg randomisation or allocation concealment Notes: Prior therapy for hyperkinesis discontinued for AE: Itching (dichotomous data) steps to max of 60mg/day (stabilised @ provided. minimum of 8 days prior to trial start. max dose btwn wks 4-8). AE: Stomach ache (dichotomous data) Info on Screening Process: 88 children Baseline: Conners-Parent scale: mean (SD) ADMIN: In 5mg tablets (identical to PEM AE: Increased crying (dichotomous data) originally examined for study, 28 not accepted, Conduct problem: PEM gp 1.14 (0.52), MPH gp 1.16 (0.44), & PLB).Split into two daily doses (morn therefore 60 accepted. PLB gp 1.17 (0.54); Conners Teacher Q (Inattentive/passive; mea and afternoon- one half hour prior to meal Impulsivity: PEM gp 1.24 (0.51), MPH gp 1.53 (0.56), PLB AE: Nose bleed (dichotomous data) gp 1.45 (0.51); AE: Anorexia & appetite Hyperactivity: PEM gp 0.80 (0.30), MPH gp 0.99 (0.36), problems(dichotomous data) PLB gp 0.98 (0.36). Conners Parent Q (Antisocial subscale; mean AE: Depression (dichotomous data) AE: Speech incoherent (dichotomous data) AE: Headache (dichotomous data) Conners Parent Q (Hyperactivity subscale; mean) AE: Appetite Increase (dichotomous data) Conners Parent Q (Conduct problem subscale; mean) AE: Eyes reddened (dichotomous data) AE: Thirsty (dichotomous data) AE: Dizziness (dichotomous data) AE: Glassy eyed (dichotomous data) AE: Rash (dichotomous data) AE: Diarrhea (dichotomous data) Data Not Used Conners Parnt/Techr AbbQ Total Score (mea change) - no variablility measure Conners Teacher Q (Various other subscales mean) - not relevant subscales Teacher/Parent/Staff 'Global Judgement' outcome - not validated scale Leaving the Study Early for Any Reason - no data Conners Parent Q (Various other subscales; mean) - not relevant subscales AE: Weight change (mean) - no data Various cognitive/activity count outcomes - no relevant outcome Conners Parent/Teacher Q Total Score (mean change) - no variablility measure AE: Various other AE's (dichotomous data) - not relevant outcomes AE: Blood pressure - no data for PLB group Leaving the Study Early due to Adverse Events - no data AE: Heart rate (bpm, mean) - no data Notes: OUTCOMES TAKEN AT: Cognitive tasks - BL & wk 8; Conners scales - BL, wks 4 & 8; AE's - 2x weekly phone calls with parent & physician rated at wks 4 & 8.

Results from this paper: Internal validity 1.1 Adequately adressed 1.2 Not reported 1.3 Not addressed 1.4 Well covered 1.5 Poorly addressed 1.6 Adequately addressed 1.7 Poorly addressed 1.8 Not reported 1.9 Not reported 1.10 Not applicable

Overall assessment of study 2.1: 1+ CONNERS1996B Study Type: RCT n= 109 Data Used Group 1N= 37 Funding: Partially supported AE: Nausea and Vomiting (dichotomous data) by Career Science Award Study Description: Comorbidity: NR Age: Mean 8 Range 6-12 Placebo - WASHOUT: single blind PLB Conners' Abbrev. Teacher Q (10-item) (mean from the NIMH. Sample: 'Children' and 'Adolescents'(%'s NR) Sex: 98 males 11 females washout-1wk Conners' Abbrev. Parent Q (10-item) (mean) DOSE: 3mg/kg: 1stweek active drug; Type of Analysis: Completer (continuous) & ITT(dichot data-AE's) Diagnosis: Continuous performance test (NOS) 6mg/kg week 3 of active drug. Week 100% ADD with Hyperactivity by DSM-III 2:NR??? Blindness: Double blind Leaving the Study Early due to Adverse Event ADMIN: Matching PLB tablets; twice daily AE: Rash (dichotomous data) Duration (days): Mean 28 (7am & 7pm) Exclusions: IQ <70 on WISC-R; postmenarchal females; Short term memory test (NOS) Group 2N= 72 Followup: 1 wk, following PLB for all. weight <20 kgs; known hypersensitivity to psychotropic Leaving the Study Early for Any Reason medications; history or presence of seizure disorder, or tic Setting: Uni-based outpatient psychiatry clinics; Bupropion - WASHOUT: single blind PLB disorder; poor physical health; abnormal hematological or Data Not Used all sites - advertisements;at 1(of 4)site n=6 p's washout-1wk clinical lab values, or EEG or EKG; Conners' Parent Q (93-item) - no data recruited from child psychiatric inpatient DOSE: 3mg/kg 1stweek active drug; Clinical Global Impressions:Severity of Illness 6mg/kg week 3 of active drug. Week admissions; USA. Notes: NB. All p's needed to be medication free for 14 days no data prior to trial start. Additional diagnostic criteria: score of 2:NR??? Notes: Randomisation: No detail moderate illness severity on Child Diagnostic Scale; Conners' Teacher questionnaire (39-item) - no ADMIN: 50mg & 75mg tablets; twice daily NB. 1wk single-blind PLB lead in, then 4wks occurrence of mean P & T scores >= 1.5 on the CPQ & data (7am & 7pm) randomised(double blind; 2:1)BUP/PLB, then CTQ (hyperact. & conduct factors) Notes: TAKEN AT:Conners Q's, CGI-S: at 1wk single-blind PLB. ie.6wks total. screening, day0 of active drug trial, days14, 28 Baseline: Screen = b4 placbo lead-in week; Baseline = Info on Screening Process: Not reported, (endpoint),& 35 (following 1wk of PLB at end); following placebo lead-in week, day b4 active drug trial except 'the number of subjects screened STM test & CPT: day 0 and 28. began. generally far exceeded the number accepted, Abbreviated Conners Parent Scale: N[completer], Mean owing to the strict entrance criteria'. (SD): Screen: PLB gp 34, 22.53(4.72); BUP gp 67, 21.64(5.00) Baseline: PLB gp 36, 20.67(6.07); BUP gp 69, 19.55(5.62) Abbreviated Conners Teacher Scale: N[completer], Mean (SD): Screen: PLB gp 32, 21.50(4.08); BUP gp 62, 20.35(5.21) Baseline: PLB gp 36, 20.58(5.89); BUP gp 69, 20.03(5.62) Results from this paper: Internal validity 1.1 Well covered 1.2 Not adequately reported 1.3 Not adequately reported 1.4 Well covered 1.5 Well covered 1.6 Adequately addressed 1.7 Adequately addressed 1.8 BUP gp: 11% (8/72); PLB gp: 5% (2/37) 1.9 Adequately addressed 1.10 Adequately addressed

Overall assessment of study 2.1: 1+ DONNELLY1986 Study Type: RCT n= 29 Data Used Group 1N= 17 Funding: NR Conners' Abbrev. Teacher Q (10-item) (mean Study Description: Non-specific comorbidity, all Age: Mean 8 Range 6-12 Desipramine hydrochloride - Leaving the Study Early due to Adverse Event Class 2 (see 'Diagnoses') Sex: all males WASHOUT:10/29 p's who had taken Sample: Largely 'Children', some 'Adolescents' Leaving the Study Early for Any Reason medication previously stopped taking it at Diagnosis: least 2wks prior to trial. Type of Analysis: ITT (NB. all p's completed Data Not Used 28% Conduct disorder by DSM-III DOSE:25mg on day 1, increased by 1 trial & provided data) Classroom motor activity (weekly activity counts) - not relevant outcome capsule/day to 100mg for remainder of Blindness: Double blind study 7% Oppositional disorder by DSM-III Urinary biochemical measures - not relevant ADMIN: 1 dose/day(morn), 25mg capsule Duration (days): Mean 14 outcome Group 2N= 12 24% Developmental disorder AE: Blood pressure - no extractable data Setting: Participants referred from local Placebo. Mean dose 3.38(sd 0.64) mg/kg (reading,maths,language) by DSM-III AE: Heart rate - no extractable data schools, US. at endpoint - WASHOUT:10/29 p's who Continous performance test (Rosveld) - not had taken medication previously stopped Notes: No detail re. randomisation. 100% ADDH by DSM-III relevant outcome taking it at least 2wks prior to trial. Info on Screening Process: P's who scored >=2 Plasma drug levels - not relevant outcome DOSE:25mg on day 1, increased by 1 SD's above average on 30-item Conners Exclusions: No specific exclusions reported, however all Plasma biochemical measures - not relevant capsule/day to 100mg for remainder of Teacher RS interviewed. Parents also participants attended regular classroom in public schools; outcome study completed 48-item Conners questionnaire, each had full scale IQ of >=80; and all had no neurologic ADMIN: 1 dose/day(morn), 25mg capsule though not clear whether this used in disorder or any major medical problem. (identical to DES) enrolment. Boys only recruited. Notes: All p's met DSM-III criteria in at least 2 settings (home, school, hospital) Baseline: Conners Abbreviated Rating Scale (Teacher- Notes: OUTCOMES TAKEN AT: Conners rated): Mean (SD) Abb.RS (Teacher) rated daily. AE's rated at BL, DES gp: 8.12(2.17); PLB gp: 7.68(3.33) day3 and day14 (endpoint) with physician-rated STESS (Subject's Treatment Emergent Side Effects Scale).BP/HR measured daily.

Results from this paper: Internal validity:

1.1 Well covered 1.2 Not reported adequately 1.3 Not reported adequately 1.4 Well covered 1.5 Adequately addressed 1.6 Adequately addressed 1.7 Adequately addressed 1.8 Zero drop-out rates in both groups 1.9 Not applicable (all p's completed trial and provided data) 1.10 Not applicable

Overall assessment of the study:

2.1 1+ FINDLING2006 Study Type: RCT n= 318 Data Used Group 1 N= 139 Funding: Celltech Americas, AE: Anorexia (dichot data) Inc. (part of UCS). Study Description: 'Pure' ADHD sample (see Age: Mean 9 Range 6-12 Methylphenidate (Extended-release, AE: Abnormal behaviour (NOS; dichotomous exclusions). Sex: 252 males 66 females Equasum XL) - WASHOUT: None Sample: 'Children'; some 'Adolescents'. data) DOSE:If p's taking 10-20mg pre-trial - Diagnosis: AE: Incidence of 'severe' rating(invstgtr; dicho 20mg; if 25-40mg pre-trial - 40mg; if Type of Analysis: ITT (LOCF) 5% ADHD Hyperactive/Impulsive subtype by AE: Cough (dichotomous data) >40mg pre-trial - 60mg. Blindness: Double blind DSM-IV ADMIN: Whole dose given once-daily- Teacher 10-item IOWA Conners (O/D morn; PLB at lunchtime. All identical Duration (days): Mean 21 component; mean) gelatin capsules. 100% ADHD by DSM-IV Parent 10-item IOWA Conners (O/D Group 2N= 46 Setting: 44 sites in , Canada, and the component; mean) USA. No further detail re. recruitment, etc. 24% ADHD Inattentive subtype by DSM-IV AE: Pyrexia (dichotomous data) Placebo - WASHOUT: None Notes: Randomised in ratio of 3:3:1 (Immediate- DOSE: As with other groups dose AE: Vomiting (dichotomous data) H release MPH: Extended-release MPH: PLB) depended on stable pre-trial dose of MP 71% ADHD Combined subtype by DSM-IV AE: Insomnia/Sleep problems(dichotomous ADMIN: Twice daily- morning & Info on Screening Process: 346 screened; 327 data) lunchtime. All identical gelatin capsules. randomised, only 318 received treatment (N=9 Exclusions: Outside age range (6-12 yrs inclusive); not on AE: Pharyngitis (dichotomous data) Group 3 N= 133 withdrawn post-randomisation for not meeting stable dose of methylphenidate for >=3 weeks prior to AE: Abdominal pain (Upper; dichotomous data all eligibility criteria; NB. Details reported only Methylphenidate (Immediate release) - screening; not attending a school setting in which a single AE: Viral infections (dichotomous data) WASHOUT: None (began trial day after for N=318). teacher could make morning and afternoon assessments of AE: Upper respiratory tract infection (dichot) completing pre-trial dose) the child's behaviour; females who had experienced Leaving the Study Early due to Adverse Event DOSE:If p's taking 10-20mg pre-trial - menarche; any comorbid psychiatric disorder requiring 20mg; if 25-40mg pre-trial - 40mg; if medication; history of seizure, tic disorder, or a family history AE: Decreased appetite (dichotomous data) >40mg pre-trial - 60mg. of Tourette's disorder; IQ <80 or functioning at level of Teacher 10-item IOWA Conners (I/O ADMIN: Half of total dose twice daily- intelligence indicative of an IQ <80; use of unapproved component; mean) morn & lunch. All identical gelatin medications; use of an investigational product within 30 days Parent 10-item IOWA Conners (I/O capsules. prior to study entry; concurrent chronic or acute illness, component; mean) diability, or medication, that might confound the results of rating tests; diagnosed with hyperthyroidism, glaucoma, or AE: Headache (dichotomous data) eating disorder; current substance abuse disorder or living AE: Irritability (dichotomous data) with someone with a current substance abuse disorder; AE: Rash (dichotomous data) demonstrated a lack of response to methylphenidate. CGI-I rating =1 or 2 (very/much improved; Notes: Diagnosis confirmed with K-SADS-PL dichot) NB. Immediate-release (IR) MPH was most commonly AE: Tics (dichotomous data) prescribed treatment at screening (70%) followed by Concerta (18%) AE: Abdominal pain (NOS; dichotomous data) Baseline: CGI Severity of Illness (% considered by AE: Appetite Increase (dichotomous data) Investigator to be 'mildly' or 'moderately' ill): AE: Nasopharyngitis (dichotomous data) MPH-IR group: 53.9%; MPH-EqXL group: 52.5%; PLB AE: 'At least one AE' (dichotomous data) group: 50.8% Data Not Used Parent 40-item SNAP - no data PGA: 'much'or 'moderately' improved (dichot data) - ?? Relevant, validated scale? Teacher 40-item SNAP - no data Leaving the Study Early for Any Reason - no data Notes: TAKEN AT: All baseline & weekly. NB. I/O = Inattentive/Overactivity; O/D = Oppositional/Defiant NB. PGA = Parent Global Assessment Scale NB. SE and 95% CI reported - SD calculated from SE.

Results from this paper: Internal validity; 1.1 Well covered 1.2 Not reported adequately 1.3 Not reported adequately 1.4 Well covered 1.5 Adequately addressed 1.6 Adequately addressed 1.7 Well covered 1.8 Unknown (allocation of drop-outs not reported). Total drop-out rate: 10% (33/318) 1.9 Poorly addressed: Analysis reported to be ITT (LOCF) however endpoint N's are less than N's randomised; Lost to Follow-up: MPH-IR gp 13/133; MPH EqXL gp: 19/133; PLB gp: 7/46. 1.10 Not reported adequately

Overall assessment of the study 2.1 1+ GITTELMANKLEIN1976A Study Type: RCT n= 166 Data Used Group 1N= 42 NB: Clear that trial double- Home Hyperactivity Scale blind in first 4wks. Not clear Study Description: 'Hyperkinetic only' Sample Age: Mean 8 Range 6-12 Placebo - ADMIN: 3 capsules/daily: 2 if double-blind maintained Sample: 'Children' Conners white: 1 in morn, 1 @ lunchtime, & 1 Sex: 140 males 15 females after this time. Notes: TAKEN AT: Baseline; 4wks (incl. PLB pink: at bedtime (White caps. matched Type of Analysis: Completer Diagnosis: data); 12wks (incl.MPH & THI & combo data MPH appearance exactly; pink caps. Blindness: Double blind 100% Hyperkinetic Reaction of Childhood by only). *PLB only admin for 4wks- concern re. matched THI appearance exactly, to maintain blind). Duration (days): DSM-II maintaining p's with severe behav.probs. ATTRITION: PLB 2% (1/42); MPH 5% (2/41); TH Group 2N= 41 12% (5/41); MPH +THI 7% (3/42) Setting: US. Exclusions: Neurological disease, such as , Methylphenidate. Mean dose End 4wks: hemiparesis, cerebral palsy, microcephaly. Psychotic, 1.78mg/kg/day; end 12wks: Notes: No mention of randomisation method or IQ<80, no telephone at home, family not fluent English- concealment. NB: MPH, THI, MPH+THI 1.66mg/kg/day - DOSE: Fixed for first speakers. No previous history of psychopharmalogical 4wks: all p's to reach max dose conditions = 12 wks; PLB condition = 4 wks treatment (i.e. >5mg/day or 10mg/day (60mg/day). only (started at same point). MPH for 2 month period); Not attending school; ADMIN:3 capsules/daily: 2 white: 1 in Info on Screening Process: Approx 400 referred Notes: In addition to DSM-II diagnostic tool: Teacher Rating morn, 1 @ lunchtime (both MPH) & 1 to research due to school behaviour problems. Scale (39-item; item: restless/hyperactive had to be rated pink: at bedtime (PLB). 166 accepted into study. Reasons for exclusion >=2 for inclusion; Home Hyperactivity Scale >=28/44 (27- were; did not meet hyperactivity criteria, parents item). withdrawing, treated elsewhere, receiving medication at referral. Baseline: NB: Age and sex demographic data reported for only those that completed trial (N=155). Conners teacher rating scale (39-item), Conners parent symptom scale (93-item) and Home Hyperactivity scale:"No differences among four treatment groups were found at Group 3N= 42 baseline" Thioridazine + methylphenidate. Mean dose See details - DOSE:Fixed first 4wks max MPH dose=60mg/day; max THI dose=200mg/day. Av's:End 4wks:MPH 1.83,THI 6.98mg/kg/day. End 12 wks:MPH 1.59,THI 3.94mg/kg/day. ADMIN:2 white caps.:1 in morn,1 @ lunchtime(both MPH)& 1 pink:@ bedtime (THI). Group 4N= 41 Thioridazine. Mean dose End 4wks: 6.0mg/kg/day; end 12wks: 4.54mg/kg/day - DOSE: Fixed for first 4wks: max dose reached = 200mg/day. ADMIN:2 white capsules: 1 in morn, 1 @ lunchtime (both PLB) & 1 pink capsule at bedtime (THI). Results from this paper: Internal validity 1.1 Well covered 1.2 Not reported 1.3 Not assessed 1.4 Adequately addressed 1.5 Well covered 1.6 Well covered 1.7 Well covered 1.8 6.6% 1.9 Poorly addressed 1.10 Not applicable

Overall assessment of study 2.1: 1+ GREENHILL2002 Study Type: RCT n= 321 Data Used Group 1 N= 158 Funding: Celltech Conners' Parent Global Index (10-item) Pharmaceuticals Inc. Study Description: 'ADHD only' Sample Age: Mean 9 Range 6-16 Modified-release methylphenidate - Pittsburgh Side Effect Questionnaire (11-item Sample: 'Children' and 'Adolescents' Sex: 257 males 57 females Modified Release=Dual phase Conners' Teacher Global Index (10-item) formulation: contains immediate release Type of Analysis: ITT (p's with 'minimal Diagnosis: Data Not Used (30% by weight) & extended release requisite efficacy data') (70%) forms of MPH. 100% ADHD by NIMH DISC-IV Clinician-rated CGI - outcome not relevant Blindness: Double blind DOSE: Wk1: 20mg, then titrated up by CGI for improvement (CGI-I) - outcome not 20mg increments. Mean doses: Duration (days): Mean 21 Exclusions: Comorbid psychiatric diagnosis; history of relevant wk1=20mg,wk2=32.3mg,wk3=40.7mg. seizure or tic disorder or a family history of Tourette's Notes: TAKEN AT:Baseline; T-scales: 3times/wk ADMIN: 3 capsules (morn) Setting: 32 centers in USA syndrome; IQ below 80; inability to follow or understand (alternating days); P-scales:once/wk. Group 2 N= 163 Notes: Stratified randomisation according to study instructions; female who had undergone menarche; ATTRITION:11% (17/158) MPH gp; 17% (28/163 Placebo - ADMIN: 3 capsules in the whether received previous drug treatment for use of , pemoline or an investigational drug PLB gp. morning, identical to the MPH capsules. ADHD. No mention of who randomised or within 30 days of study entry; concomitant use of clonidine, LOST TO F.U.:n's not incl.in ITT efficacy concealment. drugs or medications known to affect BP, analysis; safety analysis(resp)-MPH gp: 5/158; heart rate or CNS function; hyperthyroidism or glaucoma; 3/155; PLB gp: 4/163; 2/16 Info on Screening Process: 507 screened; 186 any concurrent or acute illness or disability that could D/O prior to/during 1wk single-blind PLB confound the study results. Children who had failed a washout (before randomisation). 321 previous trial of stimulants for ADHD, had required a third randomised to treatmt phase. daily dose in the afternoon or evening, had a documented allergy or intolerance to MPH or living with anyone who currently had a substance abuse disorder (excluding dependency); p's who responded to plb in washout. Notes: The National Institute of Mental Health diagnostic Interview Schedule for Children-Version 4.0. Baseline: Mean (SD) Conners' Global Index-Teacher; MPH 12.7(7.2), placebo 11.5(7.3) Conners' Global Index-Parent; MPH 13.6(6.6), placebo 12.9(7.6) CGI Severity of Disorder; MPH 4.5(0.9), placebo 4.4(0.9) Results from this paper: Internal Validity; 1.1 well covered 1.2 adequately adressed 1.3 not addressed 1.4 well covered 1.5 well covered 1.6 well covered 1.7 well covered 1.8 Methylphenidate=11%, placebo=17% 1.9 adequately addressed 1.10 not addressed

Overall assessment of study 2.1: 1+ GREENHILL2006 Study Type: RCT n= 103 Data Used Group 1N= 50 Funding: Novartis AE: Anorexia (dichot data) Pharmaceuticals Corporation Study Description: 'Pure' ADHD sample (see Age: Mean 10 Range 6-17 Placebo. Mean dose At endpoint: 26.9+/- CGI-S (moderately; markedly; severely ill; exclusions) Sex: 66 males 37 females 7.1mg/day - WASHOUT: >=7 days Sample: 'Children' & 'Adolescents' dichot) DOSE: Began at 5mg/day; Titrated (over Diagnosis: AE: Stomach discomfort (dichotomous data) 5 weeks) by 5mg/day/week (if necessary Type of Analysis: ITT(LOCF, if >=1 dose & 1 2% ADHD Hyperactive/Impulsive subtype by & tolerated), to max 30mg/day. Final 2 post-BL CADS-T assessmt) AE: Otitis media (dichotomous data) DSM-IV (psychiatric exam & ADHD module K- weeks-dose held constant. AE: Gastroenteritis (dichotomous data) Blindness: Double blind SADS-PL) ADMIN: No detail re appearance, when Leaving the Study Early for Any Reason taken, etc. Duration (days): Mean 49 100% ADHD by DSM-IV (psychiatric exam & AE: 'Notable' reduction in heart-rate (dichot) Group 2N= 53 Setting: 12 centres in the . ADHD module K-SADS-PL) AE: Vomiting (dichotomous data) Dexmethylphenidate-Extended release. AE: Insomnia/Sleep problems(dichotomous Mean dose At endpoint: 24.0+/- Notes: No detail reported re. randomisation. 22% ADHD Inattentive subtype by DSM-IV data) 7.1mg/day - WASHOUT: >=7 days Info on Screening Process: NR, only reported (psychiatric exam & ADHD module K-SADS-PL) AE: Nausea (dichotomous data) DOSE: Began at 5mg/day; Titrated (over that 103 were randomised. AE: Abdominal pain (Upper; dichotomous data 5 weeks) by 5mg/day/week (if necessary & tolerated), to max 30mg/day. Final 2 76% ADHD Combined subtype by DSM-IV AE: Upper respiratory tract infection (dichot) weeks-dose held constant. (psychiatric exam & ADHD module K-SADS-PL) Leaving the Study Early due to Adverse Event ADMIN: No detail re appearance, when AE: Headache (dichotomous data) taken, etc. Exclusions: Not attending school in a classroom setting & AE: 'At least one AE' (dichotomous data) not having the same teacher for the duration of the study who was able and willing to perform symptom assessments; AE: >=7% reduction in body weight from BL functioning below age-appropriate academic levels; females (dichot) who were pregnant (verified by compulsory pregnancy test, if AE: Influenza (dichotomous data) reached menarche), or nursing, or not on adequate and AE: Nasopharyngitis (dichotomous data) reliable contraception throughout trial; clinically significant AE: Affect lability (dichotomous data) abnormalities in vital signs, physical exams or lab tests; history of seizures or use of convulsant medication; AE: 'Notable' increase in diastolic BP (dichot) comorbid psychiatric conditions (obtained by clinical AE: Diarrhea (dichotomous data) interview); any medical condition that could: interfere with AE: Abdominal pain (NOS; dichotomous data) study participation or assessments, or pose a danger with AE: Dyspepsia (dichotomous data) admin of MPH; taking any psychotropic medications; those who had iniated psychotherapy in the last 3 months; positive AE: Irritability (dichotomous data) drug screen; history of poor response to MPH; taking AE: 'Notable' increase in systolic BP (dichot) any other investigational drug 30 days prior to study entry. AE: Fatigue (dichotomous data) Notes: NB. For boys aged 6-8: >=27 on Conners AE: Decreased appetite (dichotomous data) ADHD/DSM-IV Scale-Teacher; aged 9-11: >=24; aged 12- CGI-I rating =1 or 2 (very/much improved; 14: >=19; aged 15-17: >=14; For girls: >=16; >=13; >=12; dichot) >=6, resp. Data Not Used Baseline: Conners ADHD/DSM-IV Scale-Teacher Version CADS-Parent total score (mean) - no (CADS-T): Mean (SD) [n(d-MPH-ER)=52; n(PLB) = 47]. variablility measure d-MPH-ER group: 33.4(8.95); PLB group: 35.2(10.04) Conners ADHD/DSM-IV Scale-Parent Version (CADS-P): AE: Weight change (mean change) - no Mean (SD) [n(d-MPH-ER)=52; n(PLB) = 48]. variablility measure d-MPH-ER group: 40.1(9.23); PLB group: 38.9(8.52) CADS-Teacher subscales (inattent. & CGI-Severity rating: (% d-MPH-ER, % PLB gp, resp) hyperct.,mean) - no variablility measure 4: 66%; 60% CADS-Parent subscales (inattent. & 5: 30.2%; 38% hyperct.,mean) - no variablility measure 6: 3.8%; 2% CADS-Teacher total score (mean) - no variablility measure CHQ component scores (mean) - no variablilit measure Notes: TAKEN AT: Baseline and weekly visits throughout trial, AE's spontaneously reported.

Results from this paper: Internal Validity; 1.1 Well covered 1.2 Not reported adequately 1.3 Not reported adequately 1.4 Well covered 1.5 Adequately addressed 1.6 Well covered 1.7 Well covered 1.8 d-MPH-ER group: 9% (5/53); PLB group: 26% (13/50) 1.9 Adequately addressed (last observation carried forward for the participants who had at least one trial medication dose and those who had at least one post-baseline CADS-T assessment); Lost to Follow-up (ie. Not included in ITT analysis): d-MPH-ER = 0/53; PLB = 3/50 1.10 Adequately addressed

Overall assessment of study 2.1: 1+ GREENHILL2006A Study Type: RCT n= 200 Data Used Group 1N= 67 Funding: For trial: Not AE: Pharyngitis (dichotomous data) reported; NB. Several Study Description: 'Non-specific' comorbidity: Age: Mean 9 Range 6-16 Placebo. Mean dose 383.1(85.5)mg/day - ADHD-RS-IV School version Hyperact./Impuls WASHOUT: >=7 days B4 BL authors receive support No specific exclusions of either class 1 or 2 Sex: 144 males 54 females from several pharmaceutical comorbidities, but details NR (mean) DOSE: Began @ 1 tablet; titrated companys. Sample:'Children' (68%) & 'Adolescents' (32%) Diagnosis: AE: Nervousness (dichotomous data) (individually optimised dose):days 3-7: 2 4% ADHD Hyperactive/Impulsive subtype by tabs; days8-14:3 tabs; days 15-21: 4 tabs Type of Analysis: ITT, LOCF-although n's vary AE: Diastolic blood pressure (mm Hg, mean) DSM-IV(NIMH DISC-IV); ADHDTRS>=1.5 day 22-end 5 tabs for endpoint outcomes AE: Gastroenteritis (dichotomous data) SD's;CGI-S>=4 ADMIN:85mg 'film-coated'tablets, Blindness: Double blind ADHD-RS-IV Home version Inattention (mean identical to MOD; once daily:morn AE: Accidental injury (dichotomous data) Duration (days): Mean 63 100% ADHD by DSM-IV(NIMH DISC-IV); Group 2 N= 131 ADHDTRS>=1.5 SD's;CGI-S>=4 Leaving the Study Early for Any Reason Modafinil. Mean dose Setting: 18 centres throughout the United AE: Vomiting (dichotomous data) 361.4(90.9)mg/day - WASHOUT: >=7 States. 24% ADHD Inattentive subtype by DSM- AE: Rhinitis (dichotomous data) days B4 BL DOSE: Began @ Notes: P's 'centrally randomised' (Cephalon, IV(NIMH DISC-IV); ADHDTRS>=1.5 SD's;CGI- ADHD-RS-IV Home version Hyperact./Impuls 85mg;titrated(individually optimised Inc.) in 2:1 ratio within each centre. S>=4 (mean) dose):days 3-7 170mg; days8-14 255mg; Info on Screening Process: 295 screened, 95 CPRS:R-S ADHD Index (mean) days 15-21 340mg; day 22-end 425mg 70% ADHD Combined subtype by DSM- not enrolled (inclusion criteria not met; AE: Systolic blood pressure (mm Hg, mean) ADMIN:85mg 'film-coated' tablets, once IV(NIMH DISC-IV); ADHDTRS>=1.5 SD's;CGI- exclusion criteria met; consent withdrawn; non- daily:morn S>=4 AE: Infection (dichotomous data) compliance, lost to follow-up; other reason); AE: Decreased appetite (dichotomous data) 200 randomised Exclusions: Height & weight outside of 5th-95th percentile ; ADHD-RS-IV School Total (mean change) IQ <80; comorbid learning disabilities; score <80 on AE: Fever (dichotomous data) Weschler Individual Achievment Test; not attending full time AE: Weight loss (dichotomous data) school (ie. Receiving home schooling); not having both AE: Headache (dichotomous data) teacher and parent willing and able to participate; hisotry or current diagnosis of pervasive developmental disorder, AE: Somnolence/daytime schizophrenia or other psychotic disorders (DSM-IV axis1), tiredness(dichotomous data) any psychiatric comorbidity requiring pharmacotherapy; AE: Insomnia/Sleep problems(dichotomous evidence of suicide risk; ADHD symptoms well controlled on data) current therapy with tolerable side effects; failed to respond AE: Heart rate (bpm, mean) to 2 or more adequate courses (dose and duration) of AE: Emotional lability (dichotomous data) stimulant therapy for ADHD; cardiovascular measurements outside normal range; history of alcohol/substance abuse ADHD-RS-IV Home version Total (mean) (DSM-IV criteria); consumption of more than 250mg/day ADHD-RS-IV School version Inattention caffeine. NB. Concomitant use of prescription or (mean) nonprescription agents with psychotropic properties, AE: Abdominal pain (NOS; dichotomous data) including ADHD treatments and dietary supplements was Leaving the Study Early due to Adverse Event prhobited for 1 week prior to trial start & during study. MAO- I's & SSRI's prohibited for 2 weeks before trial and during AE: Cough increased (dichotomous data) trial. AE: Nausea (dichotomous data) Notes: NB. Age/gender info NR for n=2 who did not receive Data Not Used study drug (both allocated to PLB group) & some subtype ADHD-RS-IV School version Total (mean) - diagnosis info NR for n=2 also. Mean change reported TOVA ADHD score (mean) - not relevant Baseline: Previous ADHD treatment (MPH, outcome salts, ATX or 'Other') MOD group: 51%; PLB gp: 63% Notes: TAKEN AT: Clinic visits scheduled at ADHD-RS-IV Total Score (mean, SD) N(MOD)=131; baseline & weeks: 1,2,3,5,7,9.AE's - general N(PLB)=67 enquiry and spontaneous reporting anytime School version: MOD group: 38.8(8.9); PLB group: throughout trial. Outcomes reported are mean at 37.9(9.0); endpoint. Home version: MOD group: 41.6(8.5); PLB group: 39.3(9.3) CGI-S score (%) Moderately Ill: MOD gp 36%; PLB gp 43% Markedly Ill: MOD group 44%; PLB group 43% Severely Ill: 19%; PLB group 13% CPRS:R-S ADHD Index: MOD group 77.5(8.0); PLB group 76.4(7.8) Results from this paper: Internal Validity; 1.1 Well covered 1.2 Adequately addressed 1.3 Adequately addressed 1.4 Well covered 1.5 Well covered 1.6 Well covered 1.7 Well covered 1.8 MOD group: 25% (33/133); PLB group: 39% (26/67) 1.9 Poorly addressed: LOCF reported (including participants who had received at least one dose and had at least one postbasline primary efficacy assessment), however n's vary for different outcome scales, with no explanation. Lost to follow-up (not included in efficacy analysis): MOD group 5/133; PLB group: 1/67; Lost to follow-up (not included in safety analysis): MOD group: 2/133; PLB group: 0/67. 1.10 Not reported adequately

Overall assessment of study 2.1: 1+ HAZELL2003 Study Type: RCT n= 67 Data Used Group 1N= 29 Funding: Supported by the Conners' Teacher Rating Scale Revised (28- Australian Rotary Health Study Description: Specific Comorbidity (ODD Age: Mean 9 Range 6-14 Placebo. Mean dose NA - ADMIN: item) Research Fund or CD, NB.depression & anxiety permitted in Sex: 61 males 6 females Placebo syrup, identical (color, smell, trial- freq not reported). Conners' Parent Rating Scale Revised (48- viscosity) taken twice daily, euivalent Sample: 'Children' and 'Adolescents' Diagnosis: item) volume as those taking CLON. 100% ODD or CD by DSM-IV & t-scores NB. Mean(SD) dose MPH/DEX (mg)/kg of Type of Analysis: Efficacy ITT (when (attent.&aggress.) on CBC>=70 psychostimulant in MPH equivalents: 0.67 postbaseline data); SEs Compl. (0.39). Blindness: Double blind 100% ADHD by DSM-IV & t-scores Duration (days): Mean 42 (attent.&aggress.) on CBC>=70

Setting: Australia. Children attending psychiatric Exclusions: <3 months stimulant treatment; obsessional or pediatric clinic supervised by the author. symptoms, movement disorders or psychosis; mental Notes: Randomisation conducted by pharmacy retardation IQ<70; history of cardiac anomalies; borderline intellectual functioning and mild pervasive developmental using computer generated random table of disorder were permitted. Notes: TAKEN AT: Weekly Group 2N= 38 numbers (therefore allocation concealed). LOST TO F.U.:Efficacy: 1/38 CLON:no post- Notes: NB.CBC= Child Behaviour Checklist. Clonidine. Mean dose 0.18mg/day - baseline data(not incl.in ITT);Side Effects:4/38 Info on Screening Process: 112 screened, 45 All participants had been treated for a minimum of 3 DOSE: Wk 1:0.10mg (0.05mg morning & CLON gp,4/29 PLB gp. declined (common reason parents perceived months with either MPH or DEX prior to trial enrolment evening). Then wks2-6: increased to NB:Primary efficacy measures:Conduct & symptoms to be adequately controlled), 67 (dose & dosing schedule held constant for trial duration). 0.20mg (0.10 mg morn & evening). Hyperactive Index subscales of Conners'Parent randomised to treatment. ADMIN: CLON made into syrup, admin Baseline: Mean no. of inattention symptoms (SD): 7.16 Teacher Scales. as above. (1.54) CLON; 7.32 (1.54) PLB NB. Mean(SD) dose MPH/DEX (mg)/kg of Mean no. of hyperactice-impulsive symptoms (SD): 7.19 psychostimulant in MPH equivalents: 0.61 (1.37) CLON; 7.07 (1.49) PLB (0.28). Mean no. of oppositional-defiant symptoms (SD): 1.81 (2.09) CLON; 6.14 (1.43) PLB Mean no. of conduct symptoms (SD): 1.81 (2.09) CLON; 1.68 (1.81) PLB Mean CBCL Attention Problems T score (SD): 74.86 (7.07) CLON; 73.68 (5.91) PLB Mean CBCL Aggressive Behaviour T score (SD): 82.03 (9.51) CLON; 80.86 (7.71) PLB Results from this paper: Internal validity:

1.1 Well covered 1.2 Well covered 1.3 Well covered 1.4 Well covered 1.5 Adequately addressed - PLB group significantly older (on average by 1 yr) than CLON group. 1.6 Well covered 1.7 Well covered 1.8 8% CLON; 14% PLB 1.9 Well covered 1.10 Not applicable

Overall assessment of the study:

2.1: 1+ IALONGO1994 Study Type: RCT n= 48 Data Used Group 1N= 16 Funding: NR. CTRS Hyperkinesis Index (mean) Study Description: Non-secific cormorbidity Age: Mean 7 Range 7-11 Methylphenidate low dose. Mean dose CPRS Hyperkinesis Index (mean) (Class2 only- anxiety/depression disorders excl.) Sex: 35 males 13 females 0.4mg/kg - WASHOUT: NR Sample: 'Children' only Data Not Used DOSE:No further detail reported (ie. no Diagnosis: Wide Range Acheivement Test-Revised - not detail on dose tapering, etc.) Type of Analysis: Completer (assumption- ITT 25% Oppositional defiant disorder by DSM-IIIR relevant outcome ADMIN: Medication recieved 7 days/wk; not mentioned) (Par.interview); CP&THyperkinesis indices CTRS Conduct problems Index (mean) - not No further detail. Blindness: Double blind relevant outcome Group 2N= 16 Duration (days): Mean 98 10% Conduct disorder by DSM-IIIR Conner's Continous Performance Test - not Placebo. Mean dose NA - WASHOUT: NR (Par.interview); CP&THyperkinesis indices relevant outcome DOSE:No further detail reported Setting: USA; P's referred to uni-based Self-perception Profile for Children - not ADMIN: Medication recieved 7 days/wk; psychological clinic. 100% ADHD by DSM-IIIR (Par.interview); relevant outcome No further detail. Notes: Randomisation: No detail reported (only CP&THyperkinesis indices Multidim. Meas.of Child's Perceptions of Group 3N= 16 that p's were 'randomly assigned') Control - not relevant outcome Methylphenidate high dose. Mean dose Exclusions: IQ<70; presence of comorbid anxiety and/or Info on Screening Process: NR T's Checklist of Childrens Peer Relationships 0.8mg/kg - WASHOUT: NR depression disorder, gross physical impairments, intellectual not relevant outcome DOSE:No further detail reported (ie. no deficits, psychosis (in either child/parent). CBCL- Depression subscale - not relevant detail on dose tapering, etc.) Notes: P's only incl.in study if board-certified pediatrician outcome ADMIN: Medication recieved 7 days/wk; No further detail. and licensed clinical psychologist agreed exactly on the Structured Observation of Academic & Play diagnosis of ADHD. Psychometric testing also incl. in Settings - not relevant outcome diagnosis criteria. Baseline: NB. Sample of 21 nonclinic controls (13 male; 8 female) also tested at BL only. Mean (SD) PLB gp; MPH LD gp; MPH HD gp; Controls, resp. CPRS (Hyperkinesis index): 17.6 (3.89); 20.25(3.49); Notes: TAKEN AT: 'pre-test' and 'post-test' (14 20.92(4.95); 2.61(2.04) wks after start of medication therapy) CTRS (Hyperkinesis index): 19.75 (5.84); 16.81(7.23); LOST to F.U.: See attrition (completer data) 19.38(3.38); 3.57(3.78) No other relevant outcomes.

Results from this paper: Internal validity: 1.1 Well covered 1.2 Adequately addressed 1.3 Not addressed 1.4 Adequately addressed 1.5 Well covered 1.6 Well covered 1.7 Well covered 1.8 PLB gp: 25% (4/16); MPH LD gp: 0%; MPH HD gp: 19% (3/16) 1.9 Not addressed 1.10 Not applicable

Overall assessment of the study: 2.1: 1+ KELSEY2004 Study Type: RCT n= 197 Data Used Group 1 N= 133 Funded by Eli Lilly and ADHD Rating Scale Hyperactive/Impulsive Company. Seven authors Study Description: Nonspecific Comorbidity Age: Mean 9 Range 6-12 Atomoxetine. Mean dose NR - Subscore (including first) are (Predominantly ODD & CD) DOSE:Began Sex: 139 males 58 females employees and Sample: 'Children' ADHD Rating Scale Total Score 0.8mg/kg/day(3days),increased to shareholders of Eli Lilly and Diagnosis: ADHD Rating Scale Inattentive subscore 1.2mg/kg/day(days4-7). Wks2- Type of Analysis: ITT (incl. p's with baseline & Company. 4% ADHD mainly hyperactive by DSM-IV 4:Remained 1.2mg/kg/day (unless >=1 postBL measure) Notes: TAKEN AT: Baseline, 1,4 and 8 weeks. LOST TO F.U.: 7/133 ATX grp;3/63 PLB grp did tolerability issues).Then increased Blindness: Double blind not provide baseline & >=1 post-baseline (1.8mg/kg/day, max,& never>120mg/day) 4% ADHD with cormorbid CD ADMIN: Single daily-dose in morn Duration (days): Mean 56 measure (not included in ITT efficacy analysis).For Side effect data Lost to F.U.: 2/133 (with/without food). 27% ADHD mainly inattentive by DSM-IV Setting: 12 outpatient sites in the US. ATX gp, 0/63 PLB gp. Group 2N= 64 Notes: Randomised with a ratio of 2:1 Placebo. Mean dose NA - ADMIN: Single 35% ADHD with cormorbid ODD . (ATX:PLB). No further details given on daily-dose in morn (with/without food).NB No mention of appearance- assume randomisation and allocation concealment. identical to ATX to maintain blind? 69% ADHD Combined subtype by DSM-IV Info on Screening Process: P's recruited by referral & by advertisment. 260 screened, 63 excluded due to personal conflict, not meeting Exclusions: No DSM-IV diagnosis of ADHD; no symptoms study criteria, protocol violation, sponsor's severity score at least 1.5 SDs above age and gender decision. normative values, as assessed with the ADHD Rating Scale, for the total score or either of the inattentive or hyperactive/impulsive subscales; Serious medical illness, history of psychosis or bipolar disorder, alcohol or drug abuse within past 3 months, and ongoing use of psychoactive medications other than the study drug. Notes: Previous stimulant treatment; 53% ATX; 48% PLB NB. Trial began with 5-day washout, assessment period. Baseline: ADHD RS Total score mean (SD) ATX group 42.1 (9.2); PLB group 42.3 (7.1) Conners GIPE Total score mean (SD) ATX group 20.1 (6.1); PLB group 20.1 (5.5) Results from this paper: Internal validity:

1.1 Well covered 1.2 Adequately addressed 1.3 Not addressed 1.4 Adequately addressed 1.5 Well covered 1.6 Well covered 1.7 Well covered 1.8 19.6% (26/133) ATX; 26.6% (17/64) PLB 1.9 Poorly addressed 1.10 Not reported

Overall assessment of the study:

2.1: 1+ KOLLINS2006 Study Type: RCT n= 114 Data Used Group 1N= 53 Funding: supported by AE: Heart rate (bpm, mean) - although n's not cooperative agreement Study Description: 'Non-specific' comorbidity in Age: Mean 4 Range 3-5 Placebo - WASHOUT: 24hrs (following clear between the NIMH & several sample. cross-over phase) Sex: 85 males 29 females U.S. universities. Sample: 100% 'Preschoolers', recruited via 'Excellent response' (<=1.0 on P-T SNAP DOSE: Given equivalent PLB capsule of clinics, adverts, schools, day-care ctrs. N=1915 Diagnosis: composite) - NB. dichotomous data optimal dose reached in cross-over phase teleph screened. 53% Oppositional defiant disorder by DSM-IV SNAP (parent-teacher) composite score ADMIN: Capsules (identical to MPH), 3 (DISC, & semi-structured interview) (mean) times daily Type of Analysis: ITT (precise definition not made clear) AE: Diastolic blood pressure (mm Hg, mean) - Group 2N= 61 7% Specific phobia by DSM-IV (DISC, & semi- although n's not clear Immediate-release methylphenidate. Blindness: Double blind structured interview) AE: Systolic blood pressure (mm Hg, mean) - Mean dose 14.2+/-8.1mg/day - Duration (days): Mean 28 although n's not clear WASHOUT: 24hrs (following cross-over 3% Conduct disorder by DSM-IV (DISC, & semi- phase) Followup: 1 year (open-label maintenance Data Not Used structured interview) DOSE: Each p given optimal dose as phase following 4wk parallel RCT) Leaving the Study Early due to Adverse Events - group allocation of data not reported determined in prior cross-over phase (either 1.25; 2.5; 5 or 7.5mg/day) Setting: 6 academic sites throughout US. NB. 22% Communications Disorder by DSM-IV Leaving the Study Early for Any Reason - ?? ADMIN: Capsules, 3 times daily Duration refers only to double-blind parallel (DISC, & semi-structured interview) Allocation unknown for n=3/114 RCT phase- total duration of whole trial = 70 weeks. Notes: TAKEN AT: Endpoint of cross-over ph 25% ADHD Hyperactive/Impulsive subtype by (24hrs prior to parallel phase start) & endpoint of Notes: N=114 randomised into dbl-bl parallel DSM-IV (DISC; C(P&T)RS Hyp subsc>1.5sd's) 4wk parallel phase. AE's measured weekly RCT phase. No detail reported re. throughout parallel phase- clinician inquiries & randomisation procedure. 1% Reactive attachment disorder by DSM-IV Pittsburgh SE RS. Info on Screening Process: Following (DISC, & semi-structured interview) NB. No pre-crossover data reported for cross- diagnostic screening, all p's enrolled in 'Parent over phase. training' (10wks; n=303) - all p's who responded 12% Anxiety disorder (including OCD) by DSM- were excl. from drug trial; then dbl-bl crossover IV (DISC, & semi-structured interview) titration phase(5 wks; n=165; 5 doses MPH): if non-responders, excluded from parallel phase. 1% Adjustment disorder by DSM-IV (DISC, & semi-structured interview)

100% ADHD by DSM-IV (DISC; C(P&T)RS Hyp subsc>1.5sd's)

0% ADHD Inattentive subtype by DSM-IV (DISC; C(P&T)RS Hyp subsc>1.5sd's)

75% ADHD Combined subtype by DSM-IV (DISC; C(P&T)RS Hyp subsc>1.5sd's)

Exclusions: Age outside of range 36-65 months; age- & sex- adjusted Tscore <65 on hyperactive-impulsive subscale of both the Conners Parent & Teacher Rating Scales; score >=55 Child Global Assessment Scale; ADHD symptoms present < 9 months; IQ <70 (although lower scores considered for inclusion if composite score from the Vineland adaptive behavior scale was >70); residing with primary caregiver for <6 months; not participating in school- type program at least 2 half days/week, with at least 8 peers; systolic and diastolic BP below 95th percentile for age & gender; children/parents could not understand or follow instructions of the study; evidence of moderate to severe adverse events, or evidence of a much improved response, to any dose of MPH or another stimulant; or >5 weeks exposure to at least 30mg/day of MPH or eqivalent doses of other stimulants; use of any other psychotropic medication; taken an investigational drug in past 30 days (however episodic use of sympathomimetic decongestants for the common cold were allowed under study physician's supervision); history of motor or vocal tics or Tourette's syndrome; major medical conditions that would interfere with involvement in a long-term study or could be affected negatively by MPH; current evidence of adjustment disorder, pervasive developmental disorders (e.g. autism), psychosis, significant suicidality, or other psychiatric disorder that requires treatment with additional medication; evidence of current physical, sexual or emotional abuse; living with anyone who currently abuses stimulants or ; history of bipolar disorder in both biological parents. Notes: NB. All p's presented to cross-site panel of clinicians & only included if absolute consensus of whether p's did (/not) meet inclusion (/exclusion) criteria was obtained. Baseline: NB. Baseline outcomes measured prior to cross- over phase, and not reported separately for each group as allocated in parallel phase. Conners Teacher RS: Mean (SD) Total: 39.95(7.49); Hyperactivity: 22.29(3.49); Inattention: 17.6(5.15) Conners Parent RS: Mean (SD) Total: 35.48(8.85); Hyperactivity: 20.55(4.69); Inattention: 14.84(5.81) Results from this paper: Internal validity; 1.1 Well covered 1.2 Not reported adequately 1.3 Not reported adequately 1.4 Well covered 1.5 Not addressed adequately for parallel phase of trial. 1.6 Well covered 1.7 Well covered 1.8 During parallel phase of trial: MPH group: 15% (9/61) ; PLB group: 45% (24/53) (NB. Allocation unknown for n= 3/114) 1.9 Adequately addressed 1.10 Not reported adequately

Overall assessment of the study 2.1 1+ KRATOCHVIL2005 Study Type: RCT n= 173 Data Used Group 1 N= 127 Research Funded by Eli Lilly ADHD Rating Scale Total Score (mean and Company Study Description: Specific Comorbidity Age: Mean 11 Range 7-17 Atomoxetine + Fluoxetine. Mean dose change) (Anxiety/ Depression) Sex: 125 males 48 females Final ATX: 1.36 (SD 0.55)mg/kg/day - Sample: 'Children' & 'Adolescents' ADHD RS Hypract/Impulsv. Subscore (mean DOSE: Wk 1-3: FLX 20mL/day; From Diagnosis: change) wk4-8 ATX added-initiated at Type of Analysis: LOCF (*But not whole 66% ADHD RS Inattentive subscore (mean chang 0.5mg/kg/day, increased @wkly intervals sample- some exclusions) Dysthymia/Maj.Depres/Adjustment/Seasonal to 0.8, then to 1.2, to max of Blindness: Double blind Mood Dis. by Kiddie Schedule for Affective 1.8mg/kg/day. ADMIN: FLX single morn dose; ATX dose Duration (days): Mean 56 Disorders… divided equally into 2 daily doses. Setting: Pediatric patients at 20 sites in the US. 3% ADHD Hyperactive/Impulsive subtype by Kiddie Schedule for Affective Disorders… Notes: Randomisation ratio unbalanced (3:1 ATX+FLX: ATX+PLB) - larger tolerability & safety database in combined trtmt gp. No further detail reported. Info on Screening Process: P's 12% >1 Anxiety disorder by Kiddie Schedule for Notes: OUTCOMES TAKEN AT: Baseline, Group 2N= 46 recruited:advertisement & referral. No detail Affective Disorders… endpoint. Atomoxetine + Placebo. Mean dose Final regarding screening. LOST to FU: ATX+FLX = 11% (14/127); ATX: 1.52 (SD 0.41) mg/kg/day - DOSE: NOTE: Pretrial washout for incl.- 0% Mood + Anxiety Disorders by Kiddie ATX+PLB = 4% (2/46) (Not included in LOCF Wk 1-3: PLB only; From wk4-8 ATX Psychostimulants discont. min 2days B4 BL; p's Schedule for Affective Disorders… analysis) added-initiated at 0.5mg/kg/day, free from other psychotropics min 5x drug's increased @wkly intervals to 0.8, then to plasma elimination half-life. 99% ADHD by Kiddie Schedule for Affective 1.2, to max of 1.8mg/kg/day. Disorders… ADMIN: PLB single morn dose; ATX dose divided equally into 2 daily doses. 23% ADHD Inattentive subtype by Kiddie Schedule for Affective Disorders…

73% ADHD Combined subtype by Kiddie Schedule for Affective Disorders…

0% >1 Mood disorder by Kiddie Schedule for Affective Disorders…

67% GAD/Spec.phobia/sep.anx./OCD/Panic/Agoraph obia by Kiddie Schedule for Affective Disorders…

Exclusions: Any history of psychosis, bipolar disorder or serious medical illness; serious suicidal risk (as judged by investigator; history of drug/alcohol abuse; evidence of illicit drug use (urine drug screen); taking any other psychotropic medication Notes: Diagnosis tool specifically: Semi-structured interview and Schedule for Affective Disorders and Schizophrenia for School-aged Children-Present and Lifetime Version Baseline: (Mean, (SD)): ADHD RS Total score ATX+FLX= 40.5(8.7); ATX+PLB=41.5(8.4) ADHD RS Inattentive subscale score ATX+FLX= 22.6 (4.0); ATX+PLB= 22.8 (4.1) ADHD RS Hyperactive/Impulsive subscale score ATX+FLX= 17.9 (6.5); ATX+PLB= 18.7 (6.1) Results from this paper: Internal validity; 1.1 Well covered 1.2 Adequately addressed 1.3 Poorly addressed - FLX/PLB double blind, butnot clear if p's blinded to ATX initation. 1.4 Poorly addressed 1.5 Well covered 1.6 Well covered 1.7 Well covered 1.8 ATX+FLX 21/127 (16.5%) ; ATX + PLB 9/46 (19.6%) 1.9 Adequately addressed 1.10 Not reported

Overall assessment of the study 2.1 1+ KUPIETZ1988 Study Type: RCT n= 58 Data Used Group 1N= 19 Funding: Supported in part Conners' Abbreviated Parent Q. (10-item) by NIMH grant Study Description: Specific comorbidity Age: Mean 9 Range 7-13 Methylphenidate 0.3mg/kg - DOSE:To CTRS-39 item (Inattentiveness Factor) (mean (Dev.Reading Disorder); see exclusions. Sex: no information nearest 2.5mg(scored 5mg tablets Sample predominantly 'Children'; some Werry-Weiss-Peters Activity Scale (31-item) smallest available);All p's PLB 'Adolescents'. Diagnosis: (mean) Wks15&28(reading acheivement 100% ADD with Hyperactivity by DSM-III CTRS-39 item (Hyperactivity Factor) (mean) measurements-control for test-taking Type of Analysis: Completer ability,MPH effects) Data Not Used ADMIN:B.i.d. Blindness: Double blind 100% Developmental Reading Disorder by DSM- Devereux Elementary School Behaviour NB.ALL p's received 'reading Duration (days): Mean 196 III (DESB) RS - not relevant outcome therapy'(2x12 sessions;wks3-15 & wks16- Peabody Individual Acheivement Test - not 28) Setting: Recruited from local schools, Exclusions: WISC-R IQ<80; Any additional Axis I psychiatric relevant outcome Group 2N= 12 newspaper advertisments, Child Development diagnosis; uncorrected hearing; visual deficits; rading level PAL (Paired Associate Learning Task) - not Methylphenidate 0.5mg/kg - DOSE:To Centre of Nassau County Medical Centre. higher than 75% of their expected reading level (evaluated relevant outcome nearest 2.5mg(scored 5mg tablets with Peabody Individual Achievement Test; Gates- Devereux Child Behaviour (DCB) RS - not smallest available);All p's PLB Notes: Randomisation: No detail reported (only MacGinitie Reading Tests; Decoding Skills Test) 'randomly assigned'). relevant outcome Wks15&28(reading acheivement Notes: DSM-II diagnosis had to be supported by Teacher Gates-MacGintie Reading Mastery Tests - not measurements-control for test-taking Info on Screening Process: NR rating >2.5 (on1- 4 scale) on hyperactivity factor of Conners relevant outcome ability,MPH effects) ADMIN:B.i.d. TRS. Decoding Skills Test - not relevant outcome NB.ALL p's received 'reading Baseline: NB. BL data reported for Completers only. Short Term Memory Task (Sprague&Sleator, therapy'(2x12 sessions;wks3-15 & wks16- Mean (SD): 1977) - not relevant outcome 28) Conners TRS Hyperactivity Factor: PLB(n=12) 3.23(0.38); MPH Plasma Assay - not relevant outcome 0.3MPH(n=13) 2.95(0.60); 0.5MPH(n=11) 3.14(0.53); Group 3N= 16 Reading Grade Level - not relevant outcome 0.7MPH(n=10) 3.08(0.49). Placebo - WASHOUT: NR (for all Conners TRS Innattentiveness Factor: PLB(n=11) Notes: TAKEN AT: All at BL;Cognitive Tasks conditions) 2.74(0.81); 0.3MPH(n=8) 2.99(0.69); 0.5MPH(n=11) again at Wks2& 27(1.5 hrs after dose ingestion); ADMIN:B.i.d. 2.83(0.35); 0.7MPH(n=10) 2.46(0.50). Parent & Teacher ratings at Wks2,14& 27. NB.ALL p's received 'reading Conners Abbreviated Scale: PLB(n=11) 2.98(0.48); Reading achievements: Wks15& 28(all p's on therapy'(2x12 sessions;wks3-15 & wks16- 0.3MPH(n=14) 2.89(0.58); 0.5MPH(n=10) 3.18(0.65); PLB). 28) LOST to F.U.: PLB 31%; 0.3MPH 58%; 0.5MPH 0.7MPH(n=10) 2.92(0.49). Group 4N= 11 17%; 0.7MPH 9%. Methylphenidate 0.7mg/kg - DOSE:To nearest 2.5mg(scored 5mg tablets smallest available);All p's PLB Wks15&28(reading acheivement measurements-control for test-taking ability,MPH effects) ADMIN:B.i.d. NB.ALL p's received 'reading therapy'(2x12 sessions;wks3-15 & wks16- 28) Results from this paper: Internal validity; 1.1 Well covered 1.2 Adequately covered 1.3 No addressed 1.4 Well covered 1.5 Well covered 1.6 Well covered 1.7 Well covered 1.8 MPH 0.3 mg/kg gp: 26% (5/19); MPH 0.5 mg/kg gp: 8% (1/12); MPH 0.7 mg/kg gp: 9% (1/11); PLB gp: 25% (4/16) 1.9 Not addressed - Completer (Different n's for each scale also) 1.10 Not applicable

Overall assessment of the study 2.1: 1+ KURLAN2002 Study Type: RCT n= 136 Data Used Group 1N= 32 Funding: National Institute of Conners' Abbreviated Parent Q. (10-item) Neurological Disorders and Study Description: Specific Comorbidity Age: Mean 10 Range 7-14 Placebo - DOSE:4wk titration of CLON- Stroke grant, National (Tourettes, Tic disorder) Conner's Continous Performance Test matching PLB (tablets),then 4wks titration Sex: 116 males 20 females Center for Research Sample 'Children' & 'Adolescents' IOWA of MPH-matching PLB (gelatin capsules) Resources and Tourette Diagnosis: added,then 8wks maintenance dose both Type of Analysis: ITT Conners' Abbreviated Teacher Q. (10-item) Syndrome Association grant. 38% Oppositional defiant disorder by DSM-IV PLS's. Data Not Used Blindness: Double blind ADMIN:1 of each/day @start-increased to Children's Global Assessment Scale (C- 2-3 of each/day within few days (Match Duration (days): Mean 112 2% ADHD Hyperactive/Impulsive subtype by GAS) - outcome not relevant drug conditions) DSM-IV Setting: US, Multi-center study. Notes: Randomisation: Computer-generated 9% Conduct disorder by DSM-IV incl.stratification (center & sexual maturity status) Blocking= balance within each stratum. 100% Tourettes,Chronic:Motor tic, or Vocal Notes: TAKEN AT: Baseline (0wks), then +4wks Group 2N= 37 Allocation concealed. tic,disorder by DSM-IV +8wks, +12wks, Endpoint (+16wks). Methylphenidate - DOSE:4wk titration of LOST TO F.U.: NA. All randomised p's incl. in IT Info on Screening Process: 148, 12 excluded PLB(to match CLON gp),then 4wks analysis (LOCF). (or declined participation), therefore 136 38% Obsessive-compulsive disorder by DSM-IV titration to optimal MPH dose,then 8wks enrolled in trial, and randomised. maintenance dose-p's received MPH & CLON-matching PLB.Max MPH dose: 71% ADHD Inattentive subtype by DSM-IV 60mg/day ADMIN:5mg gelatin capsules:1/day 5% Major Depressive Disorder by DSM-IV @start-increased to 2-3/day within few days 9% Generalised Anxiety Disorder by DSM-IV Group 3N= 34 Clonidine - DOSE:4wk titration to optimal 27% ADHD Combined subtype by DSM-IV dose, 4 weeks titration of PLB (to match MPH gp), then 8 weeks maintenance dosage-p's received CLON & MPH- Exclusions: Secondary tic disorder (tardive tics, matching PLB.Max CLON dose: neuroacanthocytosis, Huntington disease), major 0.6mg/day depression, pervasive developmental disorder, autism, ADMIN: 0.1mg tablets: 1/day @start- psychosis, mental retardation, anorexia nervosa, bulimia, a increased to 2-3/day within a few days. serious cardiovascular or other medical disorder that would preclude safe use of MPH or CLON, impaired renal function, Group 4N= 33 pregnancy. Combined methylphenidate + clonidine - DOSE:4wk titration of CLON alone,then Notes: All previously prescribed medication (for ADHD, 4wks titration of MPH added,then 8wks Tics, other associated behavioural symptoms) were maintenance dose of CLON & MPH.Max stopped for 6 wks prior to trial start. Previous use of MPH or doses as in 'alone' conditions. CLON permitted- but in no case was use discontinued ADMIN:1 of each/day @start-increased to purely for participation in this trial. 2-3 of each/day within few days Baseline: Mean Conners ASQ-Teacher (SD): 16.0 (6.2) PLB; 13.2 (7.3) MPH; 16.4 (7.0) CLON; 13.1 (5.6) Comb. Mean Conners ASQ-Parent (SD): 18.1 (5.5) PLB; 17.2 (6.8) MPH; 18.9 (6.3) CLON; 18.4 (5.9) Comb. Mean Iowa Conners Total (SD): 14.4 (6.7) PLB; 12.2 (7.1) MPH; 14.1 (6.5) CLON; 11.2 (4.8) Comb. Mean C-GAS (SD): 55.0 (10.4) PLB; 56.4 (8.2) MPH; 53.9 (8.5) CLON; 55.0 (9.4) Comb. Results from this paper: Internal validity; 1.1 Well covered 1.2 Well covered 1.3 Well covered 1.4 Well covered 1.5 Well covered 1.6 Adequately addressed: Some ifferences in Baseline measures: age; ADHD subtype;Conners ASQ teacher scores. Results analysed 'change from baseline', account for this. 1.7 Well covered 1.8 MPH gp: 11%; CLON gp: 12%; MPH+CLON gp:12%; PLB gp:22%. 1.9 Well covered 1.10 Not addressed

Overall assessment of the study 2.1: 1++ LERER1977 Study Type: RCT crossover n= 50 Data Used Group 1N= 25 Funding: NR "Improvement" on CATRS (dichot: reduction o Study Description: "Pure ADHD"(assumed,no Age: Range 8-12 Placebo - WASHOUT: NA (no p's on >=4) comorbidity mentioned except exclusions) Sex: 41 males 9 females stimulant meds prior to trial) Sample pred."Children",some "adolescents" Data Not Used ADMIN:Pills, twice a day with breakfast NB.Total duration 56dys(x-over:28 dys/arm) Diagnosis: Various Handwriting Problems - not relevant and lunch- no further detail reported. 100% Minimal Brain Dysfunction by Various outcome Type of Analysis: ITT (All p's completed trial) criteria (see Notes) Blindness: Double blind Duration (days): Mean 28 Exclusions: Gross neurologic deficits; psychosis; suspected Followup: 13-26mths (MPH only) primary emotional disorders; age <8 (problems with Notes: TAKEN AT: BL; After 4wks treatment Group 2N= 25 handwriting more difficult to assess in younger children) (prior to crossover); End of 8wks (afer crossover Setting: Ohio, USA Methylphenidate - WASHOUT: NA (no p's trial) & F.U. at 13-26 months for p's who chose to Notes: MBD: Poor handwriting; Cluminess & poor motor on stimulant meds prior to trial) Notes: Randomisation: No detail (only remain on MPH post-trial. coordination; >3 abnormal ("soft") neurologic signs; DOSE: 0.6-0.7mg/kg/day, in two divided 'randomly assigned'). LOST to F.U.: None, during trial; 22% after 13- Reading &/or arithmetic deficits; short attention span, doses with breakfast and lunch. 26mths F.U. Info on Screening Process: 97 p's with MBD distractability; severe behavior or discipline problems. ADMIN:Pills, no further detail reported. referred for variety of school problems, 50 Baseline: All p's >14 on Conners Abbreviated Teacher selected for trial (no further detail reported) Rating Scale (CATRS); All p's had moderate-severe handwriting difficulties.

Results from this paper: Internal validity: 1.1 Well covered 1.2 Adequately covered 1.3 Not addressed 1.4 Poorly addressed (Treatment code broken 4/25 MPH patients due to oversedation, & subsequent dose reduction- unsure whether this was pre/post crossover) 1.5 Well covered 1.6 Poorly addressed (n=12 enrolled in special learning disability classes; all other p's receiving some tutoring in one/more academic subjects - no mention of which gps these children were randomised to). 1.7 Well covered 1.8 MPH gp: 0%; PLB gp: 0%. 1.9 Well covered (all p's completed trial) 1.10 Not applicable

Overall assessment of study: 2.1 1+/- ??????????????????????? MICHELSON2001 Study Type: RCT n= 297 Data Used Group 1N= 44 Funding- In part from Lilly CPRS-R (Mean change from BL) Research Laboratories (at Study Description: Cormorbidity: Non-specific Age: Mean 11 Range 8-18 Atomoxetine 0.5mg/kg/day. Mean dose least 7 authors (from 2 (predominantly ODD) ADHDRS Total (Change from Baseline: 0.5mg/kg/day - WASHOUT: 12-18days Sex: 212 males 85 females studies) based there) Sample: 'Children' and 'Adults' (%s not reported) means, SDs) DOSE: Started at 0.5mg//kg/day, NB. ATX dose varied in this trial Diagnosis: ADHD RS Inattentive subscore (mean chang remained this dose for duration. 39% Oppositional defiant disorder by Kiddie ADMIN: In equally divided doses: morn & Type of Analysis: ITT (for p's w BL & 1 post-BL ADHDRS Hyper/Impuls.(Change from BL: Schedule for Affective Disorders… means, SDs) late afternoon; drug in each arm identical measurement, LOCF) in appearance. Data Not Used Visits weekly:wks 1-4 then biweekly Blindness: Double blind 2% ADHD Hyperactive/Impulsive subtype by Child Health Questionnaire (mean change therafter Duration (days): Mean 56 DSM-IV & KSADS-PL & ADHD-RS-IV-P from BL) - not relevant outcome Group 2N= 85 Followup: 1 yr (however- results not reported Children's Depression Rating Scale - not 1% Mood + Anxiety Disorders by Kiddie relevant outcome Atomoxetine 1.8mg/kg/day. Mean dose here) 1.8mg/kg/day - WASHOUT: 12-18days Schedule for Affective Disorders… Notes: OUTCOMES TAKEN AT: Baseline & DOSE: Started at 0.5mg/kg/day, "titrated Setting: 13 outpatient investigative sites in the Endpoint, & each visit in between. with intermediate steps of 0.8mg/kg/day US. 100% ADHD by DSM-IV & KSADS-PL & ADHD- Lost To F.U.(not incl. in reported results): PLB gp and 1.2mg/kg/day at 1-week intervals". RS-IV-P 1% (1/84); ATX 0.5mg gp: 2% (1/44); ATX 1.2mg Notes: Randomisation: According to computer ADMIN:Equally divided doses: morn & gp: 0% (0/84); ATX 1.8mg gp: 4% (3/85). generated treatment codes from an interactive late afternoon voice-response system. 31% ADHD Inattentive subtype by DSM-IV & Visits weekly:wks 1-4 then biweekly Info on Screening Process: P's recruited by KSADS-PL & ADHD-RS-IV-P therafter advertisement and referral. 381 screened, 297 Group 3N= 84 met entry criteria and were randomised. 0% ADHD unspecified by DSM-IV & KSADS-PL & ADHD-RS-IV-P Atomoxetine 1.2mg/kg/day. Mean dose 1.2mg/kg/day - WASHOUT: 12-18days DOSE: Started at 0.5mg/kg/day, 'titrated 67% ADHD Combined subtype by DSM-IV & with intermediate steps of 0.8 & KSADS-PL & ADHD-RS-IV-P 1.2mg/kg/day @ 1-wk intervals' ADMIN:Equally divided doses: morn & Exclusions: IQ<80 (assessed by Weschler Intelligence Scale late afternoon for Children-3rd Ed); serious medical illness, comorbid Visits weekly:wks 1-4 then biweekly psychosis/bipolar disorder; history of seizure disorder; therafter ongoing use of psychoactive medications other than study drug.

Baseline: Mean (SD): PLB gp; ATX0.5 gp; ATX1.2gp; ATX1.8 gp, resp. ADHD RS total score: 38.3(8.9); 40.2(9.6); 39.2(9.2); Group 4N= 84 39.7(8.7) Placebo. Mean dose NA - WASHOUT: 12 ADHD RS inattentive: 21.4(4.0); 22.4(3.6); 22.2(4.0); 18days 22.1(4.2) ADMIN: In equally divided doses: morn & ADHD RS hyperactive: 16.9(6.6); 17.8(7.4); 16.9(7.1); late afternoon; drug in each arm identical 17.6(6.2) in appearance. CPRS-R ADHD: 27.3(6.3); 30.7(4.4); 28.0(5.6); 27.9(6.7) Visits weekly:wks 1-4 then biweekly CPRS-R hyperactive: 10.3(4.9); 12.0(4.8); 10.2(5.1); therafter 10.6(4.6) CGI-S: 4.7(0.8); 4.8(0.9); 4.8(0.9); 4.9(0.7) Results from this paper: Internal validity: 1.1 Well covered 1.2 Well covered 1.3 Adequately addressed 1.4 Not addressed 1.5 Well covered 1.6 Well covered 1.7 Adequately addressed 1.8 PLB gp: ; ATX gp: 1.9 Poorly addressed 1.10 Not addressed

Overall assessment of study: 2.1 1+

NEWCORN2005: Separate analysis of ODD comorbid sample and pure ADHD sample- useful?? MICHELSON2002 Study Type: RCT n= 171 Data Used Group 1N= 86 Funded by Eli Lilly and Conners Teacher RS-R Short form (Mean Company Study Description: Cormorbidity: Non-specific Age: Mean 10 Range 6-16 Placebo - WASHOUT: 5days(pre- change) (pred.ODD) Sex: 120 males 50 females randomisation) Sample:'Children' & 'Adolescents'(%s not ADHD Rating Scale-IV Total Score (mean ADMIN:Single daily dose-morn. Assume reported) Diagnosis: change) idenitical appearance of PLB & ATX???- NB-'once-daily' ATX admin (most other studies 40% Oppositional defiant disorder by Kiddie Conners Parent RS-R Short form (Mean not reported. twice-daily') Schedule for Affective Disorders… change) Visits weekly-2wks; biweekly thereafter Type of Analysis: ITT (for p's w BL & 1 post-BL CGI Severity Score (Mean change from BL) Group 2N= 85 measurement, LOCF) 2% ADHD Hyperactive/Impulsive subtype by ADHD RS Inattentive subscore (mean chang Atomoxetine - WASHOUT: 5days(pre- DSM-IV & KSADS-PL & ADHD-RS-IV-P randomisation) Blindness: Double blind ADHDRS Hyper/Impuls.(Change from BL: means, SDs) DOSE: began at 0.5mg/kg/day for 3days; Duration (days): Mean 42 then 0.75 for rest of wk1; wk2 increased 2% Mood + Anxiety Disorders by Kiddie Data Not Used to 1.0. At 4wks:p's CGI>2: increase to 1.5 Schedule for Affective Disorders… Parent Ratings of Behaviour (dev.for this Setting: 9 outpatient sites in the US ADMIN:Single daily dose-morn. study) - not relevant outcome Visits weekly-2wks; biweekly thereafter Notes: Randomisation: no detail provided. 3% Phobias (NOS) by Kiddie Schedule for Notes: OUTCOMES TAKEN AT: Baseline & Affective Disorders… Info on Screening Process: P's recruited by Endpoint, & each visit in between. referral & by advertisement. No details reported Lost To F.U.(not incl. in reported results): re. screening /no. excluded/etc. 100% ADHD by DSM-IV & KSADS-PL & ADHD- Different n's for each scale, PLB gp: 3.5-18.6%; RS-IV-P ATX gp:1-21%.

40% ADHD Inattentive subtype by DSM-IV & KSADS-PL & ADHD-RS-IV-P

58% ADHD Combined subtype by DSM-IV & KSADS-PL & ADHD-RS-IV-P

Exclusions: Serious medical illness, history of psychosis or bipolar disorder, alcohol or durg abuse within 3 months previous to trial-start; ongoing use of psychoactive medications other than study drug.

Baseline: Mean (SD): PLB gp; ATX gp. ADHD-IV RS total score: 36.7(8.9); 37.6(9.4) ADHD RS inattentive: 21.4(4.0); 21.9(3.5) ADHD RS hyperactive: 15.3(7.1); 15.7(8.0) CPRS: 26.5(5.8); 27.0(5.5) CTRS: 21.6(9.0); 21.5(8.7) CGI-S: 4.6(0.6); 4.7(0.6) Results from this paper: Internal validity: 1.1 Adequately addressed 1.2 Poorly addressed 1.3 Not addressed 1.4 Poorly addressed 1.5 Adequately addressed 1.6 Not addressed 1.7 Adequately addressed 1.8 ATX gp: 14% (12/85); PLB gp: 13% (11/86) 1.9 Adequately addressed 1.10 Not addressed

Overall assessment of study: 2.1 1- MICHELSON2004 Study Type: RCT n= 416 Data Used Group 1 N= 292 Funded by Eli Lilly and CPRS-Hyperact.subscale (Mean change from Company Study Description: Cormorbidity:Non- Age: Mean 10 Range 6-15 Atomoxetine. Mean dose NR - DOSE: P's BL) specific(pred.ODD) Sex: 373 males 43 females continued on same dose from completion Sample:'Children'&'Adolescents' ADHDRS Hyper/Impuls.(Change from BL: of open-label trial (i.e. 1.2-1.8mg/kg/day) NB.Relapse Prev.Study:9mth RCT after 10wk Diagnosis: means, SDs) ADMIN: Presumably same as open-label open-label ATX trial-RCT reported here 44% Oppositional defiant disorder by Kiddie ADHD RS Inattentive subscore (mean chang (i.e. twice daily divided dose); Pills Schedule for Affective Disorders… identical (incl. packaging) to PLB Type of Analysis: ITT (for p's w BL & 1 post-BL Leaving the Study Early for Any Reason measurement, LOCF) ADHDRS Total (Change from Baseline: Atomoxetine or Placebo - Following 9- 5% ADHD Hyperactive/Impulsive subtype by means, SDs) month relapse prevention trial Blindness: Double blind (Michelson2004), n=163 randomised to DSM-IV: Clin interview & confirmed by K-SADS- CGI Severity Score (Mean change from BL) Duration (days): Mean 238 PL further 6-month continuation phase of Leaving the Study Early due to Adverse Event double-blind relapse prevention trial Followup: 6 months further relapse prev.trial CTRS-ADHD index (Mean change from BL) (n=81 randomised to ATX, n=82 7% Mood + Anxiety Disorders by CDRS-R & (Buitelaar2007) randomised to PLB). Procedures as in 9- MASC Leaving Study Early: Any Reason (except month trial. Setting: 33 academic investigative centres 'Relapse') Group 2 N= 124 across world: in (24 centres), Isreal (2 100% ADHD by DSM-IV: Clin interview & AE: Weight gain (mean, kg) centres), (4 centres), Australia (3 confirmed by K-SADS-PL AE: Gain in height (mean, cm) Placebo. Mean dose NR - ADMIN: centres). CPRS-ADHD index (Mean change from BL) Presumably same as ATX (i.e. twice daily divided dose); Pills identical (incl. Notes: Randomisation: Sequence generated by 22% ADHD Inattentive subtype by DSM-IV: Clin CTRS-Hyperact.subscale (Mean change from packaging) to PLB outside vendor;allocation blind; stratified by interview & confirmed by K-SADS-PL BL) investigational site; unbalanced: more p's rand. Data Not Used to ATX than PLB. 73% ADHD Combined subtype by DSM-IV: Clin Mulitdimnsnl Anxiety Scale for Children Info on Screening Process: 604 entered open- interview & confirmed by K-SADS-PL (m.change) - not relevant outcome label trial; 416 completed open-label and were C(P/T)RS Cognitive problems subscale - not randomised into double-blind 9 month relapse- Exclusions: P's with bipolar disorder, or psycholtic illness; p's relevant subscale prevention phase of trial.Of 292 rand.to ATX, with unstable medical illness, or conditon which would Child Health Questionnaire (mean change 81 rand.to ATX & 82 rand.to PLB for further 6 require ongoing admin of psychoactive medication (other from BL) - not relevant outcome months of double-blind relapse prevention trial. than atomoxetine). CHQ-Psychosocial Summary (mean change) Notes: P's also:symptom severity>=1.5SD above U.S.age not relevant outcome & gender norms(on what scale?NR) Children's Depression Rating Scale (mean All:medical evaluation (physical examination & lab change) - not relevant outcome measures,incl. routine chemistries, function C(P/T)RS Oppositional subscale - not relevan tests,complete blood count,urinalysis,ECG). subscale Baseline: Mean (SD): ATX gp; PLB gp. ADHD-IV RS total score: 15.8(9.6); 15.7(10.0) ADHD RS inattentive: 8.6(5.1); 8.6(5.4) ADHD RS hyperactive: 7.2(5.5); 7.1(5.5) CPRS-ADHD index: 13.7(7.2); 13.3(7.6) CPRS-Hyperactivity subscale:4.5(3.8); 4.6(4.2) CTRS-ADHD index: 16.7(7.9); 17.2(8.0) CTRS-Hyperactivity subscale: 7.7(5.1); 8.1(5.5) Notes: OUTCOMES TAKEN AT:Biweekly for firs CGI-S: 2.3(1.0); 2.2(0.9) 4 post-randomisation visits, monthly thereafter to Endpoint, for both 9-month & further 6-month phases. Lost To F.U.(not incl. in reported results): Different n's for each scale, PLB gp: 0.8-25%; ATX gp:0.7-21.9%.

Results from this paper: Internal validity: 1.1 Poorly addressed 1.2 Adequately addressed 1.3 Well covered 1.4 Well covered 1.5 Well covered 1.6 Not addressed 1.7 Well covered 1.8 PLB gp: ; ATX gp: 1.9 Adequately addressed 1.10 Not addressed

Overall assessment of study: 2.1 1+

NB. Open-label trial pre RCT (10 wk trial) Initial Washout: For at least 5x the plasma half-life of any previous treatment ADMIN: all p's received open-label ATX (1.2mg/kg/day, divided as twice-daily dose; furtherincreases allowed based on clinical response to max dose of 1.8mg/kg/day) At 10 wks- efficacy assessed, then randomisation occurred at 12 wks (this delay of initiation of RCT was blind to p's and investigators). NEWCORN2006 Study Type: RCT n= 229 Data Used Group 1 N= 116 Funding: Supported by Eli AE: Nasal congestion (dichotomous data) Lilly and Co. Study Description: 'Non-specific' comorbidity, Age: Mean 10 Range 6-16 Atomoxetine (continued on effective Fell below 'Response criteria, but not but details (e.g. n's) of comorbid disorders not Sex: 163 males 66 females dose). Mean dose 4.13(sd = reported. 'Relapsed' 0.28)mg/kg/day - WASHOUT: None: P's Sample: 'Children' & 'Adolescents' Diagnosis: ADHDRS Inattn. (Investigator admin'd; mean switched from acute treatment to 1% ADHD Hyperactive/Impulsive subtype by change) randomisation procedure, time of Type of Analysis: ITT (LOCF, however n's vary DSM-IV AE: Vomiting (dichotomous data) randomisation blinded. for scales) DOSE: Kept constant on weight-adjusted AE: Pyrexia (dichotomous data) basis throughout, see mean dose. Blindness: Double blind 100% ADHD by DSM-IV AE: Diastolic blood pressure (mm Hg, mean ADMIN:No details Duration (days): Mean 240 change) Group 2 N= 113 32% ADHD Inattentive subtype by DSM-IV AE: Nausea (dichotomous data) Setting: 20 sites in the United States. NB. All Atomoxetine (decreased dose). Mean p's received 7-9 weeks of ATX acutely before ADHDRS Total (Investigator admin'd; mean dose 0.5mg/kg/day - WASHOUT: None: randomisation. 67% ADHD Combined subtype by DSM-IV change) P's switched from acute treatment to AE: Abdominal pain (Upper; dichotomous data randomisation procedure, time of Notes: No details re. randomisation. Exclusions: P's with bipolar disorder, a psychotic illness, AE: Mood swings (dichotomous data) randomisation blinded. Info on Screening Process: P's originally seizures, pervasive developmental disorder; taking AE: Cough (dichotomous data) DOSE: Kept constant on weight-adjusted enrolled in a double-blind, PLB-controlled trial: concomitant psychoactive medications; comorbid anxiety basis throughout, see mean dose. ATX vs OROS-MPH (reported previously in ADHDRS Hyp/Imp (Investigator admin'd; ADMIN:No details and tic disorders;Been treated previously with an adequate mean change) conference paper only). All p's randomised in trial of MPH or amphetamine, and did not experience some AE: Weight change (mean change) this trial 'responded' to ATX (i.e.>=40% improvement in ADHD signs, or had intolerable adverse reduction in ADHDRS total score from baseline) effects. AE: Pharyngitis streptococcal (dichotomous data) Notes: Diagnoses established with K-SADS-PL & all p's AE: Upper respiratory tract infection (dichot) >1.5 SD's above age & gender norms on ADHDRS Parent version, investigator admin's & scored. Leaving the Study Early for Any Reason NB. 'Other' concurrent psychiatric diagnoses were AE: Affect lability (dichotomous data) permitted, and were assessed by clinical interview & K- AE: Headache (dichotomous data) SADS-PL Baseline: Previous stimulant exposure: %'s Continued dose group: 63%; Decreased dose group: 58% "Relapse":ADHDRS returns to>90% NB. 'Baseline' is last reading before first dose ATX (prior to pretreatmt(dichot) initial acute trial) AE: Somnolence/daytime ADHDRS total (Mean(SD)): N(continued dose)=115; tiredness(dichotomous data) N(decreased dose)=109 AE: Irritability (dichotomous data) Continued dose group: 15.1(7.7); Decreased dose group: 14.0(7.2) AE: Decreased appetite (dichotomous data) ADHDRS Inattentive subscale: N(continued dose)=115; AE: Systolic blood pressure (mm Hg, mean N(decreased dose)=109 change) Continued dose group: 8.4(4.1); Decreased dose group: AE: Fatigue (dichotomous data) 8.3(4.4) CGI-ADHD-Severity (mean change) ADHDRS Hyperactive/impulsive subscale: N(continued dose)=115; N(decreased dose)=109 AE: Pharyngolaryngeal pain (dichotomous Continued dose group: 6.6(4.7); Decreased dose group: data) 5.7(4.4) AE: Nasopharyngitis (dichotomous data) CGI-ADHD-Severity scale: N(continued dose)=115; AE: Influenza (dichotomous data) N(decreased dose)=110 AE: 'At least one AE' (dichotomous data) Continued dose group: 2.75(1.03); Decreased dose group: 2.71(0.97) Leaving the Study Early due to Adverse Event AE: Heart rate (bpm, mean change) Data Not Used Leaving Study Early: Any Reason (except 'Relapse') - ??No data, but assume relapsed p's d/out? CHQ-Psychosocial Summary (mean change) not relevant outcome Notes: TAKEN AT: Endpoint, no further detail regarding frequency of visits during trial. NB. For 'Relapse' criteria- over 2 consecutive weeks; 'Response' = >=40% reduction from baseline on ADHDRS.

Results from this paper: Internal validity: 1.1 Well covered 1.2 Not reported adequately 1.3 Not reported adequately 1.4 Well covered 1.5 Well covered 1.6 Well covered 1.7 Adequately addressed 1.8 Continued dose group: 28% (33/116); Decreased dose group: 35% (40/113) 1.9 Poorly addressed - LOCF, but a few p's missing from endpoint outcome n's put down to 'missing values'. 1.10 Not reported adequately

Overall assessment of study: 2.1 1+ PLISZKA2000 Study Type: RCT n= 59 Data Used Group 1N= 18 One author working for IOWA Conners Teacher RS-Inatt/Hyp Watson Pharmaceuticals. Study Description: Nonspecific Comorbity Age: Mean 8 Placebo. Mean dose NA - ADMIN: P's subscale (mean) Research funded by Shire (ODD, CD, mild anxiety disorders, %s not randomly allocation to MPH algorithm of Sex: no information Richwood Inc. reported) Data Not Used PLB-admin, or ADL algorithm of PLB- Sample: 'Children' Diagnosis: Clin. Global Impressions-Improv. admin (%'s not reported). All medications 62% Oppositional defiant disorder by DISC & (Inv.rated;mean) - outcome not relevant crushed & mixed with blue food powder & Type of Analysis: ITT(if p's completed all IOWA CTRS (I/O) factor & CGI placed in opaque capsules (all identical). assess. in at least wk1) Blindness: Double blind Duration (days): Mean 21 Setting: USA, school children (Grades 1-5). 11% Conduct disorder by DISC & IOWA CTRS Notes: TAKEN AT: in wk1, T-ratings- Group 2N= 20 (I/O) factor & CGI Mon,Tues,Wed,Thurs (both morn&afternoon), P- Notes: Sample randomised but details not Methylphenidate. Mean dose 25.2mg - ratings-evening on Thurs; wk2,wk3- not made reported, no details of concealment reported. DOSE:Wk1:5mg(p's<60lb),10mg(>60lb)(1 100% ADHD by DISC & IOWA CTRS (I/O) clear when outcomes measured. /day;morn); Info on Screening Process: 73 screened, 11 factor & CGI LOST TO F.U.: 1/59 (unclear allocation) dropped Wk2:Noon dose added if no afternoon excluded (not meeting criteria). out in 1st week- not included in ITT analysis. improv.;morn dose 2x if no improv.morn. 3 parents withdrew after evaluation (unclear id Exclusions: DISC criteria for major depression episode or tic Wk3:Noon dose 2x if no improv.afternoon this was b4 or after randomisation- have Max: 50mg/25mg(>/<60kg, resp.) assumed b4). Therefore 59 randomised - disorder, or manic episode; History of psychosis or have allocation info reported only ifor n=58. signs of psychosis or significantly depressed mood on MSE; Group 3N= 20 thought disorder; Kaufman Brief Intellignce Test < 75; Other Adderall. Mean dose 12.5mg - medical ilness; currently being treated with any other non- DOSE:Wk1:5mg(p's<60lb),10mg(>60lb)(1 stimulant psychotropic medication. /day;morn); Notes: P's required to be >=1.5 SDs above mean (for Wk2:Morn dose doubled (2x) if no age/sex) on IOWA CTRS Inattention/Overactivity factor; & afternoon improv.; afternoon dose added on Conners Global Index. if no improv.evening. Wk3:noon dose added if no Baseline: IOWA Conners Teacher Rating Scale improv.afternoon. (Inattentive/Overactive); ADL 2.3 (0.5), MPH 2.2 (0.5), PLB Max: 30mg/15mg(>/<60kg, resp.) 2.2 (0.5) IOWA Conners Teacher Rating Scale (Aggession/Defiance); ADL 1.5 (1.0), MPH 1.5 (1.0), PLB 1.2 (1.1) Conners Global Index; ADL 2.1 (0.6), MPH 2.1 (0.5), PLB 2.2 (0.5). Results from this paper: Internal validity: 1.1 well covered 1.2 Poorly addressed 1.3 Not addressed 1.4 Well covered 1.5 Adequately addressed 1.6 Well covered 1.7 Well covered 1.8 PLB gp 11%, ADL gp 10%, MPH gp 5% 1.9 Adequately addressed 1.10 Not applicable

Overall assessment of study 2.1: 1+ RUGINO2003 Study Type: RCT n= 24 Data Used Group 1N= 13 Funding: NR AE: Irritability/Agitation (dichotomous data) Study Description: Nonspecific comorbidity (inc. Age: Mean 7 Range 5-15 Modafinil. Mean dose 264mg +/- 50 - ADHD Rating Scale Total Score (mean) class 1 and class 2; see 'diagnoses') Sex: 15 males 9 females WASHOUT: NR Sample: 'children' and 'adolescents' (%'s not AE: Delayed sleep onset (dichotomous data) DOSE:Began on 1 capsule(100mg)/day, reported) Diagnosis: Leaving the Study Early for Any Reason p's re-assessed every 3-10days-dose 14% Separation Anxiety by Unspecified adjusted according to efficacy, tolerability Type of Analysis: Completer reported (dichot AE: Transient mood disorder w tearfulness diagnostic tool (max dose 400mg/day). Trial concluded data converted-ITT) (dichot) when dose stable 5 days. AE: Tonsillitis/pharyngitis (dichotomous data) ADMIN:Morn Blindness: Double blind 9% Borderline IQ by Unspecified diagnostic tool AE: Transient stomachache (dichotomous Duration (days): Mean 42 Group 2N= 11 data) 14% Enuresis by Unspecified diagnostic tool Placebo. Mean dose 300mg +/- 60mg - Setting: USA, no further detail. AE: Somnolence/daytime WASHOUT: NR tiredness(dichotomous data) DOSE:Began on 1 capsule(100mg)/day, Notes: Randomisation: 'computer-generated 27% ODD or CD by Unspecified diagnostic tool AE: Transient headache (dichotomous data) p's re-assessed every 3-10days-dose randomised list' Leaving the Study Early due to Adverse Event adjusted according to efficacy, tolerability Info on Screening Process: NR, except that 18% Learning Disorder by Unspecified AE: Nausea and Vomiting (dichotomous data) (max dose 400mg/day). Trial concluded recruitment was cut short because the primary diagnostic tool when dose stable 5 days. investigator relocated to another state. AE: Decreased appetite (dichotomous data) ADMIN:Morn, capsules identical to MOD Data Not Used capsules. 18% Phobias (NOS) by Unspecified diagnostic "Other Conner's ADHD scales" - no data tool TOVA ADHD (z-score) - not relevant outcome unsure re.using z-scores 100% ADHD by DSM-IV CTRS & CPRS DSM-IV ADHD Total (t- score) - unsure re. combining two scales??? 18% ADHD Inattentive subtype by DSM-IV Parent Q:subjective impression improvement(dichot) - Unknown scale: No description of scale reported 9% ADHD Hyperactive/Impulsive subtype by Notes: TAKEN AT: Baseline, then (Unclear, but DSM-IV assume at each assessment, every 3-10 days).

73% ADHD Combined subtype by DSM-IV

Exclusions: Acute medical or uncontrolled psychiatric illness; allergy to modafinil or any of the components of the tablet; mitral valve prolapse, left ventricular hypertrophy, cardiac ischemia, clinically significant cardiac arrythmia, or history of syncope; use of the following medications within 30 days prior to study: psychoactive medications other than stimulants prescribed to manage ADHD, antiepileptics, or medications metabolised primarily through the hepatic cytochrome P450 system; more than 3 migraine headaches within 3 months before the study; female with the potential of becoming pregnant during the trial; uncontrolled seizure disorder; sleep disorder with insomnia; history of manic episodes or psychosis. Also- no reliable transportation to and from development centre; non-regular school attendance; verbal IQ <80. Notes: Additional ADHD diagnostic criteria: Average CTRS ADHD index t score >=70 & average percentile score for ADHD-RS-IV >=70. Baseline: Test of Variables of Attention (TOVA; z-scores): MOD gp: -4.92+/-3.49; PLB gp: -3.85+/-2.04 DSM-IV symptoms (CTRS & CPRS DSM-IV ADHD total t score). NB. CTRS & CPRS represented by one score ????????? MOD gp: 76.6 +/-8.8; PLB gp: 77.7+/-8.7 ADHD-RS ADHD total (mean+/-S.D.) MOD gp: 20.9+/-4.6; PLB gp: 19.1+/-3.9 Results from this paper: Internal validity:

1.1 Well covered 1.2 Adequately addressed 1.3 Adequately addressed 1.4 Well covered 1.5 Adequately addressed 1.6 Well covered 1.7 Adequately addressed 1.8 MOD gp: 15% (2/13); PLB gp: 0% (0/11) 1.9 Poorly addressed- completer analysis only 1.10 Not applicable

Overall assessment of the study:

2.1 1+ SHYTLE2002 Study Type: RCT n= 10 Data Used Group 1N= 5 Funding: NR AE: Vomiting (dichotomous data) Study Description: Comorbidity: NR, assume Age: Mean 10 Range 8-13 Nicotine (as skin patches). Mean dose AE: Headache (dichotomous data) 'non-specific' comorbidities. Sex: 6 males 4 females 5mg/16hrs - WASHOUT: 3-days(b4 Sample: 'Children' and 'adolescents' (%'s NR) AE: Somnolence/daytime baseline),all psychotropic meds Diagnosis: tiredness(dichotomous data) DOSE:5mg/16hrs Type of Analysis: ITT (all p's completed trial) 100% ADHD by DSM-IV AE: Itching under patch (dichotomous data) ADMIN:1 patch applied every morn,removed just b4 bed.If AE's-remove AE: Nightmares (dichotomous data) patch,apply next day as usual.If AE's at Exclusions: Clinically significant chronic medical conditions Blindness: Double blind history of cardiac arrhythmias, mental retardation (IQ<75); Leaving the Study Early due to Adverse Event school-patch applied after Duration (days): Mean 7 organic brain disorders; suicide potential; tobacco; drug or AE: Nausea (dichotomous data) school,removed in morn. alcohol abuse/dependence within 6 months before the study; AE: Dizziness (dichotomous data) Group 2N= 5 current use of psychotropic drugs. Females of child bearing Setting: Outpatient participants, recruited from potential asked to use contraceptive methods if sexually Leaving the Study Early for Any Reason Placebo. Mean dose NA - WASHOUT: 3- advertisments and clinical referrals. active. AE: Rapid heartbeat (dichotomous data) days(b4 baseline),all psychotropic meds DOSE:5mg/16hrs Notes: No detail on randomisation reported. AE: Stomach ache (dichotomous data) Notes: Diagnostic questionnaire used was an early version ADMIN:1 patch (identical to NIC patch) Info on Screening Process: Ages 8-18 eligible, of the MINI-KID (child & adolescent version of Mini Data Not Used applied every morn,removed just b4 bed.I only ages 8-13 enrolled. No further detail International Neuropsychiatric Interview dor DSM-IV) CPRS Learning problems subscore(t-score AE's-remove patch,apply next day as reported. reduction) - not relevant outcome; can we Baseline: Conners Parent Rating Scale (t-score (SEM)): usual.If AE's at school-patch applied after extract t-scores? Impulsive subscale: NIC gp 70(5); PLB gp 79(2) school,removed in morn. Hyperactivity subscale: NIC gp 83(3); PLB gp 80(6) Clinical Global Impression Scale (NIMH) - no CGI-Severity: data NIC gp 3.4(0.2); PLB gp: 3.2(0.4) CPRS Anxiety subfactor (t-score reduction) - not relevant outcome; can we extract t-scores CPRS Hyperactivity subfactor (t-score reduction) - ?? Can we extract t-scores? CPRS Impulsive subfactor (t-score reduction) ?? Can we extract t-scores? CPRS Psychosomatic subfactor (t-score reduction) - not relevant outcome; can we extract t-scores? CPRS Conduct problems subfactor(t-score reduction) - not relevant outcome; can we extract t-scores? Notes: OUTCOMES TAKEN AT: CPRS & CGI - at baseline and endpoint; AE's- not reported, presumably via spontaneous reporting throughou trial, and at endpoint.

Results from this paper: Internal Validity 1.1 Well covered 1.2 Not reported adequately 1.3 Not reported adequately 1.4 Well covered 1.5 Adequately addressed 1.6 Adequately addressed 1.7 Adequately addressed 1.8 NIC gp 0/5 (0%); PLB gp 0/5 (0%) 1.9 Not applicable (all p's completed trial) 1.10 Not applicable

Overall assessment of study 2.1 1+ SINGER1995 Study Type: RCT crossover n= 34 Data Used Group 1N= 34 Child Behaviour Checklist (Achenbach) Study Description: No details of method of Age: Mean 11 Range 7-14 Clonidine. Mean dose 0.05mg capsule; randomisation or allocation concealment. Sex: 31 males 3 females final total dose 0.2mg/d - Start with 1 capsule p.d (eve), added 1 additional Type of Analysis: No mention Diagnosis: capsule every wk to max daily dose of 1 Blindness: Double blind 100% ADHD by DSM-III capsule 4xdaily maintained for 2 wks; total 6 wks treatment. Then tapered at Duration (days): Mean 126 rate of 1 every other day. 1 wk washout 100% Tourette's Syndrome by DSM-III period, then medication for 2nd/3rd Setting: US. Tourette Syndrome Clinic; John treatment. Hopkins Hospital. Exclusions: No DSM-III diagnosis of ADHD or TS; In receipt Notes: Funding: grants from the Tourette Syndrome Association and the United States of other medication. Group 2N= 34 Public Health Service. Placebo - Start with 1 capsule p.d (eve), Info on Screening Process: 58 screened for Baseline: Not provided added 1 additional capsule every wk to entry, 21 excluded either because they failed to max daily dose of 1 capsule 4xdaily meet DSM-III criteria for TS or ADHD, or were maintained for 2 wks; total 6 wks receiving other medications. 37 entered the treatment. Then tapered at rate of 1 every study, 3 withdrew, data only provided for 34 other day. 1 wk washout period, then medication for 2nd/3rd treatment. Group 3N= 34 TCA - desipramine. Mean dose 25mg capsule; final total dose 100mg/d - Start with 1 capsule p.d (eve), added 1 additional capsule every wk to max daily dose of 1 capsule 4xdaily maintained for 2 wks; total 6 wks treatment. Then tapered at rate of 1 every other day. 1 wk washout period, then medication for 2nd/3rd treatment. Results from this paper: Internal validity:

1.1 Well covered 1.2 Not reported 1.3 Not addressed 1.4 Well covered 1.5 Well covered 1.6 Well covered 1.7 Well covered 1.8 8% overall 1.9 Not addressed 1.10 Not applicable

Overall assessment of the study:

2.1 - SPENCER2002A Study Type: RCT n= 127 Data Used Group 1N= 62 Funded by Eli Lilly and ADHDRS Inattentive (Change from BL: Company. Study Description: Non specific cormorbidity Age: Mean 9 Range 7-12 Placebo - INITIAL WASHOUT:2wks means, SDs) NB.MPH arm incl (to (predominately ODD) ADMIN:3 times daily for p's in 'naive' Sex: 103 males 24 females validate study design in the Sample: 'Children' (7-13) "Response" (>=25% decrease from BL -ADHD strata (to match MPH-admin pattern); event that atomoxetine Diagnosis: RS total) twice daily for p's in 'non-naive' strata. All Type of Analysis: ITT ((P's:prov.data @ BL & 1 failed to separate from 37% Oppositional defiant disorder by ADHD Rating Scale Total Score (mean study drugs identical in appearance to post-BL assessment) PLB), but only ATX vs PLB Unspecified diagnostic tool change) maintain blind. results reported. Total N=38 Blindness: Double blind Conners Parent RS-R Short form (Mean Group 2N= 65 MPH, unknown distribution Duration (days): Mean 63 1% ADHD Hyperactive/Impulsive subtype by change) Atomoxetine - INITIAL WASHOUT:2wks across Study A and Study B. DSM-IV, K-SADS-PL, ADHDRS-IV-Parent-Inv CGI-ADHD-S (mean change from BL) DOSE:Titrated (1mg/kg/day;by clinical Setting: US. Multicenter: 17 sites involved with ADHDRS Hyper/Impuls.(Change from BL: response) to 2.0mg/kg/day(90mg max 2 simultaneously-run studies (A: 7 sites; B: 10 9% Mood + Anxiety Disorders by Unspecified means, SDs) daily dose) sites, basline & endpoint data reported diagnostic tool Notes: TAKEN AT: Every visit (weekly); Change ADMIN:Daily-divided dose(morning & late separately. from baseline to endpoint extracted. afternoon) NB: +placebo taken at lunchtime for p's in 'naive' strata (to Notes: Randomization stratified by site; 12% Phobias (NOS) by Unspecified diagnostic LOST to F.U.: ATX 1-9% (ie.1/65-6/65); PBL 1- maintain MPH-admin blind) schedules generated by validated software & tool 10% (ie. 1/62-6/62) (different n's for different implemented using telephone system. scales; not incl.in ITT analysis) Info on Screening Process: 409 screened, 291 100% ADHD by DSM-IV, K-SADS-PL, ADHDRS- randomised (studies A+B) IV-Parent-Inv NB. B4 randomisation, p's stratified according to whether they were naive to psychostimulant 11% Elimination Disorders by Unspecified treatment, or not. 'Naïve strata': randomised to diagnostic tool either ATX, PLB, or MPH. 'Non-naïve strata': to ATX or PLB. 18% ADHD Inattentive subtype by DSM-IV, K- SADS-PL, ADHDRS-IV-Parent-Inv

81% ADHD Combined subtype by DSM-IV, K- SADS-PL, ADHDRS-IV-Parent-Inv

Exclusions: Characterised as poor metabolisers of CYP2D6 (based on their genotype); weight <25kg at initial visit; History of Bipolar I or II disorder or psychosis; history of organic brain disease or a seizure disorder; currently taking psychotropic medication; history of alcohol or drug abuse in the last 3 months; positive drug screen; or significant previous or current medical conditions (eg HIV, leukaemia in remission, surgically corrected congenital heart defects; below normal intelligence (according to WISC-III). Notes: ADHDRS-IV-Parent-Inv score >1.5 SDs above age & gender norm for inclusion. NB. Demographics reported for study A and study B together- assume same %'s for each as average. Baseline: Mean (SD): ATX gp; PLB gp: ADHD RS Total: 41.2 (8.9); 41.4(7.9) ADHD RS Inattentive: 22.0(3.9); 22.2(4.0) ADHD RS Hyperactive/Impulsive: 19.3(6.1); 19.2(5.5) CGI-ADHD-S: 4.9(0.8); 4.8(0.8) CPRS-ADHD Index: 27.4(6.2); 28.7(5.8) Results from this paper: Internal validity:

1.1 Adequately addressed 1.2 Well covered 1.3 Well covered 1.4 Well covered 1.5 Poorly addressed- demographics for Studies A & B compiled. 1.6 Adequately addressed 1.7 Adequately addressed 1.8 ATX gp 24.6% (16/65); PLB gp 24.2%(15/62) 1.9 Adequately addressed 1.10 Not addressed

Overall assessment of the study:

2.1 1+ SPENCER2002B Study Type: RCT n= 126 Data Used Group 1N= 64 Funded by Eli Lilly and ADHDRS Inattentive (Change from BL: Company. Study Description: Non specific cormorbidity Age: Mean 9 Range 7-12 Atomoxetine - INITIAL WASHOUT:2wks means, SDs) NB.MPH arm incl (to (predominately ODD) DOSE:Titrated (1mg/kg/day;by clinical Sex: 103 males 23 females validate study design in the Sample: 'Children' (7-13) "Response" (>=25% decrease from BL -ADHD response) to 2.0mg/kg/day(90mg max event that atomoxetine Diagnosis: RS total) daily dose) Type of Analysis: ITT ((P's:prov.data @ BL & 1 failed to separate from 37% Oppositional defiant disorder by ADHD Rating Scale Total Score (mean ADMIN:Daily-divided dose(morning & late post-BL assessment) PLB), but only ATX vs PLB Unspecified diagnostic tool change) afternoon) NB: +placebo taken at results reported. Total N=38 Blindness: Double blind Conners Parent RS-R Short form (Mean lunchtime for p's in 'naive' strata (to maintain MPH-admin blind) MPH, unknown distribution Duration (days): Mean 63 1% ADHD Hyperactive/Impulsive subtype by change) across Study A and Study B. DSM-IV, K-SADS-PL, ADHDRS-IV-Parent-Inv CGI-ADHD-S (mean change from BL) Group 2N= 62 Setting: US. Multicenter: 17 sites involved with ADHDRS Hyper/Impuls.(Change from BL: Placebo - INITIAL WASHOUT:2wks 2 simultaneously-run studies (A: 7 sites; B: 10 9% Mood + Anxiety Disorders by Unspecified means, SDs) DOSE:Titrated (1mg/kg/day;by clinical sites, basline & endpoint data reported diagnostic tool response) to 2.0mg/kg/day(90mg max separately. daily dose) ADMIN:Daily-divided dose(morning & late Notes: Randomization stratified by site; 12% Phobias (NOS) by Unspecified diagnostic afternoon) NB: +placebo taken at schedules generated by validated software & tool lunchtime for p's in 'naive' strata (to implemented using telephone system. maintain MPH-admin blind) Info on Screening Process: 409 screened 291 randomised (studies A+B) 100% ADHD by DSM-IV, K-SADS-PL, ADHDRS- Notes: TAKEN AT: Every visit (weekly); Change NB. B4 randomisation, p's stratified according IV-Parent-Inv from baseline to endpoint extracted. to whether they were naive to psychostimulant LOST to F.U.: ATX 1-5% (ie.1/64-3/64); PBL 1- treatment, or not. 'Naïve strata': randomised to 11% Elimination Disorders by Unspecified 3% (ie. 1/62-2/62) (different n's for different either ATX, PLB, or MPH. 'Non-naïve strata': to diagnostic tool scales; not incl.in ITT analysis) ATX or PLB. 18% ADHD Inattentive subtype by DSM-IV, K- SADS-PL, ADHDRS-IV-Parent-Inv

81% ADHD Combined subtype by DSM-IV, K- SADS-PL, ADHDRS-IV-Parent-Inv

Exclusions: Characterised as poor metabolisers of CYP2D6 (based on their genotype); weight <25kg at initial visit; History of Bipolar I or II disorder or psychosis; history of organic brain disease or a seizure disorder; currently taking psychotropic medication; history of alcohol or drug abuse in the last 3 months; positive drug screen; or significant previous or current medical conditions (eg HIV, leukaemia in remission, surgically corrected congenital heart defects; below normal intelligence (according to WISC-III). Notes: ADHDRS-IV-Parent-Inv score >1.5 SDs above age & gender norm for inclusion. NB. Demographics reported for study A and study B together- assume same %'s for each as average. Baseline: Mean (SD): ATX gp; PLB gp: ADHD RS Total: 37.8 (7.9); 37.6(8.0) ADHD RS Inattentive: 21.0(4.0); 21.1(3.8) ADHD RS Hyperactive/Impulsive: 16.8(6.5); 16.5(6.1) CGI-ADHD-S: 4.9(0.8); 4.9(0.8) CPRS-ADHD Index: 26.5(6.6); 26.3(5.7) Results from this paper: Internal validity:

1.1 Adequately addressed 1.2 Well covered 1.3 Well covered 1.4 Well covered 1.5 Poorly addressed- demographics for Studies A & B compiled. 1.6 Adequately addressed 1.7 Adequately addressed 1.8 ATX gp 17.2% (11/64); PLB gp 27.4%(17/62) 1.9 Adequately addressed 1.10 Not addressed Overall assessment of the study:

2.1 1+ SPENCER2002C Study Type: RCT n= 41 Data Used Group 1N= 20 Funding: Supported in part Leaving the Study Early due to Adverse Event by the Tourette's Society Study Description: Comorbidity: 'Specific': Age: Mean 10 Range 5-17 Placebo - WASHOUT: No participant was Association and a NIMH 100% history of Tic disorder; 95% current tic "Response":ADHDRS >=30% reduction & CG taking psychoactive medication within 1 Sex: 34 males 7 females grant. disorder AND 'Non-specific' Classes 1&2 (see I = 1 or 2 month of baseline assessment. diagnoses) Diagnosis: AE: Motion sickness (dichotomous data) DOSE: Titrated to a max of 3.5mg/kg by 49% At least one anxiety disorder by K-SADS-E AE: Sedation (dichotomous data) week 3 unless adverse effects developed Type of Analysis: Not clear - for ADHD ADMIN: Twice-daily dosing of 25mg outcomes appears to be ITT AE: Dry mouth (dichotmous data) tablets (identical to DES). 32% Major depression with at least moderate Blindness: Double blind Leaving the Study Early for Any Reason impairment by K-SADS-E AE: Stomach ache (dichotomous data) Duration (days): Mean 42 AE: Nausea (dichotomous data) Setting: US; Outpatient children (clinical AE: Constipation (dichotomous data) referrals to a pediatric psychopharmacology unit). 12% Current: Non-TD chronic tic AE: Unsteadiness/Dizziness (dichotomous Group 2N= 21 (motor/vocal)disorder by DSM-IV data) Notes: Separate balanced randomisation was Desipramine hydrochloride - WASHOUT: done (by pharmacy) for 4 groups: AE: Heart burn (dichotomous data) No participant was taking psychoactive preadolescent girls/boys & post-adolescent 10% Conduct disorder by K-SADS-E AE: Blurred vision (dichotomous data) medication within 1 month of baseline girls/boys. AE: Sleep difficulty (dichotomous data) assessment. DOSE: Titrated to a max of 3.5mg/kg by 48% Oppositional disorder by K-SADS-E Info on Screening Process: NR AE: Diarrhea (dichotomous data) week 3 unless adverse effects developed AE: Decreased appetite (dichotomous data) ADMIN: Twice-daily dosing of 25mg 24% Anxiety disorders (2 or more) by K-SADS-E AE: Headache (dichotomous data) tablets AE: (dichotomous data) 83% Current:Tourette disorder (TD) by DSM-IV AE: Rash (dichotomous data) Data Not Used 90% History: Tourette disorder (TD) by DSM-IV Yale Global Tic Severity Scale (YGTSS;Total mean) - not relevant outcome 100% ADHS Combined subtype by DSM-IV Global Assessment of Functioning - not relevant outcome CGI - Severity (mean) - ??? Waiting for email 30% Obsessive-compulsive disorder by K- response for data SADS-E ADHD Rating Scale Hypract/Impulsv. Subscore (mean) - ??? Waiting for email 10% History: Non-TD chronic tic response for data (motor/vocal)disorder by DSM-IV ADHD Rating Scale Combined Score (mean) ??? Waiting for email response for data Exclusions: Any clinically significant chronic medical "Response":YGTSS >=30% reduction & CGI- conditions or abnormal baseline laboratory values; IQ <75; = 1 or 2 - not relevant outcome - tic outcome clinically unstable psychiatric conditions (ie. suicidality); current bipolar disorder, psychosis, drug or alcohol abuse or ADHD Rating Scale Inattentive subscore dependence, or current use of other psychotropic drugs; (mean) - ??? Waiting for email response for pregnant or nursing females; personal history of cardiac data disease or family history of nongeriatric cardiac disease; p's Yale Global Tic Severity Scale(YGTSS;Phonic with transient tics. mean) - not relevant outcome Notes: NB. K-SADS-E administered by trained research Yale Global Tic Severity Scale (YGTSS;Motor assisants (no clinicians, as designed) with documented mean) - not relevant outcome reliability and reviewed by the lead author. Notes: OUTCOMES TAKEN AT: All outcomes taken weekly. Reports of adverse effects elicited Baseline: No data (Displayed graphically - all groups very by open-ended questionsfrom youth & parents a similar at baseline). each visit (weekly). NB. ADHD symptoms rated by clinician based on parent and teacher interviews.

Results from this paper: Internal validity:

1.1 Well covered 1.2 Adequately addressed 1.3 Adequately addressed 1.4 Well covered (Randomisation codes kept in sealed envelopes in the medical records). 1.5 Well covered 1.6 Well covered 1.7 Well covered 1.8 DES gp: 0% (0/21); PLB gp: 10% (2/20) 1.9 Poorly addressed - not mentioned at all in text, different n's reported for each outcome. For ADHD outcomes & AE outcomes- appears to be ITT (whole sample reported). 1.10 Not applicable

Overall assessment of the study:

2.1 1+ SWANSON2006 Study Type: RCT n= 190 Data Used Group 1 N= 126 Funding: Cephalon Inc., CPRS:R-S Hyperactivity (mean) Fraser, PA. Study Description: 'Pure'ADHD sample (see Age: Mean 10 Range 6-17 Modafinil - WASHOUT:see exclusions. ADHD-RS-IV School version Hyperact./Impuls excl's) Sex: 135 males 55 females DOSE: Max dose 340 or 425mg/day Sample:'Children'&'adolescents'(%'s NR). (mean) depending on weight; titrated first 7-9 NB.2wk discontinuation phase(random,dbl- Diagnosis: ADHD-RS-IV Home Total (mean change) days: 85mg day 1, increased by 85mg blind)following 7wk trial. 5% ADHD Hyperactive/Impulsive subtype by AE: Diastolic blood pressure (mm Hg, mean) every other day. DSM-IV-R ADMIN: Modafinil film-coated tablets, no Type of Analysis: ITT (inc. p's >=1dose & >=1 AE: Colds/allergies/infections (dichotomous further detail. post-BL assessment) data) 100% ADHD by DSM-IV-R Group 2N= 64 Blindness: Double blind ADHD-RS-IV Home version Inattention (mean Leaving the Study Early for Any Reason Placebo - WASHOUT:see exclusions. Duration (days): Mean 42 27% ADHD Inattentive subtype by DSM-IV-R DOSE: Max dose 340 or 425 mg/day AE: Rhinitis (dichotomous data) depending on weight; titrated first 7-9 Followup: 14 days (discontinuation phase) ADHD-RS-IV Home version Hyperact./Impuls days: 85mg day 1, increased by 85mg Setting: Multicentre, 17 centres throughout U.S. 67% ADHD Combined subtype by DSM-IV-R (mean) every other day. CPRS:R-S ADHD Index (mean) ADMIN: Tablets matched to MOD tablets, Notes: Randomised in a 2:1 ratio (MOD:PLB), no further detail. within strata defined by weight (<30 or >=30 kg) Exclusions: IQ<80 (WISC-3rd Ed.); score <80 on Weschler AE: Systolic blood pressure (mm Hg, mean) (no further detail of randomisation procedure). Individual Achievement Test, 2nd Ed.; receiving home AE: Abdominal pain (dichotomous data) schooling; history, or current diagnosis, of pervasive AE: Cough increased (dichotomous data) Info on Screening Process: 316 screened, 72 developmental disorder, schizophrenia or other psychotic didn't meet incl.criteria, 12 met excl.criteria, 22 disorders (DSM-IV-TR Axis 1); current suicide risk; other Leaving the Study Early due to Adverse Event withdrew consent, 8 were lost to follow-up, 12 psychiatric comorbidities requiring pharmacotherapy; p's CPRS:R-S Cognitive Problems/Inattention not randomised for 'other' reasons; therefore whose ADHD symptoms well-controlled, and who satisfied (mean) 190 randomised. with current therapy; p's who failed to respond to >=2 ADHD-RS-IV School version Inattention adequate courses of stimulant therapy; height or weight (mean) below 5th or above 95th percentile (National Centre for AE: Decreased appetite (dichotomous data) Health Stats growth charts); hypertension; hypotension; resting heart rate outside range of 60-115 bpm; low absolute AE: Heart rate (bpm, mean) neitrophil count; history of alcohol/substance abuse; habitual CGI-I rating =1 or 2 (very/much improved; consumption of more than 250mg/day caffeine. P's not dichot) allowed to use prescription or non-prescription medications AE: Headache (dichotomous data) with psychotropic activity (incl. other ADHD treatments, AE: Fever (dichotomous data) dietary supplements) within 1 week of baseline (within 2 weeks for MAO-I's & SSRI's) or throughout the study. ADHD-RS-IV School Total (mean change) AE: Insomnia/Sleep problems(dichotomous Notes: Additional diagnostic criteria: CGI-S >=4; total &/or data) subscale scores on ADHD-RS-IV school version at least 1.5 SD's above norms for p's age & gender. Data Not Used Child Health Questionnaire - not relevant Baseline: NB. BL data reported only for N=189 (not outcome including n=1 in MOD gp who did not receive treatment). Test of Variables of Attention (TOVA) - not CGI-S score (n/N (%)) relevant outcome Moderately ill: MOD gp 79/125(63%); PLB gp: 38/64(59%) Markedly ill: MOD gp 32/125(26%); PLB gp: 23/64(36%) Subject's Treatment Emergent Symptom Severely ill: MOD gp 14/125(11%): PLB gp: 3/64(5%) Scale (STESS) - not relevant outcome ADHD-RS-IV total score (mean (SD)): Notes: OUTCOMES TAKEN AT: Clinic visits: BL School version: MOD gp 37.7(9.1); PLB gp: 36.8(9.3) wks 1,2,3,5,7(last dbl-blind visit),9 (end Home version: 38.8(9.0); PLB gp 38.8(10.6) discontinuation phase); CGI-I each visit; CPRS:R CPRS:R-S ADHD Index (mean (SD)) S & SSRS (both parent-rated) BL, wks 3&7; MOD gp 75.7(7.4); PLB gp: 76.4(9.5) ADHD-RS-IV-home version: each visit; -school version daily. AE's spon.reported.

Results from this paper: Internal Validity; 1.1 Well covered 1.2 Not reported adequately 1.3 Not reported adequately 1.4 Well covered 1.5 Well covered 1.6 Well covered 1.7 Well covered 1.8 MOD gp: 46/126 (36.5%); PLB gp: 24/64 (37.5%). NB: Lost to follow-up (ie. not included in ITT effiacy analysis: MOD gp 6/126 (4.8%); PLB gp 1/64 (1.6%). 1.9 Adequately addressed 1.10 Not reported adequately (no mention).

Overall assessment of the study; 2.1 1+ WEISS2005 Study Type: RCT n= 153 Data Used Group 1N= 52 Funded by Eli Lilly and Clinician-rated CGI Company Study Description: Comorbity: 'non- Age: Mean 9 Range 8-12 Placebo. Mean dose NA - WASHOUT:NR ADHDRS-IV-Teacher:Inv (mean change from specific'(Pred. ODD, Learning Disorder) Sex: 123 males 30 females ADMIN:Once-daily (morn), appearance Sample: 'Children'(broadly- some 'Adolescents' BL) identical to ATX & dosing evaluated and as well) Diagnosis: Conner's Global Index: Teacher (change from 'adjusted' in the same manner. NB. Once-daily ATX 33% Oppositional defiant disorder by BL) Clinic Visits: bi/weekly Unspecified diagnostic tool Data Not Used Group 2 N= 101 Blindness: Double blind Conners' Parent Rating Scale Revised (CPRS Atomoxetine. Mean dose NR - Duration (days): Mean 49 8% Communications Disorder by Unspecified R) - no raw data-t scores only WASHOUT:NR medical and psychiatric evaluations SSRS-T - not relevant outcome DOSE:0.8mg/kg/day for 3days, then Setting: 8 investigative sites in US, 2 sites in Academic Performance Rating Scale - not increased to 1.2mg/kg/day.After 3wks if Canada, 1 in Puerto Rico. 1% ADHD Hyperactive/Impulsive subtype by relevant outcome p's>=3 on CGI-S scale,& no tolerability issues then increased to Notes: Randomisation: stratified by SADS for School-Age Children Brown Attention-Deficit Disorder 1,8mg/kg/day(max). investigational site (blocks of 6), assignment via Scale:Teacher Ver - not relevant outcome ADMIN:Once-daily (morn) interactive voice response system via 6% Motor Skills Disorder by Unspecified medical Behavioural Grade Measure - not relevant Clinic Visits: bi/weekly telephone, ATX:PLB-2:1 ratio. and psychiatric evaluations outcome Info on Screening Process: Community adverts Notes: TAKEN AT:ADHDRS-IV-Teacher:Inv used to help recruitment. 241p's screened, 153 30% Learning Disorder by LD history from T & P admin over phone 4 days before each clinic visit met inclusion criteria and were randomised; + other unspecified tools Conners Global Index-Teacher faxed to teacher 52% (46/88) who were excluded at screening at BL and endpoint only; CGI & CPRS:R-S failed to meet severity threshold on ADHDRD- 100% ADHD by DSM-IV,K-SADS- completed at each clinic visit. IV-Teacher:Inv. PL,ADHDRS:T>1.0sd's,CPRS-R:S>1.5sd's LOST TO F.U. ATX gp: 1-27%; PLB gp: 2-19% (diff.scales) 27% ADHD Inattentive subtype by SADS for School-Age Children

3% Generalised Anxiety Disorder by Unspecified diagnostic tool

72% ADHD Combined subtype by SADS for School-Age Children

Exclusions: Unavailability of a primary teacher willing to keep telephone appointments/provide ratings & reports as part of the study; significant intellectual deficit; serious medical illness; use of other pscyhotropic medication. Notes: Severity scores obtained when p's free of ADHD medication for min 5 school days. NB. Assumption here that "SADS for School-Aged Children- Present & Lifetime Version"=K-SADS-PL NB. ADHDRS:T= version IV. Baseline: Mean (SD): ATX gp; PLB gp ADHDRS-IV-T Total: 38.9(7.2); 36.7(8.4) ADHDRS-IV-T Innattentive score: 21.3(4.6); 20.7(5.2) ADHDRS-IV-T Hyperactive score: 17.5(6.2); 16.0(6.6) CGI severity score: 4.9(0.8); 4.9(0.8) Conner's Global Index-Teacher: 16.1(6.8); 16.4(5.9) Results from this paper: Internal validity; 1.1 Well covered 1.2 Adequately covered 1.3 Well covered 1.4 Adequately covered 1.5 Well covered 1.6 Not addressed 1.7 Adequately addressed 1.8 ATX gp: 16.8% (17/101); PLB gp: 7.7% (4/52) 1.9 Adequately assessed 1.10 Not reported

Overall assessment of study; 2.1 1+

NB. SSRS-T = Social Skills Rating Scale- Teacher WERNICKE2004A Study Type: RCT n= 194 Data Used Group 1 N= 102 Funding: Eli Lilly & Company ADHDRS-IV Parent Version (mean change Study Description: 'Pure ADHD': Assumption, Age: Range 7-12 Atomoxetine - INITIAL WASHOUT: 14 scores) no detail re. comorbidities reported. Sex: no information days NB. Discontinuation trial (1wk; single blind) Barkley Behaviour and Adverse Events qstnr- DOSE: Titrated based on clinical Diagnosis: modif - outcome not relevant ??? response to max dose of 2.0 mg/kg/d Type of Analysis: ITT (LOCF:P's prov 1 trtmnt & 100% Hyperkinetic disorder by DSM-IV Notes: TAKEN AT: End of each week. Change ADMIN: Evenly divided dose twice daily. 1 discontin measure) scores only reported. No info on form/appearance of Blindness: Double blind LOST TO F.U.: Unknown, ITT sample reported, intervention. Exclusions: Patients who were previously unresponsive to DISCONTINUATION PHASE: ATX Duration (days): Mean 63 N's randomised unknown. MPH; patients with motor tic or Tourette's disorder, bipolar replaced by PLB - no tapering (single disorder or a psychotic disorder. Followup: 1wk (discontinuation phase; single blind). blind) Notes: NB. No info reported re. N=randomised. N's Group 2N= 92 reported in this database are ITT sample only. Setting: Outpatient Placebo - INITIAL WASHOUT: 14 days Baseline: Data collected, not reported. Reported as mean ADMIN: No info on admin, Notes: No information given on randomisation. change in score (see outcomes). For the discontinuation form/appearance of either placebo or AP emailed Jan07 for details. phase, the acute treatment phase was considered as atomoxetine.. Info on Screening Process: Reply from author. baseline. DISCONTINUATION PHASE: Placebo for 7 days following 63 day treatment phase (single blind: p's blind, investigators not blind). Results from this paper: Internal Validity: 1.1 Well covered. 1.2 Poorly addressed 1.3 Not addressed 1.4 Adequately addressed 1.5 Not addressed 1.6 Not addressed 1.7 Adequately addressed 1.8 Not reported 1.9 Well covered 1.10 Not addressed

Overall assessment of the study 2.1 1- WIGAL2004 Study Type: RCT n= 132 Data Used Group 1N= 46 Funding: Study supported by 'Remission' (Teacher rated, SNAP <=1.0) Celgene Corporation. Study Description: Pure-ADHD sample(see Age: Mean 9 Range 6-17 Ritalin (d,l-threo-methylphenidate) - SNAP-IV-ADHD Teacher (mean change from exclusions) Sex: 116 males 16 females DOSE: Intially 5mg/dose;wks2&3:dose Sample included BL) doubled (if no therapeutic response;max 'Preschoolers','Children'&'Adolescents' Diagnosis: Clinical Global Impressions-Improvement 20mg/dose); dose constant in wk4 NB.1wk single-blind PLB lead-in precedes 4wk 1% ADHD Hyperactive/Impulsive subtype by (mean) ADMIN: Orally, b.i.d.(1st: 7-8am; trial. DSM-IV & NIMH DISC-IV (admin to parents) 'Responders' (n, CGI-I 'much'&'very 2nd:11:30am-12:30pm) Type of Analysis: ITT (P's:prov.data @ BL & 1 much'improved) Group 2N= 42 post-BL assessment) 100% ADHD by DSM-IV & NIMH DISC-IV SNAP-IV-ADHD Parent (mean change from Placebo - ADMIN: Orally, b.i.d.(1st: 7- (admin to parents) BL) 8am; 2nd:11:30am-12:30pm); All drugs Blindness: Double blind Data Not Used identical in appearance; no further detail Duration (days): Mean 28 Office Math Test - not relevant outcome regarding PLB admin provided. Setting: 12 sites across the U S Not reported how/where from p's were referred to trial. 35% ADHD Inattentive subtype by DSM-IV & Home Math Test - not relevant outcome Group 3N= 44 NIMH DISC-IV (admin to parents) Notes: Randomisation: No detail reported. Notes: TAKEN AT: All @ BL & end of PLB lead- Focalin (dexmethylphenidate) - DOSE: in, & end each wk of trial. SNAP-Parent: 3hrs & Wk1: 2.5mg/dose; wks2&3:dose doubled Info on Screening Process: 174 p's screened, 64% ADHD Combined subtype by DSM-IV & 6hrs post-dose (3pm&6pm)(SNAP teacher& CG (if no therapeutic response; max 31 not eligible (withdrawal of consent or various NIMH DISC-IV (admin to parents) scales: not specified when measures taken 10mg/dose);dose constant in wk4 exclusion criteria), 10 did not enter trial during the day). ADMIN: Orally, b.i.d.(1st: 7-8am; (withdrawal of consent, lost to f.u., etc). 1 did Exclusions: No enrolled in elementary school; outside 30% LOST to F.U.: N's unclear- AP to look at (email 2nd:11:30am-12:30pm) not enter double-blind phase (behaviour author????). deterioration in PLB lead-in). So 132 of normal body weight; postmenarche (female p's); randomised. history/evidence of cardiovascular, renal, respiratory (not incl. asthma/allergy), endocrine or immune system disease; history of substance abuse; hypersensitivity to stimulants; treatment with any invetigational drug in 30days prior to screening; any other significant central nervous systems disorder (e.g. mental retardation) tourettes; chronic tic disorder; psychosis; pervasive developmental disorder; eating disorders; OCD; impulse control disorders; sleep disorders requiring medication, major depressive disorder, GAD. Any p's taking , sedatives/hypnotics; neuroleptics/; mood stabilisers; ; beta-blockers; alpha2 agonists, thyroid medications, chronic oral steroids. Notes: Dexmethylphenidate (d-MPH; Focalin) is active d- isomer of Ritalin (d,l-threo-MPH), and was formulated to be administered at half the dose of Ritalin. Baseline: CGI-S n(%): d-MPH gp; d,l-MPH gp; PLB gp, resp. Normal, not at all/Borderline ill: 0(0.0); 0(0.0); 0(0.0) Mildly ill: 2(4.5); 2(4.3); 2(4.8) Moderately ill: 22 (50.0); 20(43.5); 25(59.5) Markedly ill: 16(36.4); 21(45.7); 9(21.4) Severely ill: 4(9.1); 3(6.5); 6(14.0) Among the most extremely ill: 0(0.0); 0(0.0); 0(0.0)

Mean(SD): d-MPH gp; d,l-MPH gp; PLB gp, resp. Teacher SNAP-ADHD: 1.4(0.7); 1.8(0.7); 1.6(0.7) Parent SNAP-ADHD: 1.5(0.6); 1.7(0.7); 1.6(0.7) Results from this paper: Internal validity; 1.1 Well covered 1.2 Adquately covered 1.3 Not reported 1.4 Adequately addressed 1.5 Well covered 1.6 Adequately covered 1.7 Adequately covered 1.8 13/132 (10%) of whole sample: allocation not reported. 1.9 Adequately addressed - see note to email author re. n's 1.10 Not addressed

Overall asessment of study; 2.1 1+ WILENS2006A Study Type: RCT n= 177 Data Used Group 1N= 87 Funding: McNeil Consumer ADHD RS (Inv.rated; >=30% decrease from and Specialty Study Description: "Pure ADHD"(no LD, CD, Age: Mean 14 Range 13-18 OROS-Methylphenidate - DOSE:(Titrated- BL) - dichot data Pharmaceuticals ODD mentioned)& see excl's Sex: 142 males 35 females open label)Started @18mg/dy-1wk; if no Sample'Adolescents'& 'Adults' Clin. Global Impressions-Improv. improvmt- 36mg/dy-1wk, etc to max NB.B4 randomisation: 1wk Washout & 1-4wk Diagnosis: (Inv.rated;dicot) 72mg/dy. P's entered dbl-bld phase on OPEN-LABEL dose-titration 100% ADHD by DSM-IV & K-SADS & CGAS Conners-Wells Scale (SR;>=30% decrease dose that led to 'improvement' on ADHD (score 41-70) from BL) RS(18mg: 7% of p's; 36mg: 28%; 54mg: Type of Analysis: ITT (LOCF) Conners-Wells Scale (Self Report) (mean 28%; 72mg: 37%) . ADMIN:Once/dy(time,appearance NOS) Exclusions: Taking any medications for ADHD at the time of change) Blindness: Double blind enrolment; history of non-response to MPH treatment; Leaving the Study Early due to Adverse Event Group 2N= 90 Duration (days): Mean 14 hypersensitivity/significant intolerance to MPH; clinically ADHD RS (Parent rated) (mean change from Placebo - DOSE:(Titrated-open label significant GI tract problems; clinically important ECG/blood BL) phase) P's entered dbl-bld phase on pressure abnormalities; coexisting medical conditions; Followup: 8wks (open-label; results not ADHD RS (Investigator rated) (mean change equivalent 'dose' of PLB that led to concurrent medications likely to interfere with safe admin of reported) from BL) 'improvement' on ADHD RS when taking MPH; requiring: clonidine, other alpha2- Setting: 15 sites across U.S. Leaving the Study Early for Any Reason MPH in open-label phase. agonists; antidepressants; SSRI'stheophylline, ADMIN: Once/day (time,appearance not Notes: Randomisation: p's "assigned a warfarin sodium, anticonvulsant agents; Tourette's syndrome Clin.Glob.Impress-Imprv. (Inv.rated;mean specified- Assume identical to OROS- randomisation number" (no further detail) (or family history of); on going seizure disorder; bipolar change) MPH arm) disorder; psychotic disorder; mood/anxiety disorder requiring Info on Screening Process: Screening NR ("two Clin. Global Impressions-Improv. drug therapy; alcohol/drug abuse (within prev.6months); (Inv.rated;mean) hundred twenty subjects were enrolled"); 27 eating disorder, marked anxiety, tension, agitation. D.O. of titration phase; 16 did not meet Data Not Used improvement criteria in time frame of open- Notes: CGAS: Children's Global Assessment Scale ADHD RS (Investigator rated) (mean) - using mean change label phase, so excluded; 177 randomised in Baseline: Mean (SD): OROS-MPH gp; PLB gp, resp. dbl-blind phase. ADHD RS (Investigator rated): 31.55(9.42); 30.99(9.64) Conners-Wells Scale (Self Report) (mean) - ADHD RS (Parent rated): 30.65(9.81); 30.99(11.55) using mean change Conners-Wells Adolescent Self-report of Symptoms Scale: ADHD RS (Parent rated) (mean) - using mean 89.81(41.44); 94.02(49.2) change Global Assessment of Efficacy - not relevant outcome Child Conflict Index - not relevant outcome Notes: TAKEN AT: Baseline & weekly throughou dbl-bld phase (Except CGI-Improvement scale onyl completed @ endpoint) LOST TO F.U.: OROS-MPH gp 0% (all incl. in ITT analysis); PLB gp 2% (2/90 not incl. in ITT analysis).

Results from this paper: Internal validity; 1.1 Well covered 1.2 Adequately addressed 1.3 Adequately addressed 1.4 Adequately addressed 1.5 Adequately addressed 1.6 Adequately addressed 1.7 Well covered 1.8 OROS MPH gp: 18% (16/87) PLB gp: 31% (28/90) 1.9 Adequately addessed-LOCF, except 2/177 (1 no efficacy data reported (AE data reported; 1 . 1.10 Not addressed

Overall assessment of study 2.1 1+ WOLRAICH2001 Study Type: RCT n= 312 Data Not Used Group 1 N= 107 Funding: ALZA Corporation Clin. Global Impressions-Improv. on behalf of Crescendo Study Description: Non-specific Age: Mean 9 Range 6-12 Immediate-release methylphenidate. (Inv.rated;dicot) - n's not clear for each arm Pharmaceuticals comorbidity(Pred.ODD;NB.PLB gp incl.4% Mean dose 29.5mg/day - DOSE:P's Sex: 258 males 54 females Corporation. GAD(Class1),other gps 0% each). IOWA Conners Parent RS-Inatt/Hyp subscale assigned(not randomly)to Sample pred.'Child';some'Preschoolers', Diagnosis: (mean) - n's not clear for each arm dose(n=28,5mg;n=41,10mg;n=25,15mg)(n some'Adolescents' 42% Oppositional defiant disorder by SNAP-IV Parent ODD subscale (mean) - not =35 titrated-open label prelim.study;n=59 Unspecified diagnostic tool relevant subscale converted-prev.trtmnt) Type of Analysis: ITT (LOCF) SNAP-IV Parent Inattention subscale (mean) ADMIN:3 PLB OROS systems + 1active IR capsule @07:30 & active IR capsules Blindness: Double blind 7% ADHD Hyperactive/Impulsive subtype by n's not clear for each arm @ 11:30 & 15:30(Double dummy- Duration (days): Mean 28 SCID for DSM-IV; IOWA; SNAP-IV; C-GAS SNAP-IV Teacher Hyperact/Impuls subscale maintain blind). (mean) - n's not clear for each arm Setting: Multicenter-14 centers in USA. P's SNAP-IV Teacher Inattention subscale recruited primarily through centralised (mean) - not relevant subscale recruitment services-radio and newspaper 11% Conduct disorder by Unspecified diagnostic IOWA Conners Parent RS-ODD subscale Group 2 N= 106 advertisments. tool (mean) - not relevant subscale Sustained-release methylphenidate. Notes: Rand.:P's1st assigned (NOT rand.) to IOWA Conners Teacher RS-ODD subscale Mean dose 34.3mg/day - DOSE:P's dose,based on prev.MPH trtmt/titration 2% Mood + Anxiety Disorders by Unspecified (mean) - not relevant subscale assigned(not randomly)to study;then rand.to OROS,IR,PLB(Stratified; diagnostic tool SNAP-IV Parent Hyperact/Impuls subscale dose(n=31,18mg;n=41,36mg;n=22,54mg) centrally at ALZA Coorporation) (mean) - n's not clear for each arm n=26 titrated-open label prelim.study;n=68 converted-prev.trtmnt) Info on Screening Process: >4000 p's made 100% ADHD by SCID for DSM-IV; IOWA; SNAP- IOWA Conners Teacher RS-Inatt/Hyp IV; C-GAS subscale (mean) - n's not clear for each arm ADMIN:3 active OROS systems + 1PLB contact-90% excluded by telephone screen. IR capsule @07:30 & PLB IR capsules @ >500 p's attended screening at clinics.210 (had SNAP-IV Teacher ODD subscale (mean) - no 11:30 & 15:30(Double dummy-maintain received MPH trtmt within 4wks) incl.; 111 (had 20% ADHD Inattentive subtype by SCID for relevant subscale blind). not previously received MPH) enrolled in dose- DSM-IV; IOWA; SNAP-IV; C-GAS Clin. Global Impressions-Improv. Group 3N= 99 titration study,then 102 of those entered current (Inv.rated;mean) - n's not clear for each arm study. 73% ADHD Combined subtype by SCID for Notes: TAKEN AT: All scales at BL; IOWA again Placebo. Mean dose NA - ADMIN:3 PLB DSM-IV; IOWA; SNAP-IV; C-GAS at day27; SNAP-IV at endpoint; AE's at OROS systems + 1PLB IR capsule days7,14,28. @07:30 & PLB IR capsules @ 11:30 & 15:30(Double dummy to maintain blind). Exclusions: Girls who had reached menarche; acute or LOST to F.U.:Varies for different scales from serious chronic disease; hypertensive to methylphenidate; 13%-24%. No information on allocation. having significant adverse experinces from MPH; taking medication that would interfere with the safe administration of methylphenidate. Patients with glaucoma, Tourette's syndrome, an ongoing seizure disorder, or a psychotic disorder. NB. For inclusion: p's having taken MPH previously, or who were currently taking

Overall assessment of study; 2.1 1+

Characteristics of Excluded Studies Reference ID Reason for Exclusion AARSKOG1977 Drug trial duration <1 wk; no pre-crossover data; no relevant outcomes (serum growth hormone concentration only) [DEX vs. L-DOPA; MPH vs. L-DOPA] ABIKOFF1985 Not an RCT [MPH in ADHD sample vs. healthy sample] ABIKOFF2005 Non-specific drug comparator ['Stimulant' + vs. 'Stimulant' + PLB]. ACKERMAN1982 No relevant outcomes; no pre-crossover data [MPH vs. PLB] ACKERMAN1983 Not whole sample ADHD; no extractable data [MPH vs. PLB] AGARWAL2001 No pre-cross-over data reported [Cross-over RCT; CLON vs. PLB] AHMANN1993 No pre-cross-over data reported [Cross-over RCT; MPH vs. PLB] AHMANN2001 Inappropriate comparator [ vs. PLB] AJIBOLA1995 No relevant outcomes; No pre-cross over data provided [MPH high dose vs. low dose vs. PLB] AKHONDZADEH2003 Unsuitable comparator [MPH vs. Seligiline] AKHONDZADEH2004 Unsuitable comparator [MPH + Zinc Sulfate vs. MPH + PLB] AKHONDZADEH2005 Unsuitable Comparator, No PLB control [MPH vs. Passiflora (passion flower)] AMAN1974 Not ADHD sample [DEX vs. MPH vs. PLB] AMAN1991A Not an RCT [MPH vs. (no control)] AMAN2003 No pre-crossover data. [MPH vs. PLB vs. ; MPH vs. PLB vs. Thioridazine]. NB. All p's: IQ<85. AMAN2004 Comination of drug trial (Risperidone + stimulants), outside scope ('no stimulants' group included p's taking stimulants with <90% compliance) [ RISP + 'stimulants' vs. PLB + 'stimulants' vs. RISP + 'no stimulants' vs. PLB + 'no stimulants'] AMERY1984 No precrossover data; no relevant outcomes [DEX vs. PLB] ANON1996D Non RCT [Letter re. CLON] ANON2002 Not an RCT: letter [D-MPH] ARNETT1996 No relevant outcomes [MPH vs. PLB] ARNOLD1972 No pre-crossover data; non-random sample [DEX vs. vs. PLB] ARNOLD1976 Inappropriate diagnosis (minimal brain dysfunction); no precrossover data [DEX vs. Levoamphetamine vs. PLB] ARNOLD1978 No extractable outcomes ('mean sums' and 'factor scores' only) [MPH vs. DEX vs. CAF] ARNOLD1989 No pre-crossover data [DEX vs. Efamol (evening primrose oil containing gamma-linolenic acid with Vitamin E) vs. PLB] ARNOLD1990 No pre-crossover data; no extractable outcomes (correlations) [DEX vs. PLB] ARNOLD2006 No pre-crossover data [ATX vs PLB] BALLINGER1984 No pre-crossover data; no relevant (or extractable) outcomes [low dose MPH vs. high dose MPH vs. PLB] BALTHAZOR1991 No relevant outcomes [MPH vs. PLB] BARCAI1971 Not ADHD sample, no relevant outcomes, no pre-crossover data [DEX vs. PLB] BAREN2000 Abstract only [MPH] BARKLEY1977 No pre-crossover data [MPH vs. PLB] BARKLEY1979 No pre-crossover data; no relevant outcomes [MPH vs. PLB] BARKLEY1979A No pre-crossover data; no relevant outcomes [MPH vs. PLB] BARKLEY1984 No relevant outcomes [MPH vs. Placebo] NB. Side effects measured BARKLEY1985 No relevant outcomes [MPH vs. Placebo] NB. Side effects measured BARKLEY1988 No relevant outcomes [MPH vs. Placebo] NB. Side effects measured. BARKLEY1989 No relevant outcomes [MPH vs. Placebo] NB. Side effects measured BARKLEY1989A No pre-crossover data [MPH vs. Placebo] BARKLEY1991 No pre-crossover data [MPH vs. PLB] NB. Comparison also for [ADD vs. ADHD] BARKLEY2000 No pre-crossover data [MPH vs. Adderall vs. PLB] BEAL1979 Inappropriate diagnosis; no relevant outcomes [MPH vs. PLB] BEAL1988 No mention of whether allocation to treatment was randomised; no relevant outcomes [MPH vs. PLB] BECKER-MATTES1985 Drug treatment duration >1 week (1 day); no pre-crossover data; no relevant outcomes [MPH vs. PLB] BEDARD2003 No relevant outcomes [MPH vs. PLB] NB. Inlcudes comparison of ADHD vs. controls BEDARD2004 No relevant outcomes [MPH vs. PLB] BEN-PAZI2006 Not entirely double-blind; No pre-crossover data; no relevant outcomes [MPH vs. PLB] BIEDERMAN2002A Drug not in scope [Adderall] BORCHERDING1989 No pre-crossover data; no relevant outcomes [MPH vs. DEX vs.PLB] BORCHERDING1990 No pre-crossover data; no relevant outcomes [MPH vs. DEX vs. PLB] BROAD1982 Innappropriate diagnosis criteria (i.e. DSM-II) [MPH vs. PLB] BROWN1979 Not clear whether RCT(methodology poorly reported), no relevant outcomes [DEX vs. (no control)]. BROWN1979A No pre-crossover data; no relevant outcomes [MPH 0.3mg/kg vs. MPH 1.0mg/kg vs. PLB] BROWN1980 Duration of drug administration <1 week; no pre-crossover data [DEX vs. PLB] BROWN1984 No pre-crossover data [MPH vs. PLB] BROWN1984A No pre-crossover data; no relevant outcomes [MPH vs. PLB] BROWN1985A Inappropriate diagnosis (not DSM, ICD, etc) [MPH vs. Cognitive Therapy vs. MPH+CT] BROWN1988 No pre-crossover data reported [MPH vs. PLB] BUHRMESTER1992 No pre-crossover data; no relevant outcomes [MPH vs. PLB] (NB. Participants drawn from same sample as Whalen1989) BUITELAAR1995 No pre-crossover data [MPH vs. vs. PLB] BUITELAAR2004 Open Label [ATX trial; no placebo arm] BUITELAAR2006 Not an RCT; No relevant outcomes [Comparison of baseline statistics across studies internationally; ATX trial] BUKSTEIN1998 No precrossover data [MPH vs. PLB] NB. Comorbidity- all p's had ODD or CD. BUKSTEIN2003 Non RCT [Commentary re. ATX] BYRNE1998 Not an RCT [MPH for ADHD vs. healthy control (no MPH)] CABALLERO2003 Non RCT [Review re. ATX] CAMPBELL1971 No pre-crossover data; no relevant outcomes (cognitive tests only) [MPH vs. PLB] CARLSON1991 No relevant outcomes [MPH vs. PLB] CARLSON1992 No pre-crossover data reported [MPH low dose vs. MPH high dose vs. PLB] CARLSON1993 No pre-crossover data; no relevant outcomes [MPH vs PLB vs. no pill] CARLSON1995 No pre-crossover data [MPH vs. DES vs. PLB vs. MPH+DES] CASAT1995 No pre-crossover data; no relevant outcomes [MPH low dose vs. MPH high dose vs. PLB] CASTELLANOS1996 No pre-crossover data; no extractable data [MPH vs. DEX. vs. PLB] CASTELLANOS1997 No relevant outcomes; no pre-crossover data [MPH vs. DEX vs. PLB] NB. Whole sample tic disorder. CHACKO2005 No precrossover data reported; no relevant outcomes (except perhaps side effects for narrrative) [MPH low vs. MPH high vs. PLB] CHATOOR1983 No relevant outcomes; no pre-crossover data [DEX vs. PLB] COHEN1987 No relevant outcomes [CLON trial] COHEN1989 No precrossover data reported [MPH vs. PLB] COLEMAN1979 No pre-crossover data; no extractable outcomes (rank sum of behavioural ratings only) [low dose MPH vs. high dose MPH vs. Pyridoxine vs. PLB] CONNERS1971 No relevant outcomes ( 'communication-organ' score from Harris- Goodenough Draw-a-Man test only') [MPH vs. DEX. Vs. PLB] CONNERS1972 No variability measured reported with results; inappropriate diagnosis (minimal brain dysfunction) [DEX vs. MPH vs. PLB; DEX vs. Pemoline vs. PLB] CONNERS1972A No variability measured reported with results; inappropriate diagnosis (minimal brain dysfunction) [DEX vs. Pemoline vs. PLB] CONNERS1975 No relevant outcomes; AEs possibly useful, but no measures of variability reported [MPH vs. PLB] CONNOR1999 Non RCT [Meta-analysis re. CLON] CONNOR2000 No extractable data [no means, SDs, f-values & significance only; MPH + CLON vs. CLON] CONNOR2000 No extractable data [no means, SDs, f-values & significance only; MPH vs. CLON] CONNOR2000 No extractable data [no means, SDs, f-values & significance only; MPH + CLON vs. MPH] CONNOR2002 Not an RCT: Review of Pelham2001 (cross-over) study [MPH vs. PLB] CONRAD1971 No variability measured reported with results; inappropriate diagnosis (ie. not DSM, ICD, etc.) [DEX vs. PLB] COOK1993 No pre-crossover data; No relevant outcomes [MPH vs. PLB] COTTON1988 No precrossover data reported [MPH vs. PLB] COX2004 No relevant outcomes; no pre-crossover data [MPH vs. OROS MPH] COX2006 No precrossover data; No relevant efficacy outcomes (driving performance and go/no-go task outcomes only) [MPH vs MAS vs PLB] CUNNINGHAM1985 Drug admin duration < 1 week; No pre-crossover data; No relevant outcomes (social interaction outcomes only) [MPH vs. PLB] DENHOFF1971 35% of sample 'probably non-hyperkinetic'; no pre-crossover data; not relevant outcome [DEX vs. PLB] DESONNEVILLE1991 Drug admin duration < 1 week; No pre-crossover data; No relevant outcomes (cognitive/ information processing outcomes only) [MPH vs. PLB] DESONNEVILLE1994 No pre-crossover data; No relevant outcomes (Information processing task outcomes only) [MPH vs. PLB] DICKERSONMAYES1993 No relevant outcomes; no precrossover data reported [MPH vs. PLB] DICKERSONMAYES1994 Not RCT; no PLB control [on MPH vs. off MPH] DITRAGLIA1991 No pre-crossover data [MPH vs. PLB] DOUGLAS1986 No pre-crossover data [MPH vs. PLB] DOUGLAS1988 No pre-crossover data [MPH (0.15 vs.0.3 vs. 0.6 mg/kg) vs. PLB] DOUGLAS1995 No pre-crossover data [MPH (0.3 vs. 0.6 vs. 0.9 mg/kg) vs. PLB] DRTILKOVA1978 No data reported (summary of findings only); cross-over trial [Antidepressants () + Diazepam vs. PLB] DRTILKOVA1990 Not an RCT (allocation not randomised; open-label) [MPH vs. Amphetaminil vs. vs. PLB] DUGGAN2000 Not an RCT (case series); no relevant, extractable outcomes [DEX vs. PLB (crossover)] DUKARM2005 Not an RCT (case series) [DEX vs. (no control)] DUPAUL1993 No pre-cross-over data reported [MPH vs. PLB] DUPAUL1994 No pre-crossover data [MPH (5 vs. 10 vs. 15) vs. PLB] DUPAUL1996 No pre-crossover data [MPH (0.16 vs. 0.29 vs. 0.42 mg/kg) vs. PLB] DYKMAN1980 No pre-crossover data [MPH vs. PLB] DYME1982 Drug admin duration < 1 week; No pre-crossover data; No relevant outcomes (neuropsychological test outcomes only) [MPH vs. PLB] EFRON1997 No pre-crossover data [MPH vs. DEX vs. PLB] EFRON1998 No pre-crossover data; no relevant outcomes [MPH vs. DEX] EFRON1999 Letter to the Editor [MPH vs. DEX] ELIA1990 No pre-crossover data; no variability measures for relevant outcomes [MPH vs. DEX vs. PLB] ELIA1991 No pre-crossover data [MPH vs. DEX vs. PLB] ELIA1993 No pre-crossover data; no relevant outcomes [MPH vs. DEX vs. PLB] EVANS1991 No pre-crossover data; No relevant outcomes [MPH vs. PLB; PEM vs. PLB] EVANS2001 No pre-crossover data [MPH (10 vs. 20 vs. 30mg) vs. PLB] FARAONE2002 No pre-crossover data; No extractable data [MPH (10 vs. 20 vs. 30 mg) vs. PLB; Adderall (5 vs. 10 vs. 15 mg) vs. PLB] FELDMAN1989 No pre-crossover data [MPH vs. PLB] FENICHEL1995 Non RCT [MPH + CLON] FIELDER1983 Drug admin duration < 1 week; No pre-crossover data; No relevant outcomes ('curiosity behavior' outcomes only) [MPH vs. PLB] FILHO2005 Single blind only [RIS vs. MPH] NB. Comorbid mental retardation sample. FINDLING2001 Unsuitable comparator, no PLB control [MPH vs. ADDERALL] FINDLING2001A No pre-crossover data; unsuitable comparator [MPH vs. PLB vs. Aderall] FINE1989 No pre-crossover data; No relevant/extractable outcomes (behavioural outcome measure not approved for inclusion- GDG decision, and no data reported) [MPH vs. PLB] FINE1993 No pre-cross-over data reported [MPH vs. PLB] FINNERTY1971 Inadequate description of diagnosis [DEX vs. PLB] FIRESTONE1978 No pre-crossover data [MPH vs. Caffeine vs. PLB] FIRESTONE1998 No pre-crossover data; no relevant outcomes [MPH (0.3 vs. 0.5mg/kg) vs. PLB] FISCHER1991 No pre-crossover data for MPH arm [MPH vs. PLB] FISCHER1998 No pre-crossover data; No relevant outcomes (behavioural outcome measure not approved for inclusion- GDG decision) [MPH vs. PLB] FISHER1978 No relevant outcomes; no pre-crossover data [DEX vs. PLB] FITZPATRICK1992 No pre-cross-over data reported [MPH vs. PLB] FLAPPER2006 No precrossover data; Order of drug administration not randomised. [MPH vs PLB] FLINTOFF1982 Drug admin duration < 1 week; No pre-crossover data; No relevant outcomes ('visual scanning' outcomes only) [MPH vs. PLB] FORNESS1991 No pre-crossover data; No relevant outcomes (reading performance outcomes only) [MPH vs. PLB] FORNESS1992 No pre-crossover data; no extractable outcomes [MPH vs. PLB] FREDERICKS2005 No an RCT; No relevant outcomes [MPH vs. PLB] FROBELSMITHEE1998 No pre-crossover data reported [MPH vs. PLB] GADOW1990 No pre-crossover data [MPH (0.3 vs. 0.6mg/kg) vs. PLB] GADOW1992 No pre-crossover data [MPH (0.1 vs. 0.3 vs. 0.5 mg/kg) vs. PLB] NB. Whole sample comorbid tic disorder. GADOW1995 No pre-crossover data [MPH (0.1 vs. 0.3 vs. 0.5 mg/kg) vs. PLB] NB. Whole sample comorbid tic disorder. GADOW1999 Not an RCT- Long-term (2 yr)observational follow-up following completion of RCT [MPH] NB. Whole sample comorbid tic disorder. GADOW2002 No pre-crossover data; no extractable outcomes (correlations only) [MPH (0.1 vs. 0.3 vs. 0.5mg/kg) vs. PLB] NB. Whole sample comorbid tic disorder. GAN1982 Drug admin duration < 1 week; No pre-crossover data; No relevant outcomes ('paired associate learning' outcomes only) [MPH vs. PLB] GARFINKEL1975 Drug admin < 7 continuous days (5 days drug, 2 days washout, 5 days drug) [MPH vs. Caffeine vs. PLB] GARFINKEL1981 Innappropriate diagnostic criteria; no pre-crossover data; no extractable outcomes [MPH vs. CAFF vs. PLB] GARFINKEL1983 No pre-crossover data [MPH vs. vs. Desipramine vs. PLB] GARFINKEL1986 No relevant outcomes [DEX vs. PLB] NB. Includes data on healthy controls given DEX. GARLAND2004 Non RCT [Review re. ATX] GILBERT2006B Drug treatment duration<1week; No precrossover data; No relevant outcomes (neurophysiological outcomes only) [MPH vs ATX] GILLBERG1997 Inappropriate comparator [Amphetamine sulphate] GILMORE2001 Not an RCT [review, MPH vs. PLB] GINSBERG2003 Review of presentation paper (not published in peer review journal). Methodology/outcome measures not clear from this review [Antidepressants () vs. PLB] GITTLEMANKLEIN1975 No mention of blindness; no extractable data [MPH vs. PLB] GOLDBERG2002 Non RCT [CLON vs. MPH vs. CLON + MPH vs. PBO] GOLDBERG2002A Non RCT [Commentary, CLON] GOLINKO1981A Not an RCT; no relevant outcomes [low-dose DEX vs. high-dose DEX vs. PLB] GOLINKO1981B No relevant outcomes; no pre-crossover data [DEX vs. PLB] GOLINKO1982 Not an RCT; Not useful for Harm narrative either (<2 months duration) [DEX vs. no control] GONZALEZHEYDRICH2005 Abstract only [MPH 18 vs. 36mg] GORDON1978 Inappropriate diagnosis; no relevant outcomes; no pre-crossover data [DEX vs. PLB] GORMAN2006 No pre-crossover data; no relevant efficacy outcomes (arithmetic task outcomes only) [MPH vs PLB] GRANGER1996 No pre-crossover data; no relevant outcomes [MPH (0.3 vs. 0.6mg/kg) vs. PLB] GREENBERG1972 Unclear diagnostic assessment; No extractable, relevant outcomes [DEX vs. vs. vs. PLB] GREENBERG1975 No pre-crossover data; NB. No relevant efficacy data (side-effect data only) [MPH vs. Imipramine vs. PLB] GREENHILL1987 No pre-crossover data; No relevant outcomes (salivary levels outcomes only) [MPH vs. PLB] GRIZENKO2006 No pre-crossover data; no relevant outcomes [MPH vs. PLB] GRIZENKO2006A No pre-crossover data; No data reported for relevant efficacy outcomes [MPH vs. PLB] GROSS1973 Not an RCT (crossover trial, but drug-order not randomised); No pre- crossover data; no validated outcomes [Antidepressant (Imipramine) vs. MPH vs. DEX vs. PLB] GROSS1976 Inadequate diagnostic tools; no pre-crossover data [DEX vs. racemic- amphetamine vs. MPH vs. PLB] GROSSTSUR1997 Not an RCT [MPH + antiepileptic drugs vs. (no control)] NB. Whole sample comorbid epilepsy. GROSSTSUR2002 No pre-crossover data [MPH vs. PLB] NB. Whole sample comorbid cerebral palsy; sample incl. some adults (18-20yrs). GRUBER2006 No precrossover data; No relevant efficacy outcomes (sleep outcomes only) [MPH vs PLB] GUALTIERI1984 No pre-crossover data [MPH vs. PLB] GUALTIERI1988 No pre-crossover data; No relevant outcomes (neuropsychological tests only; no clinical efficacy/AE outcomes) [Antidepressant (Imipramine) vs. PLB] GUALTIERI1991 No pre-crossover data [Antidepressant (Desipramine) vs. PLB] GULLEY1997 Not an RCT [n=2, case reports, MPH vs. PLB] HALLIDAY1984 No pre-crossover data; no extractable outcomes [MPH vs. PLB] HALPERIN1986 Inadequate diagnostic criteria; no relevant, extractable outcomes [MPH vs. PLB] HANDEN1990 No pre-crossover data [MPH (0.6 vs. 1.2 mg.kg.day) vs. PLB] NB. Whole sample comorbid mental retardation. HANDEN1992 No pre-crossover data [MPH (0.6 vs. 1.2 mg.kg.day) vs. PLB] NB. Whole sample comorbid mental retardation. HANDEN1994 No pre-crossover data; no extractable outcomes [MPH (0.6 vs. 1.2 mg.kg.day) vs. PLB] NB. Whole sample comorbid mental retardation. HANDEN1995 No pre-crossover data; No relevant outcomes (Independent play & academic functioning outcomes only) [MPH 0.3mg/kg vs. MPH 0.6mg/kg vs. PLB] HANDEN1996 No pre-crossover data [MPH (0.6 vs. 1.2 mg.kg.day) vs. PLB] NB. Whole sample comorbid mental retardation. HANDEN1997 Not an RCT (long term followup following [MPH vs PLB] trial). HANDEN1999 No pre-cross-over data reported [MPH vs. PLB] HANDEN2000 No pre-crossover data [MPH (0.6 vs. 1.2 mg.kg.day) vs. PLB] NB. Whole sample comorbid autism. HARTSANTORA1992 Non RCT [Narrative review re. CLON] HAZEL-FERNANDEZ2006 Drug treatment duration < 1 week; No precrossover data; No relevant outcomes (executive functioning tasks only) [MPH vs PLB] HENKER1979 No pre-crossover data; no extractable outcomes [MPH vs. PLB] HINSHAW1992 Drug admin < 1 week; No pre-crossover dat; No relevant data (no core ADHD symptom outcomes) [MPH vs PLB] HOARE2005 Open-label trial [OROS MPH (18 vs 36 vs 54 mg)] HOEPPNER1997 No pre-crossover data [MPH (0.3 vs. 0.6 mg/kg/day) vs. PLB] HORN1991 No extractable data (no raw data reported) [MPH (0.4 vs. 0.8 mg/kg) vs. PLB vs. Parent training + 'Child self-control instrucution' + MPH (0.4 vs. 0.8 mg/kg) vs. Parent training + 'Child self-control instrucution' + PLB]. HUESSY1970 Not an RCT [Antidepressants (Imipramine) vs. (no control)] HUESTIS1975 No pre-crossover data; No measure of variability reported for relevant data [MPH vs. DEX vs. Caffeine vs. PLB] HUMPHRIES1978 Drug admin < 1 week; No pre-crossover data; No relevant outcomes (Coordination and mother-infant interaction tasks only) [MPH 10 mg vs. MPH 15 mg vs. PLB] HUNT1985 No pre-cross-over data reported [CLON vs. PLB] HUNT1987 Open-label trial [oral CLON + MPH low-dose or MPH high-dose or PBO & transdermal CLON + MPH low-dose or MPH high-dose or PBO] IBAY2003 Not an RCT: Review [MPH] JAMES2001 No pre-crossover data [DEX vs. extended-release DEX vs. Adderall vs. PLB] JOHNSTON1988 No pre-crossover data (crossover occurred daily throughout trial) [MPH vs. PLB] JONKMAN1997 Drug admin < 1 week; No pre-crossover data; No relevant outcomes (ERP data only) [MPH 10 mg vs. MPH 15 mg vs. PLB] KEATING2001 Not an RCT: Review [MPH vs. PLB] KELLY1988 No pre-crossover data [MPH (5 varying doses) vs. PLB] KELLY1989 No pre-crossover data; no extractable outcomes [MPH vs PLB] KEMNER2004 Drug admin < 1 week; No relevant outcomes (ERP data only) [MPH 10 mg vs. MPH 15 mg vs. PLB] KEMNER2005 Open label [ATX vs. MPH] KENT1995 Drug admin < 1 week; no pre-crossover data [MPH 10 mg vs. MPH 15 mg vs. PLB] KENT1999 No pre-crossover data; no relevant outcomes [MPH vs. PLB] KLEIN1977 MPH arm of trial open label [BT + PLB vs. MPH alone vs. BT + MPH] KLEIN1997 Not all of sample have ADHD diagnosis [MPH vs. PLB] KLEIN2004 No relevant control comparison for drug arm- see Combination Interventions [MPH alone vs. MPH + Multimodal psychosocial treatment vs. MPH + attention control treatment] KLORMAN1979 No relevant outcomes & no pre-crossover data [MPH vs. PLB] KLORMAN1983 No relevant outcomes [MPH vs. PLB] KLORMAN1987 No pre-cross-over data reported [MPH vs. PLB] KLORMAN1988 No pre-crossover data; no extractable outcomes [MPH vs. PLB] KLORMAN1988A No pre-crossover data [MPH vs. PLB] KLORMAN1990 No pre-crossover data; no variability measures reported for relevant outcomes; possibly useful for side effects narrative [MPH vs. PLB] KLORMAN1990A No pre-cross-over data reported [MPH vs. PLB] *NB. Secondary ref to KLORMAN1988A??? Check when all MPH on database!! KLORMAN1991 No relevant outcomes [MPH vs. PLB] KLORMAN1994 No pre-cross-over data reported [MPH vs. PLB] KNIGHTS1969 No variability measure reported for relevant outcomes (Werry-Weiss- Peters scale only) [MPH vs. PLB] KNOBEL1974 Not an RCT (clinical case series); drug outside scope [Deanol vs. (no control)] KOLKO1999 No pre-cross-over data reported [MPH vs. PLB] KOLLINS1998 No relelvant outcomes [MPH (various doses) vs. PLB] & [DEX (various doses) vs. PLB] KONRAD2005 No pre-crossover data; no relevant outcomes [MPH (0.25 vs. 0.5 mg/kg) vs. PLB] KRAKOWSKI1965 Not reported whether allocation was random (cannot assume it was random) ; Not clear that the sample were uniformly diagnosed with hyperkineses; No validated efficacy/AE outcomes [Antidepressant () vs. PLB] KRATOCHVIL2001 Open-label trial [ATX vs. PLB] KRATOCHVIL2002 Open-label trial [MPH vs. ATX] KUPIETZ1976 No pre-crossover data [MPH vs. Amitriptyline vs. PLB] KURLAN2002B Non RCT [Short survey, CLON] LAW1999 P's switched by choice throughout trial; no relevant outcomes [MPH vs. PLB] LERER1976 Inadequate diagnostic criteria [MPH vs. PLB] LERNER2000 Abstract only [MPH OROS vs MPH IR] LEVY1996 No pre-crossover data; no relevant outcomes [MPH vs PLB vs ] LEWIS1975 Inappropriate diagnostic criteria ('school problems', no mention of hyperactivity) [MPH vs.Deanol vs. PLB] LIEBERMAN2000 Abstract only [MPH vs. PLB] LIJFFIJT2006 No precrossover data; No relevant outcomes ('stop and change' task outcome only) [MPH (0.5 vs 1.0 mg/kg) vs PLB] LINDSAY2006 Not an RCT (meta-analysis, references checked) [MOD vs. DEX vs. PLB] LOO1999 No relevant outcomes [MPH vs. PLB] LOO2004 No extractable data [outcome scores correlated with EEG; MPH vs. PLB] MAAYAN2003 Not an RCT; No relevant outcomes [MPH vs. (no control)] MAFFLA1981 Not an ADHD/hypekinetic sample (predominant diagnosis of sample was depression) [Antidepressants () vs. PLB] MALONE1988 No relevant outcomes [MPH vs. PLB] MALONE1993 No relevant outcomes [MPH vs. PLB] MANOS1999 Allocation not randomised; Drug allocation open-label (although dose double blind); PLB as within-p's factor (no pre-cross over data reported) [MPH vs. Aderall vs. PLB] MANOS2000 Abstract Only, inappropriate comparator [MPH vs. Aderall] MATIER1992 No relevant (extractable) outcomes [MPH vs. PLB] MATTES1983 Not an RCT [MPH vs. (no control)] MAUTNER2002 Not an RCT [MPH vs. (no control)]; Sample of ADHD, ADHD+NF1, NF1, Healthy controls. MCBRIDE1988 No pre-crossover data [MPH vs PLB] MCGOUGH2006 No precrossover data [MPH vs PLB] MCINTYRE1981 No relevant outcomes; no pre-crossover data [DEX vs. l-amphetamine vs. PLB] MCLAUGHLIN1980 Letter to the editor [MPH vs. PLB] MCNUTT1976 Not an RCT [MPH vs unmedicated] MEHTA2004 No relevant outcomes; no pre-crossover data [MPH vs. PLB] MELAMED2004 Abstract only [MPH vs. PLB] MIKKELSEN1981 No relevant outcomes; no pre-crossover data [DEX vs. PLB] MILICH1989 No relevant outcomes; no pre-crossover data [MPH vs. PLB] MILLICHAP1967 No relevant outcomes [MPH vs. PLB vs. Phenobarbital] MILLICHAP1968 No relevant outcomes; no pre-crossover data [MPH vs. PLB] MOHAMMADI2004 Inappropriate comparator; no PLB control [MPH vs. Selegiline] MONTEIROMUSTEN1997 No pre-crossover data [MPH vs. PLB] MURPHY1992 No relevant outcomes; no pre-crossover data [MPH vs. PLB] NAGELHIEMKE1984 No relevant outcomes; no pre-crossover data [MPH vs. PLB] NEMZER1986 No pre-crossover data [DEX vs. vs. PLB] NIKLES2006 Drug treatment duration<1week; No variability measures for pre- crossover data (where reported) [MPH vs DEX] NOLAN1994 No pre-crossover data; no extractable outcomes [MPH vs PLB] NOLAN1997 No relevant outcomes; no pre-crossover data [MPH vs. PLB] NOLAN1999 No relevant outcomes; no pre-crossover data [MPH vs. PLB] OESTERHELD1998 No pre-crossover data; no variability measures reported [MPH vs. PLB] OETTINGER1975 Not an RCT (letter) [DEX] OTOOLE1997 No relevant outcomes; no pre-crossover data [MPH vs. PLB] OTTINGER1985 Not an RCT; n=2, case studies [MPH vs. PLB] PALUMBO2004 Not an RCT: Review and metanalysis [MPH vs. PLB] PEARSON1996 No pre-crossover data; no variability measures reported [MPH vs. PLB] PELHAM1985 No pre-crossover data; no relevant outcomes [MPH (0.15 vs. 0.3 vs. 0.6 mg/kg) vs. PLB] PELHAM1987 No pre-crossover data; no extractable data [MPH vs. SR MPH vs. PLB] PELHAM1989 No pre-crossover data; no relevant outcomes [MPH vs. PLB] PELHAM1990 No pre-crossover data [MPH vs. SR MPH vs. SR DEX vs. Pemoline vs. PLB] PELHAM1991 No pre-crossover data; no relevant outcomes [MPH vs. PLB] PELHAM1993 No pre-cross-over data reported [MPH vs. PLB] PELHAM1993A No pre-crossover data; no relevant outcomes [MPH vs. PLB] PELHAM1999 No pre-crossover data [MPH vs. Adderall vs. PLB] PELHAM1999A No pre-crossover data [MPH vs. long-acting MPH (Concerta) vs. PLB] PELHAM2000 Abstract only [MPH vs PLB] PELHAM2000A Abstract only [MPH vs. PLB] PELHAM2001 No relevant outcomes [MPH vs. PLB] PELHAM2005 No pre-crossover data [MPH (0.45 vs. 0.9 vs. 1.8 mh/h) vs. PLB] PERWIEN2004 No relevant outcomes [ATX vs. PLB] PLISZKA1989 No pre-crossover data [MPH vs. PLB] PORGES1981 No relevant outcomes [MPH vs. PLB] PORRINO1983 No pre-crossover data [DEX vs. PLB] POTTER2004 No relevant outcomes; No pre-crossover data [MPH vs. Nicotine vs. PLB] QUINN2004 No pre-crossover data [d-MPH vs. d,l-MPH vs. PLB] RAPOPORT1971 Inadequate diagnosis; no pre-crossover data [DEX vs. Chlorpromazine vs. PLB] RAPOPORT1974 Rapoport1974: Not clear in paper whether allocation was randomised- cannot assume it was; Quinn1975: open-label [MPH vs. Imipramine vs. PLB] RAPOPORT1978 No relevant outcomes; no precrossover data [DEX vs. PLB] RAPOPORT1980A No relevant outcomes; no pre-crossover data [DEX vs. PLB] RAPOPORT1980B No relevant outcomes; no pre-crossover data [DEX vs. PLB] RAPPORT1985 No pre-crossover data; No relevant outcomes reported in results (Conners Teacher Rating Scale was administered) [MPH vs. PLB] RAPPORT1985A No pre-crossover data; no extractable data [MPH vs. PLB] RAPPORT1986 No pre-crossover data; No extractable outcomes [MPH (5 vs. 10 vs. 15 mg) vs. PLB] RAPPORT1987 No pre-crossover data [MPH (3 arms-3 doses) vs. PLB] RAPPORT1988 No pre-crossover data; no relevant outcomes [MPH (5 vs. 10 vs. 15 vs. 20mg) vs. PLB] RAPPORT1989 No relevant outcomes ; No pre-cross-over data reported [MPH vs. PLB] RAPPORT1989A No pre-crossover data [MPH vs. PLB] RAPPORT1994 No pre-crossover data; No extractable data [MPH (5 vs. 10 vs. 15 vs. 20mg) vs. PLB] RAPPORT1996 Not an RCT; case study, n=2 [MPH vs. PLB, within-subjects design] REID1984 No relevant outcomes [MPH vs. PLB] REMSCHMIDT2005 Open-label trial [varying doses of MPH vs. (no PLB)] RHODES2006 Drug treatment duration<1 week; No relevant outcomes (executive functions outcomes only) [MPH (0.3 vs 0.6 mg/kg) vs PLB] RIE1976 Inadeqaute diagnostic criteria [MPH vs. PLB] ROMAN2002 Not an RCT [MPH vs. (no control)] ROTTA1991 Not clear whether p's randomised to groups (cannot assume allocation was random) [Antidepressants (Imipramine) vs. PLB] RUPP2005 No pre-crossover data [MPH (low vs. medium vs. high dose) vs. PLB] SAFER1973 Letter to the editor [DEX] SALETU1975 No extractable relevant outcomes (and no harm data) [DEX vs. Thioridazine vs. PLB] SAMUELS2006 No relevant outcomes; no pre-crossover data reported [Stimulant (MPH or DEX or Amphetamine) vs. PLB] SANGAL2005 Open label; No relevant outcomes [ATX vs. (no control)] SARAF1974 Only 31% of sample hyperkinetic; No mention of whether allocation was randomised; No efficacy outcomes (However, potentially useful for harm analysis) [Antidepressant (Imipramine) vs. PLB] SATTERFIELD1972 Inadequate diagnostic criteria [MPH vs. PLB] SATTERFIELD1973 No details of randomisation; No relevant outcomes [MPH vs. PLB] SCHACHAR1987 No pre-crossover data; No relevant outcomes [MPH vs. PLB] SCHAIN1975 Inadequate diagnositic criteria [MPH vs. PLB] SCHERES2006 Drug treatment duration<1week; No precrossover data [MPH (5 vs 10 vs 20 mg) vs PLB] SCHERTZ1996 Not an RCT [Retrospective investigation into Stimulant use for ADHD, ie. MPH or DEX] SCHLEIFER1975 Inadequate diagnostic criteria [MPH vs. PLB] SCHNACKENBERG1971 No relevant outcomes; no pre-crossover data [MPH vs. PLB] SCHNIPPER2001 Abstract only of open label trial [MPH at different doses, no PLB] SCHVEHLA1994 Not an RCT [CLON] SCHWARTZ2004 No relevant outcomes; no pre-crossover data [MPH vs. PLB] SEBRECHTS1986 No pre-crossover data reported [MPH vs. PLB] SERRAPINHEIRO2004 Not an RCT (Open-label) [MPH vs. (no control)] SHAFRITZ2004 No relevant outcomes; no pre-crossover data [MPH vs. PLB] SHAYWITZ1990 No pre-crossover data reported [MPH vs. PLB] SHEKIM1986 No relevant outcomes; no pre-crossover data [DEX vs. PLB] SHEKIM1994 No relevant outcomes; no pre-crossover data [DEX vs. PLB] SHETTY1971 No relevant outcomes; no pre-crossover data [MPH vs. PLB] SHETTY1976 No relevant outcomes (and no harm data) [DEX vs. PLB] SHORT2004 No pre-crossover data [MPH (5 vs. 10 vs. 15mg) vs. PLB] SILVA2005 No pre-crossover data [Extended release MPH (20 vs. 40.mg) vs. OROS- MPH (18 vs. 36mg) vs PLB] SILVA2006 Treatment duration < 1 week [MPH vs PLB] No precrossover data SIMPSON1980 No relevant outcomes; no pre-crossover data [MPH vs. DEX vs. PLB] SINGER1995 No relevant outcomes & no pre-cross-over data reported [CLON vs. PLB] SLEATOR1974 No pre-crossover data reported [MPH vs. PLB] SLEATOR1974A Not an RCT; Review [MPH vs. PLB] SLEATOR1974B No pre-crossover data [MPH vs. PLB] SOLANTO1982 No pre-crossover data; No relevant efficacy data [MPH vs. PLB] SOLANTO1986 No pre-crossover data; No relevant outcomes [MPH vs. PLB] SOLANTO1989 No pre-crossover data; No relevant outcomes [MPH vs. PLB] SONUGABARKE2004 No pre-crossover data [MPH (Metadate CD vs. Concerta) vs. PLB] SOSTEK1980 Inadequte diagnostic criteria; no relevant outcomes; no precrossover data [DEX vs. PLB] SPENCER2001 Open label [ATX vs. (no control)] SPRAFKIN1996 No pre-crossover data; No extractable outcomes [MPH vs. PLB] SPRAGUE1970 Inappropriate diagnostic criteria ("emotionally disturbed children"); No relevant outcomes; no pre-crossover data [MPH vs. Thioridazine vs. PLB] SPRAGUE1977 No pre-crossover data reported [MPH (at 2 doses) vs. PLB] STARR2005 Open label [MPH vs. ATX] STEELE2006 Open-label trial [MPH (once-daily vs. immediate release)] STEIN1996 No pre-cross-over data reported [MPH vs. PLB] STEIN2003 No pre-cross-over data reported [MPH vs. PLB] STEIN2005 No pre-crossover data; no extractable data [MPH (18 vs. 36 vs. 54 mg) vs. PLB] STEINBERG1971 Inadequate diagnostic criteria; no relevant outcomes; no pre-crossover data [DEX vs. PLB] STEINGARD1994 Non RCT; Open label Cohort [CLON vs. clonazepam] STEPHENS1984 No relevant outcomes; No pre-crossover data [MPH vs. Pemoline vs. PLB] SUND2002 Not an RCT [Amphetamine or MPH vs. (no control)] SUNOHARA1997 No relevant outcomes; No pre-crossover data [MPH vs. PLB] SWANSON1976 Inadequate description of diagnostic criteria [MPH vs. PLB] SWANSON1979 No relevant outcomes [MPH vs. PLB] SWANSON1983 No pre-crossover data; No extractable outcomes [MPH (with breakfast vs. before breakfast) vs. PLB] SWANSON1991 Not an RCT: Review [MPH] SWANSON1998 No extractable data [MPH vs. PLB] SWANSON1999 No extractable (pre-crossover/parallel) data [MPH vs. PLB] SWANSON2000 Open-label trial [varying doses of MPH] SWANSON2002 Inadequate trial duration (<1 week); No pre-crossover data [MPH vs. PLB] SWANSON2004 No pre-cross-over data reported [MPH vs. PLB] SWARTWOOD1998 Open-label trial; no relevant outcomes [MPH vs. off-medication] SYRIGOUPAPAVASILIOU19 No relevant outcomes [MPH (0.3 vs. 1.0 mg/kg/day) vs. PLB] 88 SZOBOT2004 Drug treatment duration <1 week [MPH vs. PLB] TANNOCK1989 No relevant outcomes; No pre-crossover data [MPH (0.3 vs. 1.0 mg/kg) vs. PLB] TANNOCK1995 No relevant outcomes [MPH (0.3 vs. 0.6 vs. 0.9 mg/kg) vs. PLB] TANNOCK1995A No relevant efficacy outcomes; No pre-crossover data [MPH (0.3 vs. 0.6 vs. 0.9 mg/kg) vs. PLB] TAYLOR1987 Only part of sample had diagnosis of ADHD (18% Hyperkinetic disorder:ICD-9; 63% ADD-H: DSM-III) TEPNER2002 Non RCT [Abstract only re. ATX trial] TERVO2002 No pre-cross-over data reported [MPH vs. PLB] THOMSON1998 No relevant outcomes; not extractable [MPH vs. PLB] TILLERY2000 No relevant outcomes [MPH vs. PLB] TIROSH1993 No relevant outcomes; no pre-crossover data reported [MPH vs. PLB] TIROSH1993A No extracable data (correlations only) [MPH vs. PLB] TUCHA2006 No relevant outcomes; No pre-crossover data reported [MPH vs. PLB] ULLMANN1985 No pre-crossover data reported; No extractable data (no measure of variance) [MPH vs. PLB] ULLMANN1986 No precrossover data [MPH (0.3 vs. 0.5 vs. 0.8 mg/kg) vs. PLB] VANDERMEERE1999 No relevant outcomes [CLON vs. MPH vs. PLB] VARLEY1982 No pre-crossover data [MPH (5-60mg/day vs. 15-120 mg/day) vs. PLB] VARLEY1983 No pre-crossover data [MPH (0.3 vs. 0.6 mg/kg/day) vs. PLB] VARLEY1983A No pre-crossover data [MPH (0.3 vs. 0.6 mg/kg/day) vs. PLB] VELCEA2004 Non RCT [Letter re. ATX] VITIELLO2001 Commentary [MPH vs. PLB] VOLKOW2003 Editorial [MPH] VYBOROVA1984 Inappropriate comparator; single-blind trial; no pre-crossover data; no relevant efficacy outcomes (side effect data ok) [MPH vs. Amphetaminil] VYBOROVA1985 Inappropriate comparator; single-blind trial; no pre-crossover data; no relevant efficacy outcomes (side effect data ok) [MPH vs. Amphetaminil] VYSE1989 No relevant outcomes; no pre-crossover data reported [MPH (5 vs. 10 vs. 15 vs. 20 mg) vs. PLB] WALKER1988 No relevant outcomes [MPH (0.3 vs. 0.7 mg/kg) vs. PLB] WALLANDER1987 No relevant outcomes; No pre-crossover data [MPH vs. PLB] WEBER1985 No relevant outcomes [MPH (0.3 vs. 1.0 mg/kg) vs. PLB] WEINGARTNER1980 Insufficient detail of diagnostic criteria; no relevant outcomes; no pre- crossover data [DEX vs. PLB] WEINGARTNER1982 No relevant outcomes; no pre-crossover data [DEX vs. PLB] WEISS1968 Inadequate diagnostic criteria; no relevant outcomes (some harm data ok, but efficacy outcomes not based on validated scales) [DEX vs. PLB] WEISS1974 Abstract only; inappropriate comparator [MPH vs. Chlorpromazine vs. no meds.] WERNICKE2002 Not an RCT [Review, ATX] WERNICKE2003 Not an RCT (pooled-analysis of 5 trials); No relevant outcomes [ATX vs. PLB] WERRY1964 Not an RCT (Cohort: Hyperactive children vs. Controls; no intervention) WERRY1971 Inadequate diagnostic criteria [MPH vs. Halperidol vs. PLB] WERRY1974 Inadequate diagnostic criteria [MPH (0.1 vs. 0.3 vs. 0.5 (NZ) or 1.0 (US)) vs. PLB] WERRY1975 No relevant outcomes (memory tests, CPT, seat movement only); no pre- crossover data [MPH vs. low dose halperidol vs. high dose halperidol vs. PLB] WERRY1980 No pre-crossover data reported; No variability measures reported [MPH vs. Imipramine vs. PLB] WHALEN1979 No relevant outcomes [MPH vs. PLB] WHALEN1981A No extractable data: Correlations only reported [MPH vs. PLB] WHALEN1981B No extractable data: Correlations only reported [MPH vs. PLB] WHALEN1987 Not an RCT; No relevant outcomes [obervations of other children on MPH vs. PLB] WHALEN1987A No pre-crossover data; No extractable data [MPH vs. PLB] WHALEN1989 Treatment duration <1 week; No extractable data (No variability measures reported) [MPH vs. PLB] WHALEN1990 No pre-crossover data; No extractable data [MPH vs. PLB] WHITEHOUSE1980 Unspecified outcome questionnaire utilised; No variability measures reported [MPH vs. SR-MPH] WIGAL2002 Abstract only [MPH vs. PLB] WIGAL2005 Unsuitable comparator [no PLB control; ATX vs. Mised Amphetamine salts] WILENS1999A Non RCT [MPH + CLON] WILENS2001 Abstract only [MPH vs. (no control)] WILENS2003 Open-label trial [MPH vs. (no control)] WILENS2005 Open-label trial [MPH vs. (no control)] WILENS2006 Not an RCT (meta-analysis) [ATX vs. PLB] WILLIAMS2001 Abstract only [MPH vs. PLB] WINSBERG1972 Inappropriate diagnostic criteria; no pre-crossover data [DEX vs. Imipramine vs. PLB] WINSBERG1974 Inappropriate diagnostic criteria [MPH vs. DEX vs. PLB] WINSBERG1982 Not an RCT [MPH vs. PLB] WINSBERG1987 No mention that sample was randomised to conditions [MPH (0.3 vs. 0.5 vs. 0.7 mg/kg) vs. PLB] WITCHER2003 Open label trial; no control [ATX vs. (no control)] WODRICH1998 No relevant outcomes; No pre-crossover data [MPH (5 vs. 15 md/dose, bid) vs. PLB] WOLRAICH1977 Not an RCT, review [Stimulant vs. PLB] WOLRAICH2000A Abstract only [MPH vs. PLB] WORRALL1993 No pre-crossover data [MPH vs. PLB] YANG2004 Not an RCT; No relevant outcomes [MPH vs. (no control)] YELLIN1978 Inapropriate diagnosis; no pre-crossover data [MPH vs IMIP vs PLB] ZAHN1980 Inadequate description of diagnostic criteria; no relevant outcomes; no pre-crossover data [DEX vs. PLB] ZAMETKIN1984 No relevant outcomes; No pre-crossover data [DEX vs. PLB] ZAMETKIN1985 No pre-crossover data; NB. PLB is one week of each arm of trail, not separate arm [DEX vs. Monoamine Oxidase Inhibitors vs. PLB] ZAMETKIN1986 Unsuitable Comparator; Open-label [MPH vs. ] ZEINER1999 No pre-cross-over data reported [MPH vs. PLB] ZHANG2005 Open label trial; no control [ATX vs. (no control)] ZWAIGENBAUM2006 Not an RCT (n=2); No precrossover data [MPH vs PLB]